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Background Resistance to radiotherapy is frequently encountered in patients with glioblastoma multiforme. It is caused at least partially by the high glutathione content in the tumour tissue. Therefore, the administration of the glutathione synthesis inhibitor Buthionine-SR-Sulfoximine (BSO) should increase survival time. Methods BSO was tested in combination with an experimental synchrotron-based treatment, microbeam radiation therapy (MRT), characterized by spatially and periodically alternating microscopic dose distribution. One hundred thousand F98 glioma cells were injected into the right cerebral hemisphere of adult male Fischer rats to generate an orthotopic small animal model of a highly malignant brain tumour in a very advanced stage. Therapy was scheduled for day 13 after tumour cell implantation. At this time, 12.5% of the animals had already died from their disease. The surviving 24 tumour-bearing animals were randomly distributed in three experimental groups: subjected to MRT alone (Group A), to MRT plus BSO (Group B) and tumour-bearing untreated controls (Group C). Thus, half of the irradiated animals received an injection of 100 μM BSO into the tumour two hours before radiotherapy. Additional tumour-free animals, mirroring the treatment of the tumour-bearing animals, were included in the experiment. MRT was administered in bi-directional mode with arrays of quasi-parallel beams crossing at the tumour location. The width of the microbeams was ≈28 μm with a center-to-center distance of ≈400 μm, a peak dose of 350 Gy, and a valley dose of 9 Gy in the normal tissue and 18 Gy at the tumour location; thus, the peak to valley dose ratio (PVDR) was 31. Results After tumour-cell implantation, otherwise untreated rats had a mean survival time of 15 days. Twenty days after implantation, 62.5% of the animals receiving MRT alone (group A) and 75% of the rats given MRT + BSO (group B) were still alive. Thirty days after implantation, survival was 12.5% in Group A and 62.5% in Group B. There were no survivors on or beyond day 35 in Group A, but 25% were still alive in Group B. Thus, rats which underwent MRT with adjuvant BSO injection experienced the largest survival gain. Conclusions In this pilot project using an orthotopic small animal model of advanced malignant brain tumour, the injection of the glutathione inhibitor BSO with MRT significantly increased mean survival time.

For several years the ID17 Biomedical beamline at the ESRF has developed synchrotron radiation therapy preclinical programmes to treat aggressive brain tumours. Two techniques have been developed at the ESRF: a) The Microbeam Radiation Therapy (MRT) using spatially fractionated "white beam" (energies 50-300 keV) irradiation (beam widths 25-100 μm, spacing between beams 200-400 μm ) with extremely high dose rates (up to about 20 kGy/s) and depositing very high doses (300-1000 Gy) in the targeted tissue. b) The Stereotactic Synchrotron Radiation Therapy (SSRT) using spatially homogeneous monochromatic beam with the energy closely above that of the K-edge of a contrast- or chemotherapeutical agent (iodine, gadolinium, platinum) loaded into the tumour volume for obtaining a dose-enhancement. In 2005 an International review panel of oncology experts has recommended to move to clinical trials on humans in SSRT and on large animals in MRT. The works required for this program were launched in autumn 2007 with constructing a new, dedicated experimental hutch for MRT and a major upgrade of the existing sample-positioning station to a patient-positioning station for SSRT. In parallel, safety systems are developed and progressively implemented and a patient treatment-planning system developed. © 2010 American Institute of Physics.

Microbeam Radiation Therapy (MRT) uses highly collimated, quasi-parallel arrays of X-ray microbeams of 50-600 keV, produced by 2nd and 3rd generation synchrotron sources, such as the National Synchrotron Light Source (NSLS) in the U.S., and the European Synchrotron Radiation Facility (ESRF) in France, respectively. High dose rates are necessary to deliver therapeutic doses in microscopic volumes, to avoid spreading of the microbeams by cardiosynchronous movement of the tissues. A small beam divergence and a filtered white beam spectrum in the energy range between 30 and 250 keV results in the advantage of steep dose gradients with a sharper penumbra than that produced in conventional radiotherapy. MRT research over the past 20 years has allowed a vast number of results from preclinical trials on different animal models, including mice, rats, piglets and rabbits. Microbeams in the range between 10 and 100 micron width show an unprecedented sparing of normal radiosensitive tissues as well as preferential damage to malignant tumor tissues. Typically, MRT uses arrays of narrow ({approx}25-100 micron-wide) microplanar beams separated by wider (100-400 microns centre-to-centre, c-t-c) microplanar spaces. We note that thicker microbeams of 0.1-0.68 mm used by investigators at the NSLS are still called microbeams, although some invesigators inmore » the community prefer to call them minibeams. This report, however, limits it discussion to 25-100 {mu}m microbeams. Peak entrance doses of several hundreds of Gy are surprisingly well tolerated by normal tissues. High resolution dosimetry has been developed over the last two decades, but typical dose ranges are adapted to dose delivery in conventional Radiation Therapy (RT). Spatial resolution in the sub-millimetric range has been achieved, which is currently required for quality assurance measurements in Gamma-knife RT. Most typical commercially available detectors are not suitable for MRT applications at a dose rate of 16000 Gy/s, micron resolution and a dose range over several orders of magnitude. This paper will give an overview of all dosimeters tested in the past at the ESRF with their advantages and drawbacks. These detectors comprise: Ionization chambers, Alanine Dosimeters, MOSFET detectors, Gafchromic registered films, Radiochromic polymers, TLDs, Polymer gels, Fluorescent Nuclear Track Detectors (Al{sub 2}O{sub 3}:C, Mg single crystal detectors), OSL detectors and Floating Gate-based dosimetry system. The aim of such a comparison shall help with a decision on which of these approaches is most suitable for high resolution dose measurements in MRT. The principle of these detectors will be presented including a comparison for some dosimeters exposed with the same irradiation geometry, namely a 1x1 cm{sup 5} field size with microbeam exposures at the surface, 0.1 cm and 1 cm in depth of a PMMA phantom. For these test exposures, the most relevant irradiation parameters for future clinical trials have been chosen: 50 micron FWHM and 400 micron c-t-c distance. The experimental data are compared with Monte Carlo calculations.« less

Synchrotron radiation (SR) therapy is a promising alternative to treat brain tumors, whose management is limited due to the high morbidity of the surrounding healthy tissues. Several approaches are being explored by using SR at the European Synchrotron Radiation Facility (ESRF), where three techniques are under development Synchrotron Stereotactic Radiation Therapy (SSRT), Microbeam Radiation Therapy (MRT) and Minibeam Radiation Therapy (MBRT).The sucess of the preclinical studies on SSRT and MRT has paved the way to clinical trials currently in preparation at the ESRF. With this aim, different dosimetric aspects from both theoretical and experimental points of view have been assessed. In particular, the definition of safe irradiation protocols, the beam energy providing the best balance between tumor treatment and healthy tissue sparing in MRT and MBRT, the special dosimetric considerations for small field dosimetry, etc will be described. In addition, for the clinical trials, the definition of appropiate dosimetry protocols for patients according to the well established European Medical Physics recommendations will be discussed. Finally, the state of the art of the MBRT technical developments at the ESRF will be presented. In 2006 A. Dilmanian and collaborators proposed the use of thicker microbeams (0.36-0.68 mm). This new type of radiotherapymore » is the most recently implemented technique at the ESRF and it has been called MBRT. The main advantage of MBRT with respect to MRT is that it does not require high dose rates. Therefore it can be more easily applied and extended outside synchrotron sources in the future.« less