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Stereotactic ablative radiation therapy (SABR) leads to excellent local control in patients with primary or metastatic lung tumors. While there are multiple strategies for motion management in thoracic SABR, there is limited data to compare the efficacy of different approaches. We compared local tumor control by the extent of tumor motion and the motion management strategy for patients treated on the iSABR clinical trial. This is a secondary analysis of patients treated on the multicenter phase II iSABR clinical trial that utilized an individualized dosing strategy for patients with primary or metastatic lung tumors. We evaluated the extent of tumor motion on 4D CT and the motion management approach used during treatment (free breathing, breath hold [BH], or expiratory gating [EG]). For patients treated with free breathing or EG approaches, an internal target volume (ITV) was contoured based on tumor movement on the 4D CT. Patients were treated on a linear accelerator using Real-time Position Management (RPM) triggering. In-field local control rates were compared using the Kaplan-Meier method. In total, 62 patients with 63 tumors had available data on motion management. Fifteen patients (24.2%) underwent SABR with free breathing, 22 (35.5%) had BH (20 inspiratory, and 2 expiratory), and 26 (41.9%) had EG (24 amplitude based, and 2 phase based). 1-, and 2-year local control rates were 100% and 100% with free breathing, 94.7% and 83.2% with BH, and 90.7% and 78.6% with EG (p = 0.2), respectively. Overall, median maximal tumor motion was 10mm (3.5mm for tumors treated with free breathing vs 14.5mm for tumors treated with BH or EG). There was no association between local control and maximum extent of motion on 4D CT (HR = 1.01, p = 0.75). 1- and 2-year local control rates were 92.9% and 89.1% for tumors with maximal motion <10mm, and 96.3% and 82.5% for tumors with maximal motion >10mm (HR = 0.6, p = 0.53), respectively. Patients on the iSABR trial were treated with a range of motion management strategies including motion inclusive free breathing, BH and EG with no observed association between local control by treatment approach. The similar local control rates between mobile and non-mobile tumors suggests that the RPM approach used on the iSABR trial was effective. Our results will be further analyzed pending motion management data collection for the entire iSABR cohort. [ABSTRACT FROM AUTHOR]

The first clinical biology-guided radiation therapy (BgRT) system – RefleXionTM X1 - was installed and commissioned for clinical use at our institution. This study aimed at evaluating the treatment plan quality and delivery efficiency for IMRT/SBRT cases without PET-guidance. Forty-two patient plans across six cancer sites (conventionally-fractionated lung, head and neck, anus, prostate, brain, and lung SBRT) planned with the EclipseTM treatment planning system (TPS) and treated with either a TrueBeam® or Trilogy® were selected for this retrospective study. For each Eclipse VMAT plan, two corresponding plans were generated on the X1 TPS with 10 mm jaws (X1 10mm) and 20 mm jaws (X1 20mm) using our institutional planning constraints. All clinically relevant metrics in this study, including PTV D95%, PTV D2%, Conformity Index (CI), R50, organs- at-risk (OAR) constraints, and beam-on time were analyzed and compared between 126 VMAT and RefleXion plans using paired t-tests. All but three planning metrics were either equivalent or superior for the X1 10mm plans as compared to the Eclipse VMAT plans across all planning sites investigated. The Eclipse VMAT and X1 10mm plans generally achieved superior plan quality and sharper dose fall-off superior/inferior to targets as compared to the X1 20mm plans, however, the X1 20mm plans were still considered acceptable for treatment. Strong correlation was observed between the TPS-calculated beam-on time and PTV length in the superior-inferior direction for the X1 10mm (R 2 = 0. 87) and X1 20mm (R 2 = 0. 85) plans. On average, the required beam-on time increased by a factor of 1.6 across all sites for X1 10mm compared to X1 20mm plans. Clinically acceptable IMRT/SBRT treatment plans were generated with the X1 TPS for both the 10 mm and 20 mm jaw settings. The X1 10mm plans were equivalent or superior to the Eclipse VMAT plans, however the beam-on times were longer. [ABSTRACT FROM AUTHOR]

Minimizing cardiac toxicity after thoracic radiation therapy (RT) remains a clinical challenge. Mean heart dose is associated with major adverse cardiac events (MACE) and recent studies suggest RT dose to coronary arteries may better quantify risk after conformal RT. Prior studies have not evaluated RT dose to individual coronary arteries in risk modeling. We therefore sought to develop an integrated dosimetric model accounting for RT doses received by each coronary artery. We performed a retrospective study of a randomly selected representative cohort of patients with locally advanced non-small cell lung cancer. We scored cardiac events as (1) ischemic, (2) constrictive, (3) valvular, or (4) conductive. We contoured and measured doses received by the left circumflex (LCX), left anterior descending (LAD), left main coronary (LMCA), and right coronary arteries (RCA). RT doses were measured as equivalent dose in 2-Gray (Gy) fractions. Dosimetric parameters associated with cardiac toxicity were examined using cumulative incidence, competing risk regression models, receiver operator characteristic (ROC), and log-rank statistics with significance defined as two-tailed P <0.05. We identified 100 patients who received definitive RT (median=66 Gy, range=60-74 Gy) from 2006-2020. Median follow-up was 4.1 years (range, 0-11.0). Median age was 70 years (range, 38-84). Half the cohort was male (50%), a majority had smoking history (81%), and all received chemotherapy (100%). Thirty (30%) experienced MACE at a median of 13 months post-RT. Most events were ischemic (n=17, 57%) or conductive (n=13, 43%), with only 3 cases (10%) of valvular disease. Mean heart, LCX, LAD, and LMCA doses were predictive of cardiac toxicity (AUC=0.59, 0.58, 0.59, and 0.63, respectively) and were each significantly associated with MACE on univariable analysis (P <0.05). For patients with full labs available, 10-year atherosclerotic cardiovascular disease (ASCVD) risk was also associated with MACE (HR=1.31, P =0.04). Chemotherapy, age, diabetes, hypertension, prior cardiac event, and mean RCA dose were not associated with MACE. Using the log-rank statistic, we identified threshold mean doses of 1.82, 12.71, 15.45, and 31.29 Gy for the heart, LCX, LAD, and LMCA, respectively. Patients exceeding all three threshold doses to the LCX, LAD, and LMCA had a two-year rate of MACE of 57.1% versus 15.9% (P =0.005). On multivariable analysis after adjusting for ASCVD, patients exceeding all identified doses to the LCX, LAD, and LMCA were at nearly 5 times the risk of MACE (HR=4.76, P =0.0005). Our results suggest that patients receiving doses above our identified thresholds to all of the left coronary arteries (LCX, LAD, and LMCA) are at highest risk of MACE. If validated, our findings may inform RT treatment planning, where sparing of at least one vessel may lead to lower risk of MACE. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): The first clinical biology-guided radiation therapy (BgRT) system - RefleXion X1 - is installed and is being commissioned for clinical use at our institution. The system delivers 6MV-FFF beam via 50 firing positions at 850 cGy/min dose rate on 60 rpm rotating gantry with the couch advancing in 2.1 mm increments. Collimation is achieved through a binary multi-leaf collimator system composed of 64 (6.25 mm width at 850 cm SAD) leaves and 10mm or 20mm jaws. The purpose of this study was to compare the treatment plan quality and delivery efficiency for SBRT cases without PET-guidance.Materials/methods: Five lung cancer patients (50 Gy/4fx) with motion-inclusive PTV previously treated with VMAT SBRT were selected for this retrospective study. For each VMAT plan a corresponding plan was generated on the RefleXion treatment planning system (TPS) using our institutional planning constraints. VMAT SBRT plans used 1-2 partial arcs with 10MV-FFF energy and 2400 MU/min dose rate. RefleXion SBRT plans used all 50 firing positions and 1 cm jaw collimation. As plan normalization option does not yet exist in the RefleXion TPS, the plans were optimized to achieve PTV D95% coverage with 100% of prescription dose to the best of planner's ability. All clinically relevant metrics in this study, including plan PTV D95%, PTV D1%, 50% isodose volume (I50%), Conformity Index (CI), organs at risk constraints, and treatment time were analyzed and compared between VMAT and RefleXion plans using paired t-tests.Results: Clinically acceptable plans were obtained with both techniques. The average PTV volume was 14.1 ± 6.4cc. For VMAT and RefleXion plans, no statistically significant difference was observed in PTV D95%, PTV D1%, CI or I50%. Ipsilateral lung volume spared at 12.4 Gy (VS12.4) was slightly greater (31.6cc increase, P < 0.035) and skin Dmax was slightly lower (1.4 Gy decrease, P < 0.038) for RefleXion plans. Treatment beam-on time was significantly longer for RefleXion plans (23.4min increase, P < 0.0002).Conclusion: RefleXion TPS provided comparable plan quality to lung SBRT VMAT plans. Treatment beam-on time is significantly longer for the RefleXion system. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): A novel therapeutic machine that combines PET, fan beam kVCT and linear accelerator to support real-time PET-guided treatment, termed biology-guided radiotherapy (BgRT). This study reports the positioning accuracy, image quality, and dose commissioning of the kVCT imaging system of the first clinical BgRT machine at our institute.Materials/methods: The helical fan-beam kVCT subsystem consists of an X-ray tube with a voltage of 120kV and a 16-row GOS Ceramic Scintillator detector. The gantry rotation speed is 60 rpm. The tube currents are 45, 67, 133mA for 0.5 pitch; 100, 150, and 300mA for 0.5 pitch; 267 and 400mA for 1.333 pitch. The image slice thickness is 1.25mm with a field of view of 500mm and a resolution of 512 × 512. A ball-cube phantom was used to test the positioning accuracy of the kVCT subsystem with respect to the setup laser and MV beam. Catphan504 phantom was imaged with 0.5 pitch and 150mAs to test the kVCT image quality of the BgRT system, including the uniformity, noise, HU constancy, spatial resolution, geometric distortion, slice thickness, and low contrast visibility and detectability using the PIPSproTM software. The RTI MAS-2 and Piranha detectors were used to verify the accuracy of the mA and voltage. The CTDI dose was measured using a CTDI phantom and a Standard Imaging A101 pencil chamber.Results: The localization error of the ball cube phantom was -0.8, 0.9, and 0.3mm in IEC x, y, and z directions, respectively. For the Catphan504 tests, the vertical and horizontal uniformities were 0.926 and 0.857, respectively. The HU constancy tests of the air, water, polystyrene, acrylic, Delrin, Teflon were all within 40HU to the expected values. The modulation transfer function test results were 0.467, 0.528, and 0.595 lp/mm for F50, F40, and F30, respectively, which showed a comparable spatial resolution to regular CT simulators. The geometric distortion was 0.12mm and slice thickness inaccuracy was 0.13mm. The low contrast detectability was 0.734. The measured mA and voltage were within 5% of the nominal setting of 120 kV and 150 mA. The CTDIw was less than 1.4 cGy for body and 3 cGy for head with a protocol of 120 kVp, 150 mAs, and 1.25 mm slice thickness.Conclusion: This evaluation represents the kVCT characteristics of the novel BgRT system with architecture designed to accommodate CT, PET and a LINAC. The image quality and HU constancy are comparable to our CT simulators and is a useful tool for online adaptive radiotherapy. The commissioning data will serve as a standard for units installed at future clinical sites. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): To evaluate Biology-guided Radiotherapy (BgRT) plans generated using PET data acquired on the first installation of the Reflexion™ X1 system. BgRT treatment planning optimizes for fluence indirectly by calculating firing filters that best translate the X1 acquired PET image to the fluences that deliver the prescribed radiation dose. During a treatment session, the firing filters are applied to limited time sampled (LTS) PET images to calculate delivery fluences.Materials/methods: An FDG fillable phantom insert that consists of a 22 mm diameter spherical target (PTV1, ball) and a C-shape object (PTV2 with 26mm axial length, 255° partial annulus with major and minor radii of 27 mm and 12 mm) was imaged using a CT Simulator to create planning contours. The water filled insert surrounding these objects was filled with FDG to simulate a warm background. Both targets were filled with FDG, simulating a target to background ratio of 8:1. Two different BgRT treatment plans were generated for PTV1 simulating homogenous uptake, and PTV2 with an inhomogeneous FDG uptake due to necrosis (a cylinder encompassing the C shape PET avid object). A structure that is 12.5 mm away from these targets was used to simulate OAR. Two PET/CT imaging acquisitions were performed on the RefleXion X1 masking the signal outside of each target plus 10 mm margin. Two different BgRT plans were generated prescribing 50 Gy delivered in 5 fractions to each target, separately. The quality of each treatment plan was evaluated based on PTV coverage, Conformity Index at 50% and 80% isodose lines (CI50, CI80) and OAR sparing. Both BgRT plans then delivered to the independent quality assurance tool for patient specific QA verification where the 3%/3 mm gamma criteria was used.Results: BgRT plans for both homogenous and heterogenous FDG uptake targets were created successfully. Prescription dose coverages were 94.2% and 96.3% for PTV1 and PTV2, respectively. The maximum OAR doses were 30.9 and 33.0 Gy and average OAR doses were 14.4 and 20.1 Gy for PTV1 and PTV2 plans, respectively. CI50 were 7.7 and 6.8 where CI80 were 2.5 and 2.6 for PTV1 and PTV2 plans. The patient specific QA passed with 100 % for both plans.Conclusion: This is the first report of the BgRT plan creation and QA delivery using a clinical installation of the Reflexion X1 system, opening the potential towards BgRT dose delivery using the real time FDG uptake measurements to biologically guide active radiation beam delivery. The X1 system was able to optimize and deliver the BgRT plans for both homogenous and heterogenous FDG uptake scenarios. BgRT is a new paradigm of dose optimization, where a new set of optimization and evaluation approaches will be needed. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): A biologically guided radiotherapy (BgRT) system was developed and equipped with a novel O-ring gantry Linac, positron emission tomography (PET) and computed tomography technologies. This architectural design is to support real-time PET-guided treatment, termed biology-guided radiotherapy. To reduce latency between PET data acquisition and radiation delivery, the BgRT system incorporates a fast-transitioning binary multi-leaf collimator (MLC) leaves sandwiched between a split-jaw. This study reports the dosimetric commissioning of the first clinical BgRT machines at our institution, and compared with the reference data provided by the manufacturer.Materials/methods: The dosimetric commissioning of the 6 MV flattening filter-free (FFF) photon beam was characterized using a 3D water phantom and diode detectors at a source to surface distance of 85 cm. In-air profiles of 40cm x 2cm field, 40cm x 1cm field, and various leaf combinations plus in water PDD data of 12 field sizes (1.25, 2.5, 5, 10, 20 and 40 cm MLC opened leaves with 1 and 2cm jaw settings) were acquired first for beam modeling. Additional longitudinal and transverse profile scans were performed for these 12 field sizes at the depth of 1.5, 5, 10, 15 and 20 cm to verify the beam model accuracy. The relative outputs factors were measured with the W2 1mmx1mm scintillator at the depth of 10cm for the field sizes from the smallest 0.6cm x 1cm to the maximum 40cm x 2cm.Results: For the PDDs of reference field size of 10cm x 2cm measured at Stanford, the maximum doses (dmax) were 12.5mm within the manufacturer's reference range of 13 ± 0.75 mm. The percentage doses at 10cm depth (d10) at reference field size were 56.9% and 57.6% for Stanford and RefleXion measurements, respectively. The longitudinal field sizes for all tested fields were agreed within 0.5mm and the transverse off-axis ratio is within 1% in the beam core (80% of nominal field size). The output factors measured at our institute were ranging from 0.706 to 1.012 relative to the reference 10cm x 2cm field.Conclusion: This evaluation represents the first commissioning evaluation of the dosimetric characteristics of the BgRT system with architecture designed to accommodate both PET detector and LINAC subsystems. This data will serve as a clinical reference for the BgRT treatment planning system's beam model and can act as a standard for comparison and beam model improvement for units installed at future clinical sites. [ABSTRACT FROM AUTHOR]