K McCall

Dual-component model of respiratory motion based on the periodic autoregressive moving average (periodic ARMA) method

A new approach to the problem of modelling and predicting respiration motion has been implemented. This is a dual-component model, which describes the respiration motion as a non-periodic time series superimposed onto a periodic waveform. A periodic autoregressive moving average algorithm has been used to define a mathematical model of the periodic and non-periodic components of the respiration motion. The periodic components of the motion were found by projecting multiple inhale-exhale cycles onto a common subspace. The component of the respiration signal that is left after removing this periodicity is a partially autocorrelated time series and was modelled as an autoregressive moving average (ARMA) process. The accuracy of the periodic ARMA model with respect to fluctuation in amplitude and variation in length of cycles has been assessed. A respiration phantom was developed to simulate the inter-cycle variations seen in free-breathing and coached respiration patterns. At +/-14% variability in cycle length and maximum amplitude of motion, the prediction errors were 4.8% of the total motion extent for a 0.5 s ahead prediction, and 9.4% at 1.0 s lag. The prediction errors increased to 11.6% at 0.5 s and 21.6% at 1.0 s when the respiration pattern had +/-34% variations in both these parameters. Our results have shown that the accuracy of the periodic ARMA model is more strongly dependent on the variations in cycle length than the amplitude of the respiration cycles.

Comparison of Texture Features Derived from Static and Respiratory-Gated PET Images in Non-Small Cell Lung Cancer

Background PET-based texture features have been used to quantify tumor heterogeneity due to their predictive power in treatment outcome. We investigated the sensitivity of texture features to tumor motion by comparing static (3D) and respiratory-gated (4D) PET imaging. Methods Twenty-six patients (34 lesions) received 3D and 4D [18F]FDG-PET scans before the chemo-radiotherapy. The acquired 4D data were retrospectively binned into five breathing phases to create the 4D image sequence. Texture features, including Maximal correlation coefficient (MCC), Long run low gray (LRLG), Coarseness, Contrast, and Busyness, were computed within the physician-defined tumor volume. The relative difference (δ3D-4D) in each texture between the 3D- and 4D-PET imaging was calculated. Coefficient of variation (CV) was used to determine the variability in the textures between all 4D-PET phases. Correlations between tumor volume, motion amplitude, and δ3D-4D were also assessed. Results 4D-PET increased LRLG ( = 1%–2%, p<0.02), Busyness ( = 7%–19%, p<0.01), and decreased MCC ( = 1%–2%, p<7.5×10−3), Coarseness ( = 5%–10%, p<0.05) and Contrast ( = 4%–6%, p>0.08) compared to 3D-PET. Nearly negligible variability was found between the 4D phase bins with CV<5% for MCC, LRLG, and Coarseness. For Contrast and Busyness, moderate variability was found with CV = 9% and 10%, respectively. No strong correlation was found between the tumor volume and δ3D-4D for the texture features. Motion amplitude had moderate impact on δ for MCC and Busyness and no impact for LRLG, Coarseness, and Contrast. Conclusions Significant differences were found in MCC, LRLG, Coarseness, and Busyness between 3D and 4D PET imaging. The variability between phase bins for MCC, LRLG, and Coarseness was negligible, suggesting that similar quantification can be obtained from all phases. Texture features, blurred out by respiratory motion during 3D-PET acquisition, can be better resolved by 4D-PET imaging. 4D-PET textures may have better prognostic value as they are less susceptible to tumor motion.

On the impact of longitudinal breathing motion randomness for tomotherapy delivery.

The purpose of this study is to explain the unplanned longitudinal dose modulations that appear in helical tomotherapy (HT) dose distributions in the presence of irregular patient breathing. This explanation is developed by the use of longitudinal (1D) simulations of mock and surrogate data and tested with a fully 4D HT delivered plan. The 1D simulations use a typical mock breathing function which allows more flexibility to adjust various parameters. These simplified simulations are then made more realistic by using 100 surrogate waveforms all similarly scaled to produce longitudinal breathing displacements. The results include the observation that, with many waveforms used simultaneously, a voxel-by-voxel probability of a dose error from breathing is found to be proportional to the realistically random breathing amplitude relative to the beam width if the PTV is larger than the beam width and the breathing displacement amplitude. The 4D experimental test confirms that regular breathing will not result in these modulations because of the insensitivity to leaf motion for low-frequency dynamics such as breathing. These modulations mostly result from a varying average of the breathing displacements along the beam edge gradients. Regular breathing has no displacement variation over many breathing cycles. Some low-frequency interference is also possible in real situations. In the absence of more sophisticated motion management, methods that reduce the breathing amplitude or make the breathing very regular are indicated. However, for typical breathing patterns and magnitudes, motion management techniques may not be required with HT because typical breathing occurs mostly between fundamental HT treatment temporal and spatial scales. A movement beyond only discussing margins is encouraged for intensity modulated radiotherapy such that patient and machine motion interference will be minimized and beneficial averaging maximized. These results are found for homogeneous and longitudinal on-axis delivery for unplanned longitudinal dose modulations.

A phantom model demonstration of tomotherapy dose painting delivery, including managed respiratory motion without motion management

The aim of the study was to demonstrate a potential alternative scenario for accurate dose-painting (non-homogeneous planned dose) delivery at 1 cm beam width with helical tomotherapy (HT) in the presence of 1 cm, three-dimensional, intra-fraction respiratory motion, but without any active motion management. A model dose-painting experiment was planned and delivered to the average position (proper phase of a 4DCT scan) with three spherical PTV levels to approximate dose painting to compensate for hypothetical hypoxia in a model lung tumor. Realistic but regular motion was produced with the Washington University 4D Motion Phantom. A small spherical Virtual Water phantom was used to simulate a moving lung tumor inside of the LUNGMAN anthropomorphic chest phantom to simulate realistic heterogeneity uncertainties. A piece of 4 cm Gafchromic EBT film was inserted into the 6 cm diameter sphere. TomoTherapy, Inc., DQA software was used to verify the delivery performed on a TomoTherapy Hi-Art II device. The dose uncertainty in the purposeful absence of motion management and in the absence of large, low frequency drifts (periods greater than the beam width divided by the couch velocity) or randomness in the breathing displacement yields very favorable results. Instead of interference effects, only small blurring is observed because of the averaging of many breathing cycles and beamlets and the avoidance of interference. Dose painting during respiration with helical tomotherapy is feasible in certain situations without motion management. A simple recommendation is to make respiration as regular as possible without low frequency drifting. The blurring is just small enough to suggest that it may be acceptable to deliver without motion management if the motion is equal to the beam width or smaller (at respiration frequencies) when registered to the average position.

PET imaging for the quantification of biologically heterogeneous tumours: measuring the effect of relative position on image-based quantification of dose-painting targets

Quantitative imaging of tumours represents the foundation of customized therapies and adaptive patient care. As such, we have investigated the effect of patient positioning errors on the reproducibility of images of biologically heterogeneous tumours generated by a clinical PET/CT system. A commercial multi-slice PET/CT system was used to acquire 2D and 3D PET images of a phantom containing multiple spheres of known volumes and known radioactivity concentrations and suspended in an aqueous medium. The spheres served as surrogates for sub-tumour regions of biological heterogeneities with dimensions of 5-15 mm. Between image acquisitions, a motorized-arm was used to reposition the spheres in 1 mm intervals along either the radial or the axial direction. Images of the phantom were reconstructed using typical diagnostic reconstruction techniques, and these images were analysed to characterize and model the position-dependent changes in contrast recovery. A simulation study was also conducted to investigate the effect of patient position on the reproducibility of PET imaging of biologically heterogeneous head and neck (HN) tumours. For this simulation study, we calculated the changes in image intensity values that would occur with changes in the relative position of the patients at the time of imaging. PET images of two HN patients were used to simulate an imaging study that incorporated set-up errors that are typical for HN patients. One thousand randomized positioning errors were investigated for each patient. As a result of the phantom study, a position-dependent trend was identified for measurements of contrast recovery of small objects. The peak contrast recovery occurred at radial and axial positions that coincide with the centre of the image voxel. Conversely, the minimum contrast recovery occurred when the object was positioned at the edges of the image voxel. Changing the position of high contrast spheres by one-half the voxel dimension lead to errors in the measurement of contrast recovery values which were larger than 30%. However, the magnitudes of the errors were found to depend on the size of the sphere and method of image reconstruction. The error values from standard OSEM images of the 5 mm diameter sphere were 20-35%, and for the 10 mm diameter sphere were 5-10%. The position-dependent variation of contrast recovery can result in changes in spatial distribution within images of heterogeneous tumours. In experiments simulating random set-up errors during imaging of two HN patients, the expectation value of the correlation was approximately 1.0 for these tumours; however, Pearson correlation coefficient values as low as 0.8 were observed. Moreover, variations within the images can drastically change the delineation of biological target volumes. The errors in target delineation were more prominent in very heterogeneous tumours. As an example, in a pair of images with a correlation of 0.8, there was a 36% change in the volume of the dose-painting target delineated at 50%-of-max-SUV (ROI(50%)). The results of these studies indicate that the contrast recovery and spatial distributions of tracer within PET images are susceptible to changes in the position of the patient/tumour at the time of imaging. As such, random set-up errors in HN patients can result in reduced correlation between subsequent image-studies of the same tumour.

MO‐D‐M100J‐01: Dose Painting With Intensity Modulated Proton Therapy and Intensity Modulated X‐Ray Therapy: A Comparison

Purpose: To compare intensity modulated proton therapy (IMPT) versus intensity modulated x‐ray therapy (IMXT) for the delivery of nonuniform dose prescriptions based on hypoxia‐imaging, so‐called dose painting. Materials and Methods: IMXT delivered with helical tomotherapy (HT) was compared to IMPT delivered with spot scanning (SS) and distal gradient tracking (DGT). The novel DGT method places beam spots where dose prescription gradients occur along the pencil beam axis. Fundamental dosimetric properties of each modality were assessed by creating optimized plans for 144 variations of a cylindrical phantom with six boost regions embedded inside a base tumor region. Clinical cases with biologically conformal dose prescriptions based on PET with the 61 Cu ‐ATSM hypoxia imagingradiopharmaceutical were planned. The effects on the nonuniform dose distribution of delivering IMPT on a 180° arc versus equi‐spaced beams spread over 360° were investigated. Results: Phantom studies showed that nonuniform dose plan quality for tomotherapy, SS, and DGT, was similar, but DGT plans were most sensitive to phantom size and boost region proximity. IMPT reduced normal tissue integral dose by a mean factor of around two relative to IMXT. Clinical dose deviations from the prescription were comparable for all modalities, but arc IMPT deliveries markedly reduced normal tissue dose and improved critical structure sparing without compromising the dose distribution in the tumor.Conclusions: In the target volume, IMXT and IMPT deliver comparable nonuniform dose distributions. IMPT offers improved integral normal tissue dose and sparing of critical structures over IMXT, as was the case for uniform dose deliveries. DGT reduces required beam spots by a factor of about three relative to SS. IMPT dose painting will require similar management of intrafractional patient motion as for IMXT, with the additional consideration of proton spot placement uncertainty. TR Mackie has a conflict of interest due to financial interest in TomoTherapy, Inc.

[18F]-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography of LAPC4-CR Castration-Resistant Prostate Cancer Xenograft Model in Soft Tissue Compartments

Preclinical xenograft models have contributed to advancing our understanding of the molecular basis of prostate cancer and to the development of targeted therapy. However, traditional preclinical in vivo techniques using caliper measurements and survival analysis evaluate the macroscopic tumor behavior, whereas tissue sampling disrupts the microenvironment and cannot be used for longitudinal studies in the same animal. Herein, we present an in vivo study of [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) designed to evaluate the metabolism within the microenvironment of LAPC4-CR, a unique murine model of castration-resistant prostate cancer. Mice bearing LAPC4-CR subcutaneous tumors were administered [18F]-FDG via intravenous injection. After a 60-minute distribution phase, the mice were imaged on a PET/CT scanner with submillimeter resolution; and the fused PET/CT images were analyzed to evaluate tumor size, location, and metabolism across the cohort of mice. The xenograft tumors showed [18F]-FDG uptake that was independent of tumor size and was significantly greater than uptake in skeletal muscle and liver in mice (Wilcoxon signed-rank P values of .0002 and .0002, respectively). [18F]-FDG metabolism of the LAPC4-CR tumors was 2.1 ± 0.8 ID/cm3*wt, with tumor to muscle ratio of 7.4 ± 4.7 and tumor to liver background ratio of 6.7 ± 2.3. Noninvasive molecular imaging techniques such as PET/CT can be used to probe the microenvironment of tumors in vivo. This study showed that [18F]-FDG-PET/CT could be used to image and assess glucose metabolism of LAPC4-CR xenografts in vivo. Further work can investigate the use of PET/CT to quantify the metabolic response of LAPC4-CR to novel agents and combination therapies using soft tissue and possibly bone compartment xenograft models.

Method for detecting voxelwise changes in fluorodeoxyglucose-positron emission tomography brain images via background adjustment in cancer clinical trials

Abstract. An important challenge to using fluorodeoxyglucose-positron emission tomography (FDG-PET) in clinical trials of brain tumor patients is to identify malignant regions whose metabolic activity shows significant changes between pretreatment and a posttreatment scans in the presence of high normal brain background metabolism. This paper describes a semiautomated processing and analysis pipeline that is able to detect such changes objectively with a given false detection rate. Image registration and voxelwise comparison of the pre- and posttreatment images were performed. A key step is adjustment of the observed difference by the estimated background change at each voxel, thereby overcoming the confounding effect of spatially heterogeneous metabolic activity in the brain. Components of the proposed method were validated via phantom experiments and computer simulations. It achieves a false response volume accuracy of 0.4% at a significance threshold of 3 standard deviations. It is shown that the proposed methodology can detect lesion response with 100% accuracy with a tumor-to-background-ratio as low as 1.5, and it is not affected by the background brain glucose metabolism change. We also applied the method to FDG-PET patient images from a clinical trial to assess treatment effects of lapatinib, which demonstrated significant changes in metabolism corresponding to tumor regions.

MO-G-BRF-01: BEST IN PHYSICS (JOINT IMAGING-THERAPY) - Sensitivity of PET-Based Texture Features to Respiratory Motion in Non-Small Cell Lung Cancer (NSCLC).

PURPOSE PET-based texture features are used to quantify tumor heterogeneity due to their predictive power in treatment outcome. We investigated the sensitivity of texture features to tumor motion by comparing whole body (3D) and respiratory-gated (4D) PET imaging. METHODS Twenty-six patients (34 lesions) received 3D and 4D [F-18]FDG-PET scans before chemo-radiotherapy. The acquired 4D data were retrospectively binned into five breathing phases to create the 4D image sequence. Four texture features (Coarseness, Contrast, Busyness, and Complexity) were computed within the the physician-defined tumor volume. The relative difference (δ) in each measure between the 3D- and 4D-PET imaging was calculated. Wilcoxon signed-rank test (p<0.01) was used to determine if δ was significantly different from zero. Coefficient of variation (CV) was used to determine the variability in the texture features between all 4D-PET phases. Pearson correlation coefficient was used to investigate the impact of tumor size and motion amplitude on δ. RESULTS Significant differences (p<<0.01) between 3D and 4D imaging were found for Coarseness, Busyness, and Complexity. The difference for Contrast was not significant (p>0.24). 4D-PET increased Busyness (∼20%) and Complexity (∼20%), and decreased Coarseness (∼10%) and Contrast (∼5%) compared to 3D-PET. Nearly negligible variability (CV=3.9%) was found between the 4D phase bins for Coarseness and Complexity. Moderate variability was found for Contrast and Busyness (CV∼10%). Poor correlation was found between the tumor volume and δ for the texture features (R=-0.34-0.34). Motion amplitude had moderate impact on δ for Contrast and Busyness (R=-0.64- 0.54) and no impact for Coarseness and Complexity (R=-0.29-0.17). CONCLUSION Substantial differences in textures were found between 3D and 4D-PET imaging. Moreover, the variability between phase bins for Coarseness and Complexity was negligible, suggesting that similar quantification can be obtained from all phases. Texture features, blurred out by respiratory motion during 3D-PET acquisition, can be better resolved by 4D-PET imaging with any phase.

SU‐GG‐T‐108: Optimal Management of Respiratory Motion without Motion Management: A Tomotherapy Phantom Demonstration

Purpose: To demonstrate a potential alternative scenario for accurate dose painting (non‐homogeneous planned dose) delivery at the 1 cm beam width with helical tomotherapy (HT) in the presence of 1 cm, three dimensional, intra‐fraction respiratory motion, but without any active motion management. Method and Materials: A model dose painting experiment was planned and delivered to the average position (proper phase of a 4DCT scan) with three spherical PTV levels to approximate dose painting to compensate for hypothetical hypoxia in a model lungtumor. Realistic but regular motion was produced with the Washington University 4D Motion Phantom. A small spherical Virtual Water™ phantom was used to simulate a moving lungtumor inside of the LUNGMAN™ anthropomorphic chest phantom to simulate realistic heterogeneity uncertainties. A piece of 4 cm Gafchromatic EBT™ film was inserted into the 6 cm diameter sphere. The TomoTherapy, Inc. DQA™ software was used to verify the delivery performed on a TomoTherapy Hi‐Art II™ device. Results: The dose uncertainty in the purposeful absence of motion management and in the absence of large, low frequency drifts (periods greater than the beam width divided by the couch velocity) or randomness in the breathing displacement yields very favorable results. Instead of interference effects, only small blurring is observed because of the averaging of many breathing cycles and beamlets and no other frequency coherence to the modulation, likely in most cases. Conclusion: Dose painting during respiration with helical tomotherapy is feasible in certain situations without motion management. A simple recommendation is to make respiration as regular as possible without low frequency drifting. The blurring is just small enough to suggest that it may be acceptable to deliver without motion management in many situations when registered to the average position.