Intracerebral delivery of Carboplatin in combination with either 6 MV Photons or monoenergetic synchrotron X-rays are equally efficacious for treatment of the F98 rat glioma.

International audienceABSTRACT: BACKGROUND: The purpose of the present study was to compare side-by-side the therapeutic efficacy of a 6-day infusion of carboplatin, followed by X-irradiation with either 6 MV photons or synchrotron X-rays, tuned above the K-edge of Pt, for treatment of F98 glioma bearing rats. METHODS: Carboplatin was administered intracerebrally (i.c.) to F98 glioma bearing rats over 6 days using AlzetTM osmotic pumps starting 7 days after tumor implantation. Radiotherapy was delivered in a single 15 Gy fraction on day 14 using a conventional 6 MV linear accelerator (LINAC) or 78.8 keV synchrotron X-rays. RESULTS: Untreated control animals had a median survival time (MeST) of 33 days. Animals that received either carboplatin alone or irradiation alone with either 78.8 keV or 6 MV had a MeSTs 38 and 33 days, respectively. Animals that received carboplatin in combination with X-irradiation had a MeST of > 180 days with a 55% cure rate, irrespective of whether they were irradiated with either 78.8 KeV synchrotron X-rays or 6MV photons. CONCLUSIONS: These studies have conclusively demonstrated the equivalency of i.c. delivery of carboplatin in combination with X-irradiation with either 6 MV photons or synchrotron X-rays

Intracerebral delivery of 5-iodo-2'-deoxyuridine in combination with synchrotron stereotactic radiation for the therapy of the F98 glioma.

International audienceIodine-enhanced synchrotron stereotactic radiotherapy takes advantage of the radiation dose-enhancement produced by high-Z elements when irradiated with mono-energetic beams of synchrotron X-rays. In this study it has been investigated whether therapeutic efficacy could be improved using a thymidine analogue, 5-iodo-2'-deoxyuridine (IUdR), as a radiosentizing agent. IUdR was administered intracerebrally over six days to F98 glioma-bearing rats using Alzet osmotic pumps, beginning seven days after tumor implantation. On the 14th day, a single 15 Gy dose of 50 keV synchrotron X-rays was delivered to the brain. Animals were followed until the time of death and the primary endpoints of this study were the mean and median survival times. The median survival times for irradiation alone, chemotherapy alone or their combination were 44, 32 and 46 days, respectively, compared with 24 days for untreated controls. Each treatment alone significantly increased the rats' survival in comparison with the untreated group. Their combination did not, however, significantly improve survival compared with that of X-irradiation alone or chemotherapy alone. Further studies are required to understand why the combination of chemoradiotherapy was no more effective than X-irradiation alone

Synchrotron Radiation therapy from In vitro & Preclinical Results to clinical tria

International audienceBackground: Radiation therapy remains a fundamental tool for cancer treatment, but selective dose deposition within a targeted-tumor, while sparing surrounding structures, remains a challenge. This objective can be achieved by loading the tumor with high-Z elements prior delivery of radiation therapy. Synchrotron sources are ideal sources since they provide high-intensity and tunable monochromatic X-rays within the optimal energy-range

Amélioration de l'efficacité de la radiothérapie

National audienc

Chimio-radiothérapie des tumeurs cérébrales : intérêt de l'injection intratumorale de drogues antinéoplasiques

Les gliomes de haut grade sont des tumeurs cérébrales particulièrement agressives et les traitements actuels demeurent uniquement palliatifs. L efficacité des radiothérapies est sévèrement limitée par la tolérance des tissus sains, l enjeu est donc d accroître la dose et la toxicité en ciblant le tissu tumoral. Une des méthodes proposées repose sur l association de drogues anticancéreuses localisées au sein de la tumeur et d une irradiation X. Au niveau cérébral, l accumulation d un agent injecté usuellement par voie syste mique, est rendue difficile par la présence de la barrière hémato-encéphalique, qui filtre le passage des molécules à travers l endothélium vasculaire. Des techniques d injection ont été développées récemment pour délivrer des drogues directement dans le lit tumoral. Parmi elles, la méthode de convection-enhanced delivery (CED) permet d obtenir une distribution de drogue homogène et contrôlée. Les objectifs de cette thèse étaient de mettre en place et caractériser la CED puis de l appliquer au traitement des gliomes par des études précliniques. Plusieurs agents ont été testés : cisplatine, carboplatine, oxaliplatine et iododésoxyuridine et deux modalités d irradiation ont été évaluées : la radiothérapie stéréotaxique en rayonnement synchrotron (monochromatique <100 keV) et l irradiation haute énergie (6 MV) sur un accélérateur médical usuel. Les résultats obtenus révèlent que l efficacité du traitement combinant drogue platinée et rayons X est étroitement liée à celle de la chimiothérapie seule et ne dépend pas de l énergie du rayonnement utilisé. Ces résultats sont très prometteurs et ouvrent des perspectives nouvelles pour la recherche clinique.High grade gliomas are aggressive tumors for which current treatments remain palliative. Radiotherapy efficacy is restricted by the surrounding brain tissue tolerance. One method based on the concomitant use of chemotherapeutic drugs and external photon irradiation has been proposed to improve the treatment outcome. The systemic administration of drugs is not effective in achieving the therapeutic level of drug needed for brain tumor treatment. This is due to the blood brain barrier (BBB) that prevents molecules passing through the vascular endothelium. Recent methods have been developed to circumvent the BBB. Among them, convection-enhanced delivery (CED) relies on the continuous infusion of a fluid containing a therapeutic agent, under a pressure gradient. It permits a homogeneous and controlled drug distribution. The aims of this study were to characterise the CED method, and then to utilise it for glioma treatment in preclinical studies. Several drugs were tested: cisplatin, carboplatin, oxaliplatin, and iodo-deoxyuridine. Two radiation modalities were evaluated: synchrotron stereotactic radiotherapy (monochromatic beam <100 keV) and high energy irradiation (6 MV) obtained with a conventional medical linear accelerator. The results obtained reveal that the effectiveness of the combined treatment (platinated drug plus photon irradiation) is highly related to that of the chemotherapy. The data, obtained with the platinated chemotherapy, also show that high-energy X-ray irradiation (6 MV) is as effective as synchrotron X-ray irradiation. The results broaden the applicability of this chemotherapeutic approach to clinical trials.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Dosimétrie pour la radiothérapie stéréotaxique par rayonnement synchrotron : d'une vision macroscopique aux considérations microscopiques des dépôts d'énergie.

De nombreuses stratégies thérapeutiques sont explorées pour trouver un traitement curatif aux gliomes de haut grade pour lesquels il n'existe pas de réelle solution. Parmi ces techniques, la radiothérapie apporte une réponse significative mais limitée par un effet différentiel insuffisant pour éradiquer la tumeur tout en préservant les tissus sains. La radiothérapie stéréotaxique par rayonnement synchrotron permet d'augmenter cet effet différentiel en augmentant localement la dose de rayonnement au niveau de la tumeur, par l'effet synergique d'une irradiation avec des rayons-X de basse énergie (< 100 keV) en présence d'un élément lourd préalablement incorporé à la tumeur. Ce travail de doctorat s'inscrit dans le cadre de la préparation des essais cliniques de radiothérapie stéréotaxique prévus au synchrotron de Grenoble. Le premier objectif de ce travail a été l'optimisation des paramètres l'irradiation basée sur une étude dosimétrique globale des plans de traitement. Nous avons notamment montré l'intérêt d'utiliser un nombre fini et apparié de faisceaux correctement pondérés pour homogénéiser la dose dans la tumeur. La suite de ces travaux a consisté en l'étude de la répartition des dépôts d'énergie à l'échelle cellulaire prenant en compte la distribution fine de l'élément lourd dans le tissu (micro-dosimétrie). Il est en effet crucial que les photoélectrons générés sur les atomes lourds, qui restent dans l'espace extracellulaire dans le cas des agents de contraste iodés, puissent atteindre les cibles cellulaires. Cette approche microdosimétrique a été comparée à des résultats de survie cellulaire obtenus in vitro, soit sur un modèle cellulaire 3D (cellules tumorales cultivées sous forme de sphéroïdes), soit sur des cellules irradiées en suspension dans un milieu iodé.Numerous therapeutic strategies are currently being evaluated to find a curative treatment for high grade glioma. Among them, radiation therapy is partially effective but limited by the insufficient differential effect that can be reached between the dose delivered to the tumor compared to the one received by the healthy tissues. Synchrotron stereotactic radiotherapy aims at increasing this differential effect with a localized dose boost obtained by low energy x-rays stereotactic irradiations (< 100 keV) in presence of heavy elements restricted to the target area. This PhD work takes place in the general context of the future clinical trials foreseen at the European Synchrotron Radiation Facility. The first objective was to optimize the dose delivery to the target, at a macroscopic scale. We have demonstrated in particular that an even number of weighted beams was required to homogenize the tumor dose distribution. Microdosimetry studies were then performed to evaluate the dose delivered at the cellular level, taking into account the fine high-Z element distribution. These theoretical results have been compared to in vitro studies. Cell survival studies were performed using either a 3D glioma model (spheroids) or cells irradiated in suspension in an iodinated medium.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Développement d'un onduleur cryogénique à aimants permanents à l'ESRF

Un nouveau concept d'onduleur courte période et fort champ a été proposé par Toru Hara à SPring-8 en 2004 : l'onduleur cryogénique à aimants permanents (CPMU). Il s'agit de refroidir des aimants Néodyme-Fer-Bore autour de 150 K. Cela permet d'utiliser ces aimants qui ont une rémanence jusqu'à 40% supérieure à celle des aimants utilisés conventionnellement dans les onduleurs. Pour évaluer les difficultés technologiques et la faisabilité de tels onduleurs, un CPMU de 2 m de long et de 18 mm de période a été lancé à l'ESRF. Ce travail présente le design et la réalisation du CPMU à l'ESRF. Un modèle magnétostatique du CPMU est présenté, il est basé sur des mesures de courbe d'aimantation à température cryogénique réalisées au laboratoire Louis Néel. Le modèle prévoit une augmentation du champ crête de l'onduleur de 8% autour de 150 K et de l'intégrale de champ de 20 Gcm. Un banc de mesure magnétique spécifique a également été développé à l'ESRF. Ce banc permet la mesure du champ local et des intégrales de champ sous vide. Son design et sa construction sont revus. Finalement les mesures magnétiques réalisées à température ambiante et à température cryogénique sont présentées. Ces mesures valident le modèle magnétostatique et les performances attendues.In 2004, at SPring-8, Toru Hara proposed a new concept of undulator with a short period and a high field: the Cryogenic Permanent Magnet Undulator (CPMU). The purpose of this concept is to cool Nd2Fe14B magnets at 150 K. This cooling allows magnets which have a higher remanence to be used, up to 40% higher than that of the magnets traditionally used in undulators. In order to assess the technological possibility of producing such undulator, a 2 m long undulator with a 18 mm period has been proposed at the ESRF. This piece of work presents the design and the construction of this CPMU at the ESRF. First a magnetic model of the CPMU is introduced; it is based on measurements of the magnetization curve at cryogenic temperature performed at the Louis Néel Laboratory. This model forecasts an increase of the peak field of 8% and of the field integral of 0.2 Gm at around 150 K. A unique magnetic measurement bench has been developed at the ESRF. This bench allows both the in vacuum local field and field integral to be measured. Its design and construction are presented. Finally we have reviewed the measurements at room and cryogenic temperature. These measurements are in agreement with the magnetic model.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Radiotherapy by Photoactivation of Iron Nanoparticles and Mössbauer effect

International audienceThe Mössbauer effect [1], the resonant and recoil-free absorption and subsequent re-emission of γ rays by Mössbauer isotopes (e.g. 57Fe) leads to the emission of many Auger electrons (a single Auger event is comparable to more than 105 photon absorption events). These high LET electrons can induce clustered DNA damages (including Double Strand Breaks (DSB) and Locally Multiple Damaged Sites (LMDS)) if emitted in the direct vicinity of DNA. Dose (in J/kg) enhancement using Mössbauer effect has been first described in vitro by Mills et al. [2]. Since then, several studies have obtained conflicting results. The divergence of the data is mainly due to stringent experimental conditions mandatory to get Mössbauer resonance: photon energy of 14.4 keV (for 57Fe), crystalline network of the atom… Since Synchrotron radiation properties are well suited for Mössbauer resonance (high fluence and precise control on the irradiation energy), we propose to evaluate the efficiency of iron nanoparticles (NPFe) enriched in 57Fe to enhance dose deposition during radiotherapy. A sharp increase is expected in presence of nanoparticles. A preliminary experiment has been carried out at the European Synchrotron Radiation Facility ID18 (Mössbauer-dedicated beamline). Under irradiation at 14.4 keV (delta E = 0.65 meV), NPFe (synthesized as Choi described previously [3]) embedded in agarose gel produce a Nuclear Inelastic Scattering spectrum giving a density of phonon states similar to bulk iron as measured by Handke [4]. This result indicates that Mössbauer interactions can happen at room temperature in NPFe in a material with tissue-like rigidity.In parallel to this study, dose-enhancement produced by the photoelectric effect was also evaluated. F98 rodent glioma cells incubated with NPFe and irradiated at various monochromatic energies on the Beamline ID17 (30 to 80 keV) present a decreased survival rate due to photoelectrons produced by the interactions of low energy radiations with heavy atoms. We observed by ICPMS a very high concentration of the same alginate-coated magnetite nanoparticles in F98 rat glioma cells after 24h of incubation, up to a hundred of pg/cell. Those results have been confirmed by a 2D-X Ray microfluorescence experiment at the ID16B Beamline of the ESRF, showing high concentration of nanoparticles around the nucleus.To conclude, the performed experiments refine our comprehension of the physics of Mössbauer interactions, as well as confirm the theoretical basis for its application to enhance radiotherapy efficacy, and provide nanoparticles suitable to continue the study.References[1] - R. L. Mössbauer, Z. Physik 151, pp. 124-143 (1958).[2] - Mills et al., Nature 336, pp. 787-789 (1988).[3] - Choi et al., Radiation Oncology 7, 184 (2012).[4] – Handke et al., PRL B 71, 144301 (2005)

Modélisation et validation expérimentale de l'interaction rayonnement-milieu cellulaire dans le cadre de la radiothérapie par photoactivation d'éléments lourds

International audienceCertaines tumeurs résistantes, comme les gliomes de haut grade, sont encore incurables avec les moyens actuels de traitement. Une approche thérapeutique innovante utilisant l'adjonction d'éléments de Z élevé à la radiothérapie, semble offrir une voie prometteuse, en particulier en utilisant un rayonnement synchrotron. Cependant les dommages radiologiques dus à la présence de ces éléments sont mal connus. Mon travail porte sur l'étude, par simulation Monte Carlo, de l'interaction rayons X - nanoparticules d'or à une échelle micrométrique afin d'approfondir les connaissances concernant les processus physiques mis en jeu dans ce type d'approche

Modeling and experimental validation of radiation-cell interaction in radiotherapy by photon activation of gold nanoparticles

International audienceMalignant brain tumours represent a few percents of adult cancers and are the most frequent for children. Because of the delicate location, the radio sensitivity of healthy brain and the presence of the blood brain barrier, the current treatments for some of these brain cancers are not efficient. An innovative approach using X-rays in addition with heavy elements, as iodine or gold nanoparticles, seems to open a promising way. Such technique is developed at the medical beam line of European Synchrotron Radiation Facility using monochromatic X-rays in the 50-100 keV range for the treatment of resistant solid tumours such as high-grade gliomas. With this approach, a localized dose enhancement can be obtained from photoelectric effect on heavy elements introduced in the target volume. However, the physical processes and biological impact of the photon activation of heavy elements are not well understood. The experimental results can not be explained from macroscopic dose calculations, the radio-induced damages at the cell level have to be considered. The aim of this work is to model and simulate, with a Monte Carlo transport code, the interaction between radiations and cells or DNA in presence of heavy elements and to compare the results with experimental measurements carried out in two partner laboratories: laboratoire des Lésions des Acides Nucléiques at CEA of Grenoble and the INSERM team of the beam line dedicated to medical studies at ESRF. To this end, we first started to study the characteristics of the gold nanoparticles under various conditions of irradiation, for instance looking at the spectra of secondary electrons created and the deposited dose at a micrometer level around a nanoparticle. In a second hand, we will look into a more realistic model close to the experimental conditions in order to see potential correlation between a physical process modelled and a radiobiological result obtained with the experiments made at ESRF