Marco Cavallone

Thèse soutenue au Laboratoire d’Optique Appliquée (École Polytechnique) en 2021

Titre: Application of laser-plasma accelerated beams to high dose-rate radiation biology

Résumé:

Laser-plasma accelerators can produce proton and electron beams with a broad range of spectral and temporal properties. Notably, the extremely short duration of the particle bunch (< ps) allows the reach of extremely high peak dose-rate above 10⁹ Gy/s. The effect of ultra high peak dose-rate irradiation on living matter is still being debated. Few recent studies have shown different radiobiological effects of laser-driven proton beams compared to conventional beams, such as lower immediate nitroxidative stress¹ and the oscillation of cell mortality with the proton bunches repetition rate². In addition, the recent discovery of the FLASH effect³, i.e. an increase of healthy tissue tolerance at high mean dose rate irradiation (>40 Gy/s), has boosted the interest towards high dose-rate sources. The FLASH effect has been observed with both single and multi-pulse irradiation, using various combinations of temporal parameters such as mean dose-rate, peak dose-rate, dose-per-pulse, and repetition rate. The relative importance of such parameters in triggering the FLASH effect as well as the mechanisms that underpin it still need to be elucidated⁴. In this context, laser-driven particles are important tools to shed some light on the radiobiological impact of the aforementioned parameters since their properties are complementary to those of conventional and FLASH irradiation protocols.

Research conducted during my PhD focused on both laser-driven protons and electrons and tackled some of the challenging aspects related to their application to radiation biology, encompassing the source characterisation, beam transport, dosimetry and dose optimisation⁵. In this presentation, after an introduction on laser-plasma accelerated beams, I will describe radiation biology experiments with two different beams. I will start by presenting the first dosimetric characterisation of a low-energy, kHz laser-driven electron beam. The attractive property of such beams is the high repetition rate that allows for a higher stability of the delivered dose⁶. I will then present a radiobiology experiment conducted with protons generated by a low repetition rate (1 shot every ~90 minutes) and high energy-per-pulse laser. With such beams, a dose in the order of 10 Gy can be delivered in a single nanosecond pulse, thus achieving irradiation conditions that are even more extreme than those used in FLASH experiments. The source and transport beamline will be described together with preliminary results on Zebrafish embryos irradiation.

1.  Raschke, S. et al. Ultra-short laser-accelerated proton pulses have similar DNA-damaging effectiveness but produce less immediate nitroxidative stress than conventional proton beams. Sci Rep 6, 32441 (2016).

2.  Bayart, E. et al. Fast dose fractionation using ultra-short laser accelerated proton pulses can increase cancer cell mortality, which relies on functional PARP1 protein. Sci Rep 9, 10132 (2019).

3.  Favaudon, V. et al. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci. Transl. Med. 6, 245ra93-245ra93 (2014).

4.  Wilson, J. D., Hammond, E. M., Higgins, G. S. & Petersson, K. Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool’s Gold? Front. Oncol. 9, 1563 (2020).

5.  Cavallone, M. Application of laser-plasma accelerated beams to high dose-rate radiation biology. (Institut Polytechnique de Paris, 2020).

6.  Cavallone, M. et al. Dosimetric characterisation and application to radiation biology of a kHz laser-driven electron beam. Appl. Phys. B 127, 57 (2021).

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Arthur Bongrand

Thèse soutenue au LPC-Clermont en 2020

Titre: Etudes des performances d'un détecteur dédié au contrôle balistique lors des traitements d'hadronthérapie par simulation Monte-Carlo

Résumé:

L'utilisation de faisceaux d’ions (protons ou ions légers) permet d'obtenir, lors du traitement, un dépôt d'énergie localisé en fin de parcours dans une zone réduite de l'espace. Les cibles privilégiées pour cette thérapie sont les tumeurs « radiorésistantes » ou les traitements nécessitant une balistique très précise, du fait de la présence d'organes à risques à proximité de la tumeur. Cependant, comme la détermination du parcours des ions et donc de la dose délivrée est dépendante de grandeurs qui restent difficiles à mesurer précisément, d’importantes marges de sécurité doivent être prises lors de la conception du plan de traitement. En conséquence, il est nécessaire de mettre en place un système performant de contrôle balistique afin de garantir la qualité du traitement. Une des possibilités pour le contrôle balistique repose sur la mesure en temps réel de la distribution spatiale des radionucléides émetteurs de positons produits par réaction de fragmentation entre le projectile et la cible et donc sur la détection en coïncidence de deux photons. Pour cela, un premier prototype appelé Détecteur Pixélisé de Grande Acceptance (DPGA) a été conçu puis construit au sein du laboratoire de Physique de Clermont. Dans un premier temps, ce travail a permis de comparer les prédictions de deux modèles hadroniques implémentés dans Geant4 aux mesures expérimentales effectuées par une autre équipe (Dendooven et al.) à 55 MeV (non présenté ici). Ensuite, nous nous sommes attachés à caractériser les performances du DPGA et à déterminer son potentiel lors de son utilisation en faisceau clinique. Pour cela nous avons développé une simulation Monte-Carlo dédiée permettant de comprendre la physique associée, le détecteur et les expériences effectuées sur faisceau de protons 65 MeV à l’Institut méditerranéen de Protonthérapie (IMPT) de Nice. Enfin, comme le DPGA sera à terme couplé avec un système d’acquisition à grande bande passante (μTCA) autorisant l’envoi et le traitement des données mesurées en temps réel, nous avons fait une étude des performances attendues sur la ligne PROTEUS ONE de l'IMPT à 120 et 230 MeV.

Title: Studies of the performance of a detector dedicated to ballistic control during hadrontherapy treatments using Monte-Carlo simulation code

Abstract:

The use of ion beams (protons or light ions) makes it possible to obtain, during treatment, a localised energy deposit at the end of the treatment in a small area of space. The preferred targets for this therapy are "radioresistant" tumours or treatments requiring very precise ballistics, due to the presence of high-risk organs close to the tumour. However, as the determination of the ion path and thus the delivered dose is dependent on quantities that are difficult to measure precisely, large safety margins must be taken into account when designing the treatment plan. Consequently, it is necessary to set up an efficient ballistic control system in order to guarantee the quality of the treatment. One of the possibilities for ballistic control is based on the real-time measurement of the spatial distribution of positron-emitting radionuclides produced by the fragmentation reaction between the projectile and the target and thus on the coincident detection of two photons. For this purpose, a first prototype called Large Area Pixelized Detector (LAPD) was designed and built at the Clermont Physics Laboratory. Initially, this work allowed to compare the predictions of two hadronic models implemented in Geant4 with experimental measurements performed by Dendooven et al. at 55 MeV (not shown here). We then focused on characterizing the performance of the LAPD and determining its potential when used in a clinical beam. For this purpose, we developed a Monte-Carlo simulation dedicated to understand the associated physics, the detector and the experiments carried out on 65 MeV proton beam at the Institut Mediterranéen de Protonthérapie (IMPT) in Nice. Finally, as the LPAD will eventually be coupled with a high-bandwidth acquisition system (μTCA) allowing the sending and processing of the measured data in real time, we have made a study of the performances expected on the PROTEUS ONE line of the IMPT at 120 and 230 MeV.

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Léo Adenis

Séminaires Jeunes docteurs du GDR du 7 juin 2021

Title: Modelling radiotherapy effect on low-grade gliomas

Abstract:

Part of my thesis work was focused on the design and validation of a patient-scale tumor growth model and the effect of radiotherapy on this tumor. This model is based on partial differential equations, describing the processes of proliferation, diffusion, radiation damage and cell death. I have developed a genetic automatic adjustment algorithm, and used the CMA-ES stochastic automatic adjustment method, in order to reproduce the evolution of the radius of diffuse low-grade gliomas as a function of time, before and after radiotherapy of a sample of patients.

Titre: Modélisation de l'effet de la radiothérapie sur les gliomes de bas-grade

Résumé: 

Une partie de mes travaux de thèse a porté́ sur la conception et la validation d’un modèle de croissance tumeur à l’échelle d’un patient et de l’effet de la radiothérapie sur cette tumeur. Ce modèle est basé sur des équations aux dérivées partielles, décrivant les processus de prolifération, diffusion, endommagement par la radiothérapie et mort cellulaire. J'ai développé́ un algorithme génétique d’ajustement automatique, et utilisé la méthode stochastique d’ajustement automatique CMA-ES, afin de reproduire l’évolution du rayon de gliomes de bas-grade diffus en fonction du temps, avant et après radiothérapie sur un échantillon de patients.

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Tim Schneider

Séminaires Jeunes docteurs du GDR du 7 juin 2021

Title: Improving proton therapy with magnetically focussed minibeams

Abstract: Despite major advances over the last decades, the dose tolerance of normal tissue continues to be a central problem in radiation therapy, limiting for example the effective treatment of hypoxic tumours and high-grade gliomas. Proton minibeam radiation therapy (pMBRT) is a novel therapeutic strategy, combining the improved ballistics of protons with the enhanced tissue sparing potential of submillimetric, spatially fractionated beams (minibeams), that has already demonstrated its ability to significantly improve the therapeutic index for brain cancers in rats. In contrast to conventional proton therapy which uses comparatively large beam diameters of five millimetres to several centimetres, minibeams re- quire beam sizes of less than 1 mm which are challenging to create in a clinical context. So far, every implementation of pMBRT at clinically relevant beam energies could only be achieved with the help of mechanical collimators (metal blocks with thin slits or holes). However, this method is inefficient, inflexible and creates high levels of unwanted secondary particles. The optimal approach may therefore be the generation of minibeams through magnetic focussing.

In my thesis, I investigated how magnetically focussed proton minibeams can be realised in a clinical context. Starting from the computer model of a modern pencil beam scanning nozzle (the term "nozzle" describes the final elements of a clinical beamline), it could be shown that current nozzles will not be suitable for this task, since their large dimensions and the presence of too much air in the beam path make it impossible to focus the beam down to the required sizes. Instead, I developed an optimised nozzle design and evaluated it with different clinical beam models. It could be demonstrated that this design allows the generation of proton minibeams through magnetic focussing and that the new nozzle can be used with already existing technology. Moreover, a Monte Carlo study was performed to compare and quantify the differences between magnetically focussed minibeams and mechanically collimated minibeams.

Titre: Améliorer la protonthérapie avec des mini-faisceaux générés par focalisation magnétique

Résumé: Malgré d’importants progrès, la tolérance des tissus sains aux rayonnements demeure un facteur central en radiothérapie, limitant par exemple l’efficacité du traitement des gliomes de haute grade. La proton thérapie avec mini-faisceaux (proton minibeam radiation therapy, pMBRT) est une nouvelle stratégie thérapeutique qui a pour objectif d’améliorer la préservation des tissus sains en combinant les avantages balistiques des protons et le fractionnement spatial de la dose obtenu avec des faisceaux submillimétriques. Dans ce contexte, la pMBRT a déjà démontré sa capacité à augmenter l’index thérapeutique dans le traitement des tumeurs cérébrales de rats. Un défi important est la génération des mini- faisceaux dans un cadre clinique : contrairement à la radiothérapie conventionnelle qui utilise des faisceaux larges (diamètre d’environ 5 mm à plusieurs centimètres), les mini-faisceaux se caractérisent par un diamètre de moins d’un millimètre. Actuellement, la génération des mini-faisceaux de protons est réalisée à l’aide de collimateurs mécaniques (blocs en métal avec plusieurs fentes ou trous) ce qui comporte plusieurs inconvénients (notamment une très faible flexibilité, une réduction importante du débit de dose ainsi que la génération de particules secondaires indésirables). Une solution optimale pourrait être la génération des mini-faisceaux par focalisation magnétique.

Le point de départ de ma thèse était donc la question : Comment la génération des mini-faisceaux de protons par focalisation magnétique peut-elle être réalisée dans un cadre clinique ? En utilisant le modèle numérique d’un pencil beam scanning nozzle (le "nozzle" est la dernière partie d’une ligne de faisceau clinique), il a été démontré que les nozzles actuels ne sont pas adéquats pour focaliser les faisceaux de protons à la taille requise, les principales raisons étant une distance focale trop grande et une présence d’air excessive. En partant de ces conclusions, un nouveau design de nozzle optimisé a été développé. Ce nouveau modèle est capable de générer des mini-faisceaux de protons par focalisation magnétique dans des conditions réalisables avec les technologies existantes. Une étude Monte Carlo a également été menée afin de comparer et de quantifier les différences entre la génération de mini-faisceaux par collimation mécanique et par focalisation magnétique.

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Feriel Khellaf

Séminaires Jeunes docteurs du GDR du 12 avril 2021

Title: List-mode proton CT reconstruction

Abstract:

Proton therapy is used for cancer treatment to achieve better dose conformity by exploiting the energy-loss properties of protons. Proton treatment planning systems require knowledge of the stopping-power map of the patient’s anatomy to compute the absorbed dose. In clinical practice, this map is generated through a conversion from X-ray computed tomography (CT) Hounsfield units to proton stopping power relative to water (RSP). This calibration generates uncertainties as photon and proton physics are different, which leads to the use of safety margins and the reduction of dose conformity. In order to reduce uncertainties, proton CT (pCT) was proposed as a planning imaging modality since the reconstructed quantity is directly the RSP. In addition to energy loss, protons also undergo multiple Coulomb scattering (MCS) inducing non-linear paths, thus making the pCT reconstruction problem different from that of X-ray CT and degrading spatial resolution. The use of a most likely path (MLP) formalism for protons to account for the effects of MCS has improved the spatial resolution in pCT, although this formalism assumes a homogeneous medium.
The objective of this work was to improve image quality of pCT list-mode reconstruction.  First, we study the accuracy of the MLP formalism in heteregeneous media by comparing the theoretical MLP against Monte Carlo generated proton paths. Results in terms of spatial, angular, and energy distributions were analyzed to determine the maximum systematic error on the MLP and assess the impact on reconstruction.
The MLP formalism provides an additional information to the MLP estimate, which is the uncertainty envelope around the MLP. This information, included in a reconstruction algorithm, could help improve spatial resolution. In addition to MCS, the resolution of the trackers used to measure the protons' position and angle has also an impact on spatial resolution. We propose a deconvolution method using the uncertainty on the MLP estimate and the tracker resolution to improve the spatial resolution of pCT images. Results on simulated data show an improved spatial resolution in simple phantoms as well as anthropomorhpic phantoms.

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Floriane Poignant

Séminaire Jeunes Docteurs du GDR MI2B  du 12 avril 2021

Title: Physical, chemical and biological modelling for gold nanoparticle-enhanced radiation therapy: towards a better understanding and optimization of the radiosensitizing effect

Abstract:

In radiation therapy, high-Z nanoparticles such as gold nanoparticles (GNPs) have shown particularly promising radiosensitizing properties. At an early stage, an increase in dose deposition and free radical production throughout the tumor (photoelectric effect) and at sub-cellular scale (Auger cascade) might be responsible for part of the effect for low-energy X-rays. In this work, these early mechanisms are investigated with simulation tools to better quantify them and understand their impact on cell survival.

This work was based on Monte Carlo (MC) models developed to track electrons down to low energy both in water (meV) and gold (eV). In particular, the accuracy of electron transport in gold was assessed by comparing the MC predictions with experimental data in the literature.

Once validated, the MC simulation was used to quantify the energy deposited in nanotargets located near the GNP, which correlates with the probability to generate damages. These nanodosimetry results showed a significant increase of the probability of having an energy deposition in the nanotarget larger than a threshold, within 200 nm around the GNP. This suggests that GNPs may be particularly efficient at destroying biological nanotargets in its vicinity.

The MC simulation was then used to quantify chemical effects. At the macroscale, the increase of free radical production for a concentration of GNPs was calculated. Such increase correlated well with the increase of dose deposition at the macro-scale.

Finally, MC results were used together with the biophysical model NanOx to predict cell survival in presence of GNPs. NanOx was originally developed to calculate the biological dose in hadrontherapy. The Local Effect Model (LEM), currently the main biophysical model implemented for GNP-enhanced radiation therapy, was also used to calculate cell survival and to compare NanOx and LEM predictions. For a simple system where GNPs were homogeneously distributed in the cell, the increase of cell death with the biophysical model NanOx was purely due to the increase of the macroscopic dose. No increased biological effectiveness due to Auger electrons was obtained, which comes in contradiction with the LEM predictions.

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Sofia Ferreira

Séminaire Jeunes Docteurs du GDR MI2B  du 1er février 2021

Title: Inhibiting DNA repair with AsiDNA to radiosensitize pediatric brain tumors without added toxicity

Authors: Sofia Ferreira, Chloe Foray, Alberto Gatto, Magalie Larcher, Sophie Heinrich, Mihaela Lupu, Joel Mispelter, François D. Boussin, Célio Pouponnot and Marie Dutreix

Abstract: Medulloblastoma is a brain tumor of the cerebellum. It is an important cause of mortality and morbidity in pediatric oncology. Preclinical and clinical evidence showed that the DNA repair inhibitor AsiDNA improves treatments efficacy without added toxicity in adults. In our work, we investigated whether these properties of AsiDNA could be translated to medulloblastoma pediatric models, addressing a significant unmet clinical need in medulloblastoma care.
To evaluate the brain permeability of AsiDNA upon systemic delivery, we intraperitoneally injected a fluorescence form of AsiDNA in models harboring brain tumors and in models still in development. Studies evaluated toxicity associated with combination of AsiDNA with radiation in the treatment of young developing animals at subacute levels, related to growth and development, and at chronic levels, related to brain organization and cognitive skills. Efficacy of the combination of AsiDNA with radiation was tested in two different preclinical xenografted models of high-risk medulloblastoma and in a panel of medulloblastoma cell lines from different molecular subgroups and TP53 status. Role of TP53 on the AsiDNA-mediated radiosensitization was analyzed by RNA-sequencing, DNA repair recruitment, and cell death assays.
Capable of penetrating young brain tissues, AsiDNA showed no added toxicity to radiation. Combination of AsiDNA with radiotherapy improved the survival of animal models more efficiently than increasing radiation doses. Medulloblastoma radiosensitization by AsiDNA was not restricted to a specific molecular group or status of TP53. Molecular mechanisms of AsiDNA, previously observed in adult malignancies, were conserved in pediatric models and resembled dose increase when combined with irradiation.
Our results suggest that AsiDNA is an attractive candidate to improve radiotherapy in medulloblastoma, with no indication of additional toxicity in developing brain tissues.

Présentation (format video MP4)

Sébastien Curtoni:

Présentation au Séminaire Jeunes Docteurs du GDR MI2B le 1er février 2021

A diamond beam-tagging hodoscope for online ion verification in hadrontherapy by means of
time-of-flight enhanced Prompt-Gamma detection

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Abstract:
Hadrontherapy could benefit from an online ion range monitoring system. First, it would allow to
reduce ion range specific security margins currently set in the treatment planning. It could also enable
to detect discrepancies between the planned and the actual ion range during a treatment session.
Several groups are currently developing online ion range verification techniques and many of them are
based on secondary particle detection. Among them, prompt-gamma photons (PG) emission results
from inelastic nuclear interactions occurring along the ion pathway and their emission profile is thus
spatially correlated to the ion range.
The CLaRyS national collaboration is developing such PG-based monitoring systems. The originality
in CLaRyS’ approach consists in adding a beam-tagging hodoscope to the detection system which
provides spatial and temporal information on incoming ions. Combining an overall 100 ps (σ)
resolution on the ion+PG time-of-flight and single ion regime, the efficiency and sensitivity of PGbased
verification systems could be notably improved. To fulfill these requirements, the hodoscope
should be fast, radiation-hard and sensitive to single ions. In this context, diamond-based hodoscope
demonstraters are currently under development.
As synthetic diamond is available in various crystalline qualities and sizes, this work was highly
focused on the characterization carried out on commercially available samples to highlight the best
hodoscope candidate. The presentation will review the different lab and beam tests done at lab and in
different particle beam configurations with Chemical Vapor Deposition (CVD) diamond samples. Their
single ion detection efficiency, time resolution and counting capabilities were measured. Their spatial
response was also assessed with a X-ray micro-beam. The first double-sided strip prototypes,
developed during this thesis, will also be introduced. The presentation will be concluded by a brief
presentation of larger area diamond hodoscope demonstrators which are currently under construction
with dedicated front-end electronics and acquisition system.