Purpose/Objective(s) This work discusses delivery accuracy metrics for target point-of-view films used to evaluate BgRT. BgRT is a tracked delivery methodology that relies on the use of a positron emission tomography (PET) radiopharmaceutical to track and deliver the prescription dose. Intended for one or multiple PET avid targets with asynchronous non-bulk motion, delivery metrics must quantify target coverage and plan accuracy. For BgRT, we evaluated 3%/3mm gamma index inside the PTV against a novel iso-dose line to PTV “margin” metric for spatial analysis. Two studies were performed as a proof of principle demonstration of margin importance. Materials/Methods In our first study, a large torso phantom was prepared with an FDG fillable 22 mm ball target and a c-shaped avoidance structure. A 10 Gy/fraction plan was created on a medical technology company system using a planning PET image with target-to-background ratio (TBR) of 8.34:1. Contouring for the plan used a 22 mm GTV and a 32 mm PTV. The treatment used a TBR of 8.12:1 with target and background concentration of 70.07 kBq/ml and 8.63 kBq/ml, respectively. In our second study using the same phantom, a 10 Gy/fraction plan using a 26 mm target was prepared with a planning PET image with a TBR of 12.4:1. Contours for the plan used a 26 mm GTV and a 36 mm PTV. The treatment used a TBR of 12:47:1 with target and background concentration of 75.82 kBq/ml and 6.08 kBq/ml, respectively. However, the delivery was performed to a 22 mm target to model a biodistribution change. The PTV in the plan was not changed. Variable 3D sinusoidal target motion was used for all planning and treatment studies; study 1 and 2 used max amplitudes of 16 mm and 13 mm, respectively. To use the “margin” metric, both plans had ~95% PTV coverage with a conformity index (CI) of 1.03. All studies used Ashland EBT-XD film cut to approximately 10 x 10 cm2 to measure delivered dose. Analysis of the films included the calculation of the 3%/3mm gamma criterion within the PTV. Margin loss was calculated as the maximum spatial contraction from the PTV to the film recorded 97% of prescription dose iso-dose line. Acceptable margin loss was limited to 3 mm, a criterion created by the PET signal spatial uncertainty from motion. Results The irradiated film from study 1 demonstrated 0 mm of margin loss with respect to the PTV. Film 3%/3mm gamma within the PTV was 97.33%. Film from study 2 demonstrated 0 mm of margin loss but a PTV 3%/3mm gamma of 75.33%. In study 1, both the margin metric and PTV gamma produced favorable results. In study 2, PTV gamma failed, but the margin metric passed. The margin metric accounted for the biodistribution change from the 26 mm to 22 mm target, indicating coverage was maintained during treatment. Conclusion As no dosimetry metric is currently established for tracked delivery, a margin metric may be a more appropriate measure of target coverage than the conventional 3%/3mm measurement.

Purpose/Objective(s) Biology-guided radiotherapy utilizes direct photon emissions from a positron emission tomography (PET)-avid tumor to direct planned prescription dose to the tumor. The purpose of this work is to characterize the tracked dose delivery and dosimetric performance of BgRT as a function of changes in tumor location during treatment, while contrast of tumor radioactivity relative to the background concentration is kept constant. Materials/Methods A medical technology X1 system was utilized to create a conformal plan and deliver 1000 cGy dose in a single fraction. The experimental setup consisted of a cylindrical volumetric assembly (phantom) encapsulating a 22 mm ball target structure and a d avoidance structure. These structures were filled with F-18 fluorodeoxyglucose (FDG) and water solution with an activity concentration of 56.99 kBq/ml while the background was filled with 6.84 kBq/ml, providing a target-to-background ratio (TBR) of 8.18:1. Ashland EBT-XD monochromatic x-ray film was used as a primary diagnostic tool to characterize the tracked dose delivery and dosimetric performance of the system. A 5 cm by 10 cm piece of x-ray film was placed in between the two hemispheres of the 22 mm ball target. The patient-specific quality assurance (PSQA) is a helical assembly of 1,386 semiconductor diodes, widely used for quality assurance of radiation therapy plans. It measures the dose delivered by linear accelerator and compares it with the planned dose. The activity filled phantom was sealed and loaded in the patient-specific quality assurance (PSQA). Before proceeding to a 10 mm linear shift in the +IEC y-axis was applied to the 22 mm ball target with respect to the to simulate a sudden patient shift. After treatment completion the x-ray film was analyzed using green channel to obtain estimation of 3%/3 mm absolute dose gamma within the planning treatment volume (PTV) and dose profiles. Results The irradiated x-ray film demonstrated 3%/3 mm gamma within the PTV of 95.08%. Conclusion X-ray film analysis demonstrated that the delivered dose closely followed the 10 mm linear shift in the +IEC y-axis, and good dosimetric agreement was achieved between planned and delivered dose within the target.

Purpose/Objective(s) BgRT can treat one or more positron emission tomography (PET) avid tumors. To enable multi-target BgRT testing, a motion platform was developed capable of supporting up to 3 structures moving asynchronously within a large torso phantom. We characterized the performance of the platform and created a BgRT plan intended to represent multiple metastatic masses with respiratory motion. Materials/Methods The anthropomorphic phantom was engineered to support up to three 3D printed 18F-fluorodeoxyglucose (FDG) fillable PET avid targets or organs at risk (OARs). In the studied configuration, two structures were selected to be 26-mm tumors, each with 3 degrees of freedom for motion. The third, the OAR using a c-shape insert, was allowed the freedom to move in only IEC-X and IEC-Y. The movement was supported by a set of translational stages equal in number to the degrees of freedom; arms overhanging the phantom connected the stages to the targets and OAR. The phantom was placed in a prototype system. Using a no-motion simulation CT, 26-mm GTVs and 36-mm PTVs were contoured to both targets, and the c-shape was contoured as an OAR. Target 2 was selected as the therapeutic target and assigned a biology-tracking zone as a 10-mm, 25-mm, and 10-mm expansion in IEC-X, IEC-Y, and IEC-Z of its PTV. The modeling PET session used for planning was prepared with a target and OAR activity concentration of 55.57 kBq/ml and a background of 6.77 kBq/ml; the target-to-background ratio was 8.21:1. A script was written to generate 2D and 3D pseudorandomized sinusoidal respiration trajectory patterns as inputs into the motion platform during the modeling PET scan. For IEC-X, IEC-Y, and IEC-Z, target 1 had amplitude limits of 8 mm, 15 mm, and 8 mm. Target 2 was amplitude limited to 8 mm, 25 mm, and 8 mm. Target 1 was further constrained to a max velocity of 9.5 mm/s, and target 2 was constrained to 12.5 mm/s. The OAR was assigned a Cos4 motion pattern with an amplitude of 5 mm and a fixed frequency of 9.5 breaths per minute (bpm). The PET scan was used to prepare a 12.5 Gy/fraction plan. Analysis was performed by quantifying the accuracy between the theoretical and achieved trajectory positions as well as the achieved respiratory rate of each target. Plan quality was evaluated using the conformity index (CI), normalized target signal (NTS), and activity concentration (AC) for target 2. Results The commanded positions for the desired trajectories resulted in less than 100-micron error when compared against the theoretical trajectories. Target 1 achieved a respiratory rate of ~16 bpm, and target 2 achieved a rate of 14 bpm. The plan using the modeling PET scan achieved a CI of 1.17, an NTS of 7.07, and an AC of 7.96 kBq/ml. Conclusion The phantom achieved precise and asynchronous motion patterns within the range of normal respiration (12-20 bpm). The NTS and AC were above the minimum limit for a deliverable plan (NTS>2.7 and AC>5).

The results shows that BgRT is capable of tracking the tumor motion and delivering the prescribed dose to the moving target.

With sufficient tracer uptake in the target, BgRT can deliver tracked dosimetry for targets with a large respiratory motion profile. Both the good BgRT candidate and borderline cases produced clinically acceptable delivered doses, even though the borderline case was flagged by the clinical system safety checks. As expected, the delivered BgRT dose distributions were suboptimal with reduced tumor over background PET contrast.

These results demonstrate that high tracking accuracy and dosimetric accuracy can be achieved in single session, multi-target deliveries over a range of target-to-background F-FDG concentrations and target motion patterns.

Based on this initial study, accurate and reproducible dosimetry can be achieved for targets under respiratory motion using biology-guided radiotherapy over the course of a complete course of treatment. Further studies are needed to evaluate the intrafraction dosimetry of BgRT delivery under various motion models and tumor sizes.

The dual PET arcs and limited axial extent of the X1 PET subsystem results in lower system sensitivity in comparison to diagnostic PET scanners equipped with full ring and larger axial extent, as expected. With the same FDG injection, the RefleXion X1 produced SUVmax values that were 30.4 % of the diagnostic PET/CT scanners' values. Nevertheless, the X1 collected sufficient emission data to enable successful completion of emulated BgRT deliveries that met dose accuracy criteria in a clinical setting.

This study demonstrated that the BgRT system is able to deliver the prescribed dose to all targets with independent motion, even when an interruption and resumption occurs during treatment. In case such an interruption if the remaining PET activity satisfies the BgRT safety evaluation, the treatment can continue to deliver the remainder of the BgRT doses.

The new processes introduced by the BgRT technology were evaluated and found clinically feasible. Improvements are being undertaken to shorten the time required for each step and to increase patient comfort ahead of BgRT clinical implementation.

Results from this study demonstrated treatment delivery stability with consistent repeatability in the 8:1 target to background contrast condition even with diminishing PET signal from the phantom target as the activity decayed. This work shows that BgRT is capable of delivering to a cylindrical target volume that is very different from the PET avid C-shaped that was used for the plan and delivery.

This investigation demonstrated a 100% positive percent agreement between central review of this novel device images by radiation oncologists and central review of the accompanying third-party PET/CT images by radiologists. There were no cases where a positive localization by the aggregate CRRO was not confirmed by the third-party PET/CT standard, providing evidence against the likelihood of falsely positive localizations on the novel device that would inappropriately advance patients in the workflow.

Purpose/Objective(s) Biology-guided radiotherapy (BgRT) uses outgoing emissions after administration of an injected radiotracer to dynamically guide the delivery of radiation treatment to PET-avid targets. In this study, we evaluated the tracking performance of FDG-guided BGRT for two potential types of motion management (respiratory and non-respiratory (gastrointestinal)) while exploring different target shapes: spherical and non-spherical. BgRT is designed to ensure target coverage while keeping organ-at-risk (OAR) doses low. Materials/Methods A large custom anthropomorphic phantom with 2 robotic articulating arms was used to place a target and organ-at-risk inside a 27-liter water filled cavity. The targets consisted of an integrated ion chamber inside a 3D printed 22 mm sphere or a small non-spherical ovoid shape filled with FDG. The hot FDG-filled OAR consisted of either a 3D printed large C-shape annulus (mimicking a heart), large ovoid (mimicking a kidney), or a 30 mm sphere, all with integrated ion chambers. Both the 3D printed target and the OAR were filled with an 8:1 concentration ratio versus the water background. Three different 10 Gy/fraction treatment plans with two different target shapes and realistic nearby OARs were created with a 5 mm margin added to the CTV to generate the PTV. 3D printed targets and OARs were loaded with EBT-XD radiographic film. A 3D elliptical motion trajectory with breathing induced hysteresis with a maximum amplitude of +/- 12 mm was used for the respiratory motion model. An asymmetric slow-moving drift waveform with long-step shifts of +13/-5mm mm was used for the non-respiratory (gastrointestinal) motion model. Dosimetric results were evaluated based on 2-dimensional comparisons between measured film and planned dose distributions for the target and OAR. BgRT must maintain a prescription dose margin greater than 2 mm on the CTV for the three different motion experiments. Also, ion-chamber point dose and maximum film dose on the OAR must be within bounds predicted by the treatment planning system. Results BgRT was able to meet minimum margin requirements (a margin loss < 3mm) and meet prescription dose coverage in both motion management scenarios while maintaining OAR dose limits within the plan predicted bounds (see Table 1). Conclusion BgRT is able to provide motion management in complex cases that is agnostic to the type of motion. BgRT is able to maintain the PTV coverage with less than 3 mm reduction from the original 5mm margin.

Purpose/Objective(s) Biology-guided radiotherapy (BgRT) is a novel tracked dose delivery modality that uses positron emission tomography (PET) emissions to deliver hypofractionated planned fluence to the target. This study evaluated PET biodistribution changes within target during BgRT delivery. Materials/Methods Two phantom experiments were designed to evaluate the FDG signal variations and dosimetric effects under stationary target and moving target on a non-clinical investigational radiotherapy system. For the stationary case, a custom built cylindrical 4-D detector phantom insert with a spherical target of 22 mm in diameter containing 4 quadrants that can be filled independently was used to mimic homogenous and non-homogenous FDG uptake conditions. A C-shape insert was used as a PET avid OAR. For simulating PET signal loss within tumor: BgRT plan was created for the spherical target with all quadrants filled and the plan was delivered when ¾ volume of the target was PET-avid. For the PET signal gain within tumor scenario: BgRT plan was created for the same spherical CTV structure where ¾ volume of the target was filled with FDG, mimicking non-homogeneous uptake, and delivered to a full volume PET-avid target. The dosimetric accuracy of BgRT delivery was evaluated using 3%/3 mm Gamma criterion using 4-D detector measurements. Target biodistribution changes under motion was evaluated by creating a BgRT plan with an FDG filled 26 mm diameter spherical target as a CTV and C-shape OAR moving independently (target:3D respiratory, OAR: sinusoidal motions) within a large water filled phantom. During BgRT delivery the PET avid target insert was switched to a smaller 22 mm spherical insert, simulating 40% uniform PET distribution reduction within 26mm CTV. For the moving target experiment, BgRT delivered dose was evaluated using the radiographic film under the condition of CTV coverage ≥97% and maximum dose ≤130%. For all the experiments, the target and the C-shaped OAR were filled with FDG at a ratio of 8:1 with respect to the water background mimicking normal tissue uptake, and a 5 mm CTV to PTV expansion to be targeted with a prescription of 50Gy in 5 fractions. Results For the stationary scenarios, BgRT delivery at remissive and progressive conditions achieved gamma pass-rate of 93.2 and 97.7%, respectively. The CTV coverage goals for the motion experiment were met where the minimum CTV dose was 103.3% and the maximum dose was 123.8%. Conclusion This study evaluated the biodistribution changes within CTV from planning to delivery suggesting the BgRT delivery is robust with respect to daily variations of PET signal within the PTV under these experimental conditions. Clinical feasibility of BgRT needs further evaluation.

This is the first report of BgRT delivery achieving a tracked dose distribution directed at a moving target. Because tracked distributions have better conformality and normal tissue sparing than free-breathing internal tumor volume approaches, BgRT may improve the toxic-therapeutic ratio for applications such as early-stage lung cancer.