Development and Validation of Precision in Small Animal Radiotherapy Dose Monitoring
Commercial x-ray irradiator units for small animal irradiation in preliminary cancer studies have become common in radiobiology research. As institutions and researchers acquire new equipment that is simpler to use, x-ray units are typically operated by users without supervision and physics support following initial set-up and training by manufacturers. However, experiments can have widely varying methods of set-up, calibration, and dosimetry. This has led to a documented lack of reproducibility in a variety of small animal studies. A primary contributing factor in this is the lack of standardization of dose delivery in small animals. It has been noted that in some cases the extreme steepness in radiobiology response curves can lead to a change in biological response from 5% to 90% levels with a variance in dose of 10%. Large scale studies that compare dose deliveries at several sites aim to describe a clear picture of the role of inaccurate dosimetry in the documented lack of reproducibility in preclinical studies. Small animal dosimetry is typically simplified into a single look-up table tabulated by device manufacturers or institutional physics groups.
Thermoluminescent dosimeters (TLDs), specifically TLD-100 LiF chips, are generally accepted as the gold standard in kV x-ray dosimetry for small animal studies and these types of large scale projects. However, it is equally well known that these dosimeters require specific calibrations to convert light output to dose. Many comparison studies use half value layer (HVL) measurements to match TLD calibration curves to dose measurements. The dissertation will determine the appropriateness of the use of HVL as a normalizing factor for polychromatic x-ray beams.
In addition to current dosimeter technology, our laboratory developed a novel dosimeter (Nano-FOD) that uses the combination of an organic scintillator pellet and a fiber optic technology to measure dose in real time. The scintillator pellet is composed of Europium-doped yttrium oxide which was demonstrated to have improved stimulated light production in nano-particle form vs. its bulk form, so the material was adapted for our application. To expand to new applications, such as organ-specific in vivo dosimetry for small animals, several physics characteristics have been investigated to inform us of the detector’s expected behavior.
Since TLDs are known to have slight differences in response based on batch and manufacturer date, three TLD batches from our institution that had been routinely used in kV x-ray applications were acquired. Batches were purchased between 2003 and 2011. Each batch was exposed at 5 different kVp values: 135, 150, 200, 250 and 320. At each kVp, the HVLs with matching filtration (2.5 mm Al + 0.1 mm Cu) as well as the necessary filtration to match the HVL at varying kVp values within ±5% was measured. The TLDs were exposed to these beams with matching beam filtrations as well as HVL-matched beams and measured calibration curves in each beam. A linear least-square fit was applied to each calibration curve and all R2 values were greater than 0.97. There was no correlation found between HVL and calibration slope in any of the three batches. With this information, it was determined that calibration curves from HVL matching in broad spectrum beams, such as those used in small animal irradiators, can lead to dose discrepancy of up to 300% at a true dose of 200 cGy. There was less variation between doses at lower energies, such as 135 and 150 kVp. In higher energy beams, there is a larger contribution of photons at characteristic energies. To minimize dose errors, the results of this study lead us to conclude that it is necessary to match both HVL and kVp to achieve an accurate dose calibration curve for TLD-100 chips.
Our institution dosimetry protocol calls for both HVL and kVp matching inherently since calibration and exposure are usually taken in identical beams. To confirm the accuracy of our current methodologies, our x-ray irradiator and filters were recreated in the FLUKA advanced interface (flair). By modeling one of our small animal plexiglass phantoms, dose deposited in TLD dosimeters placed centrally in the phantom was calculated. These doses were compared to measured dose from TLDs and the nano-FOD. Doses agreed to within 1% between Monte Carlo and nano-FOD.
The nano-FOD has current applications in high dose rate (HDR) brachytherapy, micro beam radiation therapy and x-ray dosimetry. Previous studies determined the angular dependence, lifetime radiation effects and linearity of the dosimetry. In this dissertation, data was compiled on temperature dependence and the detector energy response in orthovoltage and megavolt (MV) x-rays. At temperatures between 5 and 46 C, the detector response fell within ±5% of the mean value. An appropriate, distance-based calibration methodology for MV x-rays that address the energy dependence of our detector was determined. These characteristics allowed us to explore other applications of the nano-FOD technology.
A clinical trial in external beam radiation therapy (EBRT) was designed to test the feasibility of using our real-time nano-particle fiber optic detector (nano-FOD) in clinical EBRT treatments. Prior to patient accrual, the detector system was enhanced with improved Cerenkov subtraction via a dual fiber system to complete preliminary calibration. To calibrate our detector, a depth-dependent calibration method using beam data tables for comparison was developed. In phantom studies, overall dose agreement to fell within 5% using this calibration curve.
In patient studies, the nano-FOD was used to measure skin dose during various types of EBRT treatments including intensity modulated radiation therapy (IMRT) and volumetric arc modulated radiation therapy (VMAT). Accrued patients were being treated for a variety of malignancies in a number of areas on the chest and lower abdomen/pelvis. All nano-FOD measurements were compared to calculated values from the clinical treatment planning system (TPS). To date, a total of 15 patients have been accrued for grand total of 56 measurements. Overall percent difference was calculated to be around 10%. In addition, the effects of bolus were investigated in this study. Bolus is used to boost skin dose and in patients were bolus was used improved accuracy to within 6% was observed. The nano-FOD is concluded to provide a viable option for skin dose monitoring in EBRT and our calibration methodology is effective in this application.
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