Reprint of “Chordoma in children: Case-report and review of literature”

We report an exceptional case of a very late local failure in a 9-year-old boy presenting with a chordoma of the cranio-cervical junction. The child was initially treated with a combination of surgical resection followed by high dose photon–proton radiation therapy. This aggressive therapy allowed a 9-year remission with minimal side-effects. Unfortunately, he subsequently presented with a local failure managed with a second full-dose course of protons. The child died one year later from local bleeding of unclear etiology

Experimental assessment of inter-centre variation in stopping-power and range prediction in particle therapy

Purpose: Experimental assessment of inter-centre variation and absolute accuracy of stopping-power ratio (SPR) prediction within 17 particle therapy centres of the European Particle Therapy Network. Material and methods: A head and body phantom with seventeen tissue-equivalent materials were scanned consecutively at the participating centres using their individual clinical CT scan protocol and translated into SPR with their in-house CT-number-to-SPR conversion. Inter-centre variation and absolute accuracy in SPR prediction were quantified for three tissue groups: lung, soft tissues and bones. The integral effect on range prediction for typical clinical beams traversing different tissues was determined for representative beam paths for the treatment of primary brain tumours as well as lung and prostate cancer. Results: An inter-centre variation in SPR prediction (2 sigma) of 8.7%, 6.3% and 1.5% relative to water was determined for bone, lung and soft-tissue surrogates in the head setup, respectively. Slightly smaller variations were observed in the body phantom (6.2%, 3.1%, 1.3%). This translated into inter-centre variation of integral range prediction (2 sigma) of 2.9%, 2.6% and 1.3% for typical beam paths of prostate-, lung-and primary brain-tumour treatments, respectively. The absolute error in range exceeded 2% in every fourth participating centre. The consideration of beam hardening and the execution of an independent HLUT validation had a positive effect, on average. Conclusion: The large inter-centre variations in SPR and range prediction justify the currently clinically used margins accounting for range uncertainty, which are of the same magnitude as the inter-centre variation. This study underlines the necessity of higher standardisation in CT-number-to-SPR conversion. (C) 2021 The Authors. Published by Elsevier B.V

Effets physiques et biologiques des faisceaux de protons balayés : mesures et modélisation pour des balayages séquentiels à haut débit

The main objective of this thesis is to develop and optimize algorithms for intensity modulated proton therapy, taking into account the physical and biological pencil beam properties. A model based on the summation and fluence weighted division of the pencil beams has been used. A new parameterization of the lateral dose distribution has been developed using a combination of three Gaussian functions. The algorithms have been implemented into a treatment planning system, then experimentally validated and compared with Monte Carlo simulations. Some approximations have been made and validated in order to achieve reasonable calculation times for clinical purposes. In a second phase, a collaboration with Institut Curie radiobiological teams has been started in order to implement radiobiological parameters and results into the optimization loop of the treatment planning process. Indeed, scanned pencil beams are pulsed and delivered at high dose rates (from 10 to 100 Gy/s), and the relative biological efficiency of protons is still relatively unknown given the wide diversity of use of these beams: the different models available and their dependence with linear energy transfers have been studied. A good agreement between dose calculations and measurements (deviations lower than 3 % and 2 mm) has been obtained. An experimental protocol has been set in order to qualify pulsed high dose rate effects and preliminary results obtained on one cell line suggested variations of the biological efficiency up to 10 %, though with large uncertainties.L'objectif principal de cette thèse est de développer et optimiser les algorithmes caractérisant les propriétés physiques et biologiques des mini-faisceaux de protons pour la réalisation des traitements avec modulation d'intensité. Un modèle basé sur la superposition et décomposition des mini-faisceaux en faisceaux élémentaires a été utilisé. Un nouveau modèle de description des mini-faisceaux primaires a été développé à partir de la sommation de trois fonctions gaussiennes. Les algorithmes ont été intégrés dans un logiciel de planification de traitement, puis validés expérimentalement et par comparaison avec des simulations Monte Carlo. Des approximations ont été réalisées et validées afin de réduire les temps de calcul en vue d'une utilisation clinique. Dans un deuxième temps, un travail en collaboration avec les équipes de radiobiologie de l'institut Curie a été réalisé afin d'introduire des résultats radiobiologiques dans l'optimisation biologique des plans de traitement. En effet, les faisceaux balayés sont délivrés avec des débits de dose très élevés (de 10 à 100 Gy/s) et de façon discontinue, et l'efficacité biologique des protons est encore relativement méconnue vue la diversité d'utilisation de ces faisceaux : les différents modèles disponibles et notamment leur dépendance avec le transfert d'énergie linéique ont été étudiés. De bons accords (écarts inférieurs à 3 % et 2 mm) ont été obtenus entre calculs et mesures de dose. Un protocole d'expérimentation pour caractériser les effets des hauts débits pulsés a été mis en place et les premiers résultats obtenus sur une lignée cellulaire suggèrent des variations d'efficacité biologique inférieures à 10 %, avec toutefois de larges incertitudes

Bio-physical effects of scanned proton beams : measurements and models for discrete high dose rates scanning systems

L'objectif principal de cette thèse est de développer et optimiser les algorithmes caractérisant les propriétés physiques et biologiques des mini-faisceaux de protons pour la réalisation des traitements avec modulation d'intensité. Un modèle basé sur la superposition et décomposition des mini-faisceaux en faisceaux élémentaires a été utilisé. Un nouveau modèle de description des mini-faisceaux primaires a été développé à partir de la sommation de trois fonctions gaussiennes. Les algorithmes ont été intégrés dans un logiciel de planification de traitement, puis validés expérimentalement et par comparaison avec des simulations Monte Carlo. Des approximations ont été réalisées et validées afin de réduire les temps de calcul en vue d'une utilisation clinique. Dans un deuxième temps, un travail en collaboration avec les équipes de radiobiologie de l'institut Curie a été réalisé afin d'introduire des résultats radiobiologiques dans l'optimisation biologique des plans de traitement. En effet, les faisceaux balayés sont délivrés avec des débits de dose très élevés (de 10 à 100 Gy/s) et de façon discontinue, et l'efficacité biologique des protons est encore relativement méconnue vue la diversité d'utilisation de ces faisceaux : les différents modèles disponibles et notamment leur dépendance avec le transfert d'énergie linéique ont été étudiés. De bons accords (écarts inférieurs à 3 % et 2 mm) ont été obtenus entre calculs et mesures de dose. Un protocole d'expérimentation pour caractériser les effets des hauts débits pulsés a été mis en place et les premiers résultats obtenus sur une lignée cellulaire suggèrent des variations d'efficacité biologique inférieures à 10 %, avec toutefois de larges incertitudes.The main objective of this thesis is to develop and optimize algorithms for intensity modulated proton therapy, taking into account the physical and biological pencil beam properties. A model based on the summation and fluence weighted division of the pencil beams has been used. A new parameterization of the lateral dose distribution has been developed using a combination of three Gaussian functions. The algorithms have been implemented into a treatment planning system, then experimentally validated and compared with Monte Carlo simulations. Some approximations have been made and validated in order to achieve reasonable calculation times for clinical purposes. In a second phase, a collaboration with Institut Curie radiobiological teams has been started in order to implement radiobiological parameters and results into the optimization loop of the treatment planning process. Indeed, scanned pencil beams are pulsed and delivered at high dose rates (from 10 to 100 Gy/s), and the relative biological efficiency of protons is still relatively unknown given the wide diversity of use of these beams: the different models available and their dependence with linear energy transfers have been studied. A good agreement between dose calculations and measurements (deviations lower than 3 % and 2 mm) has been obtained. An experimental protocol has been set in order to qualify pulsed high dose rate effects and preliminary results obtained on one cell line suggested variations of the biological efficiency up to 10 %, though with large uncertainties

Converging Proton Minibeams with Magnetic Fields for Optimized Radiation Therapy: A Proof of Concept

Proton MiniBeam Radiation Therapy (pMBRT) is a novel strategy that combines the benefits of minibeam radiation therapy with the more precise ballistics of protons to further optimize the dose distribution and reduce radiation side effects. The aim of this study is to investigate possible strategies to couple pMBRT with dipole magnetic fields to generate a converging minibeam pattern and increase the center-to-center distance between minibeams. Magnetic field optimization was performed so as to obtain the same transverse dose profile at the Bragg peak position as in a reference configuration with no magnetic field. Monte Carlo simulations reproducing realistic pencil beam scanning settings were used to compute the dose in a water phantom. We analyzed different minibeam generation techniques, such as the use of a static multislit collimator or a dynamic aperture, and different magnetic field positions, i.e., before or within the water phantom. The best results were obtained using a dynamic aperture coupled with a magnetic field within the water phantom. For a center-to-center distance increase from 4 mm to 6 mm, we obtained an increase of peak-to-valley dose ratio and decrease of valley dose above 50%. The results indicate that magnetic fields can be effectively used to improve the spatial modulation at shallow depth for enhanced healthy tissue sparing

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

International audienceObjectives: 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. Methods: The whole “Y1”-passive beamline at the ICPO, including pMBRT implementation, was modelled using the Monte Carlo GATE v. 7.0 code. A clinically relevant proton energy (100 MeV) was used as starting point. Minibeam generation by means of the brass collimator used in the first experiments was modelled. A virtual source was modelled at the exit of the beamline nozzle and outcomes were compared with dosimetric measurements performed with EBT3 gafchromic films and a diamond detector in water. Dose distributions were recorded in a water phantom and in rat CT images (7-week-old male Fischer rats). Results: The dose calculation engine was benchmarked against experimental data and was then used to assess dose distributions in CT images of a rat, resulting from different irradiation configurations used in several experiments. It reduced computational time by an order of magnitude. This allows us to speed up simulations for in vivo trials, where we obtained peak-to-valley dose ratios of 1.20 ± 0.05 and 6.1 ± 0.2 for proton minibeam irradiations targeting the tumour and crossing the rat head. Tumour eradication was observed in the 67 and 22% of the animals treated respectively. Conclusion: A Monte Carlo dose calculation engine for pMBRT implementation with mechanical collimation has been developed. This tool can be used to guide and interpret the results of in vivo trials. Advances in knowledge: This is the first Monte Carlo dose engine for pMBRT that is being used to guide preclinical trials in a clinical proton therapy centre

Preclinical dosimetry in proton minibeam radiation therapy: Robustness analysis and guidelines

International audiencePurpose: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy approach that has shown a significant increase in the therapeutic window in glioma-bearing rats compared to conventional proton therapy. The dosimetry of pMBRT is challenging and error prone due to the submillimetric beamlet sizes used. The aim of this study was to perform a robustness analysis on the setup parameters utilized in current preclinical trials and provide guidelines for reproducible dosimetry. The results of this work are intended to guide upcoming implementations of pMBRT worldwide, as well as pave the way for future clinical implementations.Methods: Monte Carlo simulations and experimental data were used to evaluate the impact of variations in setup parameters and uncertainties in collimator specifications on lateral pMBRT dose distributions. The value of each parameter was modified individually to evaluate their effect on dose distributions. Experimental dosimetry was performed by means of high-resolution detectors, that is, radiochromic films, the IBA Razor and the Microdiamond detector. New guidelines were proposed to optimize the experimental setup in pMBRT studies and perform reproducible dosimetry.Results: The sensitivity of dose distributions to uncertainties and variations in setup parameters was quantified. Quantities that define pMBRT lateral profiles (i.e., the peak-to-valley dose ratio [PVDR], peak and valley doses, and peak width) are significantly influenced by small-scale fluctuations in several of those parameters. The setup implemented at the Orsay proton therapy center for pMBRT irradiation was optimized to increase PVDRs and peak symmetry. In addition, we proposed guidelines to perform accurate and reproducible dosimetry in preclinical studies.Conclusions: This study revealed the importance of adopting guidelines and protocols tailored to the distinct dose delivery method and dose distributions in pMBRT. This new methodology leads to reproducible dosimetry, which is imperative in preclinical trials. The results and guidelines presented in this manuscript can ease the initiation of pMBRT investigations in other centers

Proton Minibeam Radiation Therapy and Arc Therapy: Proof of Concept of a Winning Alliance

International audience(1) Background: Proton Arc Therapy and Proton Minibeam Radiation Therapy are two novel therapeutic approaches with the potential to lower the normal tissue complication probability, widening the therapeutic window for radioresistant tumors. While the benefits of both modalities have been individually evaluated, their combination and its potential advantages are being assessed in this proof-of-concept study for the first time. (2) Methods: Monte Carlo simulations were employed to evaluate the dose and LET distributions in brain tumor irradiations. (3) Results: a net reduction in the dose to normal tissues (up to 90%), and the preservation of the spatial fractionation of the dose were achieved for all configurations evaluated. Additionally, Proton Minibeam Arc Therapy (pMBAT) reduces the volumes exposed to high-dose and high-LET values at expense of increased low-dose and intermediate-LET values. (4) Conclusions: pMBAT enhances the individual benefits of proton minibeams while keeping those of conventional proton arc therapy. These results might facilitate the path towards patients’ treatments since lower peak doses in normal tissues would be needed than in the case of a single array of proton minibeams

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

International audienceApplied nuclear physics and biophysics are ubiquitous in our lives and is has large impact on the society covering a variety of different topics. The field is in fast and exponential growth and in the next future new accelerators in Europe, but also worldwide, will offer to researchers even more opportunities to further explore the application of biomedical research. Some example of this vast landscape are the innovative techniques of cancer radiotherapy, as the particle therapy of cancer or the high dose/rate irradiation therapy, the study of the effect of the cosmic rays on the astronauts for radio protection purpose in long term space missions. Such a different topics have in common the biophysics effect of the ionizing radiation on living tissue. The aim of the AUSPICE project is to establish a network between the several research groups and to build a coordination of efforts so to avoid duplications and instead have synergistic interactions for biomedical research at accelerators. AUSPICE can have a large impact of the future production of this field in Europe, that sees now very active and competitive research groups, but with very poor intercommunication, usually independent funding, and with scarce cooperation. AUSPICE will create a network in an highly fractionated community, boosting the interdisciplinary approach to the problem. fostering the application of the research results in the market.Particularly care will be given to the creation a community of young researchers strongly interconnected and acting as a bridge between research and applicatio