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 microm wide, spaced 200 microm 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 mm(3) 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.

Figure 1. Schematic representation of the irradiation geometry in normal rats.

(A–C). Four arrays of 10 MBs (50 µm wide, 200 µm on-center distance) were interlaced and created a 2×2×2.2 mm³ target region where the radiation dose is homogenous. D- Gafchromic® film image of interlaced MBs; the upper part corresponds to a centre-to-centre distance of 200 µm. The radiation target corresponds to the region where all the 4 arrays of MBs interlaced. E- Dose profiles measured on the Gafchromic® film shown in (D). The red line shows the dose in the interlaced region. The dose profile produced in the spatially fractionated irradiation and which is delivered by a single array of MBs is shown with the black line.

Figure 2. Temporal MRI follow up of the radiation target.

A-D- MR characterization (T₁-weighted images 5 min after Gd-DOTA injection) of the evolution of the radio-induced lesion between D1 and D30 after exposure. E-Three-dimensional reconstruction of the irradiated target (blue) based on Gd-DOTA extravasation on T₁-weighted images at D30 after exposure. F-T₂-weighted MR images acquired irradiation and reflecting brain edema in the radiation target indicated by a white arrow. G-I Evolution of the T₁, T₂ (arbitrary values) and ADC values measured at different delays after irradiation in the radiation target (red lines) and in the contralateral hemisphere (black lines). ***: significantly different from time matched control (p<0.001).

Figure 3. Effects of interlaced vs. non-interlaced microbeam irradiations on normal brains.

MR transverse and coronal T₁w images (5 min after Gd-DOTA i.v. injection) acquired 30 days after interlaced (A) and non interlaced MRT (B). The extravasation of the constrast agent is only detectable after interlaced MRT, the 700 Gy peak dose, resulting from superimposed but non interlaced MRT does not induce Gd-DOTA extravasation in the brain parenchyma.

Figure 4. Immunohistological verification of the irradiation geometry.

pH2AX immunolabeling performed (DNA damages) at D1 (A–F) and D7 (F–J) in different brain regions reported on MR-images (K,L). The first row corresponds to the contralateral hemisphere (1 port), the second one the radiation target (4 ports) and the last one to the edges of the radiation target. Scale bars represent: 200 µm (A, C, E, G, I) and 50 µm (B, D, F, H, I).

Figure 5. Temporal immunohistological follow up of the radiation target.

(Immuno) histological study of the contralateral hemisphere (1 port) and the radiation target (4 ports) at D1 (A–L) and D30 (L–X) after irradiation. The different rows correspond to HE staining, monocyte/macrophage labeling (ED1, red labeling, nuclei counterstained with DAPI), cycling cells (Ki67 positive cells, red labeling, nuclei counterstained with DAPI), brain vessels (type-IV collagen), astrocytes (GFAP) and neurons (NeuN). Scale bar represents 200 µm.

Figure 6. GAERS cortical irradiations and EEG follow up.

A- The regions targeted in the epilepsy study were two symmetric volumes located in the two somatosensory regions of the GAERS rat cortex. Each volume consisted of two juxtaposed cylinders (left and right figures), which geometries were chosen to fit the somatosensory cortex that initiates absence seizures. Coordinates are relative to the bregma. B- Gafchromic film showing the bilateral volumes irradiated using 4 interlaced arrays of MBs with an entrance dose of 200 Gy. C- Total seizure durations measured by EEG at different times after irradiation in the control group and in the IAMB irradiated group.

Figure 7. Human-sized head Monte Carlo dosimetry.

A-PVDRs calculated at different depths for different quadratic irradiation fields. The field size is indicated in the legend together with the spacing between MBs). B-Peak and valley depth-dose curves in water for 200 µm and 400 µm spacing between MBs. C- Calculated dose profiles for a single MB array and for 4 interlaced arrays is shown for 1×1 cm² irradiation fields. An increase in dose of 18% is measured for the dose deposited in the interlaced region (black) compared with the dose in the MB path (single array, red). D- A comparison of the lateral dose profile produced by the Leksell Gamma Knife (LGK) Perfexion® (blue) with the dose deposited by interlaced MB irradiation (black) is shown for an 8 mm wide irradiation field.