Yiran Zheng

Phase II Trial of Radiosurgery to Magnetic Resonance Spectroscopy-Defined High-Risk Tumor Volumes in Patients With Glioblastoma Multiforme

PURPOSE To determine the efficacy of a Gamma Knife stereotactic radiosurgery (SRS) boost to areas of high risk determined by magnetic resonance spectroscopy (MRS) functional imaging in addition to standard radiotherapy for patients with glioblastoma (GBM). METHODS AND MATERIALS Thirty-five patients in this prospective Phase II trial underwent surgical resection or biopsy for a GBM followed by SRS directed toward areas of MRS-determined high biological activity within 2 cm of the postoperative enhancing surgical bed. The MRS regions were determined by identifying those voxels within the postoperative T2 magnetic resonance imaging volume that contained an elevated choline/N-acetylaspartate ratio in excess of 2:1. These voxels were marked, digitally fused with the SRS planning magnetic resonance image, targeted with an 8-mm isocenter per voxel, and treated using Radiation Therapy Oncology Group SRS dose guidelines. All patients then received conformal radiotherapy to a total dose of 60 Gy in 2-Gy daily fractions. The primary endpoint was overall survival. RESULTS The median survival for the entire cohort was 15.8 months. With 75% of recursive partitioning analysis (RPA) Class 3 patients still alive 18 months after treatment, the median survival for RPA Class 3 has not yet been reached. The median survivals for RPA Class 4, 5, and 6 patients were 18.7, 12.5, and 3.9 months, respectively, compared with Radiation Therapy Oncology Group radiotherapy-alone historical control survivals of 11.1, 8.9, and 4.6 months. For the 16 of 35 patients who received concurrent temozolomide in addition to protocol radiotherapeutic treatment, the median survival was 20.8 months, compared with European Organization for Research and Treatment of Cancer historical controls of 14.6 months using radiotherapy and temozolomide. Grade 3/4 toxicities possibly attributable to treatment were 11%. CONCLUSIONS This represents the first prospective trial using selective MRS-targeted functional SRS combined with radiotherapy for patients with GBM. This treatment is feasible, with acceptable toxicity and patient survivals higher than in historical controls. This study can form the basis for a multicenter, randomized trial.

Investigation of Nonuniform Dose Voxel Geometry in Monte Carlo Calculations

The purpose of this work is to investigate the efficacy of using multi-resolution nonuniform dose voxel geometry in Monte Carlo (MC) simulations. An in-house MC code based on the dose planning method MC code was developed in C++ to accommodate the nonuniform dose voxel geometry package since general purpose MC codes use their own coupled geometry packages. We devised the package in a manner that the entire calculation volume was first divided into a coarse mesh and then the coarse mesh was subdivided into nonuniform voxels with variable voxel sizes based on density difference. We name this approach as multi-resolution subdivision (MRS). It generates larger voxels in small density gradient regions and smaller voxels in large density gradient regions. To take into account the large dose gradients due to the beam penumbra, the nonuniform voxels can be further split using ray tracing starting from the beam edges. The accuracy of the implementation of the algorithm was verified by comparing with the data published by Rogers and Mohan. The discrepancy was found to be 1% to 2%, with a maximum of 3% at the interfaces. Two clinical cases were used to investigate the efficacy of nonuniform voxel geometry in the MC code. Applying our MRS approach, we started with the initial voxel size of 5 × 5 × 3 mm3, which was further divided into smaller voxels. The smallest voxel size was 1.25 × 1.25 × 3 mm3. We found that the simulation time per history for the nonuniform voxels is about 30% to 40% faster than the uniform fine voxels (1.25 × 1.25 × 3 mm3) while maintaining similar accuracy.

An Automatic Method for PET Target Segmentation Using a Lookup Table Based on Volume and Concentration Ratio

Accurate evaluation of functionally significant target volumes in combination with anatomic imaging is of primary importance for effective radiation therapy treatment planning. In this study, a method for rapid and accurate PET image segmentation and volumetrics based on phantom measurements and independent of scanner calibration was developed. A series of spheres ranging in volume from 0.5 mL to 95 mL were imaged in an anthropomorphic phantom of human thorax using two commercial PET and CT/PET scanners. The target to background radioactivity concentration ratio ranged from 3:1 to 12:1 in 11 separate phantom scanning experiments. The results confirmed that optimal segmentation thresholding depends on target volume and radioactivity concentration ratio. This information can be derived from a generalized pre-determined “lookup table” of volume and contrast dependent threshold values instead of using fitted curves derived from machine specific information. A three-step method based on the PET image intensity information alone was used to delineate volumes of interest. First, a mean intensity segmentation method was used to generate an initial estimate of target volume, and the radioactivity concentration ratio was computed by a family of recovery coefficient curves to compensate for the partial volume effect. Next, the appropriate threshold value was obtained from a phantom-generated threshold lookup table. Lastly, a threshold level set method was performed on the threshold value to further refine the target contour by reducing the limitation of global thresholding. The segmentation results were consistent for spheres greater than 2.5 mL which yielded volume average uncertainty of 11.2% in phantom studies. The results of segmented volumes were comparable to those determined by contrast-oriented method and iterative threshold method (ITM). In addition, the new volume segmentation method was applied clinically to ten patients undergoing PET/CT volume analysis for radiation therapy treatment planning of solitary lung metastases. For these patients, the average PET segmented volumes were within 8.0% of the CT volumes and were highly dependent on the extension of functionally inactive tumor volume. In summary, the current method does not require fitted threshold curves or a priori knowledge of the CT/MRI target volume. This threshold method can be universally applied to radiation therapy treatment planning with comparable accuracy, and may be useful in the rapid identification and assessment of plans containing multiple targets.

Quantitative Analysis Tools and Digital Phantoms for Deformable Image Registration Quality Assurance

This article proposes quantitative analysis tools and digital phantoms to quantify intrinsic errors of deformable image registration (DIR) systems and establish quality assurance (QA) procedures for clinical use of DIR systems utilizing local and global error analysis methods with clinically realistic digital image phantoms. Landmark-based image registration verifications are suitable only for images with significant feature points. To address this shortfall, we adapted a deformation vector field (DVF) comparison approach with new analysis techniques to quantify the results. Digital image phantoms are derived from data sets of actual patient images (a reference image set, R, a test image set, T). Image sets from the same patient taken at different times are registered with deformable methods producing a reference DVFref. Applying DVFref to the original reference image deforms T into a new image R′. The data set, R′, T, and DVFref, is from a realistic truth set and therefore can be used to analyze any DIR system and expose intrinsic errors by comparing DVFref and DVFtest. For quantitative error analysis, calculating and delineating differences between DVFs, 2 methods were used, (1) a local error analysis tool that displays deformation error magnitudes with color mapping on each image slice and (2) a global error analysis tool that calculates a deformation error histogram, which describes a cumulative probability function of errors for each anatomical structure. Three digital image phantoms were generated from three patients with a head and neck, a lung and a liver cancer. The DIR QA was evaluated using the case with head and neck.

Development and Validation of a Small Animal Immobilizer and Positioning System for the Study of Delivery of Intracranial and Extracranial Radiotherapy Using the Gamma Knife System

The purpose of this research is to establish a process of irradiating mice using the Gamma Knife as a versatile system for small animal irradiation and to validate accurate intracranial and extracranial dose delivery using this system. A stereotactic immobilization device was developed for small animals for the Gamma Knife head frame allowing for isocentric dose delivery. Intercranial positional reproducibility of a reference point from a primary reference animal was verified on an additional mouse. Extracranial positional reproducibility of the mouse aorta was verified using 3 mice. Accurate dose delivery was validated using film and thermoluminescent dosimeter measurements with a solid water phantom. Gamma Knife plans were developed to irradiate intracranial and extracranial targets. Mice were irradiated validating successful targeted radiation dose delivery. Intramouse positional variability of the right mandible reference point across 10 micro-computed tomography scans was 0.65 ± 0.48 mm. Intermouse positional reproducibility across 2 mice at the same reference point was 0.76 ± 0.46 mm. The accuracy of dose delivery was 0.67 ± 0.29 mm and 1.01 ± 0.43 mm in the coronal and sagittal planes, respectively. The planned dose delivered to a mouse phantom was 2 Gy at the 50% isodose with a measured thermoluminescent dosimeter dose of 2.9 ± 0.3 Gy. The phosphorylated form of member X of histone family H2A (γH2AX) staining of irradiated mouse brain and mouse aorta demonstrated adjacent tissue sparing. In conclusion, our system for preclinical studies of small animal irradiation using the Gamma Knife is able to accurately deliver intracranial and extracranial targeted focal radiation allowing for preclinical experiments studying focal radiation.

Experimental Validation of Monte Carlo Simulations Based on a Virtual Source Model for TomoTherapy in a RANDO Phantom

A virtual source model for Monte Carlo simulations of helical TomoTherapy has been developed previously by the authors. The purpose of this work is to perform experiments in an anthropomorphic (RANDO) phantom with the same order of complexity as in clinical treatments to validate the virtual source model to be used for quality assurance secondary check on TomoTherapy patient planning dose. Helical TomoTherapy involves complex delivery pattern with irregular beam apertures and couch movement during irradiation. Monte Carlo simulation, as the most accurate dose algorithm, is desirable in radiation dosimetry. Current Monte Carlo simulations for helical TomoTherapy adopt the full Monte Carlo model, which includes detailed modeling of individual machine component, and thus, large phase space files are required at different scoring planes. As an alternative approach, we developed a virtual source model without using the large phase space files for the patient dose calculations previously. In this work, we apply the simulation system to recompute the patient doses, which were generated by the treatment planning system in an anthropomorphic phantom to mimic the real patient treatments. We performed thermoluminescence dosimeter point dose and film measurements to compare with Monte Carlo results. Thermoluminescence dosimeter measurements show that the relative difference in both Monte Carlo and treatment planning system is within 3%, with the largest difference less than 5% for both the test plans. The film measurements demonstrated 85.7% and 98.4% passing rate using the 3 mm/3% acceptance criterion for the head and neck and lung cases, respectively. Over 95% passing rate is achieved if 4 mm/4% criterion is applied. For the dose–volume histograms, very good agreement is obtained between the Monte Carlo and treatment planning system method for both cases. The experimental results demonstrate that the virtual source model Monte Carlo system can be a viable option for the accurate dose calculation of helical TomoTherapy.

SU-F-J-121: Dosimetric Evaluation of Active Breathing Coordinator-Response Gating System Linked to Linear Accelerator in Volumetric Modulated Arc Therapy

PURPOSE To reduce internal target volume (ITV), respiratory management is a must in imaging and treatment for lung, liver, and breast cancers. We investigated the dosimetric accuracy of VMAT treatment delivery with a Response™ gating system linked to linear accelerator. METHODS The Response™ gating module designed to directly control radiation beam by breath-holding with a ABC system (Elekta AB, Stockholm, Sweden) was tested for VMAT treatments. Seven VMAT plans including three conventional and four stereotactic body radiotherapy (SBRT) cases were evaluated. Each plan was composed of two or four arcs of 6MV radiation beam with prescribed dose ranged from 1.8 to 9 Gy per fraction. Each plan was delivered continuously without gating and delivered with multiple interruptions by the ResponseTM gating module with a 20 or 30 second breath-holding period. MapCheck2 and Gafchromic EBT3 films sandwiched in MapPHAN were used to measure the delivered dose with and without gating. Films were scanned on a flatbed color scanner, and red channel was extracted for film dosimetry. Gamma analysis was performed to analyze the dosimetrical accuracy of the radiation delivery with gating. RESULTS The measured doses with gating remarkably agree with the planned dose distributions in the results of gamma index passing rate (within 20% isodose; >98% for 3%/3mm and >92% for 2%/2mm in MapCheck2, and >91% for 3%/3mm criteria in EBT3 film except one case which was for large target and highly modulated). No significant difference (student t-test: p-value < 0.0005) was shown between the doses delivered with and without gating. There was no indication of radiation gap or overlapping during deliver interruption in film dosimetry. CONCLUSION The Response™ gating system can be safely used during VMAT treatment. The accurate performance of the gating system linked to ABC can contribute to ITV reduction for SBRT using VMAT.

SU‐F‐T‐599: Volume‐Independent Conformity Index for Stereotactic Brain Tumors

PURPOSE To develop a volume-independent metric called the Gaussian Weighted Conformity Index (GWCI) for assessing conformality of stereotactic radiosurgery plans for small brain tumors. METHODS The GWCI calculates bi-directional distance by searching for corresponding points between the prescription isodose line and tumor contour, assigning different scoring weights to tumor coverage with a score of 1.0 being ideal assuming an idealized Gaussian distribution of dose around the tumor. (Figure 1, left) The GWCI penalizes tumor under-dosing three times more heavily than the prescription isodose falling outside the tumor. (Figure 1, middle) A user interface was created to calculate GWCI from images and RT structures (Figure 1, right). Patients receiving radiosurgery were randomly selected and images and RT structures were exported to MiM (MiMVista, Cleveland, OH) to calculate traditional conformality indices (CI). CIs were calculated for 39 tumors from patients receiving Gamma Knife radiosurgery (GKSRS) and from 10 tumors from patients receiving linac-based stereotactic radiosurgery (L-SRS). GWCIs were calculated for 14 tumors from patients receiving GKSRS and for 10 tumors from patients receiving L-SRS. RESULTS Conformality indices calculated from 39 GKSRS plans and 10 L-SRS plans are plotted in Figure 2 demonstrating that as tumour volume gets smaller, conformality index increases. GWCIs for 14 tumors were plotted against CIs and linear regression was performed (Figure 3) yielding GWCI = -.077*CI + 1.044 (R2 = .52). Utilizing this regression, the corresponding GWCI to a traditionally-acceptable CI of 1.5 was calculated as 0.927. CONCLUSION Limitations of current conformity metrics become apparent when applied to radiosurgery treatment plans. A GWCI tool was successfully developed which can be used to accurately score the quality of an individual treatment plan while eliminating small volume effects. A GWCI of 0.93 may be used as a volume-independent cutoff for plan conformality.

SU‐C‐211‐02: A Fast Monte Carlo Dose Algorithm for Radiotherapy Treatment Planning Based on Hybrid Adaptive Meshes

Purpose:Monte Carlo methods are considered to be the most accurate dose algorithm for radiotherapy. Variance reduction techniques such as history repetition, Russian roulette and photon splitting are employed to improve the calculation efficiency. Generally, it takes a large portion of the simulation time for two inevitable tasks, that is, voxel‐to‐voxel boundary crossing and energy deposition. The purpose of this work is to investigate the potential for additional speedup achieved by reducing the number of boundary crossing based on hybrid adaptive meshes. Method and Materials: A Monte Carlo code was developed to simulate the coupled photon‐electron transport for radiation therapy using a hybrid adaptive mesh. Photontransport was modeled in an analog fashion. The Compton scattering, photoelectric ionization and pair production were considered. For electron transport, a condensed history method was used in which the hard interactions such as inelastic collision and bremsstrahlung were simulated explicitly. The formulation by Kawrakow and Bielajew was used for electron multiple scattering. Photons and electrons were tracked on a hybrid adaptive mesh, which was generated from an initial uniform coarse mesh. The coarse uniform mesh was divided voxel‐by‐voxel into an unstructured finer mesh depending on the splitting criterion such as the density gradient. The resulting adaptive mesh contains larger voxels in smooth density areas and smaller voxels used for density regions with large gradient to retain the accuracy. Results: The speed up observed by varying the splitting level is proportional to N1/3, where N is the total number of the voxels. For the test cases, 30% of the calculation time was saved by using the adaptive meshes starting with 10mm spacing and reduced to 1.25mm voxels for high gradient regions comparing with the 1.25mm uniform meshes. Conclusions: The Monte Carlo simulations can be further accelerated based on these hybrid adaptive meshes.

SU‐E‐T‐258: Comparison of Dosimetric Characteristics Between Elekta Synergy Linear Accelerators with MLCi and Beam Modulator Collimator Heads

Purpose: Two Elekta Synergy linacs were installed; one with the Elekta MLCi2 collimator and the other was installed with the Elekta Beam Modulatorcollimator. The concept of beam matching nominally includes the capability for patients to be switched between machines during the course of treatment with nominal replanning. However with the two different MLC designs and treatment head configurations, a precise beam match is not possible and lies outside the scope of this investigation. Nevertheless, we set out to characterize the physical radiation machines parameters between the machines and highlight any significant deviations. Methods: The acceptance scanning was performed with a Blue Phantom2 from IBA Dosimetry. In conjunction with the standard Elekta acceptance testing criteria, dmax values, depth dose curves and beam profiles were acquired for all energies on both machines. The Beam ModulatorMLC has a maximum field size of 16×21 cm so the 8×8cm and 16×16cm field sizes were selected for flatness and symmetry measurements. This machine incorporates 4mm leaves and therefore could not produce the standard 10 × 10 cm field of the MCLi2 with its 10mm leaves, hence a 10.4 × 9.6 cm field was used. The resulting data was normalized, smoothed and central‐axis corrected. Results: Corresponding points on the percent depth dose curve differed by up to 0.5% beyond dmax. The dmax values for all energies were within 1 mm of each other. The largest deviation in flatness and symmetry was 1.1% and 0.7% respectively. The maximum discrepancy between the penumbra widths of the profiles was 1.1 mm. Conclusions: The physical characteristics of the photon beams were found to be surprisingly similar for the chosen reference fields even though the treatment heads and MLC design were markedly different. These results were not anticipated by installation engineers, site physicists or the manufacturers specifications.