BIOGUIDE-X: A First-in-Human Study of the Performance of Positron Emission Tomography-Guided Radiation Therapy.

PURPOSE: Positron emission tomography (PET)-guided radiation therapy is a novel tracked dose delivery modality that uses real-time PET to guide radiation therapy beamlets. The BIOGUIDE-X study was performed with sequential cohorts of participants to (1) identify the fluorodeoxyglucose (FDG) dose for PET-guided therapy and (2) confirm that the emulated dose distribution was consistent with a physician-approved radiation therapy plan. METHODS AND MATERIALS: This prospective study included participants with at least 1 FDG-avid targetable primary or metastatic tumor (2-5 cm) in the lung or bone. For cohort I, a modified 3 + 3 design was used to determine the FDG dose that would result in adequate signal for PET-guided therapy. For cohort II, PET imaging data were collected on the X1 system before the first and last fractions among patients undergoing conventional stereotactic body radiation therapy. PET-guided therapy dose distributions were modeled on the patient's computed tomography anatomy using the collected PET data at each fraction as input to an "emulated delivery" and compared with the physician-approved plan. RESULTS: Cohort I demonstrated adequate FDG activity in 6 of 6 evaluable participants (100.0%) with the first injected dose level of 15 mCi FDG. In cohort II, 4 patients with lung tumors and 5 with bone tumors were enrolled, and evaluable emulated delivery data points were collected for 17 treatment fractions. Sixteen of the 17 emulated deliveries resulted in dose distributions that were accurate with respect to the approved PET-guided therapy plan. The 17th data point was just below the 95% threshold for accuracy (dose-volume histogram score = 94.6%). All emulated fluences were physically deliverable. No toxicities were attributed to multiple FDG administrations. CONCLUSIONS: PET-guided therapy is a novel radiation therapy modality in which a radiolabeled tumor can act as its own fiducial for radiation therapy targeting. Emulated therapy dose distributions calculated from continuously acquired real-time PET data were accurate and machine-deliverable in tumors that were 2 to 5 cm in size with adequate FDG signal characteristics.

The potential of biology-guided radiation therapy in thoracic cancer: A preliminary treatment planning study.

Purpose: We investigated the feasibility of biology-guided radiotherapy (BgRT), a technique that utilizes real-time positron emission imaging to minimize tumor motion uncertainties, to spare nearby organs at risk. Methods: Volumetric modulated arc therapy (VMAT), intensity-modulated proton (IMPT) therapy, and BgRT plans were created for a paratracheal node recurrence (case 1; 60 Gy in 10 fractions) and a primary peripheral left upper lobe adenocarcinoma (case 2; 50 Gy in four fractions). Results: For case 1, BgRT produced lower bronchus V40 values compared to VMAT and IMPT. For case 2, total lung V20 was lower in the BgRT case compared to VMAT and IMPT. Conclusions: BgRT has the potential to reduce the radiation dose to proximal critical structures but requires further detailed investigation.

The technical design and concept of a PET/CT linac for biology-guided radiotherapy.

This is a summary of the design and concept of the RefleXion X1, a system for biology-guided radiotherapy (BgRT). This system is a multi-modal tomography (PET, fan-beam kVCT, and MVD) treatment machine that utilizes imaging and therapy planes for optimized beam delivery of IMRT, SBRT, SRS, and BgRT radiotherapy regimens. For BgRT delivery specifically, annihilation photons emanating outward from a PET-avid tumor are used to guide the delivery of beamlets of radiation to the tumor at sub-second latency. With the integration of PET detectors, rapid beam-station delivery, real-time tracking, and high-frequency multi-leaf collimation, the BgRT system has the potential to deliver a highly conformal treatment to malignant lesions while minimizing dose to surrounding healthy tissues. Furthermore, the potential use of a single radiotracer injection to guide radiotherapy to multiple targets opens avenues for debulking in advanced and metastatic disease states.

Biology-guided radiotherapy: redefining the role of radiotherapy in metastatic cancer.

The emerging biological understanding of metastatic cancer and proof-of-concept clinical trials suggest that debulking all gross disease holds great promise for improving patient outcomes. However, ablation of multiple targets with conventional external beam radiotherapy systems is burdensome, which limits investigation and utilization of complete metastatic ablation in the majority of patients with advanced disease. To overcome this logistical hurdle, technical innovation is necessary. Biology-guided radiotherapy (BgRT) is a new external beam radiotherapy delivery modality combining positron emission tomography-computed tomography (PET-CT) with a 6 MV linear accelerator. The key innovation is continuous response of the linear accelerator to outgoing tumor PET emissions with beamlets of radiotherapy at subsecond latency. This allows the deposited dose to track tumors in real time. Multiple new hardware and algorithmic advances further facilitate this low-latency feedback process. By transforming tumors into their own fiducials after intravenous injection of a radiotracer, BgRT has the potential to enable complete metastatic ablation in a manner efficient for a single patient and scalable to entire populations with metastatic disease. Future trends may further enhance the utility of BgRT in the clinic as this technology dovetails with other innovations in radiotherapy, including novel dose painting and fractionation schemes, radiomics, and new radiotracers.

The potential of positron emission tomography for intratreatment dynamic lung tumor tracking: a phantom study.

PURPOSE: This study aims to evaluate the potential and feasibility of positron emission tomography for dynamic lung tumor tracking during radiation treatment. The authors propose a center of mass (CoM) tumor tracking algorithm using gated-PET images combined with a respiratory monitor and investigate the geometric accuracy of the proposed algorithm. METHODS: The proposed PET dynamic lung tumor tracking algorithm estimated the target position information through the CoM of the segmented target volume on gated PET images reconstructed from accumulated coincidence events. The information was continuously updated throughout a scan based on the assumption that real-time processing was supported (actual processing time at each frame ≈ 10 s). External respiratory motion and list-mode PET data were acquired from a phantom programmed to move with measured respiratory traces (external respiratory motion and internal target motion) from human subjects, for which the ground truth target position was known as a function of time. The phantom was cylindrical with six hollow sphere targets (10, 13, 17, 22, 28, and 37 mm in diameter). The measured respiratory traces consisted of two sets: (1) 1D-measured motion from ten healthy volunteers and (2) 3D-measured motion from four lung cancer patients. The authors evaluated the geometric accuracy of the proposed algorithm by quantifying estimation errors (Euclidean distance) between the actual motion of targets (1D-motion and 3D-motion traces) and CoM trajectories estimated by the proposed algorithm as a function of time. RESULTS: The time-averaged error of 1D-motion traces over all trajectories of all targets was 1.6 mm. The error trajectories decreased with time as coincidence events were accumulated. The overall error trajectory of 1D-motion traces converged to within 2 mm in approximately 90 s. As expected, more accurate results were obtained for larger targets. For example, for the 37 mm target, the average error over all 1D-motion traces was 1.1 mm; and for the 10 mm target, the average error over all 1D-motion traces was 2.8 mm. The overall time-averaged error of 3D-motion traces was 1.6 mm, which was comparable to that of the 1D-motion traces. There were small variations in the errors between the 3D-motion traces, although the motion trajectories were very different. The accuracy of the estimates was consistent for all targets except for the smallest. CONCLUSIONS: The authors developed an algorithm for dynamic lung tumor tracking using list-mode PET data and a respiratory motion signal, and demonstrated proof-of-principle for PET-guided lung tumor tracking. The overall tracking error in phantom studies is less than 2 mm.

Toward a planning scheme for emission guided radiation therapy (EGRT): FDG based tumor tracking in a metastatic breast cancer patient.

PURPOSE: Emission guided radiation therapy (EGRT) is a new modality that uses PET emissions in real-time for direct tumor tracking during radiation delivery. Radiation beamlets are delivered along positron emission tomography (PET) lines of response (LORs) by a fast rotating ring therapy unit consisting of a linear accelerator (Linac) and PET detectors. The feasibility of tumor tracking and a primitive modulation method to compensate for attenuation have been demonstrated using a 4D digital phantom in our prior work. However, the essential capability of achieving dose modulation as in conventional intensity modulated radiation therapy (IMRT) treatments remains absent. In this work, the authors develop a planning scheme for EGRT to accomplish sophisticated intensity modulation based on an IMRT plan while preserving tumor tracking. METHODS: The planning scheme utilizes a precomputed LOR response probability distribution to achieve desired IMRT planning modulation with effects of inhomogeneous attenuation and nonuniform background activity distribution accounted for. Evaluation studies are performed on a 4D digital patient with a simulated lung tumor and a clinical patient who has a moving breast cancer metastasis in the lung. The Linac dose delivery is simulated using a voxel-based Monte Carlo algorithm. The IMRT plan is optimized for a planning target volume (PTV) that encompasses the tumor motion using the MOSEK package and a Pinnacle3™ workstation (Philips Healthcare, Fitchburg, WI) for digital and clinical patients, respectively. To obtain the emission data for both patients, the Geant4 application for tomographic emission (GATE) package and a commercial PET scanner are used. As a comparison, 3D and helical IMRT treatments covering the same PTV based on the same IMRT plan are simulated. RESULTS: 3D and helical IMRT treatments show similar dose distribution. In the digital patient case, compared with the 3D IMRT treatment, EGRT achieves a 15.1% relative increase in dose to 95% of the gross tumor volume (GTV) and a 31.8% increase to 50% of the GTV. In the patient case, EGRT yields a 15.2% relative increase in dose to 95% of the GTV and a 20.7% increase to 50% of the GTV. The organs at risk (OARs) doses are kept similar or lower for EGRT in both cases. Tumor tracking is observed in the presence of planning modulation in all EGRT treatments. CONCLUSIONS: As compared to conventional IMRT treatments, the proposed EGRT planning scheme allows an escalated target dose while keeping dose to the OARs within the same planning limits. With the capabilities of incorporating planning modulation and accurate tumor tracking, EGRT has the potential to greatly improve targeting in radiation therapy and enable a practical and effective implementation of 4D radiation therapy for planning and delivery.

Emission guided radiation therapy for lung and prostate cancers: a feasibility study on a digital patient.

PURPOSE: Accurate tumor tracking remains a challenge in current radiation therapy. Many strategies including image guided radiation therapy alleviate the problem to certain extents. The authors propose a new modality called emission guided radiation therapy (EGRT) to accurately and directly track the tumor based on its biological signature. This work is to demonstrate the feasibility of EGRT under two clinical scenarios using a 4D digital patient model. METHODS: EGRT uses lines of response (LOR's) from positron emission events to direct beamlets of therapeutic radiation through the emission sites inside a tumor. This is accomplished by a radiation delivery system consisting of a Linac and positron emission tomography (PET) detectors on a fast rotating closed-ring gantry. During the treatment of radiotracer-administrated cancer patients, PET detectors collect LOR's from tumor uptake sites and the Linac responds in nearly real-time with beamlets of radiation along the same LOR paths. Moving tumors are therefore treated with a high targeting accuracy. Based on the EGRT concept, the authors design a treatment method with additional modulation algorithms including attenuation correction and an integrated boost scheme. Performance is evaluated using simulations of a lung tumor case with 3D motion and a prostate tumor case with setup errors. The emission process is simulated by Geant4 Application for Tomographic Emission package (GATE) and Linac dose delivery is simulated using a voxel-based Monte Carlo algorithm (VMC++). RESULTS: In the lung case with attenuation correction, compared to a conventional helical treatment, EGRT achieves a 41% relative increase in dose to 95% of the gross tumor volume (GTV) and a 55% increase to 50% of the GTV. All dose distributions are normalized for the same dose to the lung. In the prostate case with the integrated boost and no setup error, EGRT yields a 19% and 55% relative dose increase to 95% and 50% of the GTV, respectively, when all methods are normalized for the same dose to the rectum. In the prostate case with integrated boost where setup error is present, EGRT contributes a 21% and 52% relative dose increase to 95% and 50% of the GTV, respectively. CONCLUSIONS: As a new radiation therapy modality with inherent tumor tracking, EGRT has the potential to substantially improve targeting in radiation therapy in the presence of intrafractional and interfractional motion.

Fourier properties of the fan-beam sinogram.

PURPOSE: P. R. Edholm, R. M. Lewitt, and B. Lindholm, "Novel properties of the Fourier decomposition of the sinogram," in Proceedings of the International Workshop on Physics and Engineering of Computerized Multidimensional Imaging and Processing [Proc. SPIE 671, 8-18 (1986)] described properties of a parallel beam projection sinogram with respect to its radial and angular frequencies. The purpose is to perform a similar derivation to arrive at corresponding properties of a fan-beam projection sinogram for both the equal-angle and equal-spaced detector sampling scenarios. METHODS: One of the derived properties is an approximately zero-energy region in the two-dimensional Fourier transform of the full fan-beam sinogram. This region is in the form of a double-wedge, similar to the parallel beam case, but different in that it is asymmetric with respect to the frequency axes. The authors characterize this region for a point object and validate the derived properties in both a simulation and a head CT data set. The authors apply these results in an application using algebraic reconstruction. RESULTS: In the equal-angle case, the domain of the zero region is (q,k) for which / k/(k-q) / > R/L, where q and k are the frequency variables associated with the detector and view angular positions, respectively, R is the radial support of the object, and L is the source-to-isocenter distance. A filter was designed to retain only sinogram frequencies corresponding to a specified radial support. The filtered sinogram was used to reconstruct the same radial support of the head CT data. As an example application of this concept, the double-wedge filter was used to computationally improve region of interest iterative reconstruction. CONCLUSIONS: Interesting properties of the fan-beam sinogram exist and may be exploited in some applications.

Fourier rebinning algorithm for inverse geometry CT.

Inverse geometry computed tomography (IGCT) is a new type of volumetric CT geometry that employs a large array of x-ray sources opposite a smaller detector array. Volumetric coverage and high isotropic resolution produce very large data sets and therefore require a computationally efficient three-dimensional reconstruction algorithm. The purpose of this work was to adapt and evaluate a fast algorithm based on Defrise's Fourier rebinning (FORE), originally developed for positron emission tomography. The results were compared with the average of FDK reconstructions from each source row. The FORE algorithm is an order of magnitude faster than the FDK-type method for the case of 11 source rows. In the center of the field-of-view both algorithms exhibited the same resolution and noise performance. FORE exhibited some resolution loss (and less noise) in the periphery of the field-of-view. FORE appears to be a fast and reasonably accurate reconstruction method for IGCT.

Reduction of truncation artifacts in rapid 3D articular cartilage imaging.

PURPOSE: To reduce Gibbs ringing artifact in three-dimensional (3D) articular knee cartilage imaging with linear prediction (LP). MATERIALS AND METHODS: A reconstruction method using LP in 3D was applied to truncated data sets of six healthy knees. The technique first linearizes the data before applying the prediction algorithm. Three radiologists blindly reviewed and ranked images of the full, truncated, and predicted data sets. Statistical analysis of the radiologists' reviews was performed for image quality, clinical acceptability of the images, and equivalence with the gold standard. RESULTS: LP applied to 3D knee cartilage imaging allows for 40% decreased scan time while providing image quality with statistical equivalence to a full data set. CONCLUSION: 3D spoiled gradient echo imaging (SPGR) knee cartilage imaging requires significant scan time. This 40% reduction in scan time will allow such scans to be more feasible without sacrificing clinical acceptability.

Inverse-geometry volumetric CT system with multiple detector arrays for wide field-of-view imaging.

Current volumetric computed tomography (CT) methods require seconds to acquire a thick volume (>8 cm) with high resolution. Inverse-geometry CT (IGCT) is a new system geometry under investigation that is anticipated to be able to image a thick volume in a single gantry rotation with isotropic resolution and no cone-beam artifacts. IGCT employs a large array of source spots opposite a smaller detector array. The in-plane field of view (FOV) is primarily determined by the size of the source array, in much the same way that the FOV is determined by the size of the detector array in a conventional CT system. Thus, the size of the source array can be a limitation on the achievable FOV. We propose adding additional detector arrays, spaced apart laterally, to increase the in-plane FOV while still using a modestly sized source array. We determine optimal detector placement to maximize the FOV while obtaining relatively uniform sampling. We also demonstrate low wasted radiation of the proposed system through design and simulation of a pre-patient collimator. Reconstructions from simulated projection data show no artifacts when combining the data from the detector arrays. Finally, to demonstrate feasibility of the concept, an anthropomorphic thorax phantom containing a porcine heart was scanned on a prototype table-top system. The reconstructed axial images demonstrate a 45 cm in-plane FOV using a 23 cm source array.

A prototype table-top inverse-geometry volumetric CT system.

A table-top volumetric CT system has been implemented that is able to image a 5-cm-thick volume in one circular scan with no cone-beam artifacts. The prototype inverse-geometry CT (IGCT) scanner consists of a large-area, scanned x-ray source and a detector array that is smaller in the transverse direction. The IGCT geometry provides sufficient volumetric sampling because the source and detector have the same axial, or slice direction, extent. This paper describes the implementation of the table-top IGCT scanner, which is based on the NexRay Scanning-Beam Digital X-ray system (NexRay, Inc., Los Gatos, CA) and an investigation of the system performance. The alignment and flat-field calibration procedures are described, along with a summary of the reconstruction algorithm. The resolution and noise performance of the prototype IGCT system are studied through experiments and further supported by analytical predictions and simulations. To study the presence of cone-beam artifacts, a "Defrise" phantom was scanned on both the prototype IGCT scanner and a micro CT system with a +/-5 cone angle for a 4.5-cm volume thickness. Images of inner ear specimens are presented and compared to those from clinical CT systems. Results showed that the prototype IGCT system has a 0.25-mm isotropic resolution and that noise comparable to that from a clinical scanner with equivalent spatial resolution is achievable. The measured MTF and noise values agreed reasonably well with theoretical predictions and computer simulations. The IGCT system was able to faithfully reconstruct the laminated pattern of the Defrise phantom while the micro CT system suffered severe cone-beam artifacts for the same object. The inner ear acquisition verified that the IGCT system can image a complex anatomical object, and the resulting images exhibited more high-resolution details than the clinical CT acquisition. Overall, the successful implementation of the prototype system supports the IGCT concept for single-rotation volumetric scanning free from cone-beam artifacts.