Calculation method for novel upright CT scanner isodose curves.

PURPOSE: A computational method based on Monte-Carlo calculations is presented and used to calculate isodose curves for a new upright and tilting CT scanner useful for radiation protection purposes. METHODS: The TOPAS code platform with imported CAD files for key components was used to construct a calculation space for the scanner. A sphere of water acts as the patient would by creating scatter out of the bore. Maximum intensity dose maps are calculated for various possible tilt angles to make sure radiation protection for site planning uses the maximum possible dose everywhere. RESULTS: The resulting maximum intensity isodose lines are more rounded than ones for just a single tilt angle and so closer to isotropic. These maximum intensity curves are closer to the isotropic assumption used in CTDI or DLP based methods of site planning and radiation protection. The isodose lines are similar to those of a standard CT scanner, just tilted upwards. There is more metal above the beam that lessens the dose above versus below isocenter. CONCLUSION: Aside from the orientation, this upright scanner is very similar to a typical CT scanner, and nothing different for shielding needs to be done for this new upright tilting CT scanner, because an isotropic scatter source is often assumed for any CT scanner.

Relative thoracic changes from supine to upright patient position: A proton collaborative group study.

This study presents position changes of a few radiotherapy-relevant thoracic organs between upright and typical supine patient orientations. Using tools in a commercial treatment planning system (TPS), key anatomical distances were measured for four-dimensional CT data sets and analyzed for the two patient orientations. The uncertainty was calculated as the 95% confidence interval (CI) on the relative difference for each of the four analyzed changes for upright relative to supine, as follows: the distance of the bottom of the heart to the top of the sternum, it changed +2.6% or +4 mm (95% CI [+0.30%,+4.9%]); the distance of the center of the C3 vertebra to the backrest, it changed +29% (95% CI [+22%,+36%]); the contoured left and right lungs increased their volumes respectively: +17% (95% CI [+12%,+21%]) for the left, and +9.9% (95% CI [+4.1%,+16%]); and lastly, the distance from the top of the sternum to the top of the liver, but its uncertainty far exceeded the average change by a factor of two. This last result is therefore inconclusive, the others show that with 95% confidence that a change in internal positions is observed for lung volumes and heart position that could be important for upright treatments.

Evaluation of radixact motion synchrony for 3D respiratory motion: Modeling accuracy and dosimetric fidelity.

The Radixact® linear accelerator contains the motion Synchrony system, which tracks and compensates for intrafraction patient motion. For respiratory motion, the system models the motion of the target and synchronizes the delivery of radiation with this motion using the jaws and multi-leaf collimators (MLCs). It was the purpose of this work to determine the ability of the Synchrony system to track and compensate for different phantom motions using a delivery quality assurance (DQA) workflow. Thirteen helical plans were created on static datasets from liver, lung, and pancreas subjects. Dose distributions were measured using a Delta4® Phantom+ mounted on a Hexamotion® stage for the following three case scenarios for each plan: (a) no phantom motion and no Synchrony (M0S0), (b) phantom motion and no Synchrony (M1S0), and (c) phantom motion with Synchrony (M1S1). The LEDs were placed on the Phantom+ for the 13 patient cases and were placed on a separate one-dimensional surrogate stage for additional studies to investigate the effect of separate target and surrogate motion. The root-mean-square (RMS) error between the Synchrony-modeled positions and the programmed phantom positions was <1.5 mm for all Synchrony deliveries with the LEDs on the Phantom+. The tracking errors increased slightly when the LEDs were placed on the surrogate stage but were similar to tracking errors observed for other motion tracking systems such as CyberKnife Synchrony. One-dimensional profiles indicate the effects of motion interplay and dose blurring present in several of the M1S0 plans that are not present in the M1S1 plans. All 13 of the M1S1 measured doses had gamma pass rates (3%/2 mm/10%T) compared to the planned dose > 90%. Only two of the M1S0 measured doses had gamma pass rates > 90%. Motion Synchrony offers a potential alternative to the current, ITV-based motion management strategy for helical tomotherapy deliveries.

Investigation of probabilistic optimization for tomotherapy.

This work builds on a suite of studies related to the 'interplay', or lack thereof, for respiratory motion with helical tomotherapy (HT). It helps explain why HT treatments without active motion management had clinical outcomes that matched positive expectations. An analytical calculation is performed to illuminate the frequency range for which interplay-type dose errors could occur. Then, an experiment is performed which completes a suite of tests. The experiment shows the potential for a stable motion probability distribution function (PDF) with HT and respiratory motion. This PDF enables one to use a motion-robust or probabilistic optimization to intrinsically include respiratory motion into the treatment planning. The reason why HT is robust to respiratory motion is related to the beam modulation sampling of the tumor motion. Because active tracking-based motion management is more complicated for a variety of reasons, HT optimization that is robust to motion is a useful alternative for those many patients that cannot benefit from active motion management.

Interstitial diffuse optical probe with spectral fitting to measure dynamic tumor hypoxia.

Understanding the dynamic nature of tumor hypoxia is vital for cancer therapy. The presence of oxygen within a tumor during radiation therapy increases the likelihood of local control. We used a novel interstitial diffuse optical probe to make real-time measurements of blood volume fraction and hemoglobin oxygen saturation within a tumor at a high temporal resolution. This device was initially characterized and benchmarked using a customized vessel designed to control hemoglobin oxygen saturation and blood volume in a solution of blood with different concentrations of an oxygen scavenger, tetrakis (hydroxymethyl) phosphonium chloride. The optical device was found to consistently monitor the changes in oxygen saturation and these changes correlated to the concentration of the oxygen scavenger added. In near-simultaneous measurements of blood volume and oxygen saturation in tumor-bearing mice, the changes in blood volume fraction and oxygen saturation measured with the interstitial diffuse optical probe were benchmarked against photoacoustic imaging system to track and compare temporal dynamics of oxygen saturation and blood volume in a patient-derived xenograft model of hypopharyngeal carcinoma. Positive correlations between our device and photoacoustic imaging in measuring blood volume and oxygen saturation were observed.

Report of AAPM Task Group 235 Radiochromic Film Dosimetry: An Update to TG-55.

The use of radiochromic film (RCF) dosimetry in radiation therapy is extensive due to its high level of achievable accuracy for a wide range of dose values and its suitability under a variety of measurement conditions. However, since the publication of the 1998 AAPM Task Group 55, Report No. 63 on RCF dosimetry, the chemistry, composition, and readout systems for RCFs have evolved steadily. There are several challenges in using the new RCFs, readout systems and validation of the results depending on their applications. Accurate RCF dosimetry requires understanding of RCF selection, handling and calibration methods, calibration curves, dose conversion methods, correction methodologies as well as selection, operation and quality assurance (QA) programs of the readout systems. Acquiring this level of knowledge is not straight forward, even for some experienced users. This Task Group report addresses these issues and provides a basic understanding of available RCF models, dosimetric characteristics and properties, advantages and limitations, configurations, and overall elemental compositions of the RCFs that have changed over the past 20 yr. In addition, this report provides specific guidelines for data processing and analysis schemes and correction methodologies for clinical applications in radiation therapy.

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.

Corrigendum: Potential role of the glycolytic oscillator in acute hypoxia in tumors (2015 Phys. Med. Biol. 60 9215).

At the time of publication, our group had performed short tandem repeat (STR) testing on the SCC22B cell line and believed that had been correctly identified. As part of a recent comprehensive process to confirm the identity of cell lines in use in our lab, we repeated STR testing on all cell lines. These results were compared to the ExPASy Cellosaurus database (http://web.expasy.org/cellosaurus/). One cell line used in this manuscript was a near perfect match for T24 (CVCL_0554), a bladder carcinoma cell line commonly found as a cellular contaminant. Although we are unable to test the exact cells used in this manuscript, we believe that the cells labeled as SCC22B are most likely to actually be T24. The authors believe that neither the results nor the conclusions have been significantly changed on the basis of the specific cell line utilized.

A delivery transfer function (DTF) analysis for helical tomotherapy.

The previous theoretical work of a delivery transfer function (DTF) in radiotherapy is expanded to include the unique intensity modulation method of helical tomotherapy. In addition to the collimation of each beamlet, and the Gaussian scatter convolution spreading of the dose that other radiotherapy units have, helical tomotherapy uses 51 small arcs of varying lengths to adjust the intensity. The blurring from these arcs is not taken into account during treatment planning. A theoretical DTF is constructed, and a calculation is performed which includes this unique source motion in relation to the other DTF components. Various typical delivery parameters are used to generate resolution maps for a constant intensity projection. Near the isocenter, the transverse (to a given beam direction) blurring is small but at larger radii (>6 cm), the source blurring dominates over leaf size. For most clinical situations, this inherent source motion blurring is expected to be negligible.

On the making of sharp longitudinal dose profiles with helical tomotherapy.

Since the beam width on the helical tomotherapy machine produced by TomoTherapy Inc., is typically a few centimeters in the longitudinal direction (into the bore), the optimizer must choose to have a relatively high intensity local to the inside edge of a tumor or planning treatment volume (PTV) when avoiding an immediately adjacent organ at risk (OAR), either superior or inferior. By using a standalone version of the TomoTherapy dose calculator, a realistic beam is applied to idealized deconvolution schemes including the MATLAB Optimizer Toolbox for a simple one-dimensional PTV with adjacent OARs. The results are compared to a clinical example on the TomoTherapy planning station. It is learned that a Gibbs phenomenon type of oscillation in the dose within the tumor under these special circumstances is not unique to TomoTherapy, but is related to the attempt to form a sharp dose gradient-sharper than the beam profile with typical optimization constraints set to achieve a uniform dose as close as possible to the prescription. The clinical implication is that the Gibbs-induced cold spots force the dose to increase in the PTV if a typical PTV dose-volume constraint is used. It is recommended that the dose prescription be smoothed prior to optimization or the dosimetric goals for an OAR adjacent to the PTV are such that a sharp dose falloff is not demanded, especially if the user reduces the requirements that such an OAR be of both high importance and immediately adjacent to the PTV edge.

Radiation Promptly Alters Cancer Live Cell Metabolic Fluxes: An In Vitro Demonstration.

Quantitative data is presented that shows significant changes in cellular metabolism in a head and neck cancer cell line 30 min after irradiation. A head and neck cancer cell line (UM-SCC-22B) and a comparable normal cell line, normal oral keratinocyte (NOK) were each separately exposed to 10 Gy and treated with a control drug for disrupting metabolism (potassium cyanide; KCN). The metabolic changes were measured live by fluorescence lifetime imaging of the intrinsically fluorescent intermediate metabolite nicotinamide adenosine dinucleotide (NADH) fluorescence; this method is sensitive to the ratio of bound to free NADH. The results indicated a prompt shift in metabolic signature in the cancer cell line, but not in the normal cell line. Control KCN treatment demonstrated expected metabolic fluxes due to mitochondrial disruption. The detected radiation shift in the cancer cells was blunted in the presence of both a radical scavenger and a HIF-1α inhibitor. The HIF-1α abundance as detected by immunohistochemical staining also increased substantially for these cancer cells, but not for the normal cells. This type of live-cell metabolic monitoring could be helpful for future real-time studies and in designing adaptive radiotherapy approaches.

Confirmation, refinement, and extension of a study in intrafraction motion interplay with sliding jaw motion.

The interplay between a constant scan speed and intrafraction oscillatory motion produces interesting fluence intensity modulations along the axis of motion that are sensitive to the motion function, as originally shown in a classic paper by Yu et al. [Phys. Med. Biol. 43, 91-104 (1998)]. The fluence intensity profiles are explored in this note for an intuitive understanding, then compared with Yu et al., and finally further explored for the effects of low scan speed and random components of both intrafraction and interfraction motion. At slow scan speeds typical of helical tomotherapy, these fluence intensity modulations are only a few percent. With the addition of only a small amount of cycle-to-cycle randomness in frequency and amplitude, the fluence intensity profiles change dramatically. It is further shown that after a typical 30-fraction treatment, the sensitivities displayed in the single fraction fluence intensity profiles greatly diminish.

Modelling simple helically delivered dose distributions.

In a previous paper, we described quality assurance procedures for Hi-Art helical tomotherapy machines. Here, we develop further some ideas discussed briefly in that paper. Simple helically generated dose distributions are modelled, and relationships between these dose distributions and underlying characteristics of Hi-Art treatment systems are elucidated. In particular, we describe the dependence of dose levels along the central axis of a cylinder aligned coaxially with a Hi-Art machine on fan beam width, couch velocity and helical delivery lengths. The impact on these dose levels of angular variations in gantry speed or output per linear accelerator pulse is also explored.

Potential role of the glycolytic oscillator in acute hypoxia in tumors.

Tumor acute hypoxia has a dynamic component that is also, at least partially, coherent. Using blood oxygen level dependent magnetic resonance imaging, we observed coherent oscillations in hemoglobin saturation dynamics in cell line xenograft models of head and neck squamous cell carcinoma. We posit a well-established biochemical nonlinear oscillatory mechanism called the glycolytic oscillator as a potential cause of the coherent oscillations in tumors. These data suggest that metabolic changes within individual tumor cells may affect the local tumor microenvironment including oxygen availability and therefore radiosensitivity. These individual cells can synchronize the oscillations in patches of similar intermediate glucose levels. These alterations have potentially important implications for radiation therapy and are a potential target for optimizing the cancer response to radiation.

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.

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.

Confirmation, refinement, and extension of a study in intrafraction motion interplay with sliding jaw motion.

The interplay between a constant scan speed and intrafraction oscillatory motion produces interesting fluence intensity modulations along the axis of motion that are sensitive to the motion function, as originally shown in a classic paper by Yu et al. [Phys. Med. Biol. 43, 91-104 (1998)]. The fluence intensity profiles are explored in this note for an intuitive understanding, then compared with Yu et al., and finally further explored for the effects of low scan speed and random components of both intrafraction and interfraction motion. At slow scan speeds typical of helical tomotherapy, these fluence intensity modulations are only a few percent. With the addition of only a small amount of cycle-to-cycle randomness in frequency and amplitude, the fluence intensity profiles change dramatically. It is further shown that after a typical 30-fraction treatment, the sensitivities displayed in the single fraction fluence intensity profiles greatly diminish.