M Hadsell

A first generation compact microbeam radiation therapy system based on carbon nanotube X-ray technology

We have developed a compact microbeam radiation therapy device using carbon nanotube cathodes to create a linear array of narrow focal line segments on a tungsten anode and a custom collimator assembly to select a slice of the resulting wedge-shaped radiation pattern. Effective focal line width was measured to be 131 μm, resulting in a microbeam width of ∼300 μm. The instantaneous dose rate was projected to be 2 Gy/s at full-power. Peak to valley dose ratio was measured to be >17 when a 1.4 mm microbeam separation was employed. Finally, multiple microbeams were delivered to a mouse with beam paths verified through histology.

Fiber-optic detector for real time dosimetry of a micro-planar x-ray beam.

PURPOSE Here, the authors describe a dosimetry measurement technique for microbeam radiation therapy using a nanoparticle-terminated fiber-optic dosimeter (nano-FOD). METHODS The nano-FOD was placed in the center of a 2 cm diameter mouse phantom to measure the deep tissue dose and lateral beam profile of a planar x-ray microbeam. RESULTS The continuous dose rate at the x-ray microbeam peak measured with the nano-FOD was 1.91 ± 0.06 cGy s(-1), a value 2.7% higher than that determined via radiochromic film measurements (1.86 ± 0.15 cGy s(-1)). The nano-FOD-determined lateral beam full-width half max value of 420 μm exceeded that measured using radiochromic film (320 μm). Due to the 8° angle of the collimated microbeam and resulting volumetric effects within the scintillator, the profile measurements reported here are estimated to achieve a resolution of ∼0.1 mm; however, for a beam angle of 0°, the theoretical resolution would approach the thickness of the scintillator (∼0.01 mm). CONCLUSIONS This work provides proof-of-concept data and demonstrates that the novel nano-FOD device can be used to perform real-time dosimetry in microbeam radiation therapy to measure the continuous dose rate at the x-ray microbeam peak as well as the lateral beam shape.

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

PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

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.

TH‐A‐BRB‐04: Vascular Response to Microbeam Radiation Therapy in Vivo Using a Murine Window Chamber Tumor Model

Microbeam Radiation Therapy(MRT) has shown a marked tumor‐specific effect. The tissue‐sparing property of this unique treatment is possibly facilitated by efficient normal‐vessel repair mechanisms, contrary to the catastrophic disruption of poorly regulated tumor‐associated vasculature. However, significant controversy exists with regard to the role of endothelial cell death in radiation response. It is possible that the direct killing of tumor vasculature may increase radiation response within the tumor due to either oxygen/nutrient deprivation or through the “bystander effect”. The aim of this study was to characterize the vascular response to MRT in vivo using a murine window chamber model over an extended time course. MRTtreatment at various doses (300 micron single beam, 0Gy, 50Gy, 80Gy) was applied to the murine window chamber tumor model. Changes in tumor‐associated vasculature after the MRTtreatment utilizing intravital microscopy were profound. A robust angiogenic response was clearly present along the microbeam track in what appeared to be clusters of vessel proliferation following MRT of 50 and 80Gy. This distinctive pattern of angiogenesis was imaged through Day 7, as the irradiated track and regional microenvironment were infiltrated with a dense vascular network. In more recent experiments, we have observed infiltration of tumor cells along pre‐existing vascular networks adjacent to the microbeam, to distant unirradiated sites. These types of responses were not seen in controls or in chambers following wide beam irradiation to the entire window at comparable doses. This behavior strongly suggests that the treatment is promoting epithelial mesenchymal transition, angiogenesis and local invasion. Although these observations are for microbeam treatments, the biology being observed could equally be applied to the issue of marginal miss, which is of concern for high dose conformal radiotherapy. The window chamber model provides a novel approach to direct visualization of the longitudinal vascular changes following treatment with MRT. These findings suggest that radiation induced angiogenesis at sites adjacent to the MRT beam may play an important role in modifying the tumor microenvironment. Such a response may have significant implications with regard to the understood mechanism of radiation‐induced cell death. Learning Objectives: 1. Be able to describe concept of microbeam irradiation 2. Understand underlying mechanisms and implications of driving angiogenic response of tumor after irradiation This work was supported by NIH/NCI grant CA40355 and DoD grant BC083195.

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‐144‐06: Dosimetric Characterization of a Prototype Nanotechnology Microbeam Radiation Therapy Device Using Gafchromic EBT2 Film

PURPOSE Currently there is lack of dosimetry technology for the compact microbeam radiation therapy device we recently developed using field emission based carbon nanotube cathode technology. This is due to the fact that our beam width can be as small as 250μm, restricting the use of normal characterization methods. We demonstrate that with proper calibration and analysis that Gafchromic EBT2 film can be used to characterize our microbeam irradiator for radiobiological mechanistic studies in mice. METHODS Our compact microbeam radiation therapy device employs a 160mm × 160um focal line and collimator to deliver an orthovoltage microplanar beam. Specialized phantoms were created to properly measure typical dosimetric quantities including PDD and TMR in addition to other quantities specific to microbeam dose distributions and our source. Gafchromic EBT2 film, cross calibrated earlier to a conventional ion chamber in the uncollimated beam, was used for all measurements. RESULTS While TMR and PDD results for this study were fairly typical, measurements more specific to our source and beam geometry showed unique results. The beam width as a function of distance from the source displayed a steeper increase than would be expected from strictly geometric considerations, probably due to collimator scatter. In addition, the decline in dose with distance from the source was much less severe than expected, as displayed by a linear fit in the tested domain. CONCLUSION Gafchromic EBT2 film was an excellent choice for the initial characterization of our experimental microbeam device, as shown by the expected forms of the PDD and TMR curves. In addition, the slower drop in dose with distance from the source is consistent with the fact that our device uses a focal line and not a point. Finally, data gathered here will provide a good starting point for a customized treatment planning system specific to our irradiator.

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 braintumors 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

WE‐E‐BRE‐06: High‐Dose Microbeam Radiation Induces Different Responses in Tumor Microenvironment Compared to Conventional Seamless Radiation in Window Chamber Tumor Models

PURPOSE Microbeam radiation therapy and GRID therapy are different forms of Spatially-Fractioned Radiation Therapy (SFRT) that is fundamentally different from the conventional seamless and temporally fractionated radiation therapy. SFRT is characterized by a ultra-high dose (10s -100s Gy) dose single treatment with drastic inhomogeneity pattern of given spatial frequencies. Preclinical and limited clinical studies have shown that the SFRT treatments may offer significant improvements in reducing treatment toxicity, especially for those patients who have not benefited from the state-of-the-art radiation therapy approaches. This preliminary study aims to elucidate the underlying working mechanisms of SFRT, which currently remains poorly understood. METHODS A genetically engineered 4T1 murine mammary carcinoma cell line and nude mice skin fold window chamber were used. A nanotechnology-based 160kV x-ray irradiator delivered 50Gy (entrance dose) single treatments of microbeam or seamless radiation. Animals were in 3 groups: mock, seamless radiation, and 300μm microbeam radiation. The windows were imaged using a hyperspectral system to capture total hemoglobin/saturation, GFP fluorescence emission, RFP fluorescence emission, and vessel density at 9 time points up to 7 days post radiation. RESULTS We found unique physiologic changes in different tumor/normal tissue regions and differential effects between seamless and microbeam treatments. They include 1) compared to microbeam and mock radiation seamless radiation damaged more microvasculature in tumor-surrounding normal tissue, 2) a pronounced angiogenic effect was observed with vascular proliferation in the microbeam irradiated portion of the tumor days post treatment (no such effect observed in seamless and mock groups), and 3) a notable change in tumor vascular orientation was observed where vessels initially oriented parallel to the beam length were replaced by vessels running perpendicular to the irradiation portion of the tumor. CONCLUSION Our preliminary study indicated that microbeam radiation modified tumor microenvironment in ways significantly different than of the conventional seamless radiation.

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.