Microbeam radiation therapy (MRT) uses highly collimated, quasi-parallel arrays of X-ray microbeams of 50–600 keV, produced by third generation synchrotron sources, such as the European Synchrotron Radiation Facility (ESRF), in France. The main advantages of highly brilliant synchrotron sources are an extremely high dose rate and very small beam divergence. High dose rates are necessary to deliver therapeutic doses in microscopic volumes, to avoid spreading of the microbeams by cardiosynchronous movement of the tissues. The minimal beam divergence results in the advantage of steeper dose gradients delivered to a tumor target, thus achieving a higher dose deposition in the target volume in fractions of seconds, with a sharper penumbra than that produced in conventional radiotherapy. MRT research over the past 20 years has yielded many results from preclinical trials based on different animal models, including mice, rats, piglets and rabbits. Typically, MRT uses arrays of narrow (∼25–100 μm wide) microplanar beams separated by wider (100–400 μm centre-to-centre) microplanar spaces. The height of these microbeams typically varies from 1 to 100 mm, depending on the target and the desired preselected field size to be irradiated. Peak entrance doses of several hundreds of Gy are surprisingly well tolerated by normal tissues, up to ∼2 yr after irradiation, and at the same time show a preferential damage of malignant tumor tissues; these effects of MRT have now been extensively studied over nearly two decades. More recently, some biological in vivo effects of synchrotron X-ray beams in the millimeter range (0.68–0.95 mm, centre-to-centre distances 1.2–4 mm), which may differ to some extent from those of microscopic beams, have been followed up to ∼7 months after irradiation. Comparisons between broad-beam irradiation and MRT indicate a higher tumor control for the same sparing of normal tissue in the latter, even if a substantial fraction of tumor cells are not receiving a radiotoxic level of radiation. The hypothesis of a selective radiovulnerability of the tumor vasculature versus normal blood vessels by MRT, and of the cellular and molecular mechanisms involved remains under investigation. The paper highlights the history of MRT including salient biological findings after microbeam irradiation with emphasis on the vascular components and the tolerance of the central nervous system. Details on experimental and theoretical dosimetry of microbeams, core issues and possible therapeutic applications of MRT are presented.

Effects of pulsed, spatially fractionated, microscopic synchrotron X-ray beams on normal and tumoral brain tissue.

Purpose: The purpose of this study was to assess the early effects of microbeam irradiation on the vascular permeability and volume in the parietal cortex of normal nude mice using two-photon microscopy and immunohistochemistry. Methods and Materials: The upper part of the left hemisphere of 55 mice was irradiated anteroposteriorly using 18 vertically oriented beams (width 25 μm, interdistance 211 μm; peak entrance doses: 312 or 1000 Gy). At different times after microbeam exposure, the microvasculature in the cortex was analyzed using intravital two-photon microscopy after intravascular injection of fluorescein isothiocyanate (FITC)-dextrans and sulforhodamine B (SRB). Changes of the vascular volume were observed at the FITC wavelength over a maximum depth of 650 μm from the dura. The vascular permeability was detected as extravasations of SRB. Results: For all times (12 h to 1 month) after microbeam irradiation and for both doses, the FITC-dextran remained in the vessels. No significant change in vascular volume was observed between 12 h and 3 months after irradiation. Diffusion of SRB was observed in microbeam irradiated regions from 12 h until 12 days only after a 1000 Gy exposure. Conclusion: No radiation damage to the microvasculature was detected in normal brain tissue after a 312 Gy microbeam irradiation. This dose would be more appropriate than 1000 Gy for the treatment of brain tumors using crossfired microbeams.

In vivo two-photon microscopy study of short-term effects of microbeam irradiation on normal mouse brain microvasculature.

PURPOSE: Synchrotron microbeam radiation therapy (MRT) relies on spatial fractionation of the incident photon beam into parallel micron-wide beams. Our aim was to analyze the effects of MRT on normal brain and 9L gliosarcoma tissues, particularly on blood vessels. METHODS AND MATERIALS: Responses to MRT (two arrays, one lateral, one anteroposterior (2 × 400 Gy), intersecting orthogonally in the tumor region) were studied during 6 weeks using MRI, immunohistochemistry, and vascular endothelial growth factor Western blot. RESULTS: MRT increased the median survival time of irradiated rats (×3.25), significantly increased blood vessel permeability, and inhibited tumor growth; a cytotoxic effect on 9L cells was detected 5 days after irradiation. Significant decreases in tumoral blood volume fraction and vessel diameter were measured from 8 days after irradiation, due to loss of endothelial cells in tumors as detected by immunochemistry. Edema was observed in the normal brain exposed to both crossfired arrays about 6 weeks after irradiation. This edema was associated with changes in blood vessel morphology and an overexpression of vascular endothelial growth factor. Conversely, vascular parameters and vessel morphology in brain regions exposed to one of the two arrays were not damaged, and there was no loss of vascular endothelia. CONCLUSIONS: We show for the first time that preferential damage of MRT to tumor vessels versus preservation of radioresistant normal brain vessels contributes to the efficient palliation of 9L gliosarcomas in rats. Molecular pathways of repair mechanisms in normal and tumoral vascular networks after MRT may be essential for the improvement of such differential effects on the vasculature.

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Preferential effect of synchrotron microbeam radiation therapy on intracerebral 9L gliosarcoma vascular networks.

Microbeam radiation therapy (MRT), a form of experimental radiosurgery of tumours using multiple parallel, planar, micrometres-wide, synchrotron-generated X-ray beams ('microbeams'), can safely deliver radiation doses to contiguous normal animal tissues that are much higher than the maximum doses tolerated by the same normal tissues of animals or patients from any standard millimetres-wide radiosurgical beam. An array of parallel microbeams, even in doses that cause little damage to radiosensitive developing tissues, for example, the chick chorioallantoic membrane, can inhibit growth or ablate some transplanted malignant tumours in rodents. The cerebella of 100 normal 20 to 38g suckling Sprague-Dawley rat pups and of 13 normal 5 to 12kg weanling Yorkshire piglets were irradiated with an array of parallel, synchrotron-wiggler-generated X-ray microbeams in doses overlapping the MRT-relevant range (about 50-600Gy) using the ID17 wiggler beamline tangential to the 6GeV electron synchrotron ring at the European Synchrotron Radiation Facility in Grenoble, France. Subsequent favourable development of most animals over at least 1 year suggests that MRT might be used to treat children's brain tumours with less risk to the development of the central nervous system than is presently the case when using wider beams.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-8749.2007.00577.x

Prospects for microbeam radiation therapy of brain tumours in children to reduce neurological sequelae.

Microbeam radiation therapy (MRT) is being performed by using an array of narrow rectangular x-ray beams (typical beam sizes 25 {mu}mx1 cm), positioned close to each other (typically 200 {mu}m separation), to irradiate a target tissue. The ratio of peak-to-valley doses (PVDR's) in the composite dose distribution has been found to be strongly correlated with the normal tissue tolerance and the therapeutic effect of MRT. In this work a Monte Carlo (MC) study of the depth- and lateral-dose profiles in water for single x-ray microbeams of different shapes and energies has been performed with the MC code PENELOPE. The contributions to the dose deposition from different interaction types have been determined at different distances from the center of the microbeam. The dependence of the peak dose, in a water phantom, on the microbeam field size used in the preclinical trials, has been demonstrated. Composite dose distributions for an array of microbeams were obtained using superposition algorithms and PVDR's were determined and compared with literature results obtained with other Monte Carlo codes. The dependence of the PVDR's on microbeam width, x-ray energy used, and on the separation between adjacent microbeams has been studied in detail.

Determination of dosimetrical quantities used in microbeam radiation therapy (MRT) with Monte Carlo simulations.

Clinical microbeam radiation therapy (MRT) will require a multislit collimator with adjustable uniform slit widths to enable reliable Monte Carlo-based treatment planning. Such a collimator has been designed, fabricated of >99% tungsten [W] by Tecomet/Viasys (Woburn, Massachusetts, USA) and installed at the 6GeV electron-wiggler-generated hard x-ray ID17 beamline of the European Synchrotron Radiation Facility. Its pair of 125 parallel, 8mm deep, 0.100mm wide radiolucent slits, 0.400mm on center, are perfused with nitrogen gas [N2] to dissipate heat during irradiation. Major improvements in uniformity of microbeam widths and good peak/valley dose ratios combined with a very high dose rate in targeted tissues have been achieved.

Characterization of a tungsten/gas multislit collimator for microbeam radiation therapy at the European Synchrotron Radiation Facility

Microbeam Radiation Therapy (MRT) is a technique utilizing the fact that normal tissue can sustain high doses of radiation in small volumes without significant damage. The synchrotron generated X-ray beam, used for the treatment, is collimated and delivered in an array of narrow micrometer-sized planar rectangular fields. In this work, the Monte Carlo code PENELOPE was used for simulating the dose deposition. This code provides an accurate treatment of low-energy electron transport which is important when performing dose calculations in micron-sized ranges. A comparison with earlier results was done for a few typical cases. The buildup of dose near the phantom surface and the lateral variation of dose around the microbeams were also studied. It was confirmed that the dose in the valley region mainly depends on Compton scattered electrons and that the electron scattering model used in the MC code is a key point. Finally a comparison between MC simulations and experimental microdosimetry, with radiochromic films and MOSFET detectors, gave important indications on possible refinements of the MC simulations for future investigations.

Dosimetric studies of microbeam radiation therapy (MRT) with Monte Carlo simulations

Erratum: “Characterization of a tungsten/gas multislit collimator „TMSC... for microbeam radiation therapy at the European Synchrotron Radiation Facility”†Rev. Sci. Instrum. 76, 064303 „2005...‡ E. Brauer-Krisch, A. Bravin, L. Zhang, and E. Siegbahn European Synchrotron Radiation Facility, B.P.220, 38043 Grenoble, France J. Stepanek Unterriedstrasse 33, 5412 Gebenstorf, Switzerland H. Blattmann Niederwiesstrasse 13 C, CH-5427 Untersiggenthal, Switzerland D. N. Slatkin P.O. Box 334, Essex, Connecticut 06426 J.-O. Gebbers Institute of Pathology, Kantonsspital Luzern, 6000 Lucerne, Switzerland M. Jasmin Tecomet Subsidiary, Viasys Healthcare Inc., 170 New Boston Street, Woburn, Massachusetts 01801 J. A. Laissue Institute of Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland Received 18 January 2006; accepted 22 January 2006; published online 16 March 2006 DOI: 10.1063/1.2173954

Erratum: “Characterization of a tungsten/gas multislit collimator (TMSC) for microbeam radiation therapy at the European Synchrotron Radiation Facility”[Rev. Sci. Instrum. 76, 064303 (2005)]

J. Stepanek

Papers

Determination of dosimetrical quantities used in microbeam radiation therapy (MRT) with Monte Carlo simulations.

Characterization of a tungsten/gas multislit collimator for microbeam radiation therapy at the European Synchrotron Radiation Facility

Dosimetric studies of microbeam radiation therapy (MRT) with Monte Carlo simulations

Erratum: “Characterization of a tungsten/gas multislit collimator (TMSC) for microbeam radiation therapy at the European Synchrotron Radiation Facility”[Rev. Sci. Instrum. 76, 064303 (2005)]