D Barbee

Comparison of intensity modulated x-ray therapy and intensity modulated proton therapy for selective subvolume boosting: a phantom study

Selective subvolume boosting can theoretically improve tumour control probability while maintaining normal tissue complication probabilities similar to those of uniform dose distributions. In this work the abilities of intensity-modulated x-ray therapy (IMXT) and intensity-modulated proton therapy (IMPT) to deliver boosts to multiple subvolumes of varying size and proximities are compared in a thorough phantom study. IMXT plans were created using the step-and-shoot (IMXT-SAS) and helical tomotherapy (IMXT-HT) methods. IMPT plans were created with the spot scanning (IMPT-SS) and distal gradient tracking (IMPT-DGT) methods. IMPT-DGT is a generalization of the distal edge tracking method designed to reduce the number of proton beam spots required to deliver non-uniform dose distributions relative to IMPT-SS. The IMPT methods were delivered over both 180 degrees and 360 degrees arcs. The IMXT-SAS and IMPT-SS methods optimally satisfied the non-uniform dose prescriptions the least and the most, respectively. The IMPT delivery methods reduced the normal tissue integral dose by a factor of about 2 relative to the IMXT delivery methods, regardless of the delivery arc. The IMPT-DGT method reduced the number of proton beam spots by a factor of about 3 relative to the IMPT-SS method.

Paraquat is excluded by the blood brain barrier in rhesus macaque: An in vivo pet study

Environmental factors have long been thought to have a role in the etiology of idiopathic Parkinsons disease (PD). Since the discovery of the selective neurotoxicity of MPTP to dopamine cells, suspicion has focused on paraquat, a common herbicide with chemical structure similar to 1-methyl-4-phenylpyridinium (MPP+), the MPTP metabolite responsible for its neurotoxicity. Although in vitro evidence for paraquat neurotoxicity to dopamine cells is well established, its in vivo effects have been ambiguous because paraquat is di-cationic in plasma, which raises questions about its ability to cross the blood brain barrier. This study assessed the brain uptake of [(11)C]-paraquat in adult male rhesus macaques using quantitative PET imaging. Results showed minimal uptake of [(11)C]-paraquat in the macaque brain. The highest concentrations of paraquat were seen in the pineal gland and the lateral ventricles. Global brain concentrations including those in known dopamine areas were consistent with the blood volume in those structures. This acute exposure study found that paraquat is excluded from the brain by the blood brain barrier and thus does not readily support the causative role of paraquat exposure in idiopathic Parkinsons disease.

A method for partial volume correction of PET-imaged tumor heterogeneity using expectation maximization with a spatially varying point spread function

Tumor heterogeneities observed in positron emission tomography (PET) imaging are frequently compromised by partial volume effects which may affect treatment prognosis, assessment or future implementations such as biologically optimized treatment planning (dose painting). This paper presents a method for partial volume correction of PET-imaged heterogeneous tumors. A point source was scanned on a GE Discovery LS at positions of increasing radii from the scanners center to obtain the spatially varying point spread function (PSF). PSF images were fit in three dimensions to Gaussian distributions using least squares optimization. Continuous expressions were devised for each Gaussian width as a function of radial distance, allowing for generation of the system PSF at any position in space. A spatially varying partial volume correction (SV-PVC) technique was developed using expectation maximization (EM) and a stopping criterion based on the methods correction matrix generated for each iteration. The SV-PVC was validated using a standard tumor phantom and a tumor heterogeneity phantom and was applied to a heterogeneous patient tumor. SV-PVC results were compared to results obtained from spatially invariant partial volume correction (SINV-PVC), which used directionally uniform three-dimensional kernels. SV-PVC of the standard tumor phantom increased the maximum observed sphere activity by 55 and 40% for 10 and 13 mm diameter spheres, respectively. Tumor heterogeneity phantom results demonstrated that as net changes in the EM correction matrix decreased below 35%, further iterations improved overall quantitative accuracy by less than 1%. SV-PVC of clinically observed tumors frequently exhibited changes of +/-30% in regions of heterogeneity. The SV-PVC method implemented spatially varying kernel widths and automatically determined the number of iterations for optimal restoration, parameters which are arbitrarily chosen in SINV-PVC. Comparing SV-PVC to SINV-PVC demonstrated that similar results could be reached using both methods, but large differences result for the arbitrary selection of SINV-PVC parameters. The presented SV-PVC method was performed without user intervention, requiring only a tumor mask as input. Research involving PET-imaged tumor heterogeneity should include correcting for partial volume effects to improve the quantitative accuracy of results.

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.

WE‐D‐ValB‐01: Effects of PET Reconstruction Parameters On the Delineation of Heterogeneous Target Volumes

Purpose As emerging radiotherapy techniques incorporate biological targeting of sub‐tumor volumes, steps must be taken to ensure the validity of the assumed substructures. This study measures the effects of PET image reconstruction on heterogeneous target definitions both in vivo and in a phantom. Method and Materials: A known heterogeneous phantom composed of Y‐86 and Ge‐68 spheres with an F‐18 background altering signal‐to‐background ratios tested the accuracy of reconstructions using ordered subset expectation maximization (OSEM) with varying numbers of iterations and filtered backprojection (FBP) with Hanning, Shepp‐Logan, and ramp filters. In vivo measurements used heterogeneously proliferating tumorimages obtained from a canine tumorimaged using [F‐18]FLT at three stages of treatment using the same reconstruction methods. Difference images and standard deviations were used to assess the reconstruction differences. A three‐dimensional form of the Moran I(d) spatial statistic was used to assess global heterogeneity at various correlation distances. Results: Absolute difference images from FBP and 2 iteration OSEM reconstructions showed internal tumor voxel clusters deviating by more than 10% of the maximum SUV of the reference image (OSEM20) and relative voxel values varying by as much as 40% in tumor periphery. Image differences in OSEM reconstructions significantly decreased after 10 iterations, accompanied by decreases in the standard deviation of differences and slight increases in heterogeneity as global I(d) values decreased. FBP reconstructions both underestimated (Hanning, Shepp‐Logan) and overestimated (ramp) global heterogeneity I(d) relative to reference values, but large standard deviations of absolute difference indicated images compared poorly to the reference. Conclusion:Tumor heterogeneity obtained through PET may vary by at least 10% internally with larger variability at the periphery, greatly affecting both tumor volume delineation and internal heterogeneity. Prescriptions for dose painting based on proliferation measures can vary widely with the reconstruction algorithm.

SU‐FF‐J‐176: Assessing the Impact of Partial Volume Correction On Dose Painting

Purpose:Tumor heterogeneities identified by PETimaging suffer from partial volume effects (PVE) due to the scanners limited resolution. This study establishes the necessity for including partial volume correction in dose painting prescriptions. Method and Materials: A previously reported iterative partial volume correction (PVC) method, specific to heterogeneous tumors, was applied to 15 tumors exhibiting heterogeneous uptake of [Cu‐61]Cu‐ATSM, a hypoxia surrogate marker. Dose painting prescriptions were generated from PETimages using two techniques: a linear transformation converting SUV to dose, and a threshold method creating boost regions for SUVs greater than 3. All prescriptions implemented minimum tumor dose constraints of 50 Gy. Continuous prescriptions linearly redistributed dose about the mean tumor SUV, yielding a mean tumor dose of 70 Gy. Thresholding prescribed an additional 20 Gy to the boost region. Doses were optimized for each prescription using an in‐house helical tomotherapy planning system. Results: PVC images exhibited redistribution of mid‐range SUVs to higher/lower SUVs with heterogeneity uptake differences of ±25–30%. However, average dose differences for linear transformation dose painting were ±5–10%, due to the transforms ratio of base dose to boost dose. The average dose differences for threshold transformation dose painting were dependent on threshold level and the tumor SUV distribution. In cases where the mean tumor SUV was approximately equivalent to the threshold SUV, PVC increased and decreased boost volumes in equal amounts. However, with mean or max tumor SUVs below threshold values, PVC significantly increased boost volumes, creating boost regions where none previously existed. Conclusion: PVC alters the volume and magnitude of regions receiving redistributed boost doses. PVC frequently reveals tumor heterogeneities where none were previously observed due to PVE, which should be included in dose painting prescriptions. Institutions intending to implement PET‐based dose painting should understand and correct for partial volume effects prior to generating prescriptions.

TH‐D‐304A‐08: Quantitative PET Imaging of Heterogeneous Tumors: The Influence of Patient Position On Recovered Activity

Purpose: Dose‐painting will require precise quantification of uptake within sub‐regions of heterogeneous tumors. We have measured and characterized the effect of patient positioning on heterogeneity within PET images for 2D and 3D acquisition. Methods and Materials: Position‐dependent variations in recovery coefficients (RC) were measured on a multi‐slice PET imaging system using a phantom of five P 18P F‐filled spheres: two10mm and 15mm diameter, one 5mm. Spheres of each size were repositioned in 1mm increments between acquisitions while two kept stationary. 2D and 3D coincident counts were acquired at 4 minutes‐per‐position, and images generated with iterative reconstruction protocols. Measured RC variations were used to calculate expected SUV changes within heterogeneous tumors, for patient positions sampled from distributions of axial, radial, and angular uncertainties associated with head and neck (HN) cancer.Results: For sub‐voxel shifts in axial direction, the peak‐to‐trough RC values (RCBPTB) in 2D mode were 41%, 8% for 5mm and 10mm diameter sub‐regions. In 3D mode, these axial RCBPTB values were 24% and 7%. RCBPTB for radial shifts were 31% and 14% for images acquired in 2D mode, and 37% and 12% for 3D acquisition. All RCBPTB for15mm spheres were within the noise background, as determined from measurements of the stationary spheres.Random adjustments of head position resulted in notable changes in visual appearance and spatial distribution within PET images. For a very heterogeneous HN tumor, estimated population correlation coefficient between images was 0.8 (n = 1000 images × 696 voxels). However, correlation between individual images ranged from 1.0 to 0.6. Conclusion: Reproducibility is necessary for quantitative PET imaging; stable and precise voxel values will result in reliable voxel‐based image analysis. However, sub‐voxel verification of position of tumor sub‐regions is impossible, so shift‐interpolated images, which correspond to more reproducible mean RC values, could potentially reduce this systematic uncertainty.

SU‐FF‐J‐142: Sensitivity of Treatment Assessment to Different PET Normalization Techniques

Purpose: Assessment of treatment outcome based on PETimaging requires accurate and robust patient‐specific normalization of tracer uptake. This study investigates the sensitivity of treatment response as a function of various PETimaging normalization methods. Materials and Methods: Fourteen patients undergoing molecular targeted therapy received [18F]FLT (cellularproliferation marker) PET/CT scans that were acquired pre, mid and post therapy. SUV normalization was performed using body weight (BW), body surface area (BSA), and lean body mass (LBM). Dependence of treatment response outcome on the normalization technique was evaluated both experimentally and analytically. Additional normalization of the SUVs was performed using an external reference source comprised of Ge‐68 to reduce the inherent variations in scanner stability. Robustness of treatment response outcome was assessed by evaluating ratios of both corrected and uncorrected SUVs. Results: The absolute mean values of the SUVs were 2.3 ± 0.8, 1.4 ± 0.4, and 0.05±0.02 for BW, LBM, and BSA respectively. Despite a substantial difference in their values, the treatment response ratios between the post and pre scans were found to be within 0.3% on average for all types of SUV normalizations. For the largest weight change of about 6%, the difference between treatment response ratios was less than 1% for SUVs based on BSA versus LBM and it was about 3%for SUVs based on BSA versus BW. After reference source normalization, the treatment response ratios shifted by 5.5%. For post and mid scans, the treatment response ratios shifted by −2.4% after reference source normalization. Conclusions: The type of SUV normalization technique used does not affect treatment response assessment unless there is a significant change in weight. On the other hand, the treatment response is influenced by normalization with the external reference source.

TH‐D‐AUD C‐05: Assessment of Heterogeneity Change in Tumors Over Time Course of Treatment

Purpose:Tumors are known to be heterogeneous but it is unclear whether and how heterogeneity changes throughout therapy. The purpose of this work was to quantitatively assess proliferative heterogeneity over time course of treatment.Method and Materials:Tumor heterogeneity and its temporal development were investigated for patients undergoing either radiotherapy or chemotherapy. Six radiotherapy patients were imaged prior to radiation therapy and 2–3 weeks after the first scan while receiving treatment. Four chemotherapy patients were imaged with FLT‐PET prior to treatment, during Sunitinib malate therapy (week 4) and during withdrawal (week 6). Spatial statistics were used to assess proliferative heterogeneity over tumor volume. Global Moran I statistics with inverse distance weighting were used to estimate the overall degree of spatial autocorrelation in cell proliferation. Proliferation clusters were visualized using local G statistics, which identified local regions of strong autocorrelation. Results: No significant changes in tumor heterogeneity during radiation therapy were seen, with the mean change in Moran I throughout treatment of only −2.5±6.9 %. On the contrary, chemotherapy patients showed changes in tumor heterogeneity over the time course of treatment. Moran I changed by −14.5±3.7 % from pre‐treatment to week 4 and 13.0±8.1 % from week 4 to week 6. The correlation coefficient between chemotherapy response and change in Moran I from pre‐treatment to week 4 was 0.75. On the other hand, no strong correlation between the initial heterogeneity and response to treatment was observed. Conclusion: Results showed that spatial statistics successfully provide a measure of tumor heterogeneity and its changes over the course of treatment. The heterogeneity changes depend upon treatment type and response to treatment.