Technical advances in x-ray microbeam radiation therapy.

In the last 25 years microbeam radiation therapy (MRT) has emerged as a promising alternative to conventional radiation therapy at large, third generation synchrotrons. In MRT, a multi-slit collimator modulates a kilovoltage x-ray beam on a micrometer scale, creating peak dose areas with unconventionally high doses of several hundred Grays separated by low dose valley regions, where the dose remains well below the tissue tolerance level. Pre-clinical evidence demonstrates that such beam geometries lead to substantially reduced damage to normal tissue at equal tumour control rates and hence drastically increase the therapeutic window. Although the mechanisms behind MRT are still to be elucidated, previous studies indicate that immune response, tumour microenvironment, and the microvasculature may play a crucial role. Beyond tumour therapy, MRT has also been suggested as a microsurgical tool in neurological disorders and as a primer for drug delivery. The physical properties of MRT demand innovative medical physics and engineering solutions for safe treatment delivery. This article reviews technical developments in MRT and discusses existing solutions for dosimetric validation, reliable treatment planning and safety. Instrumentation at synchrotron facilities, including beam production, collimators and patient positioning systems, is also discussed. Specific solutions reviewed in this article include: dosimetry techniques that can cope with high spatial resolution, low photon energies and extremely high dose rates of up to 15 000 Gy s-1, dose calculation algorithms-apart from pure Monte Carlo Simulations-to overcome the challenge of small voxel sizes and a wide dynamic dose-range, and the use of dose-enhancing nanoparticles to combat the limited penetrability of a kilovoltage energy spectrum. Finally, concepts for alternative compact microbeam sources are presented, such as inverse Compton scattering set-ups and carbon nanotube x-ray tubes, that may facilitate the transfer of MRT into a hospital-based clinical environment. Intensive research in recent years has resulted in practical solutions to most of the technical challenges in MRT. Treatment planning, dosimetry and patient safety systems at synchrotrons have matured to a point that first veterinary and clinical studies in MRT are within reach. Should these studies confirm the promising results of pre-clinical studies, the authors are confident that MRT will become an effective new radiotherapy option for certain patients.

First experimental measurement of the effect of cardio-synchronous brain motion on the dose distribution during microbeam radiation therapy.

PURPOSE: Microbeam radiation therapy (MRT) is an emerging radiation oncology modality ideal for treating inoperable brain tumors. MRT employs quasi-parallel beams of low-energy x rays produced from modern synchrotrons. A tungsten carbide multislit collimator (MSC) spatially fractionates the broad beam into rectangular beams. In this study, the MSC creates beams 50 µm wide ("peaks") separated by a center-to-center distance of 400 µm ("valleys"). The peak to valley dose ratio (PVDR) is of critical importance to the efficacy of MRT. The underlying radiobiological advantage of MRT relies on high peak dose for tumor control and low valley dose for healthy tissue sparing. Cardio synchronous brain motion of the order 100-200 µm is comparable to microbeam width and spacing. The motion can have a detrimental effect on the PVDR, full width at half maximum (FWHM) of the microbeams, and ultimately the dose distribution. We present the first experimental measurement of the effect of brain motion on MRT dose distribution. Dosimetry in MRT is difficult due to the high dose rate (up to 15-20 kGy/s) and small field sizes. METHODS: A real-time dosimetry system based on a single silicon strip detector (SSSD) has been developed with spatial resolution ~10 µm. The SSSD was placed in a water-equivalent phantom and scanned through the microbeam distribution. A monodirectional positioning stage reproduced brain motion during the acquisition. Microbeam profiles were reconstructed from the SSSD and compared with Geant4 simulation and radiochromic HD-V2 film. RESULTS: The SSSD is able to reconstruct dose profiles within 2 µm compared to film. When brain motion is applied the SSSD shows a two time increase in FWHM of profiles and 50% reduction in PVDR. This is confirmed by Geant4 and film data. CONCLUSIONS: Motion-induced misalignment and distortion of microbeams at treatment delivery will result in a reduced PVDR and increased irradiation of additional healthy tissue compromising the radiobiological effectiveness of MRT. The SSSD was able to reconstruct dose profiles under motion conditions and predict similar effects on FWHM and PVDR as by the simulation. The SSSD is a simple to setup, real-time detector which can provide time-resolved high spatial resolution dosimetry of microbeams in MRT.

Film dosimetry studies for patient specific quality assurance in microbeam radiation therapy.

Microbeam radiation therapy (MRT) uses synchrotron arrays of X-ray microbeams to take advantage of the spatial fractionation effect for normal tissue sparing. In this study, radiochromic film dosimetry was performed for a treatment where MRT is introduced as a dose boost in a hypofractionated stereotactic radiotherapy (SRT) scheme. The isocenter dose was measured using an ionization chamber and two dimensional dose distributions were determined using radiochromic films. To compare the measured dose distribution to the MRT treatment plan, peak and valley were displayed in separate dosemaps. The measured and computed isocenter doses were compared and a two-dimensional 2%/2 mm normalized γ-index analysis with a 90% passing rate criterion was computed. For SRT, a difference of 2.6% was observed in the dose at the isocenter from the treatment plan and film measurement, with a passing rate of 96% for the γ-index analysis. For MRT, peak and valley doses differences of 25.6% and 8.2% were observed, respectively but passing rates of 96% and 90% respectively were obtained from the normalized γ-index maps. The differences in isocenter doses measured in MRT should be further investigated. We present the methodology of patient specific quality assurance (QA) for studying MRT dose distributions and discuss ideas to improve absolute dosimetry. This patient specific QA will be used for large animal trials quality assurance where MRT will be administered as a dose boost in conventional SRT. The observed remaining discrepancies should be studied against approximations in the TPS phantom materials, beams characteristics or film read-out procedures.

Synchrotron Microbeam Radiation Therapy as a New Approach for the Treatment of Radioresistant Melanoma: Potential Underlying Mechanisms.

PURPOSE: Synchrotron microbeam radiation therapy (MRT) is a method that spatially distributes the x-ray beam into several microbeams of very high dose (peak dose), regularly separated by low-dose intervals (valley dose). MRT selectively spares normal tissues, relative to conventional (uniform broad beam [BB]) radiation therapy. METHODS AND MATERIALS: To evaluate the effect of MRT on radioresistant melanoma, B16-F10 murine melanomas were implanted into mice ears. Tumors were either treated with MRT (407.6 Gy peak; 6.2 Gy valley dose) or uniform BB irradiation (6.2 Gy). RESULTS: MRT induced significantly longer tumor regrowth delay than did BB irradiation. A significant 24% reduction in blood vessel perfusion was observed 5 days after MRT, and the cell proliferation index was significantly lower in melanomas treated by MRT compared with BB. MRT provoked a greater induction of senescence in melanoma cells. Bio-Plex analyses revealed enhanced concentration of monocyte-attracting chemokines in the MRT group: MCP-1 at D5, MIP-1α, MIP-1ß, IL12p40, and RANTES at D9. This was associated with leukocytic infiltration at D9 after MRT, attributed mainly to CD8 T cells, natural killer cells, and macrophages. CONCLUSIONS: In light of its potential to disrupt blood vessels that promote infiltration of the tumor by immune cells and its induction of senescence, MRT could be a new therapeutic approach for radioresistant melanoma.

Introducing the concept of spiral microbeam radiation therapy (spiralMRT).

MOTIVATION: With interlaced microbeam radiation therapy (MRT) a first kilovoltage radiotherapy (RT) concept combining spatially fractionated entrance beams and homogeneous dose distribution at the target exists. However, this technique suffers from its high sensitivity to positioning errors of the target relative to the radiation source. With spiral microbeam radiation therapy (spiralMRT), this publication introduces a new irradiation geometry, offering similar spatial fractionation properties as interlaced MRT, while being less vulnerable to target positioning uncertainties. METHODS: The dose distributions achievable with spiralMRT in a simplified human head geometry were calculated with Monte Carlo simulations based on Geant4 and the dependence of the result on the microbeam pitch, total field size, and photon energy were analysed. A comparison with interlaced MRT and conventional megavoltage tomotherapy was carried out. RESULTS: SpiralMRT can deliver homogeneous dose distributions, while using spatially fractionated entrance beams. The valley dose of spiralMRT entrance beams is by up to 40% lower than the corresponding tomotherapy dose, thus indicating a better normal tissue sparing. The optimum photon energy is found to be around [Formula: see text]. CONCLUSIONS: SpiralMRT is a promising approach to delivering homogeneous dose distributions with spatially fractionated entrance beams, possibly decreasing normal tissue side effects in hypofractionated RT.

Effects of Synchrotron X-Ray Micro-beam Irradiation on Normal Mouse Ear Pinnae.

PURPOSE: To analyze the effects of micro-beam irradiation (MBI) on the normal tissues of the mouse ear. METHODS AND MATERIALS: Normal mouse ears are a unique model, which in addition to skin contain striated muscles, cartilage, blood and lymphatic vessels, and few hair follicles. This renders the mouse ear an excellent model for complex tissue studies. The ears of C57BL6 mice were exposed to MBI (50-µm-wide micro-beams, spaced 200 µm between centers) with peak entrance doses of 200, 400, or 800 Gy (at ultra-high dose rates). Tissue samples were examined histopathologically, with conventional light and electron microscopy, at 2, 7, 15, 30, and 240 days after irradiation (dpi). Sham-irradiated animals acted as controls. RESULTS: Only an entrance dose of 800 Gy caused a significant increase in the thickness of both epidermal and dermal ear compartments seen from 15 to 30 dpi; the number of sebaceous glands was significantly reduced by 30 dpi. The numbers of apoptotic bodies and infiltrating leukocytes peaked between 15 and 30 dpi. Lymphatic vessels were prominently enlarged at 15 up to 240 dpi. Sarcomere lesions in striated muscle were observed after all doses, starting from 2 dpi; scar tissue within individual beam paths remained visible up to 240 dpi. Cartilage and blood vessel changes remained histologically inconspicuous. CONCLUSIONS: Normal tissues such as skin, cartilage, and blood and lymphatic vessels are highly tolerant to MBI after entrance doses up to 400 Gy. The striated muscles appeared to be the most sensitive to MBI. Those findings should be taken into consideration in future micro-beam radiation therapy treatment schedules.

Hybrid dose calculation: a dose calculation algorithm for microbeam radiation therapy.

Microbeam radiation therapy (MRT) is still a preclinical approach in radiation oncology that uses planar micrometre wide beamlets with extremely high peak doses, separated by a few hundred micrometre wide low dose regions. Abundant preclinical evidence demonstrates that MRT spares normal tissue more effectively than conventional radiation therapy, at equivalent tumour control. In order to launch first clinical trials, accurate and efficient dose calculation methods are an inevitable prerequisite. In this work a hybrid dose calculation approach is presented that is based on a combination of Monte Carlo and kernel based dose calculation. In various examples the performance of the algorithm is compared to purely Monte Carlo and purely kernel based dose calculations. The accuracy of the developed algorithm is comparable to conventional pure Monte Carlo calculations. In particular for inhomogeneous materials the hybrid dose calculation algorithm out-performs purely convolution based dose calculation approaches. It is demonstrated that the hybrid algorithm can efficiently calculate even complicated pencil beam and cross firing beam geometries. The required calculation times are substantially lower than for pure Monte Carlo calculations.

X-Tream quality assurance in synchrotron X-ray microbeam radiation therapy.

Microbeam radiation therapy (MRT) is a novel irradiation technique for brain tumours treatment currently under development at the European Synchrotron Radiation Facility in Grenoble, France. The technique is based on the spatial fractionation of a highly brilliant synchrotron X-ray beam into an array of microbeams using a multi-slit collimator (MSC). After promising pre-clinical results, veterinary trials have recently commenced requiring the need for dedicated quality assurance (QA) procedures. The quality of MRT treatment demands reproducible and precise spatial fractionation of the incoming synchrotron beam. The intensity profile of the microbeams must also be quickly and quantitatively characterized prior to each treatment for comparison with that used for input to the dose-planning calculations. The Centre for Medical Radiation Physics (University of Wollongong, Australia) has developed an X-ray treatment monitoring system (X-Tream) which incorporates a high-spatial-resolution silicon strip detector (SSD) specifically designed for MRT. In-air measurements of the horizontal profile of the intrinsic microbeam X-ray field in order to determine the relative intensity of each microbeam are presented, and the alignment of the MSC is also assessed. The results show that the SSD is able to resolve individual microbeams which therefore provides invaluable QA of the horizontal field size and microbeam number and shape. They also demonstrate that the SSD used in the X-Tream system is very sensitive to any small misalignment of the MSC. In order to allow as rapid QA as possible, a fast alignment procedure of the SSD based on X-ray imaging with a low-intensity low-energy beam has been developed and is presented in this publication.

Conformal image-guided microbeam radiation therapy at the ESRF biomedical beamline ID17.

PURPOSE: Upcoming veterinary trials in microbeam radiation therapy (MRT) demand for more advanced irradiation techniques than in preclinical research with small animals. The treatment of deep-seated tumors in cats and dogs with MRT requires sophisticated irradiation geometries from multiple ports, which impose further efforts to spare the normal tissue surrounding the target. METHODS: This work presents the development and benchmarking of a precise patient alignment protocol for MRT at the biomedical beamline ID17 of the European Synchrotron Radiation Facility (ESRF). The positioning of the patient prior to irradiation is verified by taking x-ray projection images from different angles. RESULTS: Using four external fiducial markers of 1.7 mm diameter and computed tomography-based treatment planning, a target alignment error of less than 2 mm can be achieved with an angular deviation of less than 2(∘). Minor improvements on the protocol and the use of smaller markers indicate that even a precision better than 1 mm is technically feasible. Detailed investigations concerning the imaging dose lead to the conclusion that doses for skull radiographs lie in the same range as dose reference levels for human head radiographs. A currently used online dose monitor for MRT has been proven to give reliable results for the imaging beam. CONCLUSIONS: The ESRF biomedical beamline ID17 is technically ready to apply conformal image-guided MRT from multiple ports to large animals during future veterinary trials.

Energy spectra considerations for synchrotron radiotherapy trials on the ID17 bio-medical beamline at the European Synchrotron Radiation Facility.

The aim of this study was to validate the kilovoltage X-ray energy spectrum on the ID17 beamline at the European Synchrotron Radiation Facility (ESRF). The purpose of such validation was to provide an accurate energy spectrum as the input to a computerized treatment planning system, which will be used in synchrotron microbeam radiotherapy trials at the ESRF. Calculated and measured energy spectra on ID17 have been reported previously but recent additions and safety modifications to the beamline for veterinary trials warranted a fresh investigation. The authors used an established methodology to compare X-ray attenuation measurements in copper sheets (referred to as half value layer measurements in the radiotherapy field) with the predictions of a theoretical model. A cylindrical ionization chamber in air was used to record the relative attenuation of the X-ray beam intensity by increasing thicknesses of high-purity copper sheets. The authors measured the half value layers in copper for two beamline configurations, which corresponded to differing spectral conditions. The authors obtained good agreement between the measured and predicted half value layers for the two beamline configurations. The measured first half value layer was 1.754 ± 0.035 mm Cu and 1.962 ± 0.039 mm Cu for the two spectral conditions, compared with theoretical predictions of 1.763 ± 0.039 mm Cu and 1.984 ± 0.044 mm Cu, respectively. The calculated mean energies for the two conditions were 105 keV and 110 keV and there was not a substantial difference in the calculated percentage depth dose curves in water between the different spectral conditions. The authors observed a difference between their calculated energy spectra and the spectra previously reported by other authors, particularly at energies greater than 100 keV. The validation of the beam spectrum by the copper half value layer measurements means the authors can provide an accurate spectrum as an input to a treatment planning system for the forthcoming veterinary trials of microbeam radiotherapy to spontaneous tumours in cats and dogs.

Medical physics aspects of the synchrotron radiation therapies: Microbeam radiation therapy (MRT) and synchrotron stereotactic radiotherapy (SSRT).

Stereotactic Synchrotron Radiotherapy (SSRT) and Microbeam Radiation Therapy (MRT) are both novel approaches to treat brain tumor and potentially other tumors using synchrotron radiation. Although the techniques differ by their principles, SSRT and MRT share certain common aspects with the possibility of combining their advantages in the future. For MRT, the technique uses highly collimated, quasi-parallel arrays of X-ray microbeams between 50 and 600 keV. Important features of highly brilliant Synchrotron sources are a very small beam divergence and an extremely high dose rate. The minimal beam divergence allows the insertion of so called Multi Slit Collimators (MSC) to produce spatially fractionated beams of typically ∼25-75 micron-wide microplanar beams separated by wider (100-400 microns center-to-center(ctc)) spaces with a very sharp penumbra. Peak entrance doses of several hundreds of Gy are extremely well tolerated by normal tissues and at the same time provide a higher therapeutic index for various tumor models in rodents. The hypothesis of a selective radio-vulnerability of the tumor vasculature versus normal blood vessels by MRT was recently more solidified. SSRT (Synchrotron Stereotactic Radiotherapy) is based on a local drug uptake of high-Z elements in tumors followed by stereotactic irradiation with 80 keV photons to enhance the dose deposition only within the tumor. With SSRT already in its clinical trial stage at the ESRF, most medical physics problems are already solved and the implemented solutions are briefly described, while the medical physics aspects in MRT will be discussed in more detail in this paper.