High-Precision Radiosurgical Dose Delivery by Interlaced Microbeam Arrays of High-Flux Low-Energy Synchrotron X-Rays

Abstract

Microbeam Radiation Therapy (MRT) is a preclinical form of radiosurgery dedicated to brain tumor treatment. It uses micrometer-wide synchrotron-generated X-ray beams on the basis of spatial beam fractionation. Due to the radioresistance of normal brain vasculature to MRT, a continuous blood supply can be maintained which would in part explain the surprising tolerance of normal tissues to very high radiation doses (hundreds of Gy). Based on this well described normal tissue sparing effect of microplanar beams, we developed a new irradiation geometry which allows the delivery of a high uniform dose deposition at a given brain target whereas surrounding normal tissues are irradiated by well tolerated parallel microbeams only. Normal rat brains were exposed to 4 focally interlaced arrays of 10 microplanar beams (52 µm wide, spaced 200 µm on-center, 50 to 350 keV in energy range), targeted from 4 different ports, with a peak entrance dose of 200Gy each, to deliver an homogenous dose to a target volume of 7 mm3 in the caudate nucleus. Magnetic resonance imaging follow-up of rats showed a highly localized increase in blood vessel permeability, starting 1 week after irradiation. Contrast agent diffusion was confined to the target volume and was still observed 1 month after irradiation, along with histopathological changes, including damaged blood vessels. No changes in vessel permeability were detected in the normal brain tissue surrounding the target. The interlacing radiation-induced reduction of spontaneous seizures of epileptic rats illustrated the potential pre-clinical applications of this new irradiation geometry. Finally, Monte Carlo simulations performed on a human-sized head phantom suggested that synchrotron photons can be used for human radiosurgical applications. Our data show that interlaced microbeam irradiation allows a high homogeneous dose deposition in a brain target and leads to a confined tissue necrosis while sparing surrounding tissues. The use of synchrotron-generated X-rays enables delivery of high doses for destruction of small focal regions in human brains, with sharper dose fall-offs than those described in any other conventional radiation therapy.

Preferential Effect of Synchrotron Microbeam Radiation Therapy on Intracerebral 9L Gliosarcoma Vascular Networks

“…Most important, the tumor targeting for MRT used preclinically must be improved and adapted to clinical standards. Irradiation fields must be limited to the tumor; image-guided, non-coplanar irradiation methods that limit normal tissue damage should be adopted (15,24).…”

Tolerance of Arteries to Microplanar X-Ray Beams

“…Arrays of microbeams applied from different ports on a target form a radiotoxic field in depth and cause minimal normal tissue damage within single arrays around the solid tumor volume (5,26). For brain tumors, in the first phase of clinical trials at the ESRF in dogs and cats, only unidirectional or simple cross-fired MRT will be applied to a depth of 7 cm(4) or less, by use of arrays of 50-mm-wide microplanar beams, with center-to-center spacing of 400 mm.…”

An Overview of Non-drug Therapies for the Treatment of Epilepsy

“…In interlaced microbeam radiotherapy (IntMRT), brain will be rotated around a centre of rotation using goniometer by interlacing microbeams to deliver and deposit a high homogenous radiation dose precisely into distinct regions of brain, with no extensions on surrounding tissues; this is called IntMRT [88] . This irradiation allows a 200 times greater lateral dose fall-off than conventional radiotherapy.…”