Evaluation of a micro ionization chamber for dosimetric measurements in image-guided preclinical irradiation platforms

Image-guided small animal irradiation platforms deliver small radiation fields in the medium energy x-ray range. Commissioning of such platforms, followed by dosimetric verification of treatment planning, are mostly performed with radiochromic film. There is a need for independent measurement methods, traceable to primary standards, with the added advantage of immediacy in obtaining results. This investigation characterizes a small volume ionization chamber in medium energy x-rays for reference dosimetry in preclinical irradiation research platforms. The detector was exposed to a set of reference x-ray beams (0.5 to 4 mm Cu HVL). Leakage, reproducibility, linearity, response to detector's orientation, dose rate, and energy dependence were determined for a 3D PinPoint ionization chamber (PTW 31022). Polarity and ion recombination were also studied. Absorbed doses at 2 cm depth were compared, derived either by applying the experimentally determined cross-calibration coefficient at a typical small animal radiation platform "user's" quality (0.84 mm Cu HVL) or by interpolation from air kerma calibration coefficients in a set of reference beam qualities. In the range of reference x-ray beams, correction for ion recombination was less than 0.1%. The largest polarity correction was 1.4% (for 4 mm Cu HVL). Calibration and correction factors were experimentally determined. Measurements of absorbed dose with the PTW 31022, in conditions different from reference were successfully compared to measurements with a secondary standard ionization chamber. The implementation of an End-to-End test for delivery of image-targeted small field plans resulted in differences smaller than 3% between measured and treatment planning calculated doses. The investigation of the properties and response of a PTW 31022 small volume ionization chamber in medium energy x-rays and small fields can contribute to improve measurement uncertainties evaluation for reference and relative dosimetry of small fields delivered by preclinical irradiators while maintaining the traceability chain to primary standards

Optimizing dual energy cone beam CT protocols for preclinical imaging and radiation research

Objective: The aim of this work was to investigate whether quantitative dual-energy CT (DECT) imaging is feasible for small animal irradiators with an integrated cone-beam CT (CBCT) system. Methods: The optimal imaging protocols were determined by analyzing different energy combinations and dose levels. The influence of beam hardening effects and the performance of a beam hardening correction (BHC) were investigated. In addition, two systems from different manufacturers were compared in terms of errors in the extracted effective atomic numbers (Z(eff)) and relative electron densities (rho(e)) for phantom inserts with known elemental compositions and relative electron densities. Results: The optimal energy combination was determined to be 50 and 90kVp. For this combination, Z(eff) and r rho(e) can be extracted with a mean error of 0.11 and 0.010, respectively, at a dose level of 60cGy. Conclusion: Quantitative DECT imaging is feasible for small animal irradiators with an integrated CBCT system. To obtain the best results, optimizing the imaging protocols is required. Well-separated X-ray spectra and a sufficient dose level should be used to minimize the error and noise for Z(eff) and rho(e). When no BHC is applied in the image reconstruction, the size of the calibration phantom should match the size of the imaged object to limit the influence of beam hardening effects. No significant differences in Z(eff) and rho(e) errors are observed between the two systems from different manufacturers. Advances in knowledge: This is the first study that investigates quantitative DECT imaging for small animal irradiators with an integrated CBCT system

In vivo dose measurement using TLDs and MOSFET dosimeters for cardiac radiosurgery.

In vivo measurements were made of the dose delivered to animal models in an effort to develop a method for treating cardiac arrhythmia using radiation. This treatment would replace RF energy (currently used to create cardiac scar) with ionizing radiation. In the current study, the pulmonary vein ostia of animal models were irradiated with 6 MV X-rays in order to produce a scar that would block aberrant signals characteristic of atrial fibrillation. The CyberKnife radiosurgery system was used to deliver planned treatments of 20-35 Gy in a single fraction to four animals. The Synchrony system was used to track respiratory motion of the heart, while the contractile motion of the heart was untracked. The dose was measured on the epicardial surface near the right pulmonary vein and on the esophagus using surgically implanted TLD dosimeters, or in the coronary sinus using a MOSFET dosimeter placed using a catheter. The doses measured on the epicardium with TLDs averaged 5% less than predicted for those locations, while doses measured in the coronary sinus with the MOSFET sensor nearest the target averaged 6% less than the predicted dose. The measurements on the esophagus averaged 25% less than predicted. These results provide an indication of the accuracy with which the treatment planning methods accounted for the motion of the target, with its respiratory and cardiac components. This is the first report on the accuracy of CyberKnife dose delivery to cardiac targets

An open environment CT-US fusion for tissue segmentation during interventional guidance.

Therapeutic ultrasound (US) can be noninvasively focused to activate drugs, ablate tumors and deliver drugs beyond the blood brain barrier. However, well-controlled guidance of US therapy requires fusion with a navigational modality, such as magnetic resonance imaging (MRI) or X-ray computed tomography (CT). Here, we developed and validated tissue characterization using a fusion between US and CT. The performance of the CT/US fusion was quantified by the calibration error, target registration error and fiducial registration error. Met-1 tumors in the fat pads of 12 female FVB mice provided a model of developing breast cancer with which to evaluate CT-based tissue segmentation. Hounsfield units (HU) within the tumor and surrounding fat pad were quantified, validated with histology and segmented for parametric analysis (fat: -300 to 0 HU, protein-rich: 1 to 300 HU, and bone: HU>300). Our open source CT/US fusion system differentiated soft tissue, bone and fat with a spatial accuracy of ∼1 mm. Region of interest (ROI) analysis of the tumor and surrounding fat pad using a 1 mm(2) ROI resulted in mean HU of 68±44 within the tumor and -97±52 within the fat pad adjacent to the tumor (p<0.005). The tumor area measured by CT and histology was correlated (r(2) = 0.92), while the area designated as fat decreased with increasing tumor size (r(2) = 0.51). Analysis of CT and histology images of the tumor and surrounding fat pad revealed an average percentage of fat of 65.3% vs. 75.2%, 36.5% vs. 48.4%, and 31.6% vs. 38.5% for tumors <75 mm(3), 75-150 mm(3) and >150 mm(3), respectively. Further, CT mapped bone-soft tissue interfaces near the acoustic beam during real-time imaging. Combined CT/US is a feasible method for guiding interventions by tracking the acoustic focus within a pre-acquired CT image volume and characterizing tissues proximal to and surrounding the acoustic focus

Development and Commissioning of an Independent Peer Review System for a Small Animal Irradiator

Dosimetry for small animal irradiators lacks the standardization of clinical radiotherapy practice, yet plays a central translational role in human trial design. The purpose of this work was to improve the dosimetric accuracy and consistency of animal studies by developing an independent peer review system to verify dose delivery from animal irradiators. This study focused on the development of a mouse phantom and characterization of the thermoluminescent dosimetry system for a commonly used small animal irradiator. First, a mouse model and irradiation stand were designed with the purpose of being used in a mailable audit. Two mouse phantoms were machined from high impact polystyrene; one accommodated three thermoluminescent dosimeters (TLD) and the other an Exradin A1SL 0.053 cc ion chamber (Standard Imaging, Middleton, WI) for cross-comparison with the TLD. An acrylic irradiation stand was constructed to allow users to align the mouse phantom to the irradiator’s isocenter. Second, the mouse system was commissioned in a small animal irradiator using a 225 kVp beam. A pseudo tissue-air ratio was determined using the ion chamber mouse phantom. The dose rate was determined using the TG-61 “in-air” method, along with the measured half-value layer of the beam. The response of the TLD in the mouse phantom was characterized under identical irradiation conditions. Lastly, the commissioned mouse system was mailed to two institutions to verify feasibility of the service. We designed a robust, user-friendly mouse phantom and foldable irradiation stand, ideal for a mail audit service. The system was commissioned at 225 kVp in a small animal irradiator. The energy correction factor for TLD in the mouse phantom was 0.792 (SD=0.006) relative to 60Co. This factor can be applied to validate dose delivered in this model of animal irradiator. The feasibility of the independent peer review system was demonstrated by verifying beam output and small animal dosimetry for two institutions. We established and commissioned a methodology for independent peer review of mouse dosimetry for a commonly used animal irradiator. This methodology can be used to characterize other commercially available orthovoltage irradiators

Development of a small animal conformal irradiator with dual energy x-ray computed tomography imaging for kilovoltage dosimetry

External beam radiotherapy has become technically sophisticated with image guided radiation therapy (IGRT) and intensity modulated radiation therapy (IMRT). These technologies allow for precise delivery of radiation to geometric targets in cancer patients. However, many questions remain on how to best define targets based on biological information, such as functional imaging, and how to combine radiation with other cancer therapies. To help answer these questions, small animal preclinical studies are needed to generate data to inform clinical trials. However, the precise radiation delivery capabilities of IGRT and IMRT have not been available in the preclinical labs. To enable translational experiments and to address the lack of preclinical radiotherapy technology, a commercial micro-CT was first developed into an image-guided conformal radiotherapy system in this thesis. Computerized asymmetric jaws were constructed, implemented and characterized for the system. A Monte Carlo dose calculation package was successfully configured for the system and verified with film measurements. Respiratory gated imaging and radiotherapy was demonstrated with a phantom and in animals. Secondly, accurate radiation dosimetry reduces uncertainties in preclinical experiments. To achieve accurate dose calculations in the kilovoltage x-ray range where photoelectric effects and Compton scattering dominate, knowledge of material composition and density is needed. Dual energy micro-CT was optimized (including choice of x-ray beam peak voltages, filtrations, and duration) and evaluated for the purpose of characterizing materials. Dual energy CT techniques developed for clinical scanners were adapted and examined for micro-CT. A set of micro-CT phantoms consisting of 11 plastic materials and solutions that spanned a relevant range of compositions was designed and constructed. Initial experiments found beam-hardening image artefacts limited accurate measurements. By switching to a more sensitive detector, x-ray spectra with additional beam filtration were possible and resulted in reduced beam-hardening effects. This improved dual energy micro-CT measurement accuracy of material composition and density. In conclusion, a small animal image-guided conformal radiotherapy system was developed and commissioned for preclinical studies. Dual energy micro-CT was demonstrated as a method to characterize materials to improve kilovoltage dose calculation. This integrated micro-CT based small animal image-guided radiation platform has enabled numerous pre-clinical studies

Quantitative Bioluminescence Tomography-guided System for Conformal Irradiation In Vivo

Although cone-beam CT (CBCT) has been used to guide irradiation for pre-clinical radiotherapy(RT) research, it is limited to localize soft tissue target especially in a low imaging contrast environment. Knowledge of target shape is a fundamental need for RT. Without such information to guide radiation, normal tissue can be irradiated unnecessarily, leading to experimental uncertainties. Recognition of this need led us to develop quantitative bioluminescence tomography (QBLT), which provides strong imaging contrast to localize optical targets. We demonstrated its capability of guiding conformal RT using an orthotopic bioluminescent glioblastoma (GBM) model. With multi-projection and multi-spectral bioluminescence imaging and a novel spectral derivative method, our QBLT system is able to reconstruct GBM with localization accuracy <1mm. An optimal threshold was determined to delineate QBLT reconstructed gross target volume (GTV_{QBLT}), which provides the best overlap between the GTV_{QBLT} and CBCT contrast labeled GBM (GTV), used as the ground truth for the GBM volume. To account for the uncertainty of QBLT in target localization and volume delineation, we also innovated a margin design; a 0.5mm margin was determined and added to GTV_{QBLT} to form a planning target volume (PTV_{QBLT}), which largely improved tumor coverage from 75% (0mm margin) to 98% and the corresponding variation (n=10) of the tumor coverage was significantly reduced. Moreover, with prescribed dose 5Gy covering 95% of PTV_{QBLT}, QBLT-guided 7-field conformal RT can irradiate 99.4 \pm 1.0% of GTV vs. 65.5 \pm 18.5% with conventional single field irradiation (n=10). Our QBLT-guided system provides a unique opportunity for researchers to guide irradiation for soft tissue targets and increase rigorous and reproducibility of scientific discovery

Preliminary study for small animal preclinical hadrontherapy facility

Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and gamma index test. This work represents the first step towards the realization of a preclinical hadrontherapy facility at INFN-LNS in Catania for the future in vivo studies

Dosimetry and characterization of a 25‐MeV proton beam line for preclinical radiobiology research

International audienc