Demonstration of real-time positron emission tomography biology-guided radiotherapy delivery to targets.

BACKGROUND: Biology-guided radiotherapy (BgRT) is a novel technology that uses positron emission tomography (PET) data to direct radiotherapy delivery in real-time. BgRT enables the precise delivery of radiation doses based on the PET signals emanating from PET-avid tumors on the fly. In this way, BgRT uniquely utilizes radiotracer uptake as a biological beacon for controlling and adjusting dose delivery in real-time to account for target motion. PURPOSE: To demonstrate using real-time PET for BgRT delivery on the RefleXion X1 radiotherapy machine. The X1 radiotherapy machine is a rotating ring-gantry radiotherapy system that generates a nominal 6MV photon beam, PET, and computed tomography (CT) components. The system utilizes emitted photons from PET-avid targets to deliver effective radiation beamlets or pulses to the tumor in real-time. METHODS: This study demonstrated a real-time PET BgRT delivery experiment under three scenarios. These scenarios included BgRT delivering to (S1 ) a static target in a homogeneous and heterogeneous environment, (S2 ) a static target with a hot avoidance structure and partial PET-avid target, and (S3 ) a moving target. The first step was to create stereotactic body radiotherapy (SBRT) and BgRT plans (offline PET data supported) using RefleXion's custom-built treatment planning system (TPS). Additionally, to create a BgRT plan using PET-guided delivery, the targets were filled with 18F-Fluorodeoxyglucose (FDG), which represents a tumor/target, that is, PET-avid. The background materials were created in the insert with homogeneous water medium (for S1 ) and heterogeneous water with styrofoam mesh medium. A heterogeneous background medium simulated soft tissue surrounding the tumor. The treatment plan was then delivered to the experimental setups using a pre-commercial version of the X1 machine. As a final step, the dosimetric accuracy for S1 and S2 was assessed using the ArcCheck analysis tool-the gamma criteria of 3%/3 mm. For S3 , the delivery dose was quantified using EBT-XD radiochromic film. The accuracy criteria were based on coverage, where 100% of the clinical target volume (CTV) receives at least 97% of the prescription dose, and the maximum dose in the CTV was ≤130% of the maximum planned dose (97 % ≤ CTV ≤ 130%). RESULTS: For the S1, both SBRT and BgRT deliveries had gamma pass rates greater than 95% (SBRT range: 96.9%-100%, BgRT range: 95.2%-98.9%), while in S2 , the gamma pass rate was 98% for SBRT and between 95.2% and 98.9% for BgRT plan delivering. For S3 , both SBRT and BgRT motion deliveries met CTV dose coverage requirements, with BgRT plans delivering a very high dose to the target. The CTV dose ranges were (a) SBRT:100.4%-120.4%, and (b) BgRT: 121.3%-139.9%. CONCLUSIONS: This phantom-based study demonstrated that PET signals from PET-avid tumors can be utilized to direct real-time dose delivery to the tumor accurately, which is comparable to the dosimetric accuracy of SBRT. Furthermore, BgRT delivered a PET-signal controlled dose to the moving target, equivalent to the dose distribution to the static target. A future study will compare the performance of BgRT with conventional image-guided radiotherapy.

Evaluation of fan-beam kilovoltage computed tomography image quality on a novel biological-guided radiotherapy platform.

Background and Purpose: A recently developed biology-guided radiotherapy platform, equipped with positron emission tomography (PET) and computed tomography (CT), provides both anatomical and functional image guidance for radiotherapy. This study aimed to characterize performance of the kilovoltage CT (kVCT) system on this platform using standard quality metrics measured on phantom and patient images, using CT simulator images as reference. Materials and Methods: Image quality metrics, including spatial resolution/modular transfer function (MTF), slice sensitivity profile (SSP), noise performance and image uniformity, contrast-noise ratio (CNR) and low-contrast resolution, geometric accuracy, and CT number (HU) accuracy, were evaluated on phantom images. Patient images were evaluated mainly qualitatively. Results: On phantom images the MTF10% is about 0.68 lp/mm for kVCT in PET/CT Linac. The SSP agreed with nominal slice thickness within 0.7 mm. The diameter of the smallest visible target (1% contrast) is about 5 mm using medium dose mode. The image uniformity is within 2.0 HU. The geometric accuracy tests passed within 0.5 mm. Relative to CT simulator images, the noise is generally higher and the CNR is lower in PET/CT Linac kVCT images. The CT number accuracy is comparable between the two systems with maximum deviation from the phantom manufacturer range within 25 HU. On patient images, higher spatial resolution and image noise are observed on PET/CT Linac kVCT images. Conclusions: Major image quality metrics of the PET/CT Linac kVCT were within vendor-recommended tolerances. Better spatial resolution but higher noise and better/comparable low contrast visibility were observed as compared to a CT simulator when images were acquired with clinical protocols.

Preclinical Evaluation of 89Zr-Panitumumab for Biology-Guided Radiation Therapy.

PURPOSE: Biology-guided radiation therapy (BgRT) uses real-time line-of-response data from on-board positron emission tomography (PET) detectors to guide beamlet delivery during therapeutic radiation. The current workflow requires 18F-fluorodeoxyglucose (FDG) administration daily before each treatment fraction. However, there are advantages to reducing the number of tracer injections by using a PET tracer with a longer decay time. In this context, we investigated 89Zr-panitumumab (89Zr-Pan), an antibody PET tracer with a half-life of 78 hours that can be imaged for up to 9 days using PET. METHODS AND MATERIALS: The BgRT workflow was evaluated preclinically in mouse colorectal cancer xenografts (HCT116) using small-animal positron emission tomography/computed tomography (PET/CT) for imaging and image-guided kilovoltage conformal irradiation for therapy. Mice (n = 5 per group) received 7 MBq of 89Zr-Pan as a single dose 2 weeks after tumor induction, with or without fractionated radiation therapy (RT; 6 × 6.6 Gy) to the tumor region. The mice were imaged longitudinally to assess the kinetics of the tracer over 9 days. PET images were then analyzed to determine the stability of the PET signal in irradiated tumors over time. RESULTS: Mice in the treatment group experienced complete tumor regression, whereas those in the control group were killed because of tumor burden. PET imaging of 89Zr-Pan showed well-delineated tumors with minimal background in both groups. On day 9 postinjection, tumor uptake of 89Zr-Pan was 7.2 ± 1.7 in the control group versus 5.2 ± 0.5 in the treatment group (mean percentage of injected dose per gram of tissue [%ID/g] ± SD; P = .07), both significantly higher than FDG uptake (1.1 ± 0.5 %ID/g) 1 hour postinjection. To assess BgRT feasibility, the clinical eligibility criteria was computed using human-equivalent uptake values that were extrapolated from preclinical PET data. Based on this semiquantitative analysis, BgRT may be feasible for 5 consecutive days after a single 740-MBq injection of 89Zr-Pan. CONCLUSIONS: This study indicates the potential of long-lived antibody-based PET tracers for guiding clinical BgRT.

Image-mode performance characterisation of a positron emission tomography subsystem designed for Biology-guided radiotherapy (BgRT).

OBJECTIVES: In this study, we characterise the imaging-mode performance of the positron emission tomography (PET) subsystem of the RefleXion X1 machine using the NEMA NU-2 2018 standard. METHODS: The X1 machine consists of two symmetrically opposing 900 arcs of PET detectors incorporated into the architecture of a ring-gantry linear accelerator rotating up to 60 RPM. PET emissions from a tumour are detected by the PET detectors and used to guide the delivery of radiation beam. Imaging performance of the PET subsystem on X1 machine was evaluated based on sensitivity of the PET detectors, spatial resolution, count-loss performance, image quality, and daily system performance check. RESULTS: PET subsystem sensitivity was measured as 0.183 and 0.161 cps/kBq at the center and off-center positions, respectively. Spatial resolution: average FWHM values of 4.3, 5.1, and 6.7 mm for the point sources at 1, 10, and 20 cm off center, respectively were recorded. For count loss, max NECR: 2.63 kcps, max true coincidence rate: 5.56 kcps, and scatter fraction: 39.8%. The 10 mm sphere was not visible. Image-quality contrast values were: 29.6%, 64.9%, 66.5%, 81.8%, 81.2%, and background variability: 14.8%, 12.4%, 10.3%, 8.8%, 8.3%, for the 13, 17, 22, 28, 37 mm sphere sizes, respectively. CONCLUSIONS: When operating in an imaging mode, the spatial resolution and image contrast of the X1 PET subsystem were comparable to those of typical diagnostic imaging systems for large spheres, while the sensitivity and count rate were lower due to the significantly smaller PET detector area in the X1 system. Clinical efficacy when used in BgRT remains to be validated. ADVANCES IN KNOWLEDGE: This is the first performance evaluation of the PET subsystem on the novel BgRT machine. The dual arcs rotating PET subsystem on RefleXion X1 machine performance is comparable to those of the typical diagnostic PET system based on the spatial resolution and image contrast for larger spheres.

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.

Intrafractional relationship changes between an external breathing signal and fiducial marker positions in pancreatic cancer patients.

BACKGROUND AND PURPOSE: The purpose of this study of pancreatic cancer patients treated with respiratory-guided stereotactic body radiotherapy (SBRT) on a standard linac was to investigate (a) the intrafractional relationship change (IRC) between a breathing signal and the tumor position, (b) the impact of IRC on the delivered dose, and (c) potential IRC predictors. MATERIALS AND METHODS: We retrospectively investigated 10 pancreatic cancer patients with 2-4 implanted fiducial markers in the tumor treated with SBRT. Fluoroscopic images were acquired before and after treatment delivery simultaneously with the abdominal breathing motion. We quantified the IRC as the change in fiducial location for a given breathing amplitude in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions from before to after treatment delivery. The treatment plans were re-calculated after changing the isocenter coordinates according to the IRCs. Four treatment- or patient-related factors were investigated as potential predictors for IRC using linear models. RESULTS: The average (±1 SD) absolute IRCs in the LR, AP, and SI directions were 1.2 ± 1.2 mm, 0.7 ± 0.7 mm, and 1.1 ± 0.8 mm, respectively. The average 3D IRC was 2.0 ± 1.3 mm (range: 0.4-5.3 mm) for a median treatment delivery time of 8.5 min (range: 5.7-19.9 min; n = 31 fractions). The dose coverage of the internal target volume (ITV) decreased by more than 3% points in three of 31 fractions. In those cases, the 3D IRC had been larger than 4.3 mm. The 3D IRC was found to correlate with changes in the minimum breathing amplitude during treatment delivery. CONCLUSION: On average, 2 mm of treatment delivery accuracy was lost due to IRC. Periodical intrafractional imaging is needed to safely deliver respiratory-guided SBRT.

Sensitivity Analysis of the Integral Quality Monitoring System® Using Monte Carlo Simulation.

The Integral Quality Monitoring (IQM) System is a real-time beam output verifying system that validates the integrity and accuracy of patient treatment plan (TP) data during radiation treatment. The purpose of this study was to evaluate the sensitivity of the IQM to errors in segment using EGSnrc/BEAMnrc Monte Carlo (MC) codes. Sensitivity analysis (SA) techniques were applied to study the significance of small alterations of field sizes (segments) on the IQM signal response. One hundred and eighty multileaf segments were analyzed with methods that include scatter plots (SP), brute force, variance-based (VAR), and standard regression coefficient SA. The segments were altered randomly within ±1, ±2, and ±3 mm leaf steps for 10 MV photon beams. SP analysis gradient and VAR maximum index are 1.045 and 0.556 for the smallest segment while the largest segment has the value of 0.018 and 0.504, respectively. The brute force and standard regression displayed maximum sensitivity indices around the unaltered segments. These tests conclusively indicated that the IQM was more sensitive to alterations of small segments compared to larger segments. This is important since small segment variation will cause a higher dose output variation that should be picked up during online beam monitoring.