Ew Izaguirre

MicroRT - Small animal conformal irradiator

A novel small animal conformal radiation therapy system has been designed and prototyped: MicroRT. The microRT system integrates multimodality imaging, radiation treatment planning, and conformal radiation therapy that utilizes a clinical 192Ir isotope high dose rate source as the radiation source (teletherapy). A multiparameter dose calculation algorithm based on Monte Carlo dose distribution simulations is used to efficiently and accurately calculate doses for treatment planning purposes. A series of precisely machined tungsten collimators mounted onto a cylindrical collimator assembly is used to provide the radiation beam portals. The current design allows a source-to-target distance range of 1-8 cm at four beam angles: 0 degrees (beam oriented down), 90 degrees, 180 degrees, and 270 degrees. The animal is anesthetized and placed in an immobilization device with built-in fiducial markers and scanned using a computed tomography, magnetic resonance, or positron emission tomography scanner prior to irradiation. Treatment plans using up to four beam orientations are created utilizing a custom treatment planning system-microRTP. A three-axis computer-controlled stage that supports and accurately positions the animals is programmed to place the animal relative to the radiation beams according to the microRTP plan. The microRT system positioning accuracy was found to be submillimeter. The radiation source is guided through one of four catheter channels and placed in line with the tungsten collimators to deliver the conformal radiation treatment. The microRT hardware specifications, the accuracy of the treatment planning and positioning systems, and some typical procedures for radiobiological experiments that can be performed with the microRT device are presented.

Feasibility of small animal cranial irradiation with the microRT system

PURPOSE To develop and validate methods for small-animal CNS radiotherapy using the microRT system. MATERIALS AND METHODS A custom head immobilizer was designed and built to integrate with a pre-existing microRT animal couch. The Delrin couch-immobilizer assembly, compatible with multiple imaging modalities (CT, microCT, microMR, microPET, microSPECT, optical), was first imaged via CT in order to verify the safety and reproducibility of the immobilization method. Once verified, the subject animals were CT-scanned while positioned within the couch-immobilizer assembly for treatment planning purposes. The resultant images were then imported into CERR, an in-house-developed research treatment planning system, and registered to the microRTP treatment planning space using rigid registration. The targeted brain was then contoured and conformal radiotherapy plans were constructed for two separate studies: (1) a whole-brain irradiation comprised of two lateral beams at the 90 degree and 270 degree microRT treatment positions and (2) a hemispheric (left-brain) irradiation comprised of a single A-P vertex beam at the 0 degree microRT treatment position. During treatment, subject animals (n=48) were positioned to the CERR-generated treatment coordinates using the three-axis microRT motor positioning system and were irradiated using a clinical Ir-192 high-dose-rate remote after-loading system. The radiation treatment course consisted of 5 Gy fractions, 3 days per week. 90% of the subjects received a total dose of 30 Gy and 10% received a dose of 60 Gy. RESULTS Image analysis verified the safety and reproducibility of the immobilizer. CT scans generated from repeated reloading and repositioning of the same subject animal in the couch-immobilizer assembly were fused to a baseline CT. The resultant analysis revealed a 0.09 mm average, center-of-mass translocation and negligible volumetric error in the contoured, murine brain. The experimental use of the head immobilizer added 0.1 mm to microRT spatial uncertainty along each axis. Overall, the total spatial uncertainty for the prescribed treatments was +/-0.3 mm in all three axes, a 0.2 mm functional improvement over the original version of microRT. Subject tolerance was good, with minimal observed side effects and a low procedure-induced mortality rate. Throughput was high, with average treatment times of 7.72 and 3.13 min/animal for the whole-brain and hemispheric plans, respectively (dependent on source strength). CONCLUSIONS The method described exhibits conformality more in line with the size differential between human and animal patients than provided by previous prevalent approaches. Using pretreatment imaging and microRT-specific treatment planning, our method can deliver an accurate, conformal dose distribution to the targeted murine brain (or a subregion of the brain) while minimizing excess dose to the surrounding tissue. Thus, preclinical animal studies assessing the radiotherapeutic response of both normal and malignant CNS tissue to complex dose distributions, which closer resemble human-type radiotherapy, are better enabled. The procedural and mechanistic framework for this method logically provides for future adaptation into other murine target organs or regions.

Novel chemo-sensitizing agent, ERW1227B, impairs cellular motility and enhances cell death in glioblastomas

Glioblastomas display variable phenotypes that include increased drug-resistance associated with enhanced migratory and anti-apoptotic characteristics. These shared characteristics contribute to failure of clinical treatment regimens. Identification of novel compounds that promote cell death and impair cellular motility is a logical strategy to develop more effective clinical protocols. We recently described the ability of the small molecule, KCC009, a tissue transglutaminase (TG2) inhibitor, to sensitize glioblastoma cells to chemotherapy. In the current study, we synthesized a series of related compounds that show variable ability to promote cell death and impair motility in glioblastomas, irrespective of their ability to inhibit TG2. Each compound has a 3-bromo-4,5-dihydroisoxazole component that presumably reacts with nucleophilic cysteine thiol residues in the active sites of proteins that have an affinity to the small molecule. Our studies focused on the effects of the compound, ERW1227B. Treatment of glioblastoma cells with ERW1227B was associated with both down-regulation of the PI-3 kinase/Akt pathway, which enhanced cell death; as well as disruption of focal adhesive complexes and intracellular actin fibers, which impaired cellular mobility. Bioassays as well as time-lapse photography of glioblastoma cells treated with ERW1227B showed cell death and rapid loss of cellular motility. Mice studies with in vivo glioblastoma models demonstrated the ability of ERW1227B to sensitize tumor cells to cell death after treatment with either chemotherapy or radiation. The above findings identify ERW1227B as a potential novel therapeutic agent in the treatment of glioblastomas.

TH‐C‐204B‐10: Implementation of a Small Animal Image Guided Microirradiator: The MicroIGRT

Purpose: Implementation of a conformal small animal image guided microirradiation therapy instrument (microIGRT) consisting of a cone beam microCT subsystem for submillimeter low dose structural imagingimage guided radiotherapy and orthovoltage conformal microirradiation with high dose rate and high throughput. Method and Materials: The microCT subsystem is based on an 80kVp micro‐focus x‐ray source with 75×75 μm2 focal spot and a flat panel amorphous silicondetector with 1024×1024 pixels. The irradiator consists of a high power commercially available 320 kVp orthovoltage source with a 0.4×0.4 mm2 focal spot that can be operated at a nominal power of 800W. The beam characteristics are controlled with two variable jaws used to pre‐collimate the radiation beam along each orthogonal direction. An aperture exchange mechanism is used to conform the beam cross section by using computer generated apertures. The microCT radiationdose the orthovoltage source spectral output and dose rate are under evaluation using a mouse digital phantom and a pencil beam algorithm. Results:CTimaging with micrometric resolution is achievable using 128 projections and a maximum radiationdose of 2cGy. Automatic animal positioning and handling is performed within sub‐millimeter precision. The treatment beam can be aimed at different latitude and longitude angles and translated with 500 μm steps. The source was tested to deliver a radiationdose rate of 20 Gy/min when is filtered to a half‐value layer of 4.6 mm Cu. Conclusion: We present our progress and initial tests of a highly conformal image guided small animal microirradiator.

TU‐C‐BRB‐01: Commissioning and Characterization of a Dual Gantry Image Guided Orthovoltage Micro Irradiator for Preclinical Small Animal Radiobiological Experiments

Purpose: The purpose of this study was to accurately commission and characterize our small animalimage guided micro irradiator, the microIGRT, for preclinical translational radiobiological research. The microIGRT has a dual gantry architecture with a microCT subsystem gantry for low dose high resolution anatomical imaging and treatment planning, and a second coaxial microRT subsystem gantry for conformal image guided orthovoltage irradiation. Methods: The microCT image resolution, contrast, and dose were evaluated with specialized phantoms and animal models. The micro RT subsystem percent depth dose, beam profile, multibeam irradiation precision and conformality, animal repositioning accuracy, mechanical resolution, and dosimetric accuracy were measured using specialized phantoms equipped with radiochromic film. For each measurement, results were compared with standards adapted from external beam Linac and patient quality assurance protocols scaled to animal dimensions and orthovoltage energies. Results: The microCT dose is 4.15 cGy/scan for 100 um imaging resolution, up to 33.2 cGy/scan for 800 um imaging resolution. The percent depth dose for a 300 kVp beam with 3.8 mm of Cu HVL is 2.7 cGy/mm with a buildup of 2.8 mm. A 1 cm2 standard square field has a 265 um penumbra, 7% homogeneity, and 9% symmetry. Anatomical positioning is within 500 um for fractionated treatments and multibeam isocentric irradiation central axis uncertainty is within a 150 um radius for three, four, and five coplanar beam treatments. Conclusions: We characterized the small animal microIGRT developed by our group to provide complete parameterization of the instruments imaging and treatment capabilities. Anatomical imaging, irradiation distributions, and beam dosimetry indicate that our system satisfies requirements established by scaling clinical imaging and radiotherapy protocols to animal models to perform clinically relevant translational radiobiological experiments.

TU‐C‐BRD‐06: Preclinical Image Guided Microirradiators: Concepts, Design and Implementation

We will introduce small animalimage guided microirradiators by reviewing the concepts and requirements for high resolution and high conformality irradiation of tumors implanted in small animal limbs (xenograft tumor models), animalorgans and spontaneous tumor models. We will present two preclinical microirradiators developed by our group, a brachytherapy based microirradiator and an orthovoltage x‐ray source based microirradiator. The brachytherapy irradiator has been constructed around a commercial 192 Ir high‐dose rate (HDR) remote afterloader source in a teletherapy geometry. The system consists of a set of exchangeable tungstencollimators (from 2.5 to 5.5 mm diameter) mounted on an aluminum cylindrical support. An HDR catheter is then used to transport the source to the pre‐determined dwell position that centers the source at the collimator hole. With this microirradiator, the anatomical image is obtained using an external clinical CT operated at maximum resolution and coregistration is achieved using fiducial markers. The x‐ray orthovoltage microirradiator has an onboard cone beam microCT subsystem for submillimeter low dose anatomical imaging. The microCT and the ontrovoltage x‐ray source are aligned using a common rotation axis in a tandem configuration. An axial motorized animal bed transfers the animal from the microCT subsystem to the microirradiation subsystem. The microCT subsystem was constructed using an 80 kVp micro‐focus x‐ray source with a 75 × 75 um2 focal spot and a flat panel amorphous silicon detector with 1024 × 1024 pixels. The orthovoltage irradiator subsystem was constructed using a 320 kVp x‐ray source with dual focus spots (0.4 × 0.4 mm2 at 800W and 1 × 1 mm2 at 1800 W). The orthovoltage beam is collimated using orthogonal jaws and exchangeable apertures. The treatment beam can be aimed at different latitudinal and longitudinal angles in steps of 2 arcmin. and translated at 100 μm steps (x, y and z). The beam cross sections can be modulated with submillimeter precision using steps of 50 μm. The system is designed to deliver a maximum dose rate of 40 Gy/ min. These irradiators are operated under a common small animal irradiation facility that accepts campus wide preclinical projects. We will conclude our presentation by presenting examples of ongoing radiobiological projects that will allow us to illustrate the performance and operation of both irradiators.

TU‐C‐108‐05: High Density Organic Scintillator Arrays for High Resolution Stereotactic Body Radiation Therapy Dosimetry

Purpose: Radiation oncology patients receiving stereotactic body radiation therapy (SBRT) are treated with high dose and high dose rate treatment procedures in which delivered dose should be recorded, and verified for quality assurance and patient safety. We implemented a high resolution scintillating fiber detector array to perform high resolution dosimetry of SBRT fields. Materials: Scintillating fibers have a water equivalent attenuation coefficient, excellent reproducibility, stability and a linear response versus dose, do not require any polarizing voltage, and are water impermeable. We constructed a high resolution dosimeter based on an array of sub‐millimeter organic fiber sensors mounted on a supporting frame that provides support, alignment, and buildup material. The fiber detector interface consists of a high density linear array of high speed linear photodetectors. The analog output is transmitted to a high throughput parallel data acquisition system integrated with a dedicated computer for signal processing, analysis, and recording. The detector was specially designed to perform high resolution dosimetric verification of small SBRT fields delivered with conventional dose rates (600 MU/min) to high dose rate flattening filter free beams (up to 2400 MU/min). Results: We determined fiber sensor sensitivity and linearity response with respect to beam intensity field size and dose. Detector spatial resolution is 0.5 mm and linearity response with respect to beam intensity and field size was within 2% for photon beams from 6MV to 18 MV and electron beams from 6 MeV to 20 MeV. Spatial beam profiles were compared with film dosimetry showing excellent agreement within 3% in the penumbra region. Conclusions: The development of this technology addresses the need for high resolution dosimeters for SBRT. The developed detector provides accurate dose, beam localization, and beam profile verification and will be a valuable tool for quality assurance of SBRT treatments.

SU‐E‐T‐430: Planning and Dosimetric Comparison of the Gamma Knife Convolution and TMR 10 Algorithms

PURPOSE To compare the dose distributions for identical treatment plans calculated by the Gamma Knife TMR 10 and convolution algorithms and measured with film dosimetry. METHODS An anthropomorphic head phantom was CT imaged with EBT2 film placed between each of seven axial sections. The resulting data set was used to plan three 16mm collimated targets on the Gamma Knife Perfexion, with each target centered on a film plane. Target 1 was placed within a homogeneous region while Targets 2 and 3 were placed in heterogeneous regions, i.e. tissue-air and bone-tissue interfaces, respectively. Plans using the same targets were made using both the TMR 10 and convolution algorithms. The prescription was delivered to the phantom using the TMR 10 treatment plans after which the convolution treatment plans were adjusted to Result in identical treatment times, thus ensuring identical dose delivery. Film dosimetry was done to determine actual dose delivered at target center and was compared to the predicted dose for each algorithm. RESULTS While there was strong correlation between both algorithms, the convolution algorithm predicted a higher delivered maximum dose than TMR 10, up to 2.5% higher in homogeneous tissue and up to 7% near an air cavity. Film dosimetry results were consistent with the convolution algorithm predictions, with an error of less than three percent. CONCLUSION The Gamma Knife convolution algorithm predicts delivered dose to a clinically acceptable level, which was confirmed by film dosimetry. However, film in an anthropomorphic head phantom may not be adequate to measure the most significant differences between the two algorithms. Precise stereotactic treatments will require precise dosimetry, and a phantom developed specifically with Gamma Knife geometry in mind may be necessary to fully characterize the dosimetry at anatomy interfaces.

TU‐C‐BRB‐09: In Silico Model of Glioblastoma Tumor Microenvironment to Predict Radiotherapy Outcome

Purpose: We developed a tumor model for glioblastomas with the aim to study tumor growth, transition from avascular to vascular, oxygenation effects, cell repair, and to predict glioma control or recurrence when the malignancy is treated with ionizing radiation.Methods: Anatomical structures imaged using MRI were contoured and compartmentalized to simulate white matter, grey matter, and vasculature structures proximal to a simulated glioblastoma tumor. The gliomas were modeled using micro compartments to represent groups of tumor cells of the same structure and functionality. The model incorporates the interactions between healthy and tumor tissue using a mechanistic approach based on forces and link strengths between cells and the extra cellular matrix. The evolution and response of the cells to biomolecules, nutrients, and oxygen distribution were modeled through discrete transport and diffusion equations. Cell biology was simulated using parameters that represent nutrient consumption, cell cycle, cell history, and cell oxygenation. The delivered dose was modeled using a probabilistic approach to compute the likelihood of DNA damage and repair. Results: We successfully simulated tumor growth, invasion, and disruption of the local anatomy and tumorcontrol or recurrence under ionizing radiation stress. We modeled tumorradiotherapy under hypoxic and oxic conditions. Results of these numerical experiments show qualitative agreement with observed tumor evolution and response to ionizing radiationtreatment. Transition from an avascular to a vascular tumor and recruitment of blood vessels was also successfully modeled. Spatial resolution of compartments is higher than current imaging devices, making our model a valuable tool to link simulations with anatomical and functional imaging.Conclusions: We developed a micro compartmental model of glioblastoma tumors to evaluate the role of the local anatomy and the microenvironment oxygenation when the malignancy is treated with ionizing radiation. The model can be used to predict glioblastoma growth and response to radiotherapy.

TU‐C‐BRB‐07: Comparison of Preclinical and Clinical Conformal Radiation Therapy Techniques and Protocols to Establish a Translational Pathway

Purpose: The purpose of this study was to compare the techniques and protocols used in clinical radiation therapy and recently developed preclinical image guided micro irradiation to establish a link between small animal conformal irradiation and clinical treatment protocols. This work will establish protocols that, according to treatment site, will facilitate the translation of conclusions from radiobiological experiments to clinical applications, fostering the advancement of radiotherapy.Methods: Data was gathered using our small animal image guided micro irradiation device, the microIGRT, as an example of preclinical techniques which mimic equivalent clinical treatment protocols. The microIGRT utilizes fractionated treatments, multibeam irradiations, modulated beams, image guided treatment verification, and doses to emulate clinical protocols. Consequently, it is well suited to establish parametric comparisons between clinical and preclinical techniques. In this study, we concentrated on two treatment sites, brain and lung, to define treatment conformality index, homogeneity, penumbra, PDD, and fractionated doses to establish a link to guide radiobiological experiments using clinical protocols as a gold standard. Results: Three and five beam irradiations were delivered to a small animal body and head phantom with radiochromic film to simulate lung and braintreatment. A three beam irradiation to the lung yielded a 625 um penumbra. Compare this value with a human treatment penumbra of 1 cm, and penumbra scales as the ratio between body sizes. The homogeneity of our system is similar to the 10% typically used in clinical treatment planning.Conclusions: By comparing preclinical and clinical treatment metrics, the extent of translation can be determined and improved, leading to better understanding of preclinical results and improved correlation with clinical procedures. This will lead to more clinically based preclinical experiments and improve translation efficiency between the two testing environments, thus providing new clinical treatment strategies and improved human cancer treatment.