Preclinical Applications of Multi-Platform Imaging in Animal Models of Cancer.

In animal models of cancer, oncologic imaging has evolved from a simple assessment of tumor location and size to sophisticated multimodality exploration of molecular, physiologic, genetic, immunologic, and biochemical events at microscopic to macroscopic levels, performed noninvasively and sometimes in real time. Here, we briefly review animal imaging technology and molecular imaging probes together with selected applications from recent literature. Fast and sensitive optical imaging is primarily used to track luciferase-expressing tumor cells, image molecular targets with fluorescence probes, and to report on metabolic and physiologic phenotypes using smart switchable luminescent probes. MicroPET/single-photon emission CT have proven to be two of the most translational modalities for molecular and metabolic imaging of cancers: immuno-PET is a promising and rapidly evolving area of imaging research. Sophisticated MRI techniques provide high-resolution images of small metastases, tumor inflammation, perfusion, oxygenation, and acidity. Disseminated tumors to the bone and lung are easily detected by microCT, while ultrasound provides real-time visualization of tumor vasculature and perfusion. Recently available photoacoustic imaging provides real-time evaluation of vascular patency, oxygenation, and nanoparticle distributions. New hybrid instruments, such as PET-MRI, promise more convenient combination of the capabilities of each modality, enabling enhanced research efficacy and throughput.

The Current State of Physics Plan Review Training in Medical Physics Residency Programs in North America.

PURPOSE: This study aimed to identify the current state of residency training in physics plan reviews. METHODS AND MATERIALS: A voluntary, anonymous survey was sent to all program directors of accredited therapeutic medical physics residency programs in North America. Survey questions were developed to determine whether and how residents are trained in physics plan reviews. Survey questions were developed using expert validation and cognitive pretesting. RESULTS: Using a prospectively approved study (COMIRB 18-1073), responses were collected from 70 program directors, representing a 70% response rate. All respondents (100%) designated patient safety to be the purpose of physics plan reviews. Of the respondents, 94% indicated that physicists should first receive training in physics plan reviews while in a residency program. The vast majority of respondents (99%) provide training to residents in physics plan reviews. Although 57 programs (81% of respondents) have residents perform physics plan reviews as part of clinical practice (with varying levels of independence), 13 programs (19% of respondents) do not. The majority of respondents use the following training methods: observe staff physicists (96%), perform supervised reviews on actual patients for training or clinical practice (93%), use a checklist (80%), and read reference materials (62%). Although simulation plans with embedded errors would be implemented by 71% of respondents, they are currently used in only 19% of programs. CONCLUSIONS: The present study is the first to characterize chart-check teaching practices in medical physics residency programs. The vast majority of programs currently train residents in physics plan reviews. The most common teaching methods are observing and performing physics plan reviews, but there is variability in the level of resident involvement in clinical practice for physics plan reviews. There is room for the field to consider advancing current training methods, which is especially important given the critical roles that physics plan reviews have with regard to patient safety.

Simulation of x-ray-induced acoustic imaging for absolute dosimetry: Accuracy of image reconstruction methods.

PURPOSE: Three-dimensional in-vivo dose verification is one of the standing challenges in radiation therapy. X-ray-induced acoustic tomography has recently been proposed as an imaging method for use in in-vivo dosimetry. The aim of this study was to investigate the accuracy of reconstructing three-dimensional (3D) absolute dose using x-ray-induced acoustic tomography. We performed this investigation using two different tomographic dose reconstruction techniques. METHODS: Two examples of 3D dose reconstruction techniques for x-ray acoustic imaging are investigated. Dose distributions are calculated for varying field sizes using a clinical treatment planning system. The induced acoustic pressure waves which are generated by the increase in temperature due to the absorption of pulsed MV x-rays are simulated using an advanced numerical modeling package for acoustic wave propagation in the time domain. Two imaging techniques, back projection and iterative time reversal, are used to reconstruct the 3D dose distribution in a water phantom with open fields. Image analysis is performed and reconstructed depth dose curves from x-ray acoustic imaging are compared to the depth dose curves calculated from the treatment planning system. Calculated field sizes from the reconstructed dose profiles by back projection and time reversal are compared to the planned field size to determine their accuracy. The iterative time reversal imaging technique is also used to reconstruct dose in an example clinical dose distribution. Image analysis of this clinical test case is performed using the gamma passing rate. In addition, gamma passing rates are used to validate the stopping criteria in the iterative time reversal method. RESULTS: Water phantom simulations showed that back projection does not adequately reconstruct the shape and intensity of the depth dose. When compared to the depth of maximum dose calculated by a treatment planning system, the maximum dose depth by back projection is shifted deeper by 55 and 75 mm for 4 × 4 cm and 10 × 10 cm field sizes, respectively. The reconstructed depth dose by iterative time reversal accurately agrees with the planned depth dose for a 4 × 4 cm field size and is shifted deeper by 12 mm for the 10 × 10 cm field size. When reconstructing field sizes, the back projection method leads to 18% and 35% larger sizes for the 4 × 4 cm and 10 × 10 cm fields, respectively, whereas the iterative time reversal method reconstructs both field sizes with < 2% error. For the clinical dose distribution, we were able to reconstruct the dose delivered by a 1 degree sub-arc with a good accuracy. The reconstructed and planned doses were compared using gamma analysis, with> 96% gamma passing rate at 3%/2 mm. CONCLUSIONS: Our results show that the 3D x-ray acoustic reconstructed dose by iterative time reversal is considerably more accurate than the dose reconstructed by back projection. Iterative time reversal imaging has a potential for use in 3D absolute dosimetry.

Electromagnetic wave propagation in a fast pulse line ion accelerator.

PURPOSE: The pulse line ion accelerator (PLIA) is a low-cost accelerator concept originally designed to accelerate heavy ions. Our group has been investigating the use of PLIA to accelerate light ions and believe a multi-stage PLIA could be useful for short half-life PET isotope production. The goal of this work was to develop a single prototype fast PLIA structure and demonstrate electromagnetic wave propagation using a high-voltage pulser. MATERIALS AND METHODS: A 1.6 m fast PLIA structure (wave speed > 107  m/s) was constructed along with a high-voltage, sinusoidal pulse generator. The latter uses capacitive voltage doubling and spark gap switching. A step-up transformer couples voltage from the pulser to the PLIA coil. Voltage measurements on the coil were made in air using a high-voltage resistive probe, while capacitive probes placed along the length of the PLIA were used to measure wave propagation with the PLIA structure filled with transformer oil. RESULTS: Voltage measurements acquired on the primary and secondary coils of the transformer coupler in air demonstrated a peak-to-peak voltage step-up of 4.2 relative to the pulser DC charging voltage. The maximum voltage time-rate-of-change on the PLIA coil was 0.76 × 1013  V/s. Capacitive probe measurements indicated voltage oscillations on the PLIA coil with half-period equal to 43 ± 0.9 ns and wave speed (with oil) of 1.2 × 107  m/s. Average and peak accelerating gradients were conservatively estimated to be 0.44 and 0.60 MV/m, respectively, with a charging voltage of 55 kV. Wave propagation was demonstrated at these gradients without flashover at a vacuum pressure of 9 × 10-6  Torr. Submerging the pulser in oil would allow for charging voltages up to 150 kV and produce accelerating gradients >1.2 MV/m. CONCLUSIONS: Use of a multi-stage, fast PLIA for light ion acceleration could provide a low-cost complement to cyclotrons for the production of short half-life isotopes used for PET imaging, including carbon-11, nitrogen-13, oxygen-15, and fluorine-18.

Implementation and operation of incident learning across a newly-created health system.

PURPOSE: The purpose of this work is to describe our experience launching an expanded incident learning system for patient safety and quality that takes into account aspects beyond therapeutic dose delivery, specifically imaging/simulation incidents, medical care incidents, and operational issues. METHODS: Our ILS was designed for a newly created health system comprised of a midsized academic hospital and two smaller community hospitals. The main design goal was to create a highly sensitive system to capture as much information throughout the department as possible. Reports were classified according to incidents and near misses involving therapeutic radiation, imaging/simulation, and patient care (not involving radiation), unsafe conditions, operational issues, and accolades/suggestions. Reports were analyzed according to impact on various steps in the process of care. Actions made in response to reports were assessed and characterized by intervention reliability. RESULTS: A total of 1125 reports were submitted in the first 23 months. For all three departments, therapeutic radiation incidents and near misses consisted of less than one-third of all reports submitted. For the midsized academic department, operational issues and unsafe conditions comprised the largest percentage of reports (70%). Although the majority of reports impacted steps related to the technical aspects of treatment (simulation, planning, and treatment delivery), 20% impacted other steps such as scheduling or clinic visits. More than 160 actions were performed in response to reports. Of these actions, 63 were quality improvement interventions to improve practices, while 97 were learning actions for raising awareness. CONCLUSIONS: We have developed an ILS that identifies issues related to the entire process of care delivery in radiation oncology, as evidenced by frequent and varied reported events. By identifying a broad spectrum of issues in a department, opportunities for improvement can be identified.

Design considerations for a pulse line ion accelerator (PLIA)-based PET isotope generator.

PURPOSE: Positron emission tomography (PET) imaging remains limited due to the cost associated with on-site production of short half-life, positron-emitting isotopes. In this work, we examine the use of a pulse line ion accelerator (PLIA) to accelerate protons for single-dose PET isotope production. METHODS: Time-domain electromagnetic field and particle-in-cell (PIC) simulations were performed for a 1.5-m PLIA structure modeled in CST Microwave Studio and Particle Studio software. Scaled measurements from a kV ramp-pulse generator were incorporated into the simulations to accelerate a 1 A, 50 ns proton beam injected with initial kinetic energy of 100 keV. A uniform, 3 T, solenoidal magnetic field was used to provide external beam focusing. Electromagnetic fields and particle phase space were recorded with ns resolution for subsequent analysis. RESULTS: Applying a scaled 100 kV, 20 ns ramped voltage pulse to the PLIA input resulted in a travelling electric field wave inside the structure with accelerating gradient of 2.4 MV/m. The observed wave speed was 1.2 × 107 m/s and is in good agreement with theoretical predictions. Phase space monitors showed both acceleration and bunching of the proton beam, with a maximum kinetic energy of 2.5 MeV, observed at the exit of the single PLIA stage. Evaluation of beam position monitors at different locations in the accelerator showed bunch compression and minimal beam divergence, illustrating that the 3 T field is adequate to contain the beam over the length of the PLIA structure. CONCLUSION: Simulations performed in this work demonstrate the feasibility of using a PLIA structure to accelerate protons with MV/m level gradients. Combining several PLIA stages in series could allow for a low-cost accelerator suitable for dose-on-demand PET isotope production.

Practical implementation of quality improvement for high-dose-rate brachytherapy.

PURPOSE: High-dose-rate (HDR) brachytherapy is a high-risk procedure with serious errors reported in the medical literature. Our goal was to develop a quality improvement framework for HDR brachytherapy using a multidisciplinary approach. This work describes the time, personnel, and materials involved in implementation as well as staff-reported safety benefits of quality improvement checklists. METHODS AND MATERIALS: Quality improvement was achieved using a department-wide multidisciplinary approach. Process mapping of the entire HDR program, from initial scheduling through follow-up, was performed. The scope of the project was narrowed to the point of treatment delivery. Two types of multidisciplinary checklists were created: a safety-timeout checklist to ensure safety-critical actions were performed before treatment initiation; and detailed procedure checklists that served as written procedures for physicians, physicists, dosimetrists, and nurses. Implementation was carried out through initial training led by various staff members, creation of visual training guides, piloting and use of checklists for all treatments, and auditing of checklist compliance. RESULTS: Process maps of the entire HDR program were generated and used to guide subsequent changes in the treatment delivery process. A single safety-timeout checklist and the individual procedure checklists were created and used at the time of treatment delivery. The 3-month audit showed that the safety-timeout checklist was used for 100% of treatment fractions. Individual procedure checklists were used for 85% of fractions. All cross-covering physicians and physicists continued to use these checklists 100% of the time. Staff survey results indicated improvements in safety and increased benefits for cross-covering staff. CONCLUSIONS: In using a multidisciplinary approach to quality improvement, process mapping and comprehensive checklists for HDR treatment delivery have been implemented. This has resulted in improved practices that are optimal in our department. This experience can provide others with practical strategies toward implementing such changes in their own facilities.

Safety of contralateral submandibular gland sparing in locally advanced oropharyngeal cancers: A multicenter review.

BACKGROUND: Previous groups have shown contralateral submandibular gland sparing to improve xerostomia with safe outcomes, but primarily in early-stage disease. In this study, we present a large cohort of patients with locally advanced head and neck cancer that underwent contralateral submandibular gland-sparing radiotherapy, to demonstrate feasibility and safety specifically in patients with locally advanced disease. METHODS: We retrospectively analyzed patients who were treated prospectively with contralateral submandibular gland sparing. Only patients who underwent bilateral neck radiotherapy with contralateral submandibular gland doses <39 Gy were included. RESULTS: We identified 71 patients. Approximately 80% of patients had ≥N2b disease. The contralateral submandibular gland mean dose was 33 Gy and, at a median follow-up of 27.3 months, no patients experienced treatment failure in the contralateral level IB lymph nodes. CONCLUSION: Xerostomia remains a significant morbidity despite parotid sparing and can be minimized further by contralateral submandibular gland sparing. These data provide important preliminary evidence that contralateral submandibular gland sparing is feasible and may be safe even in locally advanced cancers.

Dose painting to treat single-lobe prostate cancer with hypofractionated high-dose radiation using targeted external beam radiation: Is it feasible?

Targeted focal therapy strategies for treating single-lobe prostate cancer are under investigation. In this planning study, we investigate the feasibility of treating a portion of the prostate to full-dose external beam radiation with reduced dose to the opposite lobe, compared with full-dose radiation delivered to the entire gland using hypofractionated radiation. For 10 consecutive patients with low- to intermediate-risk prostate cancer, 2 hypofractionated, single-arc volumetric-modulated arc therapy (VMAT) plans were designed. The first plan (standard hypofractionation regimen [STD]) included the entire prostate gland, treated to 70 Gy delivered in 28 fractions. The second dose painting plan (DP) encompassed the involved lobe treated to 70 Gy delivered in 28 fractions, whereas the opposing, uninvolved lobe received 50.4 Gy in 28 fractions. Mean dose to the opposing neurovascular bundle (NVB) was considerably lower for DP vs STD, with a mean dose of 53.9 vs 72.3 Gy (p < 0.001). Mean penile bulb dose was 18.6 Gy for DP vs 19.2 Gy for STD (p = 0.880). Mean rectal dose was 21.0 Gy for DP vs 22.8 Gy for STD (p = 0.356). Rectum V70 (the volume receiving ≥70 Gy) was 2.01% for DP vs 2.74% for STD (p = 0.328). Bladder V70 was 1.69% for DP vs 2.78% for STD (p = 0.232). Planning target volume (PTV) maximum dose points were 76.5 and 76.3 Gy for DP and STD, respectively (p = 0.760). This study demonstrates the feasibility of using VMAT for partial-lobe prostate radiation in patients with prostate cancer involving 1 lobe. Partial-lobe prostate plans appeared to spare adjacent critical structures including the opposite NVB.

Calculating tumor trajectory and dose-of-the-day using cone-beam CT projections.

PURPOSE: Cone-beam CT (CBCT) projection images provide anatomical data in real-time over several respiratory cycles, forming a comprehensive picture of tumor movement. The authors developed and validated a method which uses these projections to determine the trajectory of and dose to highly mobile tumors during each fraction of treatment. METHODS: CBCT images of a respiration phantom were acquired, the trajectory of which mimicked a lung tumor with high amplitude (up to 2.5 cm) and hysteresis. A template-matching algorithm was used to identify the location of a steel BB in each CBCT projection, and a Gaussian probability density function for the absolute BB position was calculated which best fit the observed trajectory of the BB in the imager geometry. Two modifications of the trajectory reconstruction were investigated: first, using respiratory phase information to refine the trajectory estimation (Phase), and second, using the Monte Carlo (MC) method to sample the estimated Gaussian tumor position distribution. The accuracies of the proposed methods were evaluated by comparing the known and calculated BB trajectories in phantom-simulated clinical scenarios using abdominal tumor volumes. RESULTS: With all methods, the mean position of the BB was determined with accuracy better than 0.1 mm, and root-mean-square trajectory errors averaged 3.8% ± 1.1% of the marker amplitude. Dosimetric calculations using Phase methods were more accurate, with mean absolute error less than 0.5%, and with error less than 1% in the highest-noise trajectory. MC-based trajectories prevent the overestimation of dose, but when viewed in an absolute sense, add a small amount of dosimetric error (<0.1%). CONCLUSIONS: Marker trajectory and target dose-of-the-day were accurately calculated using CBCT projections. This technique provides a method to evaluate highly mobile tumors using ordinary CBCT data, and could facilitate better strategies to mitigate or compensate for motion during stereotactic body radiotherapy.

Fan-beam intensity modulated proton therapy.

PURPOSE: This paper presents a concept for a proton therapy system capable of delivering intensity modulated proton therapy using a fan beam of protons. This system would allow present and future gantry-based facilities to deliver state-of-the-art proton therapy with the greater normal tissue sparing made possible by intensity modulation techniques. METHODS: A method for producing a divergent fan beam of protons using a pair of electromagnetic quadrupoles is described and particle transport through the quadrupole doublet is simulated using a commercially available software package. To manipulate the fan beam of protons, a modulation device is developed. This modulator inserts or retracts acrylic leaves of varying thickness from subsections of the fan beam. Each subsection, or beam channel, creates what effectively becomes a beam spot within the fan area. Each channel is able to provide 0-255 mm of range shift for its associated beam spot, or stop the beam and act as an intensity modulator. Results of particle transport simulations through the quadrupole system are incorporated into the MCNPX Monte Carlo transport code along with a model of the range and intensity modulation device. Several design parameters were investigated and optimized, culminating in the ability to create topotherapy treatment plans using distal-edge tracking on both phantom and patient datasets. RESULTS: Beam transport calculations show that a pair of electromagnetic quadrupoles can be used to create a divergent fan beam of 200 MeV protons over a distance of 2.1 m. The quadrupole lengths were 30 and 48 cm, respectively, with transverse field gradients less than 20 T/m, which is within the range of water-cooled magnets for the quadrupole radii used. MCNPX simulations of topotherapy treatment plans suggest that, when using the distal edge tracking delivery method, many delivery angles are more important than insisting on narrow beam channel widths in order to obtain conformal target coverage. Overall, the sharp distal falloff of a proton depth-dose distribution was found to provide sufficient control over the dose distribution to meet objectives, even with coarse lateral resolution and channel widths as large as 2 cm. Treatment plans on both phantom and patient data show that dose conformity suffers when treatments are delivered from less than approximately ten angles. Treatment time for a sample prostate delivery is estimated to be on the order of 10 min, and neutron production is estimated to be comparable to that found for existing collimated systems. CONCLUSIONS: Fan beam proton therapy is a method of delivering intensity modulated proton therapy which may be employed as an alternative to magnetic scanning systems. A fan beam of protons can be created by a set of quadrupole magnets and modified by a dual-purpose range and intensity modulator. This can be used to deliver inversely planned treatments, with spot intensities optimized to meet user defined dose objectives. Additionally, the ability of a fan beam delivery system to effectively treat multiple beam spots simultaneously may provide advantages as compared to spot scanning deliveries.

A detailed evaluation of TomoDirect 3DCRT planning for whole-breast radiation therapy.

The goal of this work was to develop planning strategies for whole-breast radiotherapy (WBRT) using TomoDirect three-dimensional conformal radiation therapy (TD-3DCRT) and to compare TD-3DCRT with conventional 3DCRT and TD intensity-modulated radiation therapy (TD-IMRT) to evaluate differences in WBRT plan quality. Computed tomography (CT) images of 10 women were used to generate 150 WBRT plans, varying in target structures, field width (FW), pitch, and number of beams. Effects on target and external maximum doses (EMD), organ-at-risk (OAR) doses, and treatment time were assessed for each parameter to establish an optimal planning technique. Using this technique, TD-3DCRT plans were generated and compared with TD-IMRT and standard 3DCRT plans. FW 5.0cm with pitch = 0.250cm significantly decreased EMD without increasing lung V20Gy. Increasing number of beams from 2 to 6 and using an additional breast planning structure decreased EMD though increased lung V20Gy. Changes in pitch had minimal effect on plan metrics. TD-3DCRT plans were subsequently generated using FW 5.0cm, pitch = 0.250cm, and 2 beams, with additional beams or planning structures added to decrease EMD when necessary. TD-3DCRT and TD-IMRT significantly decreased target maximum dose compared to standard 3DCRT. FW 5.0cm with 2 to 6 beams or novel planning structures or both allow for TD-3DCRT WBRT plans with excellent target coverage and OAR doses. TD-3DCRT plans are comparable to plans generated using TD-IMRT and provide an alternative to conventional 3DCRT for WBRT.

MRI patterns of T1 enhancing radiation necrosis versus tumour recurrence in high-grade gliomas.

INTRODUCTION: Despite the emergence of new imaging technologies, the differentiation of treatment-related changes from recurrent tumour in patients with high-grade gliomas remains a difficult challenge. We evaluated whether specific MRI (magnetic resonance imaging) T1 post-contrast enhancement patterns can help to distinguish between radiation necrosis and tumour recurrence. METHODS: This study was approved by local institutional review board. Fifty-one patients with World Health Organization grade III-IV glioma underwent reoperation after prior chemoradiation. The percentage of radiation necrosis versus recurrent tumour in reoperation specimens was estimated by an experienced neuropathologist. Enhancement patterns on T1 post-contrast sequences from the MRIs obtained prior to reoperation were evaluated according to pathology. RESULTS: T1 contrast enhancement patterns correlating with recurrent tumour included focal solid nodules and solid uniform enhancement with distinct margins. Eighty-five per cent (17/20) of patients with ≥70% recurrent tumour at reoperation demonstrated one of these patterns on preoperative MRI. Enhancement patterns correlating with radiation necrosis included a hazy mesh-like diffuse enhancement and rim enhancement with feathery indistinct margins. Ninety-four per cent (17/18) of patients with ≥70% radiation necrosis demonstrated one of these two patterns. Thirteen cases had more mixed pathology (>30% of tumour/necrosis) and demonstrated patterns associated with recurrence and/or necrosis. Compared to MR spectroscopy performed in 10 patients, enhancement patterns on MRI were just as accurate in predicting pathologic diagnosis. CONCLUSION: Identifying distinct patterns of contrast enhancement on MRI may help to differentiate between radiation necrosis and tumour recurrence in high-grade gliomas.

A generalized 2D pencil beam scaling algorithm for proton dose calculation in heterogeneous slab geometries.

PURPOSE: Pencil beam algorithms are commonly used for proton therapy dose calculations. Szymanowski and Oelfke ["Two-dimensional pencil beam scaling: An improved proton dose algorithm for heterogeneous media," Phys. Med. Biol. 47, 3313-3330 (2002)] developed a two-dimensional (2D) scaling algorithm which accurately models the radial pencil beam width as a function of depth in heterogeneous slab geometries using a scaled expression for the radial kernel width in water as a function of depth and kinetic energy. However, an assumption made in the derivation of the technique limits its range of validity to cases where the input expression for the radial kernel width in water is derived from a local scattering power model. The goal of this work is to derive a generalized form of 2D pencil beam scaling that is independent of the scattering power model and appropriate for use with any expression for the radial kernel width in water as a function of depth. METHODS: Using Fermi-Eyges transport theory, the authors derive an expression for the radial pencil beam width in heterogeneous slab geometries which is independent of the proton scattering power and related quantities. The authors then perform test calculations in homogeneous and heterogeneous slab phantoms using both the original 2D scaling model and the new model with expressions for the radial kernel width in water computed from both local and nonlocal scattering power models, as well as a nonlocal parameterization of Molière scattering theory. In addition to kernel width calculations, dose calculations are also performed for a narrow Gaussian proton beam. RESULTS: Pencil beam width calculations indicate that both 2D scaling formalisms perform well when the radial kernel width in water is derived from a local scattering power model. Computing the radial kernel width from a nonlocal scattering model results in the local 2D scaling formula under-predicting the pencil beam width by as much as 1.4 mm (21%) at the depth of the Bragg peak for a 220 MeV proton beam in homogeneous water. This translates into a 32% dose discrepancy for a 5 mm Gaussian proton beam. Similar trends were observed for calculations made in heterogeneous slab phantoms where it was also noted that errors tend to increase with greater beam penetration. The generalized 2D scaling model performs well in all situations, with a maximum dose error of 0.3% at the Bragg peak in a heterogeneous phantom containing 3 cm of hard bone. CONCLUSIONS: The authors have derived a generalized form of 2D pencil beam scaling which is independent of the proton scattering power model and robust to the functional form of the radial kernel width in water used for the calculations. Sample calculations made with this model show excellent agreement with expected values in both homogeneous water and heterogeneous phantoms.

Sparing the larynx and esophageal inlet expedites feeding tube removal in patients with stage III-IV oropharyngeal squamous cell carcinoma treated with intensity-modulated radiotherapy.

OBJECTIVES/HYPOTHESIS: To evaluate the effect of larynx and esophageal inlet sparing on dysphagia recovery after intensity-modulated radiotherapy (IMRT) for stage III-IV oropharyngeal squamous cell carcinoma. STUDY DESIGN: Retrospective study. METHODS: Of 88 patients treated with IMRT, 38 were planned with a larynx + esophageal inlet mean dose <50 Gy constraint, 27 with a larynx alone mean dose constraint of <50 Gy, and 23 without a larynx/esophagus constraint. All had a percutaneous endoscopic gastrostomy (PEG) tube placed before IMRT, which was removed when the patient could swallow and maintain weight. All IMRT plans were retrieved, and the larynx; esophageal inlet; and superior, middle, and inferior constrictors were contoured. Dosimetric data were correlated with PEG tube dependence duration. RESULTS: The PEG tube was removed within 3, 6, 9, and 12 months after IMRT in 24%, 61%, 71%, and 83% of patients, respectively. Median times to PEG tube removal were 3.7 and 8.6 months (P = .0029) in patients planned with or without a larynx/larynx + esophageal inlet dose constraint. A mean dose to the larynx + esophageal inlet of ≤60 Gy reduced the median PEG tube duration from 10.8 to 6.1 months (P = .02), compared to >60 Gy. Mean pharyngeal constrictor doses in patients receiving a mean dose to the larynx + esophageal inlet of ≤50 Gy versus >50 Gy were: 60 Gy and 69 Gy, 55 Gy and 67 Gy, and 47 Gy and 57 Gy, for the superior, middle, and inferior constrictors, respectively (P < .0001). CONCLUSIONS: A dose constraint on the larynx and esophageal inlet during IMRT planning reduces dose to pharyngeal constrictors and expedites PEG tube removal.

High-dose MVCT image guidance for stereotactic body radiation therapy.

PURPOSE: Stereotactic body radiation therapy (SBRT) is a potent treatment for early stage primary and limited metastatic disease. Accurate tumor localization is essential to administer SBRT safely and effectively. Tomotherapy combines helical IMRT with onboard megavoltage CT (MVCT) imaging and is well suited for SBRT; however, MVCT results in reduced soft tissue contrast and increased image noise compared with kilovoltage CT. The goal of this work was to investigate the use of increased imaging doses on a clinical tomotherapy machine to improve image quality for SBRT image guidance. METHODS: Two nonstandard, high-dose imaging modes were created on a tomotherapy machine by increasing the linear accelerator (LINAC) pulse rate from the nominal setting of 80 Hz, to 160 Hz and 300 Hz, respectively. Weighted CT dose indexes (wCTDIs) were measured for the standard, medium, and high-dose modes in a 30 cm solid water phantom using a calibrated A1SL ion chamber. Image quality was assessed from scans of a customized image quality phantom. Metrics evaluated include: contrast-to-noise ratios (CNRs), high-contrast spatial resolution, image uniformity, and percent image noise. In addition, two patients receiving SBRT were localized using high-dose MVCT scans. Raw detector data collected after each scan were used to reconstruct standard-dose images for comparison. RESULTS: MVCT scans acquired using a pitch of 1.0 resulted in wCTDI values of 2.2, 4.7, and 8.5 cGy for the standard, medium, and high-dose modes respectively. CNR values for both low and high-contrast materials were found to increase with the square root of dose. Axial high-contrast spatial resolution was comparable for all imaging modes at 0.5 lp∕mm. Image uniformity was improved and percent noise decreased as the imaging dose increased. Similar improvements in image quality were observed in patient images, with decreases in image noise being the most notable. CONCLUSIONS: High-dose imaging modes are made possible on a clinical tomotherapy machine by increasing the LINAC pulse rate. Increasing the imaging dose results in increased CNRs; making it easier to distinguish the boundaries of low contrast objects. The imaging dose levels observed in this work are considered acceptable at our institution for SBRT treatments delivered in 3-5 fractions.

Normal liver tissue density dose response in patients treated with stereotactic body radiation therapy for liver metastases.

PURPOSE: To evaluate the temporal dose response of normal liver tissue for patients with liver metastases treated with stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Ninety-nine noncontrast follow-up computed tomography (CT) scans of 34 patients who received SBRT between 2004 and 2011 were retrospectively analyzed at a median of 8 months post-SBRT (range, 0.7-36 months). SBRT-induced normal liver tissue density changes in follow-up CT scans were evaluated at 2, 6, 10, 15, and 27 months. The dose distributions from planning CTs were mapped to follow-up CTs to relate the mean Hounsfield unit change (ΔHU) to dose received over the range 0-55 Gy in 3-5 fractions. An absolute density change of 7 HU was considered a significant radiographic change in normal liver tissue. RESULTS: Increasing radiation dose was linearly correlated with lower post-SBRT liver tissue density (slope, -0.65 ΔHU/5 Gy). The threshold for significant change (-7 ΔHU) was observed in the range of 30-35 Gy. This effect did not vary significantly over the time intervals evaluated. CONCLUSIONS: SBRT induces a dose-dependent and relatively time-independent hypodense radiation reaction within normal liver tissue that is characterized by a decrease of >7 HU in liver density for doses >30-35 Gy.

Fluorodeoxyglucose positron emission tomography response and normal tissue regeneration after stereotactic body radiotherapy to liver metastases.

PURPOSE: To characterize changes in standardized uptake value (SUV) in positron emission tomography (PET) scans and determine the pace of normal tissue regeneration after stereotactic body radiation therapy (SBRT) for solid tumor liver metastases. METHODS AND MATERIALS: We reviewed records of patients with liver metastases treated with SBRT to ≥40 Gy in 3-5 fractions. Evaluable patients had pretreatment PET and ≥1 post-treatment PET. Each PET/CT scan was fused to the planning computed tomography (CT) scan. The maximum SUV (SUV(max)) for each lesion and the total liver volume were measured on each PET/CT scan. Maximum SUV levels before and after SBRT were recorded. RESULTS: Twenty-seven patients with 35 treated liver lesions were studied. The median follow-up was 15.7 months (range, 1.5-38.4 mo), with 5 PET scans per patient (range, 2-14). Exponential decay curve fitting (r=0.97) showed that SUV(max) declined to a plateau of 3.1 for controlled lesions at 5 months after SBRT. The estimated SUV(max) decay half-time was 2.0 months. The SUV(max) in controlled lesions fluctuated up to 4.2 during follow-up and later declined; this level is close to 2 standard deviations above the mean normal liver SUV(max) (4.01). A failure cutoff of SUV(max) ≥6 is twice the calculated plateau SUV(max) of controlled lesions. Parenchymal liver volume decreased by 20% at 3-6 months and regenerated to a new baseline level approximately 10% below the pretreatment level at 12 months. CONCLUSIONS: Maximum SUV decreases over the first months after SBRT to plateau at 3.1, similar to the median SUV(max) of normal livers. Transient moderate increases in SUV(max) may be observed after SBRT. We propose a cutoff SUV(max) ≥6, twice the baseline normal liver SUV(max), to score local failure by PET criteria. Post-SBRT values between 4 and 6 would be suspicious for local tumor persistence or recurrence. The volume of normal liver reached nadir 3-6 months after SBRT and regenerated within the next 6 months.

TomoTherapy MLC verification using exit detector data.

PURPOSE: Treatment delivery verification (DV) is important in the field of intensity modulated radiation therapy (IMRT). While IMRT and image guided radiation therapy (IGRT), allow us to create more conformal plans and enables the use of tighter margins, an erroneously executed plan can have detrimental effects on the treatment outcome. The purpose of this study is to develop a DV technique to verify TomoTherapy's multileaf collimator (MLC) using the onboard mega-voltage CT detectors. METHODS: The proposed DV method uses temporal changes in the MVCT detector signal to predict actual leaf open times delivered on the treatment machine. Penumbra and scattered radiation effects may produce confounding results when determining leaf open times from the raw detector data. To reduce the impact of the effects, an iterative, Richardson-Lucy (R-L) deconvolution algorithm is applied. Optical sensors installed on each MLC leaf are used to verify the accuracy of the DV technique. The robustness of the DV technique is examined by introducing different attenuation materials in the beam. Additionally, the DV technique has been used to investigate several clinical plans which failed to pass delivery quality assurance (DQA) and was successful in identifying MLC timing discrepancies as the root cause. RESULTS: The leaf open time extracted from the exit detector showed good agreement with the optical sensors under a variety of conditions. Detector-measured leaf open times agreed with optical sensor data to within 0.2 ms, and 99% of the results agreed within 8.5 ms. These results changed little when attenuation was added in the beam. For the clinical plans failing DQA, the dose calculated from reconstructed leaf open times played an instrumental role in discovering the root-cause of the problem. Throughout the retrospective study, it is found that the reconstructed dose always agrees with measured doses to within 1%. CONCLUSIONS: The exit detectors in the TomoTherapy treatment systems can provide valuable information about MLC behavior during delivery. A technique to estimate the TomoTherapy binary MLC leaf open time from exit detector signals is described. This technique is shown to be both robust and accurate for delivery verification.

Estimated radiation pneumonitis risk after photon versus proton therapy alone or combined with chemotherapy for lung cancer.

BACKGROUND: Traditionally, radiation therapy plans are optimized without consideration of chemotherapy. Here, we model the risk of radiation pneumonitis (RP) in the presence of a possible interaction between chemotherapy and radiation dose distribution. MATERIAL AND METHODS: Three alternative treatment plans are compared in 18 non-small cell lung cancer patients previously treated with helical tomotherapy; the tomotherapy plan, an intensity modulated proton therapy plan (IMPT) and a three dimensional conformal radiotherapy (3D-CRT) plan. All plans are optimized without consideration of the chemotherapy effect. The effect of chemotherapy is modeled as an independent cell killing process using a uniform chemotherapy equivalent radiation dose (CERD) added to the entire organ at risk. We estimate the risk of grade 3 or higher RP (G3RP) using the critical volume model. RESULTS: The mean risk of clinical G3RP at zero CERD is 5% for tomotherapy (range: 1-18 %) and 14% for 3D-CRT (range 2-49%). When the CERD exceeds 9 Gy, however, the risk of RP with the tomotherapy plans become higher than the 3D-CRT plans. The IMPT plans are less toxic both at zero CERD (mean 2%, range 1-5%) and at CERD = 10 Gy (mean 7%, range 1-28%). Tomotherapy yields a lower risk of RP than 3D-CRT for 17/18 patients at zero CERD, but only for 7/18 patients at CERD = 10 Gy. IMPT gives the lowest risk of all plans for 17/18 patients at zero CERD and for all patients with CERD = 10 Gy. CONCLUSIONS: The low dose bath from highly conformal photon techniques may become relevant for lung toxicity when radiation is combined with cytotoxic chemotherapy as shown here. Proton therapy allows highly conformal delivery while minimizing the low dose bath potentially interacting with chemotherapy. Thus, intensive drug-radiation combinations could be an interesting indication for selecting patients for proton therapy. It is likely that the IMRT plans would perform better if the CERD was accounted for during optimization, but more clinical data is required to facilitate evidence-based plan optimization in the multi-modality setting.