A Hope

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.

4D‐CT motion estimation using deformable image registration and 5D respiratory motion modeling

Four-dimensional computed tomography (4D-CT) imaging technology has been developed for radiation therapy to provide tumor and organ images at the different breathing phases. In this work, a procedure is proposed for estimating and modeling the respiratory motion field from acquired 4D-CT imaging data and predicting tissue motion at the different breathing phases. The 4D-CT image data consist of series of multislice CT volume segments acquired in ciné mode. A modified optical flow deformable image registration algorithm is used to compute the image motion from the CT segments to a common full volume 3D-CT reference. This reference volume is reconstructed using the acquired 4D-CT data at the end-of-exhalation phase. The segments are optimally aligned to the reference volume according to a proposed a priori alignment procedure. The registration is applied using a multigrid approach and a feature-preserving image downsampling maxfilter to achieve better computational speed and higher registration accuracy. The registration accuracy is about 1.1 +/- 0.8 mm for the lung region according to our verification using manually selected landmarks and artificially deformed CT volumes. The estimated motion fields are fitted to two 5D (spatial 3D+tidal volume+airflow rate) motion models: forward model and inverse model. The forward model predicts tissue movements and the inverse model predicts CT density changes as a function of tidal volume and airflow rate. A leave-one-out procedure is used to validate these motion models. The estimated modeling prediction errors are about 0.3 mm for the forward model and 0.4 mm for the inverse model.

Dose response explorer: an integrated open-source tool for exploring and modelling radiotherapy dose–volume outcome relationships

Radiotherapy treatment outcome models are a complicated function of treatment, clinical and biological factors. Our objective is to provide clinicians and scientists with an accurate, flexible and user-friendly software tool to explore radiotherapy outcomes data and build statistical tumour control or normal tissue complications models. The software tool, called the dose response explorer system (DREES), is based on Matlab, and uses a named-field structure array data type. DREES/Matlab in combination with another open-source tool (CERR) provides an environment for analysing treatment outcomes. DREES provides many radiotherapy outcome modelling features, including (1) fitting of analytical normal tissue complication probability (NTCP) and tumour control probability (TCP) models, (2) combined modelling of multiple dose-volume variables (e.g., mean dose, max dose, etc) and clinical factors (age, gender, stage, etc) using multi-term regression modelling, (3) manual or automated selection of logistic or actuarial model variables using bootstrap statistical resampling, (4) estimation of uncertainty in model parameters, (5) performance assessment of univariate and multivariate analyses using Spearmans rank correlation and chi-square statistics, boxplots, nomograms, Kaplan-Meier survival plots, and receiver operating characteristics curves, and (6) graphical capabilities to visualize NTCP or TCP prediction versus selected variable models using various plots. DREES provides clinical researchers with a tool customized for radiotherapy outcome modelling. DREES is freely distributed. We expect to continue developing DREES based on user feedback.

Targeted Inhibition of Cyclic AMP Phosphodiesterase-4 Promotes Brain Tumor Regression

Purpose: As favorable outcomes from malignant brain tumors remain limited by poor survival and treatment-related toxicity, novel approaches to cure are essential. Previously, we identified the cyclic AMP phosphodiesterase-4 (PDE4) inhibitor Rolipram as a potent antitumor agent. Here, we investigate the role of PDE4 in brain tumors and examine the utility of PDE4 as a therapeutic target. Experimental Design: Immunohistochemistry was used to evaluate the expression pattern of a subfamily of PDE4, PDE4A, in multiple brain tumor types. To evaluate the effect of PDE4A on growth, a brain-specific isoform, PDE4A1 was overexpressed in xenografts of Daoy medulloblastoma and U87 glioblastoma cells. To determine therapeutic potential of PDE4 inhibition, Rolipram, temozolomide, and radiation were tested alone and in combination on mice bearing intracranial U87 xenografts. Results: We found that PDE4A is expressed in medulloblastoma, glioblastoma, oligodendroglioma, ependymoma, and meningioma. Moreover, when PDE4A1 was overexpressed in Daoy medulloblastoma and U87 glioblastoma cells, in vivo doubling times were significantly shorter for PDE4A1-overexpressing xenografts compared with controls. In long-term survival and bioluminescence studies, Rolipram in combination with first-line therapy for malignant gliomas (temozolomide and conformal radiation therapy) enhanced the survival of mice bearing intracranial xenografts of U87 glioblastoma cells. Bioluminescence imaging indicated that whereas temozolomide and radiation therapy arrested intracranial tumor growth, the addition of Rolipram to this regimen resulted in tumor regression. Conclusions: This study shows that PDE4 is widely expressed in brain tumors and promotes their growth and that inhibition with Rolipram overcomes tumor resistance and mediates tumor regression.

Progress toward a microradiation therapy small animal conformal irradiator

Microradiation therapy (microRT) systems are being designed to provide conformal radiation therapy to small animals enabling quantitative radiation response evaluation. We used a Monte Carlo approach to estimate the radiation dose distributions from proposed blueprints and developed a beam model to aid in the microRT system design process. This process was applied to a prototype irradiator that uses a small (3 mm long and 3 mm in diameter), cylindrical, high-activity 192Ir source delivering the radiation beam using custom-fabricated tungsten collimators. The BEAMnrc Monte Carlo code was used to simulate dose distributions from these prototype collimators. Simulations were performed at three source-to-surface distances (50, 60, and 70 mm), and with five circular field sizes (5, 7.5, 10, 12.5, and 15 mm). A dose to a 50 X 50 X 50 mm3 water phantom with 1 X 1 X 1 mm3 voxel spacing was computed. A multiparameter dose calculation algorithm was developed to efficiently and accurately calculate doses for treatment planning exercises. The parametrization was selected so that the parameters varied smoothly as a function of depth, source-to-surface distance, and field size, allowing interpolation for geometries that were not simulated using the Monte Carlo simulation. Direct comparison of the model with the Monte Carlo simulations showed that the variations were within 5% error for field sizes larger than 10 mm, and up to 10% for smaller field sizes.

A prospective study of differences in duodenum compared to remaining small bowel motion between radiation treatments: Implications for radiation dose escalation in carcinoma of the pancreas

PurposeAs a foundation for a dose escalation trial, we sought to characterize duodenal and non-duodenal small bowel organ motion between fractions of pancreatic radiation therapy.Patients and methodsNine patients (4 women, 5 men) undergoing radiation therapy were enrolled in this prospective study. The patients had up to four weekly CT scans performed during their course of radiation therapy. Pancreas, duodenum and non-duodenal small bowel were then contoured for each CT scan. On the initial scan, a four-field plan was generated to fully cover the pancreas. This plan was registered to each subsequent CT scan. Dose-volume histogram (DVH) analyses were performed for the duodenum, non-duodenal small bowel, large bowel, and pancreas.ResultsWith significant individual variation, the volume of duodenum receiving at least 80% of the prescribed dose was consistently greater than the remaining small bowel. In the patient with the largest inter-fraction variation, the fractional volume of non-duodenal small bowel irradiated to at least the 80% isodose line ranged from 1% to 20%. In the patient with the largest inter-fraction variation, the fractional volume of duodenum irradiated to at least the 80% isodose line ranged from 30% to 100%.ConclusionThe volume of small bowel irradiated during four-field pancreatic radiation therapy changes substantially between fractions. This suggests dose escalation may be possible. However, dose limits to the duodenum should be stricter than for other segments of small bowel.

Retrospective Monte Carlo dose calculations with limited beam weight information

An important unresolved issue in outcomes analysis for lung complications is the effect of poor or completely lacking heterogeneity corrections in previously archived treatment plans. To estimate this effect, we developed a novel method based on Monte Carlo (MC) dose calculations which can be applied retrospectively to RTOG/AAPM-style archived treatment plans (ATP). We applied this method to 218 archived nonsmall cell lung cancer lung treatment plans that were originally calculated either without heterogeneity corrections or with primitive corrections. To retrospectively specify beam weights and wedges, beams were broken into Monte Carlo-generated beamlets, simulated using the VMC++ code, and mathematical optimization was used to match the archived water-based dose distributions. The derived beam weights (and any wedge effects) were then applied to Monte Carlo beamlets regenerated based on the patient computed tomography densities. Validation of the process was performed against five comparable lung treatment plans generated using a commercial convolution/superposition implementation. For the application here (normal lung, esophagus, and planning target volume dose distributions), the agreement was very good. Resulting MC and convolution/superposition values were similar when dose distributions without heterogeneity corrections or dose distributions with corrections were compared. When applied to the archived plans (218), the average absolute percent difference between water-based MC and water-based ATPs, for doses above 2.5% of the maximum dose was 1.8+/-0.6%. The average absolute percent difference between heterogeneity-corrected MC and water-based ATPs increased to 3.1+/-0.9%. The average absolute percent difference between the MC heterogeneity-corrected and the ATP heterogeneity-corrected dose distributions was 3.8+/-1.6% (available in 132/218 archives). The entire dose-volume-histograms for lung, tumor, and esophagus from the different calculation methods, as well as specific dose metrics, were compared. The average difference in maximum lung dose between water-based ATPs and heterogeneity-corrected MC dose distributions was -1.0+/-2.1 Gy. Potential errors in relying on primitive heterogeneity corrections are most evident from a comparison of maximum lung doses, for which the average MC heterogeneity-corrected values were 5.3+/-2.8 Gy less than the ATP heterogeneity-corrected values. We have demonstrated that recalculation of archived dose distributions, without explicit information about beam weights or wedges, is feasible using beamlet-based optimization methods. The method provides heterogeneity-corrected dose data consistent with convolution-superposition calculations and is one feasible approach for improving dosimetric data for outcomes analyses.

A Novel Murine Model for Localized Radiation Necrosis and its Characterization using Advanced Magnetic Resonance Imaging

PURPOSE To develop a murine model of radiation necrosis using fractionated, subtotal cranial irradiation; and to investigate the imaging signature of radiation-induced tissue damage using advanced magnetic resonance imaging techniques. METHODS AND MATERIALS Twenty-four mice each received 60 Gy of hemispheric (left) irradiation in 10 equal fractions. Magnetic resonance images at 4.7 T were subsequently collected using T1-, T2-, and diffusion sequences at selected time points after irradiation. After imaging, animals were killed and their brains fixed for correlative histologic analysis. RESULTS Contrast-enhanced T1- and T2-weighted magnetic resonance images at months 2, 3, and 4 showed changes consistent with progressive radiation necrosis. Quantitatively, mean diffusivity was significantly higher (mean = 0.86, 1.13, and 1.24 microm(2)/ms at 2, 3, and 4 months, respectively) in radiated brain, compared with contralateral untreated brain tissue (mean = 0.78, 0.82, and 0.83 microm(2)/ms) (p < 0.0001). Histology reflected changes typically seen in radiation necrosis. CONCLUSIONS This murine model of radiation necrosis will facilitate investigation of imaging biomarkers that distinguish between radiation necrosis and tumor recurrence. In addition, this preclinical study supports clinical data suggesting that diffusion-weighted imaging may be helpful in answering this diagnostic question in clinical settings.

TH-C-230A-08: A Prototype Rotational Immobilization System for a Proposed Static-Gantry MicroRT Device with Tomographic Capabilities

Purpose: Proposed small animal irradiation devices are typically isocentric gantry systems. Multi‐axis gantry systems require significant resources to develop and maintain. A static gantry system could provide the functionality of a multi‐axis gantry via subject rotation if subject motion could be minimized. In this study, we evaluated internal organ motion of mice within a prototype immobilization device during rotation. Method and Materials: Mice were anesthetized and immobilized in a prototype device designed to rigidly support animal positioning during rotation along the cranio‐caudal axis. The head and tail of the mouse were allowed to extend beyond the immobilization device as an internal control. Validation of internal and external immobilization was assessed using computed tomographyimaging at multiple rotation angles. CTimages were co‐registered (translated/rotated) using our research treatment planning system (CERR) into a common reference frame. Internal organ motion was assessed qualitatively by examination of internal anatomy in overlaid multiplane CTimages. Quantitative evaluation of organ motion was assessed by delineating organ structures in CERR and comparing relative organ volumes and centers of mass. Results:CTimaging demonstrated minimal exterior contour changes (<1mm) in the immobilized regions during rotation. Un‐immobilized regions demonstrated the expected gravitational positional changes. Internal organs demonstrated sub‐millimeter changes in organ centers of mass (heart and lung) and small (<5 mm3) changes in volume during rotation. These variations were similar to the differences when the same CT was re‐contoured multiple times by the same operator and likely represent intra‐observer contouring variations. Conclusion: A microRT device with a stationary irradiator, collimator, tomographic imaging system, and rotating subject would reduce the overall cost and complexity of the unit. This study demonstrates rotational immobilization of small animals is feasible. This work supported in part by NIH R21 CA108677 and by a grant Varian, Inc.

TH-C-224C-02: MicroRT/microRTP: A Conformal Small Animal Planning and Irradiation System

Purpose: We have developed a novel small animal radiation therapy device (microRT), which integrates multi‐modality imaging,radiation treatment planning, and conformal radiation therapy. In this study, we evaluated the accuracy of the treatment planning and positioning systems of the microRT device. Method and Materials: The microRT system utilizes a clinical 192Ir HDR source collimated via machined tungsten inserts to deliver photon beams at a source to target distances of 1–8cm at four angles (0, 90, 180, and 270). Beams were modeled using Monte Carlo and a parameterized analytic dose engine was created. Radiochromic film (5mm steps) in a solid water phantom was used to evaluate actual delivered doses in multiple planes. Treatment plans using these beams were created by a custom treatment planning system (microRTP) based on imported fiducial‐registered imaging (CT, MR, PET) of animals immobilized in the treatment position. A three‐axis computer‐controlled stage supports and positions animals in the beams according to the microRTP plan. Validation of the positioning system was performed using a phantom and images of phantom and collimator via a kV C‐arm. Results: The analytic dosemodel agreed with the Monte‐Carlo predicted dose within 5% and 10% outside and inside the 1 mm deep build‐up regions, respectively. Film dosimetry agreed with the analytic model within 10% and also demonstrated an effective field diameter of 8mm at 17mm from the source. The 192Ir line source geometry caused a radial anisotropy of up to 12% at 17 mm depth from the source. The positioning accuracy of the animal support hardware was sub‐millimeter. Conclusions: The microRT system provides conformal radiation therapy based on pre‐treatment imaging and planning for small animal models of cancer and tissue injury. This work supported in part by NIH R21 CA108677 and by a grant from Varian, Inc.