Microbeam Radiation Therapy System Research Articles

Verification of micro-beam irradiation

Micro-beam Radiation Therapy (MRT) is an experimental radiation therapy with provocative experimental data indicating potential for improved efficacy in some diseases. Here we demonstrated a comprehensive micro-beam verification method utilizing high resolution (50pm) PRESAGE/Micro-Optical-CT 3D Dosimetry. A small PRESAGE cylindrical dosimeter was irradiated by a novel compact Carbon-Nano-Tube (CNT) field emission based MRT system. The Percentage Depth Dose (PDD), Peak-to-Valley Dose Ratio (PVDR) and beam width (FWHM) data were obtained and analyzed from a three strips radiation experiment. A fast dose drop-off with depth, a preserved beam width with depth (an averaged FWHM across three beams remains constant (405.3um, sigma=13.2um) between depth of 3.0~14.0mm), and a high PVDR value (increases with depth from 6.3 at 3.0mm depth to 8.6 at 14.0mm depth) were discovered during this verification process. Some operating procedures such as precise dosimeter mounting, robust mechanical motions (especially rotation) and stray-light artifact management were optimized and developed to achieve a more accurate and dosimetric verification method.

Pilot study for compact microbeam radiation therapy using a carbon nanotube field emission micro-CT scanner.

Microbeam radiation therapy (MRT) is defined as the use of parallel, microplanar x-ray beams with an energy spectrum between 50 and 300 keV for cancer treatment and brain radiosurgery. Up until now, the possibilities of MRT have mainly been studied using synchrotron sources due to their high flux (100s Gy/s) and approximately parallel x-ray paths. The authors have proposed a compact x-ray based MRT system capable of delivering MRT dose distributions at a high dose rate. This system would employ carbon nanotube (CNT) field emission technology to create an x-ray source array that surrounds the target of irradiation. Using such a geometry, multiple collimators would shape the irradiation from this array into multiple microbeams that would then overlap or interlace in the target region. This pilot study demonstrates the feasibility of attaining a high dose rate and parallel microbeam beams using such a system. The microbeam dose distribution was generated by our CNT micro-CT scanner (100 μm focal spot) and a custom-made microbeam collimator. An alignment assembly was fabricated and attached to the scanner in order to collimate and superimpose beams coming from different gantry positions. The MRT dose distribution was measured using two orthogonal radiochromic films embedded inside a cylindrical phantom. This target was irradiated with microbeams incident from 44 different gantry angles to simulate an array of x-ray sources as in the proposed compact CNT-based MRT system. Finally, phantom translation in a direction perpendicular to the microplanar beams was used to simulate the use of multiple parallel microbeams. Microbeams delivered from 44 gantry angles were superimposed to form a single microbeam dose distribution in the phantom with a FWHM of 300 μm (calculated value was 290 μm). Also, during the multiple beam simulation, a peak to valley dose ratio of ~10 was found when the phantom translation distance was roughly 4x the beam width. The first prototype CNT-based x-ray tube dedicated to the development of compact MRT technology development was proposed and planned based on the preliminary experimental results presented here and the previous corresponding Monte Carlo simulations. The authors have demonstrated the feasibility of creating microbeam dose distributions at a high dose rate using a proposed compact MRT system. The flexibility of CNT field emission x-ray sources could possibly bring compact and low cost MRT devices to the larger research community and assist in the translational research of this promising new approach to radiation therapy.

WE‐E‐108‐04: X‐Ray Fluorescence Imaging Guided Microbeam Radiation Therapy

Purpose: We demonstrate the feasibility of x‐ray fluorescence for quick and accurate image guidance for targeted irradiation of small animal tumor models in Microbeam Radiation Therapy (MRT). Methods: A reduced‐dose treatment beam excites x‐ray fluorescence from contrast agents preferentially‐accumulating at tumor sites. Intensity profiles of the fluorescence signal are mapped as the mouse injected with the contrast agent is moved through the field of view. The tumor location is identified as the regions with high fluorescence intensities. For this feasibility study, our compact small‐animal MRT system and a mouse head phantom were used. The MRT device uses a carbon nanotube (CNT) field emission x‐ray source array operating at 160kVp and adjustable‐width external collimator to generate microbeam radiation at a microbeam dose rate of ∼1Gy/min. A phantom consisting of an acrylic rod inserted into a mouse skull accurately represents the attenuation of the head. The rod contains ∼1.5mm diameter holes separated by 4mm, filled with 12mg/mL iodine solution, similar to the reported tumor concentration from IC injection. The phantom was translated through the treatment beam in 600um steps, 20 seconds per step. The fluorescence signal was recorded using a slit‐collimated spectrum analyzer. Results: Processed spectra displayed fluorescent intensity peaks corresponding with locations of iodine solution in the phantom. The FWHMs of these peaks are 1.78mm and 1.72mm. The actual diameters of corresponding regions are 1.56mm and 1.47mm, indicating ∼250um uncertainty. Conclusion: Preliminary results demonstrated feasibility of x‐ray fluorescence for guidance in MRT. The acquisition time for a 15mm head phantom is ∼8 minutes, within the reported retention time of the contrast agent. ∼250um uncertainty is comparable to results from our in vivo brain tumor‐bearing mouse experiment using MRI and x‐ray image guidance. The x‐ray fluorescent method is substantially faster. The process will be further optimized and validated with in‐vivo studies.

SU‐F‐500‐10: Targeted Delivery of Microbeam Irradiation and Initial Mouse Brain Tumor Model Studies Using a Table Top MRT System

Purpose: Microbeam radiation therapy (MRT) is an experimental and preclinical radiotherapy method for cancer treatment that has been shown, in animal studies, to have the capability to selectively eradicate tumor without damaging normal tissue functions. The reliance of MRT on synchrotron radiation has prevented widespread research in this field and is a major roadblock for future clinical applications. Our goal is to develop a compact image‐guided MRT system based on high power distributed x‐ray source array and explore the radiobiology behind MRT using various mouse brain tumor models. Methods: We developed a novel protocol of combined MRI/x‐ray radiograph image‐guided MRT which enables irradiating two mice simultaneously. This protocol proceeds as follows: tumor localization with MRI, landmark identification with x‐ray projections, registration between the two images to determine the relative location of the tumor in the RT coordinate space, and treatment with the microbeam irradiator. We evaluated the targeting accuracy and tumor cell response of the protocol with U87 MG human glioma tumor bearing mice using γ‐H2AX staining. A survival study of U87 human glioma tumor bearing mice treated with three‐microbeam MRT (32Gy/beam) was carried out using this protocol. Results: The average targeting accuracy measured in the γ‐H2AX stained slices was about 280 μrn which is well below our beamwidth (350 μrn). In the survival study, U87 tumor mice treated using this MRT protocol showed an average survival time of 45 days, an extension of 6 days compared with 39 days in the control group. Conclusion: The initial tumor mice studies have demonstrated the feasibility of MRI/x‐ray radiograph guided MRT treatment in animal research. We believe this image‐guide MRT protocol could enable more efficient animal experiments with various brain tumor models to better understand MRT mechanisms.

SU-D-144-04: Physiologically Gated Microbeam Radiation Therapy Using Electronically Controlled Field Emission X-Ray Source Array

Purpose: Microbeam radiation therapy (MRT) is an experimental pre‐clinical technique using arrays of microscopically‐thin, low‐energy X‐ray radiation to treat radio‐resistant, deep‐seated tumors. All previous MRT experiments were performed using synchrotron radiation. We have developed a compact MRT small animal system using carbon nanotube (CNT) field emission x‐ray technology. Our purpose is to incorporate respiratory gating to the MRT system, minimizing motion blurring and increasing the peak‐to‐valley‐dose ratio (PVDR), which is important for normal tissue sparing. Methods: A prototype CNT MRT system was employed. The intrinsically divergent radiation is collimated into ∼300um microbeams using an external collimator. Parallel microbeam planes were delivered by translating the object perpendicular to the microbeam plane in a step‐and‐shoot fashion. The device generated an average entrance dose rate of 1Gy/minute. For respiratory‐gated irradiation, electron field emission from CNT cathodes was synchronized with the respiratory cycle of the mouse so x‐ray radiation is only extracted during the motionless phase of respiration.A phantom simulating mouse respiration used a servo motor pushing on a pressure sensor in a typical breathing pattern. A control program used the signal to trigger x‐ray irradiation during the motionless phase. Two experiments were run: a single line irradiation at 160 kVp delivering 0.9 Gy/min for 5 minutes, and three such lines of irradiation separated by 900um. Dose profiles were measured with EBT2 Gafchromic dosimetry films. Results: A single beam showed a FWTM increase from 638 to 1088um with un‐gated motion. With gating, the FWTM was 669um, similar to the motionless case.PVDR quantifies MRT effectiveness in the case of multiple lines. Motion reduces PVDR 50 percent; with gating PVDR is almost entirely recovered, 5.5 percent higher than without motion. Conclusion: Gated MRT largely eliminates microbeam broadening from physiological motion, maintaining high PVDR. The technique increases precision and will be tested during MRT treatments.

SU-D-144-07: Preliminary Characterization of Microbeam Radiation Using Very High Resolution 3D Dosimetry

Purpose: Compact microbeam radiation therapy (MRT) recently became feasible through the development of carbon‐nanotube based distributed x‐ray array technology. This work investigates the feasibility of novel highresolution 3D dosimetry techniques (50μm isotropic) for the challenging task of characterizing microbeam irradiations of nominal width 300–400μm. Methods: A cylindrical PRESAGE 3D dosimeter (20mm diameter, 22mm long) was irradiated with three parallel microbeams generated by a prototype compact MRT system for small animal research developed at UNC. The carbon nanotube field emission x‐ray source array is designed to produce x‐rays up to 160 kV which are collimated to microbeam radiation through an external collimator. The entrance dose used in this study was estimated from EBT2 film to be 32 Gy. A 50μm isotropic 3D dose distribution was obtained by imaging the dosimeter in the Duke Micro Optical‐CT Scanner (DMicrOS), an in‐house, bi‐telecentric optical CT system optimized for high‐resolution optical tomography. Preliminary analysis of microbeam characteristics was performed on a ROI averaged across the central 10mm of the dosimeter. Beam width (FWHM), percent depth dose (PDD), and peak‐to‐valley dose ratio (PVDR) were measured as a function of depth along the irradiated beam paths. Results: Beam width measurements indicated that the average FWHM across all three beams remained constant (405.3μm, σ =13.2μm) between depths of 3.00–14.00mm. PDD measurements were normalized to values at 3.00mm depth (to avoid bias due to possible optical artifact at the dosimeter surface) and showed a falloff to 82.9–90.5% at 14.00mm depth. PVDR increased with depth from 6.3 at 3.00mm depth to 8.6 at 14.00mm depth. Conclusion: These preliminary results from the DMicrOS/PRESAGE 3D dosimetry system show strong potential for uniquely comprehensive verification of microbeam irradiations. Future work is required to investigate the potential of stray‐light artifacts in this extreme geometry. NIH R01CA100835

Physiologically gated micro-beam radiation therapy using electronically controlled field emission x-ray source array.

Micro-beam radiation therapy (MRT) uses parallel planes of high dose narrow (10-100 um in width) radiation beams separated by a fraction of a millimeter to treat cancerous tumors. This experimental therapy method based on synchrotron radiation has been shown to spare normal tissue at up to 1000Gy of entrance dose while still being effective in tumor eradication and extending the lifetime of tumor-bearing small animal models. Motion during the treatment can result in significant movement of micro beam positions resulting in broader beam width and lower peak to valley dose ratio (PVDR), and thus can reduce the effectiveness of the MRT. Recently we have developed the first bench-top image guided MRT system for small animal treatment using a high powered carbon nanotube (CNT) x-ray source array. The CNT field emission x-ray source can be electronically synchronized to an external triggering signal to enable physiologically gated firing of x-ray radiation to minimize motion blurring. Here we report the results of phantom study of respiratory gated MRT. A simulation of mouse breathing was performed using a servo motor. Preliminary results show that without gating the micro beam full width at tenth maximum (FWTM) can increase by 70% and PVDR can decrease up to 50%. But with proper gating, both the beam width and PVDR changes can be negligible. Future experiments will involve irradiation of mouse models and comparing histology stains between the controls and the gated irradiation.

Monte Carlo simulation of a compact microbeam radiotherapy system based on carbon nanotube field emission technology

Microbeam radiation therapy (MRT) is an experimental radiotherapy technique that has shown potent antitumor effects with minimal damage to normal tissue in animal studies. This unique form of radiation is currently only produced in a few large synchrotron accelerator research facilities in the world. To promote widespread translational research on this promising treatment technology we have proposed and are in the initial development stages of a compact MRT system that is based on carbon nanotube field emission x-ray technology. We report on a Monte Carlo based feasibility study of the compact MRT system design. Monte Carlo calculations were performed using EGSnrc-based codes. The proposed small animal research MRT device design includes carbon nanotube cathodes shaped to match the corresponding MRT collimator apertures, a common reflection anode with filter, and a MRT collimator. Each collimator aperture is sized to deliver a beam width ranging from 30 to 200 μm at 18.6 cm source-to-axis distance. Design parameters studied with Monte Carlo include electron energy, cathode design, anode angle, filtration, and collimator design. Calculations were performed for single and multibeam configurations. Increasing the energy from 100 kVp to 160 kVp increased the photon fluence through the collimator by a factor of 1.7. Both energies produced a largely uniform fluence along the long dimension of the microbeam, with 5% decreases in intensity near the edges. The isocentric dose rate for 160 kVp was calculated to be 700 Gy∕min∕A in the center of a 3 cm diameter target. Scatter contributions resulting from collimator size were found to produce only small (<7%) changes in the dose rate for field widths greater than 50 μm. Dose vs depth was weakly dependent on filtration material. The peak-to-valley ratio varied from 10 to 100 as the separation between adjacent microbeams varies from 150 to 1000 μm. Monte Carlo simulations demonstrate that the proposed compact MRT system design is capable of delivering a sufficient dose rate and peak-to-valley ratio for small animal MRT studies.

TH-E-218-10: Feasibility Demonstration and Initial Construction of an Integrated Carbon Nanotube Micro-CT System for Compact Microbeam Radiation Therapy Image Guidance

Purpose: Synchrotron generated Microbeam Radiation Therapy (MRT) has been shown to cause significant damage to radioresistant brain tumors while sparing surrounding normal tissues in rats. The potential translation of this experimental type of therapy to clinical use is hindered by the fact that the mechanism behind MRT is still not fully understood and by the lack of widely available MRT devices. We have developed a prototype compact MRT system based on carbon nanotube (CNT) field emission x-ray technology in the hopes of enabling more cancer biologists to explore the radiobiology behind MRT. Our purpose in this study is to begin the integration of a micro-CT scanner with the MRT system for image guided MRT delivery. Methods: We tested the feasibility of using the micro-CT scanner in conjunction with the MRT system by designing a specialized phantom to be scanned, targeted, and irradiated by two pre-existing independent systems. After scanning, the phantom was visualized by our treatment planning software ‘Micro-PLUNC’, where the desired beam pattern was inserted into the reconstructed images of the phantom. Afterwards, positioning parameters were calculated to allow for the beams to be delivered at the planned locations within the phantom. Finally, the phantom was irradiated with internal Gafchromic films to verify the delivered dose pattern. Results: A pre-determined microbeam pattern was successfully delivered to within +/− 150 um accuracy. Films placed on the phantom holder and within the phantom itself confirmed the desired dose pattern. Based on this study, construction of the Micro-CT guided MRT dual system was begun. Conclusions: The feasibility of using our existing Micro-CT technology as image guidance for MRT was displayed. When integration is fully completed, the new system will allow for precise dose delivery in small animals and will prevent wasting dose in areas outside the treatment volume. Funding sources include: NCI C-CCNE, NCI GO grant

MO‐G‐BRB‐04: Feasibility Study of a Nanotechnology‐Enabled Desktop Image‐Guided Microbeam Radiation Therapy System

Purpose: Microbeam radiation therapy (MRT) is a preclinical and radical radiotherapy treatment that has significant potentials for clinical applications. Animal studies have shown that, although only a small fraction of the tumor volume is within the paths of the microbeams, the entire tumor can be eradicated with no damage to the function of normal tissues. However the lack of MRT delivery systems prevents most cancer researchers from MRT laboratory research and hinders the translation to clinical application. We propose to develop the world first desktop image‐ guided MRT system for cancer research now and potential clinical treatment in the future. Methods: The key challenge for a desktop MRT system is dose rate and the enabling technology is the recently emerged carbon nanotube (CNT) based spatially distributed x‐ray source technology. We have performed the corresponding simulations on the x‐ray tube electron optics and the anode heat dissipation. Monte Carlo simulation was used to evaluate the dosimetric characteristics of the system. A prototype MRT device was also constructed to validate the system design and the simulation results. Results: We have already carried out initial feasibility studies and the results indicate that this novel nanotechnology‐enabled desktop MRT system is capable of producing characteristic MRT radiation comparable to the MRT radiation produced by the synchrotron facilities. Conclusions: We strongly believe that there is a great potential to translate this promising MRT treatment from animal research to widespread clinical application. Because of the relative low cost and compactness of the proposed MRT system, once developed, the MRT treatment technology can be made readily available and affordable for widespread research and clinical application in US and beyond to benefit all cancer patients.

TH‐C‐220‐01: Pilot Study for the Development of Clinical Microbeam Radiation Therapy Using a Carbon Nanotube Field Emission Micro‐CT Scanner

Purpose: The possibilities of microbeam radiation therapy (MRT) up until now have mainly been studied using synchrotron sources due to their high flux (100s Gy/sec) and approximately parallel X‐ray paths. We wish to show that both of these advantages are also attainable with the use of carbon nanotube (CNT) field emission based X‐ray source arrays, and that by using this type of source a compact MRT system may be possible. Methods: The study was performed with our CNT micro‐CT scanner (100μm focal spot). A microbeam collimator alignment assembly with the capability to collimate and superimpose beams coming from different gantry positions was fabricated and attached to the scanner. Two orthogonal dosimetric films (Gafchromic EBT2) were embedded inside a cylindrical phantom to record the MRT dose distribution. Microbeams were fired at this target from 44 different entry angles to simulate an array of sources. In a separate experiment, phantom translation was used to simulate multiple parallel beams. Results: Forty‐four beams were superimposed in the phantom to produce a single microbeam dose profile with a FWHM of 310m (expected value was 280μm) indicating proper collimator alignment. A new MRT‐ specific tube was proposed and commissioned based on the preliminary experimental results and the corresponding Monte Carlo simulations. The estimated dose rate for this proposed tube was calculated to be over 100 Gy/sec from these initial measurements. Also, during the multiple beam simulation, a reasonable peak to valley dose ratio (∼12) was found when the translation distance was roughly 4x the beam width. Conclusions: We have shown that it will not only be possible to create microbeams with our CNT sources, but that the flexibility of these field emission sources will open the field of MRT study to the larger research community and possibly bring effective and compact MRT devices to the clinical environment.