Biology-guided Radiotherapy Research Articles

Feasibility of Biology-guided Radiotherapy (BgRT) Targeting Fluorodeoxyglucose (FDG) avid liver metastases

IntroductionBiology-guided radiotherapy (BgRT) is a novel radiation delivery approach utilizing fluorodeoxyglucose (FDG) activity on positron emission tomography (PET) imaging performed in real-time to track and direct RT. Our institution recently acquired the RefleXion X1 BgRT system and sought to assess the feasibility of targeting metastatic sites in various organs, including the liver. However, in order for BgRT to function appropriate, adequate contrast in FDG activity between the tumor and the background tissue, referred to as the normalized SUV (NSUV), is necessary for optimal functioning of BgRT.MethodsWe reviewed the charts of 50 lung adenocarcinoma patients with liver metastases. The following variables were collected: SUVmax and SUVmean for each liver metastasis, SUVmean and SUVmax at 5 and 10 mm radially from the lesion, and NSUV at 5 mm and 10 mm (SUVmax of the liver metastasis divided by SUV mean at 5 mm at 10 mm respectively).Results82 measurable liver metastases were included in the final analysis. The average SUVbackground of liver was 2.26 (95% confidence interval [CI] 2.17–2.35); average SUVmean for liver metastases was 5.31 (95% CI 4.87–5.75), and average SUVmax of liver metastases was 9.19 (95% CI 7.59–10.78). The average SUVmean at 5 mm and 10 mm radially from each lesion were 3.08 (95% CI 3.00-2.16) and 2.60 (95% CI 2.52–2.68), respectively. The mean NSUV at 5 mm and 10 mm were 3.13 (95% CI 2.53–3.73) and 3.69 (95% CI 3.00-4.41) respectively. Furthermore, 90% of lesions had NSUV greater than 1.45 at 5 mm and greater than 1.77 at 10 mm.ConclusionsThis is the first study to comprehensively characterize FDG contrast between the liver tumor and background, referred to as NSUV. Due to the high background SUV normally found in the liver, this work will be valuable for guiding optimization of BgRT for treating liver metastases in the future using the RefleXion® X1 and potentially other similar BgRT platforms.

Biology-guided radiotherapy in metastatic prostate cancer: time to push the envelope?

The therapeutic landscape of metastatic prostate cancer has undergone a profound revolution in recent years. In addition to the introduction of novel molecules in the clinics, the field has witnessed a tremendous development of functional imaging modalities adding new biological insights which can ultimately inform tailored treatment strategies, including local therapies. The evolution and rise of Stereotactic Body Radiotherapy (SBRT) have been particularly notable in patients with oligometastatic disease, where it has been demonstrated to be a safe and effective treatment strategy yielding favorable results in terms of disease control and improved oncological outcomes. The possibility of debulking all sites of disease, matched with the ambition of potentially extending this treatment paradigm to polymetastatic patients in the not-too-distant future, makes Biology-guided Radiotherapy (BgRT) an attractive paradigm which can be used in conjunction with systemic therapy in the management of patients with metastatic prostate cancer.

Commissioning of a novel PET-Linac for biology-guided radiotherapy (BgRT).

Biology-guided radiotherapy (BgRT) is a novel radiotherapy delivery technique that utilizes the tumor itself to guide dynamic delivery of treatment dose to the tumor. The RefleXion X1 system is the first radiotherapy system developed to deliver SCINTIX® BgRT. The X1 is characterized by its split arc design, employing two 90-degree positron emission tomography (PET) arcs to guide therapeutic radiation beams in real time, currently cleared by FDA to treat bone and lung tumors. This study aims to comprehensively evaluate the capabilities of the SCINTIX radiotherapy delivery system by evaluating its sensitivity to changes in PET contrast, its adaptability in the context of patient motion, and its performance across a spectrum of prescription doses. A series of experimental scenarios, both static and dynamic, were designed to assess the SCINTIX BgRT system's performance, including an end-to-end test. These experiments involved a range of factors, including changes in PET contrast, motion, and prescription doses. Measurements were performed using a custom-made ArcCHECK insert which included a 2.2cm spherical target and a c-shape structure that can be filled with a PET tracer with varying concentrations. Sinusoidal and cosine4 motion patterns, simulating patient breathing, was used to test the SCINTIX system's ability to deliver BgRT during motion-induced challenges. Each experiment was evaluated against specific metrics, including Activity Concentration (AC), Normalized Target Signal (NTS), and Biology Tracking Zone (BTZ) bounded dose-volume histogram (bDVH) pass rates. The accuracy of the delivered BgRT doses on ArcCHECK and EBT-XD film were evaluated using gamma 3%/2mm and 3%/3mm analysis. In static scenarios, the X1 system consistently demonstrated precision and robustness in SCINTIX dose delivery. The end-to-end delivery to the spherical target yielded good results, with AC and NTS values surpassing the critical thresholds of 5 kBq/mL and 2, respectively. Furthermore, bDVH analysis consistently confirmed 100% pass rates. These results were reaffirmed in scenarios involving changes in PET contrast, emphasizing the system's ability to adapt to varying PET avidities. Gamma analysis with 3%/2mm (10% dose threshold) criteria consistently achieved pass rates>91.5% for the static tests. In dynamic SCINTIX delivery scenarios, the X1 system exhibited adaptability under conditions of motion. Sinusoidal and cosine4 motion patterns resulted in 3%/3mm gamma pass rates>87%. Moreover, the comparison with gated stereotactic body radiotherapy (SBRT) delivery on a conventional c-arm Linac resulted in 93.9% gamma pass rates and used as comparison to evaluate the interplay effect. The 1cm step shift tests showed low overall gamma pass rates of 60.3% in ArcCHECK measurements, while the doses in the PTV agreed with the plan with 99.9% for 3%/3mm measured with film. The comprehensive evaluation of the X1 radiotherapy delivery system for SCINTIX BgRT demonstrated good agreement for the static tests. The system consistently achieved critical metrics and delivered the BgRT doses per plan. The motion tests demonstrated its ability to co-localize the dose where the PET signal is and deliver acceptable BgRT dose distributions.

2628: Dosimetric evaluation of Biology-guided Radiotherapy for locally recurrent prostate cancer

2628: Dosimetric evaluation of Biology-guided Radiotherapy for locally recurrent prostate cancer

Advancements and future directions in positron emission tomography-guided radiotherapy: a narrative review.

Positron emission tomography (PET) imaging has been useful in delineating tumor volumes and allowing for improved radiation treatment. The field of PET-guided radiotherapy is rapidly growing and will have significant impact on radiotherapy delivery in the future. This narrative review provides an overview of the current state of PET-guided radiotherapy as well as the future directions of the field. For this narrative review, PubMed was searched for articles from 2010-2023. A total of 18 keywords or phrases were searched to provide an overview of PET-guided radiotherapy, radiotracers, the role of PET-guided radiotherapy in oligometastatic disease, and biology-guided radiotherapy (BgRT). The first 300 results for each keyword were searched and relevant articles were extracted. The references of these articles were also reviewed for relevant articles. In radiotherapy, 18F-2-fluoro-2-deoxy-D-glucose (F-FDG or FDG) is the major radiotracer for PET and when combined with computed tomography (CT) scan allows for anatomic visualization of metabolically active malignancy. Novel radiotracers are being explored to delineate certain cell types and numerous tumor metrics including metabolism, hypoxia, vascularity, and cellular proliferation. This molecular and functional imaging will provide improved tumor characterization. Through these radiotracers, radiation plans can employ dose painting by creating different dose levels based upon specific risk factors of the target volume. Additionally, biologic imaging during radiotherapy can allow for adaptation of the radiation plan based on response to treatment. Dose painting and adaptive radiotherapy should improve the therapeutic ratio through more selective dose delivery. The novel PET-linear accelerator hopes to combine these techniques and more by using radiotracers to deliver BgRT. The areas of radiotracer uptake will serve as fiducials to guide radiotherapy to themselves. This technique may prove promising in the growing area of oligometastatic radiation treatment. Significant challenges exist for the future of PET-guided radiotherapy. However, with the advancements being made, PET imaging is set to change the delivery of radiotherapy.

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

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. 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. 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%/3mm. 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%). 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%. 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.

Workflow Considerations for Biology-Guided Radiotherapy (BgRT) Implementation.

Biology-guided radiotherapy (BgRT) is a novel platform that combines real-time PET imaging with a 6MV Linac to target tumors. The performance and safety of BgRT was assessed in the BIOGUIDE-X clinical trial. This study aims to report on the BgRT workflow steps and assess the time required for each step of the BgRT process during this trial. A total of nine patients were enrolled in the second Cohort of the BIOGUIDE-X study which included patients treated with stereotactic body radiotherapy (SBRT) for lung tumors (5) and bone tumors (4). The pre-treatment BgRT workflow includes CT simulation, contouring, imaging-only (BgRT Modeling) PET acquisition, BgRT planning, patient specific QA and plan approval. The imaging-only PET acquisition on the X1 collects a representative PET volumetric 3D image and is an input to develop the BgRT treatment plan. The steps during the BgRT delivery session are kVCT localization, PET pre-scan, PET evaluation and BgRT delivery. The PET PreScan is a 1-pass short-duration PET acquisition that is used to confirm that the PET biodistribution on the day of treatment is consistent with that of the imaging-only PET. During BIOGUIDE-X, the BgRT delivery step was replaced by a 4-pass long-PET acquisition that was used to emulate the expected BgRT dose distribution without turning the beam on. To assess BgRT workflow, times from 18F-FDG injection to image-only PET acquisition, 18F-FDG injection to PET pre-scan, Pre-scan to PET evaluation, and PET evaluation to BgRT delivery (long PET acquisition) were recorded. Time between the 18F-FDG injection and the X1 imaging-only PET scan was 84 ± 19 minutes which includes time for 18F-FDG update. Average time to perform imaging-only PET scan was 26 ± 4 minutes. During the BgRT 'delivery' session, the mean time between the kVCT acquisition and PET pre-scan acquisition was 7 ± 3 minutes. The mean time to acquire a 1-pass PET pre-scan was 6 ± 1 then followed by 6 ± 1 minutes for the PET pre-scan dose calculation to estimate the BgRT doses that it would have delivered for this fraction. On average, the PET reconstruction, the PET signal localization verification and the evaluation of safety metrics took 11 ± 4 minutes. The mean time for BgRT 'delivery' was 27 ± 5 minutes based on the 4-pass long PET acquisition. Time from the start of the BgRT session to the end of the BgRT 'delivery' with this version of the investigative product release was 65 ± 9 minutes. 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.

Characterization of Biology-Guided Radiotherapy Accuracy as a Function of PET Tracer Uptake

To characterize the tracking capability and dosimetric accuracy of biology-guided radiotherapy (BgRT) under clinically relevant PET tracer uptake scenarios relative to the background. A custom-made anthropomorphic phantom filled with a liquid 18F-FDG solution including two embedded fillable 22 mm diameter spherical structures mimicking GTV (= CTV) and OAR was coupled to motion stages to create an independent 3D respiratory motion with 22 mm maximum range for target and a 5 mm 1D sinusoidal motion in the OAR. The biology-tracking zone (BTZ) was generated by adding 5 mm margin to the motion extent. The three BgRT scenarios studied were representative of tumors with good (8:1), borderline (4:1) and undesired (2:1) PET biodistributions compared to background. The clinical safety limit of BgRT uses Activity Concentration within the BTZ (AC ≥ 5 kBq/ml) and Normalized Target Signal as a contrast metric (NTS ≧ 2.7 for planning and ≧ 2 for delivery). The BgRT deliveries were repeated 3 times with radiochromic film and integrated ion chamber capturing the target and OAR doses. Tracked dosimetry was assessed using a margin-loss calculation defined as the maximum linear difference in distance between the planned and delivered 97% prescription iso-dose lines. The imaging-only PET images used to create BgRT plans had an AC of 7.0, 5.3, and 1.6 kBq/ml with an NTS of 6.8, 5.3, and 1.8 for 8:1, 4:1, and 2:1 concentrations, respectively. Qualitatively, the target was not visible on the planning PET images 2:1 loading scenario. At delivery, the mean pre-scan activity concentrations were 6.8, 4.7, and 3.7 kBq/ml with corresponding mean NTS of 3.7, 2.6, 1.5 for 8:1, 4:1 and 2:1 deliveries. The pre-scan values of AC or NTS did not satisfy the clinical system safety limits for 4:1 and 2:1 ratio experiments, but the engineering software allowed for the delivery to capture the resulting doses. The deliveries showed a prescription dose coverage to the CTV of 100% for the 8:1 and 4:1 cases, but 88% for the 2:1 case. When compared to the planned dose values, the delivered minimum doses were -7.6%, -8.6% and -10.9%, whereas the maximum dose differences in CTV were 1.2%, 0% and -4.8% of the planned dose distributions of the 8:1, 4:1 and 2:1 cases, respectively. Calculated margin losses were -2.3, -3.8, and -5.5 mm, for the 8:1, 4:1, and 2:1 cases, respectively. The maximum OAR doses were less than the maximum doses predicted on the bounded DVH curves for all scenarios. 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.

Dosimetric Plan Evaluation of Biology Guided Radiotherapy Using [18F]-DCFPyL PSMA Radiotracer in Patients with Prostate Cancer

The X1 system represents a cutting-edge solution in radiotherapy delivery, with its capability to perform Biology Guided Radiotherapy (BgRT). The system utilizes real-time positron emission tomography (PET) signal as biological fiducials to provide tracked dose delivery and is initially available for use with [18F]-Fluorodeoxyglucose (FDG). The aim of this research study is to assess the quality of BgRT treatment plans for prostate cancer using patients' PSMA PET images obtained on the X1 system. Sixteen patients with at least one PET-avid tumor identified on their whole-body diagnostic PSMA PET scan were selected. These patients were scanned on X1 following their diagnostic scan without additional radiotracer administration. Based on the X1 PET images, a BgRT plan was created for each patient, with the prescription dose determined by the location of treatment sites. The planning objectives of organs-at-risk (OARs) were established in accordance with the 2018 Timmerman guidelines. Target coverage objective was the dose covering 95% (D95%) of the planning target volume (PTV) to be higher than 100%. The following parameters were analyzed: PTV D95%, the minimal dose (Dmin) of gross tumor volume (GTV), plan maximum dose (Dmax), conformity index (CI), gradient index (GI), and maximum point dose (D0.03cc) to the nearest OARs. The X1 BgRT planning system also generated dose volume histogram (DVH) bounds, which model variations in BgRT delivery. The low boundary of GTV Dmin, representing the minimum GTV dose in the worst-case scenario, was recorded. BgRT plans were created for all patients, except for one where the target signal was indistinguishable from the bladder. The prescription dose was 2700 cGy or 3000 cGy in 3 fractions for lymph node lesions, 2400 cGy to 3000 cGy in 3 fractions for bone metastasis, and 4500 cGy in 5 fractions for lesions in prostate. All plans met the dose constraints for OARs as per the Timmerman guidelines. The Dmax of all plans was 129.9% ± 6.9% (mean ± standard deviation). The PTV D95% and GTV Dmin were 101.7% ± 1.0% and 111.0% ± 7.6%, respectively. The low boundary of GTV Dmin was 95.9% ± 5.8%. The CI and GI were 1.22 ± 0.11 and 9.40 ± 2.12, respectively. The D0.03cc to nearest OARs was 84.6% ± 25.4%. The estimated treatment time was 699 ± 228 seconds. This study is a pioneering effort to evaluate the quality of BgRT plans for prostate cancer patients using the [18F]-DCFPyL PSMA radiotracer. Our results showed that all BgRT plans met the planning objectives defined in the Timmerman protocol. BgRT with [18F]-DCFPyL represents a promising treatment modality for patients with prostate cancer. Further research is needed to validate this approach, including a comprehensive assessment of the dosimetric and tracking accuracy through physical measurements.

Evaluation of Treatment Interruptions and Recovery during Biology-Guided Radiotherapy Delivery

A Biology-guided Radiotherapy (BgRT) based device is designed to use Positron Emission Tomography (PET) signals to achieve tracked dose delivery. The goal of this study is to investigate the dose delivery accuracy in case of interruption during BgRT treatment, and resumption in a separate treatment session for a multi-target delivery, as the PET activity continues to decay. A custom-built large anthropomorphic phantom (LAP) including a 26 mm spherical target with 3D independent motion and two 22 mm spherical targets with 1D sinusoidal motion embedded in water was used. All three targets were filled with FGD in an 8:1 target to background uptake ratio (41.52 kBq/ml in target and 5.19 kBq/ml in background). During BgRT delivery, the treatment was intentionally paused during delivery to the second target and the current treatment session was ended to generate a partial fraction. Then the partial fraction was continued in a new session, where the CT scan localization and PET pre-scan were repeated using the existing PET activity present in the phantom. The newly acquired PET pre-scan, was then used to determine if sufficient PET counts were present to resume treatment delivery. The interruption and recovery algorithm is designed to calculate the fluence that needs to be delivered to the remaining targets as well as the residual fluence to be given to the targets that have already received partial dose prior to the interruption. Once the new fluence is recomputed, the treatment is resumed. The delivered doses were captured using radiochromic film (EBT-XD) inserted in the target as well as post-treatment dose calculations based on the delivered beamlet sequence to evaluate the results in terms of dosimetric coverage and margin loss. The margin loss is calculated as the maximum difference between the distance from the Clinical Target Volume (CTV) contour to the 97% isodose contour in the treatment plan and the on the film. The dosimetric coverage is defined as the percentage of voxels within the CTV that lies within 97% and 130% of the prescribed dose. As shown in the table below, a margin loss of less than 3 mm for all targets and 100% CTV coverage was achieved. After treatment interruptions, the PET safety evaluation based on the PET pre-scan helped to determine whether the treatment could be continued on the same day using the same injected PET activity (an NTS value ≧ 2 and AC value ≧ 5 kBq/ml). 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.

Analysis of the Measured FDG Uptake from the First-in-Human Clinical Trial of Biology-Guided Radiotherapy

The RefleXion X1 system is a novel linear accelerator equipped with dual 90° PET arcs incorporated into its architecture to capture emissions from tumors and designed to respond by directing the radiation beam towards target. This study reports on the measured FDG uptake from the first in human multi-institutional clinical trial (BIOGUIDE-X) evaluating the performance and safety of the RefleXion X1 PET-LINAC. A total of nine patients treated with stereotactic body radiotherapy (SBRT) for lung (5) and bone (4) tumors were enrolled in the Cohort II of this study after screening their pre-study diagnostic PET/CT, acquired up to 60 days prior to enrollment, to ensure their tumor size between 2 to 5 cm and SUVmax >6. After CT simulation, the tumor and OARs were delineated, and patients had a 4-pass Imaging-only (BgRT Modeling) PET/CT acquisition on the X1 system to generate biology-guided radiotherapy (BgRT) plans. Before the patients' first and last SBRT fractions, they were injected with FDG, and short PET pre-scan (1-pass) was performed on the X1 followed by a long-PET acquisition (4-pass) to emulate the expected BgRT dose distribution without firing beam. Patients were also imaged on a third-party diagnostic PET/CT scanner after the last-fraction X1 scan. This study compares the SUVmax from the screening PET/CT, X1 Imaging-only scan, X1 PET pre-scan and long scan before the first and last-fractions, and final diagnostic PET/CT. The median time from injection to PET imaging was 84 ± 15.4 mins for X1 Imaging-only (used for generating BgRT plans), 77 ± 21.6 mins for X1 pre-scan (safety check before treatment start), 108+/- 22 mins for X1 long-PET (used to emulate treatment delivery), and 161 ± 23 mins for final diagnostic PET. For a nominal 10 mCi injection, the mean SUVmax for screening imaging performed on the diagnostic PET/CT was 10.8 ± 4.3. For a 15 mCi nominal injection, the mean SUVmax calculated on the X1 was 5.3 ± 2.6, 5.4 ± 2.0, 5.5 ± 2.6, 5.2 ± 1.8 and 5.4 ± 2.2 for the Imaging-only, first-fraction PET pre-scan, first-fraction long PET scan, last-fraction PET pre-scan, and last-fraction long PET scan, respectively. The overall median SUVmax for all patients across all timepoints and scans with X1 was calculated to be 4.8 with a range of 2.4 to 9.8. The median SUVmax for the diagnostic PET/CT scan after the last fraction X1 scan was 15.8 with a range of 8.5 to 27.7. 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.

Towards Biology-Guided Radiotherapy Planning and Delivery on a Novel O-Ring PET-Linac Platform: Extended Beyond Bone and Lung Lesions

Biology-guided radiotherapy (BgRT) with FDG signal collected via an on-board positron emission tomography (PET) system integrated in an O-ring gantry Linac was recently cleared by the FDA for lung and bone lesions. This study aims to determine if BgRT plans, guided via PET signal, are clinically acceptable for FDG-avid lesions in disease sites beyond bone and lung. Ten patients previously treated for lesions in the liver, head and neck (HN), pancreas, renal and pelvic-abdominal lymph nodes were identified. Diagnostic PET/CT images of these treatment sites were first collected and processed/converted to mimic PET images that are acquired on PET-Linac and would be used to guide the delivery. For BgRT planning, the PTV was generated with 5 mm margin from GTV and a Biology Tracking Zone was generated including the anticipated full range of target motion. BgRT plans, guided by the emulated PET signal, were generated with 46Gy in 3 fractions for liver and 40Gy in 5 fractions for all other sites. BgRT plan deliverability was first assessed by evaluating the Activity Concentration (AC) and Normalized Target Signals (NTS) on converted PET images with the goal to meet NTS >2 (hard constraint) and AC >5kBq/ml (goal). BgRT plan quality was then evaluated with institutional guidelines on PTV coverage, OAR doses, conformity index (CI) and Heterogeneity index (HI). BgRT plans were successfully generated for 11 target lesions among ten patients. The average diagnostic PET SUV, derived NTS and AC on converted PET images were 12.62, 9.33 and 12.10 kBq/ml, respectively. All images met the NTS constraints, and 8/11 plans met the AC goal for deliverability. All plans met the OAR hard constraints such as max dose on duodenum, small bowel, large bowel and spinal cord. Five of 11 plans had a limiting GI structure that resulted in an expected reduction in PTV coverage with an average PTV V100% = 77.9%, CI of 1.4, HI of 1.36 and max dose of 133.8%. The other 6 of 11 cases met the PTV V100% = 95%, had an average CI of 1.1, HI of 1.28 and Dmax of 127.67%. The estimated average time for BgRT delivery was 17 mins 25 secs. Although these plan parameters are deemed to be clinically acceptable, heterogeneity was detected inside the target region and suboptimal dose fall off was observed in some cases that may be caused by current implementation. This preliminary study showed that BgRT plans were generated successfully with emulated PET images on 11 treatment sites covering HN, abdominal and pelvic regions. All plans met NTS constraints and 8 out of 11 met AC goals for deliverability. The plan quality of all BgRT plans were clinically acceptable based on institutional constraints. Further investigations are required to test more patients/sites for BgRT plan feasibility. Dosimetric benefit from margin reduction of BgRT target should also be investigated in future study.

Imaging Performance of the PET Scan on a Novel Ring Gantry-Based PET/CT Linear Accelerator System in the First-in-Human Study of Biology-Guided Radiotherapy

Biology-guided radiotherapy (BgRT) is a novel tracked dose delivery modality using real-time positron emission tomography (PET) to guide radiotherapy beamlets. The present study was performed with sequential cohorts of participants to evaluate the performance and safety of BgRT. Primary endpoints were previously reported. We hereby report on one of the secondary endpoints assessing a novel treatment planning machine with integrated dual kVCT/PET imaging ("novel device") performance in comparison to a third-party diagnostic PET/CT scan. This single-arm, open-label, prospective study included participants with at least 1 FDG-avid targetable primary or metastatic tumor (≥2cm and ≤5cm) in the lung or bone. PET imaging data were collected on the novel device and on a third-party diagnostic PET/CT performed in sequence once at the planning timepoint in Cohort I, and immediately before the last fraction among patients undergoing stereotactic radiotherapy in Cohort II. Three central read radiation oncologists (CRRO) provided an interpretation of the novel device PET scans which were compared to an agreement standard based on 3 central radiologists' review of the paired diagnostic PET/CT scan. Positive percent agreement for localization of the target tumor within the biology-tracking zone (BTZ) was the key metric because it reflects whether advancing patients to subsequent steps in the BgRT workflow based on the novel device's imaging was ultimately appropriate. In Cohort 1, 6 image comparisons were performed. The positive (%) agreement for the aggregate radiation oncologist review was 100% (5/5), reflecting that in all 5 cases where the aggregate radiation oncologists deemed the tumor to fall within the BTZ based upon the novel device PET images, the central radiologists came to the same conclusion upon review of the paired diagnostic PET/CT images. The overall (%) agreement for the aggregate radiation oncologist review was 83.3% (5/6): localization was not established on the novel device in 1 case, even though it was established on the diagnostic PET/CT. This would not pose risk in real world practice as BgRT candidacy would be aborted for tumors not visible on the novel device. In Cohort II, among the 7 image comparisons, there was 100% positive percent agreement between the aggregate CRRO and the agreement standard as the localization criteria was met in both scans for all 7 patients. This was concordant with a 100% overall percent agreement. 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.

Decay Series Dose Delivery Validation of a Biology-Guided Radiotherapy (BgRT) Methodology

In this work, we compared the accuracy between the planned dose estimated by a commercial BgRT treatment planning system to the measured delivered dose by the BgRT treatment delivery device. The dose delivered was measured with the Sun Nuclear ArcCHECK device containing a customized phantom filled with fluorodeoxyglucose F18 (FDG) with a fixed target to background activity concentration ratio. The BgRT approach was evaluated for its capacity to accurately deliver a planned dose to a phantom target of an increasingly limited PET signal due to radioactive decay. The Sun Nuclear ArcCHECK is a helical detector assembly of 1,386 diodes around a 15 cm diameter cavity designed for quality assurance of linear accelerator (LINAC) driven therapies. In this work, the ArcCHECK was loaded with a cylindrical phantom containing a 22 mm diameter homogenous ball and a C-shape insert. The ball target was designated as an organ at risk (OAR) with appropriate dose constraints applied, and the C-shaped insert was designated as the target. The C-shaped target was used to simulate a tumor with a necrotic core. A cylindrical planning/gross tumor volume was placed around the C-shape, providing a test case of delivery to a partially PET-avid target. The target and OAR were filled with 58.46 kBq/mL of FDG and the background with 7.30 kBq/mL, giving an approximate target to background ratio of 8:1. A kVCT localization scan, a short PET pre-treatment scan, and a LINAC treatment sequence (1000 cGy per fraction) were performed each run with four runs performed over a duration of ∼3.5 hours (1.9 half-lives). The ArcCHECK measured the delivered dose during each LINAC treatment sequence and compared it to the plan predicted dose. The relative dose (RD) and absolute dose (AD) gamma values were then calculated for each run using Sun Nuclear's proprietary software with a gamma pass rate criterion of 3mm/3%. The PET scans for runs 1-4 were completed with background activity concentrations of 5.49 kBq/ml, 3.95 kBq/ml, 2.79 kBq/ml, and 2.02 kBq/ml, respectively. The scans further reported 17.48 kBq/ml, 12.26 kBq/ml, 7.93 kBq/ml, and 6.95 kBq/ml as the mean activity concentrations for the cylindrical gross tumor volume of the planned treatment. After treatment delivery, the resulting RD gamma values were 98%, 94%, 93%, and 95% and AD gamma values were 98%, 93%, 92%, and 94% for runs 1-4. 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.

Intrafraction Dosimetric Evaluation of Biology-Guided Radiotherapy to a Target Under Respiratory Motion

To evaluate the reproducibility and variability of biology-guided radiotherapy (BgRT) treatments using a large anthropomorphic phantom modeling the motion amplitude of a lung tumor. RefleXion X1 is equipped with two opposing 90 degrees PET detector arcs to capture the radionuclide emissions and direct the 6MV Linac to treat the lesions in real time. A custom-built phantom filled with a liquid [¹⁸F]Fluorodeoxyglucose (FDG) solution was used. Fillable target and OAR structures were 3D printed and attached to motion stages. The GTV = CTV was matched to the spherical 22 mm diameter target, and the PTV was a 5 mm expansion from the CTV volume. The Biology Tracking Zone (BTZ) was generated after adding 5 mm margin to the motion extent of the CTV. The OAR was a large C-shape annulus (emulating a heart) that was approximately 3 cm from the target. The 3D independent motion trajectory of the target was designed to mimic lung motion: range of +5.8 mm to -4.9 mm in LR, range of +14.4 mm to -11.3 mm in SI, and range of +5.2 mm to -5.1 mm in AP directions. The OAR motion waveform used a 1D sinusoidal pattern with a 5 mm amplitude in SI direction. The target and the OAR were filled with 40 kBq/mL while the background had 5 kBq/mL FDG. A BgRT Modeling (imaging-only) PET acquisition was performed using RefleXion X1 and used to generate a 4-fraction BgRT treatment plan prescribing 10 Gy/fraction to PTV. For each delivery, target, OAR and background were filled with the same FDG concentrations as in the BgRT Modeling PET planning scan. Dosimetry to the target and OAR were both measured using an ion-chamber (Exradin A14SL) and film in the coronal plane through the center of the GTV for all 4 fractions. The mean activity concentration within the (BTZ) was 7.4 ± 0.8 kBq/mL. The calculated signal-to-noise ratio metric (Normalized Target Signal) within the BTZ was 4.0 ± 0.3. Total treatment times were all less than 35 minutes (34.3 ± 0.2). Prescription dose coverage to the CTV for all 4 fractions was 100%. Ion chamber measurements in the CTV were -1.6 ± 1.3% relative to the planned dose over the active area of the ion-chamber. Minimum and maximum doses to the CTV, measured on film, were -7.7 ± 2.2% and 1.3 ± 1.4%, calculated relative to the planned dose distribution, respectively. The OAR maximum point dose measured on film was -8.7 ± 2.9%, calculated relative to the maximum OAR dose predicted on the bounded dose-volume histogram. 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.

Comparison of AI-Based Auto-Segmentation Quality with Different Daily IGRT Imaging Modalities for Adaptive Radiotherapy Treatment Planning

Modern AI-based auto-segmentation tools may be applied on daily computed tomography (CT) images in an image-guided radiotherapy course to facilitate evaluation of anatomical variations and adaptive treatment planning. However, most AI auto-segmentation models are trained with high-quality diagnostic or planning CT image data. This study aims to evaluate and compare auto-segmentation quality by an AI-based auto-segmentation system with different daily CT imaging modalities. We retrospectively retrieved daily IGRT images for sixty patients. Among them, twenty patients were treated on helical tomotherapy with daily megavoltage CT (MVCT) scans, twenty patients were treated on conventional Linacs with daily cone-beam CT (CBCT) scans, and twenty patients were treated on a biology-guided radiotherapy (BgRT)-capable machine with daily fan-beam kilovoltage CT (kVCT) scans. With each treatment modality, ten patients received daily CT scans in the pelvic region while the other ten received daily CT scans in the thoracic region. An auto-segmentation system using a convolutional neural network algorithm was trained in-house with historical treatment planning CT and contouring data to generate auto-segmentation models for the pelvic and thoracic regions, respectively. Normal organs were first delineated the auto-segmentation system on the daily CT images and then drawn by an experienced planner. A set of metrics including the dice similarity coefficient (DSC), Jaccard similarity index, and Hausdorff distance were used to evaluate the quality of the auto segmentation results compared with manual contours. The auto-segmentation contours on the kVCT images showed higher average DSC compared to those on the MVCT and CBCT images for all the major organs in both the pelvic and thoracic regions including the bladder, rectum, bowel, left and right femurs, esophagus, heart, left and right lung, and spinal cord. With the kVCT images, the average DSC ranged from 0.52±0.22 to 0.996±0.005. In the pelvic region, the largest absolute difference in DSC was observed for the bowel volume with an average DSC of 0.69±0.16, 0.49±0.27, and 0.32±0.25 for the kVCT, MVCT, and CBCT images, respectively (p-value < 0.05 with unpaired t-tests between kVCT and the other two imaging modalities); in the thoracic region, the largest absolute difference in DSC was observed for the esophagus with an average DSC of 0.63±0.16, 0.22±0.08, and 0.15±0.18 for the kVCT, MVCT, and CBCT images, respectively (p-value < 0.05 with unpaired t-tests between kVCT and the other two imaging modalities). Similar results were observed with other metrics. The AI-based auto segmentation system showed improved agreement with manual contouring when using kVCT images from the BgRT capable machine compared to MVCT or CBCT images. However, manual correction is necessary on auto-segmentation results from all imaging modalities especially for organs with limited contrast from surrounding tissues.

Reproducibility and Repeatability of Pelvic Radiomics Features with Daily Imaging on a Novel Biology-Guided Radiotherapy Machine Compared to Daily Imaging on Other Radiotherapy Delivery Systems

Radiomics features extracted from computed tomography (CT) images have the potential of being used as imaging biomarkers in diagnostic and prognostic models for prostate cancer. This study aims to evaluate reproducibility and repeatability of radiomics features using daily CT images from a novel biology-guided radiotherapy (BgRT)-capable machine compared to other daily CT imaging modalities from other radiotherapy delivery systems. We retrospectively selected thirty male patients treated to the pelvic region at our institution. Among the thirty patients, ten patients were treated on a BgRT-capable machine with daily fan-beam kilovoltage CT (kVCT) scans, ten patients were treated on a conventional Linac with daily cone-beam CT (CBCT) scans, and ten patients were treated on helical tomotherapy with daily megavoltage CT (MVCT) scans. The prostate gland and femoral heads were delineated on planning CT images and on CT images at the first treatment fraction. After all the CT images were resampled to have an identical voxel size, 107 radiomics features were calculated for the prostate and femoral heads on both the planning CT images and daily CT images. Concordance correlation coefficient (CCC) and Pearson's correlation coefficient (r) were calculated to evaluate radiomics feature reproducibility between the planning CT images and pre-treatment CT scans at the first treatment fraction. To evaluate radiomics feature repeatability with kVCT images on the BgRT-capable machine, a total of ten treatment sessions with repeat kVCT scans on the BgRT-capable machine were retrieved and radiomics features were compared between the first and the second kVCT scans. For the prostate gland volume, high concordance (CCC > 0.8) was found for 8, 6, and 0 radiomics features with the first-fraction kVCT, CBCT, and MVCT images, respectively, in relation to the planning CT images, while there was strong correlation (r > 0.8) in 38, 22, and 5 radiomics features in the kVCT, CBCT, and MVCT images, respectively, in relation to the planning CT images. For the left and right femoral heads, high concordance (CCC > 0.8) was found in no more than two radiomics features with the kVCT, CBCT, or MVCT images in relation to the planning CT images. Based on repeat kVCT scan data, 97 (90.7%) radiomics features showed high concordance (CCC > 0.8) in repeat kVCT scans with 98 (91.6%) features showing high correlation (Pearson's correlation coefficient > 0.8) for the prostate gland volume. A small number of radiomics features were found to show strong reproducibility between daily CT images on the first fraction and the planning CT images with the three IGRT CT modalities in this study. On the other hand, our results indicated that strong reproducibility was found with more radiomics features with daily kVCT images from the BgRT-capable machine compared to daily CBCT and MVCT images for the prostate gland. Strong repeatability was also found with most radiomics features in daily kVCT images.

Mitigation of IMRT/SBRT Treatment Planning Errors on the First Biology-Guided Radiotherapy System Using FMEA within Six Sigma Framework

Utilize the Six Sigma methodology and Failure Mode and Effect Analysis (FMEA) to prevent and mitigate errors in IMRT/SBRT treatment planning with the first clinical installation of biology-guided radiotherapy (BgRT) system. The Six Sigma approach consisted of five phases: Define-Measure-Analyze-Improve-Control. The Define-Measure-Analyze phases consisted of process mapping and an FMEA of the IMRT/SBRT treatment planning process on the BgRT system. The multidisciplinary team outlined the workflow process and identified the failure modes associated with the plan check items using AAPM TG-100 recommendations. Items with the highest average risk priority numbers (RPN) and Severity ≥7 were prioritized for automation using the treatment planning system scripting API (ESAPI). The Improve phase consisted of developing ESAPI scripts prior to the launch of the BgRT system to improve efficiency and safety. In the Control phase, the FMEA ranking was re-evaluated 1-year post-clinical launch. Overall, 100 plan check items were identified where the RPN values ranged from 10.2 to 429.0. Fifty of these items (50%) were suitable for automation within ESAPI. Of the 10 highest-risk items (Table 1), 8 were suitable for automation. Based on the results of the FMEA, two scripts were developed: Planning Assistant used by the planner during preparation for planning and the Automated Plan Check used by the planner and the plan checker during plan preparation for treatment. At 1-year post-clinical launch, the scripts were used for 80 patients successfully treated in 1747 fractions. During this period only 3 errors were reported: omitted bolus during treatment, nomenclature error in the BgRT system plan prescription, and dose tracking plan not approved following physics plan check. The average RPN pre-scripts was 138.0 compared to the average post-scripts RPN of 47.8 (p < 0.05) signifying a safer process. Implementing new technology into the clinic can be an error-prone process where the likelihood of errors increases with increasing pressure to implement the technology quickly. To limit errors in the clinical implementation of the first BgRT system, the Six Sigma methodology was utilized to identify failure modes, establish quality control checks, and re-evaluate these checks 1-year post-clinical launch.

Dosimetric Accuracy of Multi-Target Biology-Guided Radiotherapy Treatments in a Single Session

We present the first dosimetric measurements of single session, multi-target BgRT deliveries using a clinically realistic motion phantom on a research-only version of the RefleXion X1 system. A custom-made anthropomorphic phantom of a human torso with embedded fillable targets mimicking 18F-FDG-avid lesions was used. From the three embedded spherical targets, Target 1 was 26 mm in diameter coupled with a 3D independent respiratory motion with 22 mm range, whereas Target 2 and 3 were 22 mm in diameter and moved with a 1D 5 mm maximum sinusoidal motion. The 18F-FDG concentration in the background cavity of the phantom was 5 kBq/ml, and the targets were loaded with 10:1, 8:1 and 6:1 contrast relative to the background for Targets 1, 2, 3, respectively. Spherical structures were contoured as GTVs (CTV = GTV) and a 5 mm margin was added to create PTVs. Motion extent of the tumors were captured to create biological tracking zones for each target. Treatment plans were generated using a research version of the Reflexion treatment planning software to deliver 8 Gy/fx to the PTVs. The treatment delivery was repeated 2 times, and each time the phantom was refilled according to the plan. PET image evaluation metrics for each of the three targets were also recorded. Target dosimetry was measured using a combination of radiographic film and ion chamber. The maximum distance between the 97% prescription isodose line from the plan and the film measurements was used to characterize the dosimetric accuracy of the tracked deliveries. CTV and PTV min, max, and mean doses measured on film were also recorded for each target. Treatment plans were successfully created with 100% prescription dose coverage to each target loaded with different FDG ratios. Total treatment times for the single-plan, three-target deliveries were less than 80 minutes. PET evaluation metrics at imaging-only and pre-scan, and planning and film dosimetry to the GTV and PTV for each of the three targets is shown in table below (mean ± standard deviation of both deliveries). The CTV dose coverage was maintained for all targets. The shrinkage distance of the 97% prescription dose isodose line on the film plane for all three targets was less than 3 mm for both tests, and ranged from -0.4 to -2.34 mm. 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 18F-FDG concentrations and target motion patterns.

Development of the Independent Dose Verification Method for the Ring Gantry PET/CT Linac

The RefleXion Xi is a new external beam radiotherapy delivery modality combining kilovoltage fan-beam CT and on-board PET for Biology-guided Radiotherapy. Although the machine shares similar components with the Tomotherapy machine, it has unique hardware features such as stationary beam delivery system with couch increments. The goal of this study is to develop an in-house independent secondary dose calculation method for this ring gantry PET/CT Linac. The method aggregates the beam intensities at each discrete firing gantry angle and couch moving position. The non-uniform intensity map is decomposed into a series of segments of uniform beam intensities, and then coordinates of beam segments were modified based on the relative distance from the dose calculation point to keep the calculation point in the same spot along the gantry rotation. The dose to the calculation point of each segment is determined by using measured tissue-maximum-ratio, output factors, and off-axis ratio by independent binary collimators. Two-dimensional convolution method is applied to integrate all dose contribution components in segment areas for efficient calculation. The final dose is obtained by summing all dose to the calculation point of segments for all firing gantry angle and couch position. Twenty patients with different treatment sites including head and neck, prostate, and lung regions were analyzed. Comparison of the point dose calculated by the independent program to that calculated by the planning system has shown reasonable agreement within ±5%. The independent dose verification program has been developed as an initial patient specific QA for improving patient safety. Further study will be performed to enhance the accuracy and reliability by including additional leakage and scatter models.