Radiation Therapy Workflow and Dosimetric Analysis from a Phase 1/2 Trial of Noninvasive Cardiac Radioablation for Ventricular Tachycardia

      Purpose

      A prospective phase 1/2 trial for electrophysiologic guided noninvasive cardiac radioablation treatment of ventricular tachycardia (ENCORE-VT) demonstrating efficacy for arrhythmia control has recently been reported. The treatment workflow, report dose-volume metrics, and overall process improvements are described here.

      Methods and Materials

      Patients receiving 25 Gy in a single fraction to the cardiac ventricular tachycardia substrate (identified on presimulation multimodality imaging) on the phase 1/2 trial were included for analysis. Planning target volume (PTV), R50, monitor unit ratio, and gradient measure values were compared over time using statistical process control. Outlier values in the dose-volume histogram (DVH) for PTV and organs at risk were identified by calculating inner fences based on the interquartile range. Median heart substructure doses are also reported.

      Results

      For the 16 trial patients included, the median target volumes for the gross “target” volumes, internal target volumes, and PTVs were 25.1 cm3 (minimum: 11.5 cm3, maximum: 54.9 cm3), 30.1 cm3 (17.7, 81.6), and 97.9 cm3 (66, 208.5), respectively. On statistical process control analysis, there was a significant decrease in PTV volume among the more recent cohort of cases and mean doses to the nontargeted heart (heart – PTV). Two patients had heart-minus-PTV, esophagus, and stomach DVH data significantly higher than inner fence, and 3 patients had spinal cord DVH data higher than the inner fence, but in all cases the deviations were clinically acceptable. Subjective decreases were seen in the R50, gradient measure, and treatment time from the first to last patient in this series. All plans were verified in phantom with ionization chamber measurements within 2.9% of the expected dose value.

      Conclusions

      Over the duration of this trial, PTV volumes to the cardiac substrate target decreased significantly, and organ-at-risk constraints were met for all cases. Future directions for this clinical process will include incorporating knowledge-based planning techniques and evaluating the need for substructure optimization.
      Summary
      In this manuscript, the authors detail the complete workflow for cardiac stereotactic body radiation therapy that was performed to treat patients with refractory ventricular tachycardia on a recently completed phase 1/2 trial. Included in this report are the dose-volume metrics for the clinical targets, organs at risk, and cardiac substructures, and the changes in these metrics over time from continuous process review.

      Introduction

      Ventricular tachycardia (VT) is a cardiac arrhythmia characterized by an abnormally rapid heart rhythm that can progress to a fatal arrhythmia resulting in sudden cardiac death. This condition typically develops in patients with scar tissue after cardiac injury, which alters the normal sequence of electrical conduction in the heart. This anatomic and physiologic disturbance allows the ventricles to enter an independent and uncontrollable accelerated rhythm. In addition to placement of an implantable cardiac defibrillator (ICD), VT has traditionally been treated medically with antiarrhythmic drugs and through interventional approaches such as invasive catheter ablation. However, even in optimally selected patients, 1-year VT recurrence approaches 50%.
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      Catheter ablation for the treatment of electrical storm in patients with implantable cardioverter-defibrillators: Short- and long-term outcomes in a prospective single-center study.
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      Irrigated radiofrequency catheter ablation guided by electroanatomic mapping for recurrent ventricular tachycardia after myocardial infarction: The multicenter thermocool ventricular tachycardia ablation trial.
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      Catheter ablation of recurrent scar-related ventricular tachycardia using electroanatomical mapping and irrigated ablation technology: Results of the prospective multicenter Euro-VT-study.
      Few options exist for patients with medically refractory VT, and the morbidity and mortality of refractory VT is significant.
      As part of a multidisciplinary collaboration between cardiology and radiation oncology, we recently published our early experience with noninvasive imaging followed by stereotactic body radiation therapy (SBRT) to the arrhythmogenic scar region for patients with refractory VT.
      • Cuculich P.S.
      • Schill M.R.
      • Kashani R.
      • et al.
      Noninvasive cardiac radiation for ablation of ventricular tachycardia.
      In 5 patients treated for clinical need, we described a significant reduction in VT burden after a single fraction of 25 Gy to the arrhythmogenic target without any significant acute toxicity. Recently, our team completed an institutional phase 1/2 clinical study (Electrophysiologic-guided Noninvasive Cardiac Radioablation for Treatment of Ventricular Tachycardia, ENCORE-VT, NCT02919618) demonstrating efficacy in arrhythmia cessation.
      • Robinson C.G.
      • Samson P.P.
      • Moore K.M.S.
      • et al.
      Phase II trial of electrophysiology-guided noninvasive cardiac radioablation for ventricular tachycardia.
      Here, we detail our clinical workflow and cardiac target volumes and dosimetric analysis of the targets, organs at risk (OARs), and cardiac substructures. Finally, we address the learning curve encountered with this novel trial and describe process modifications made during the course of the study to improve efficiency of treatment delivery and target conformity.

      Methods and Materials

      Detailed patient selection criteria for the trial is available on ClinicalTrials.gov (NCT02919618). Included in this analysis are the 16 consecutive patients treated on trial using volumetric modulated arc therapy (VMAT) on a linear accelerator equipped for stereotactic radiosurgery. This trial was approved by our local institutional board review with independent Data Safety and Monitoring Committee oversight. Enrolled patients received multimodality noninvasive cardiac imaging including cardiac magnetic resonance imaging (MRI), positron emission tomography (PET), and myocardial perfusion imaging using single-photon emission computed tomography (CT).
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      • Schill M.R.
      • Kashani R.
      • et al.
      Noninvasive cardiac radiation for ablation of ventricular tachycardia.
      All but 1 patient had implantable cardioverter defibrillators (ICDs) and underwent a specific risk-mitigation strategy and additional consent for MRI.
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      • Costa H.S.
      • Silva P.D.
      • et al.
      Assessing the risks associated with mri in patients with a pacemaker or defibrillator.
      Physiologic mapping of the arrhythmogenic area was performed with electrocardiographic imaging during intentional induction of ventricular tachycardia using a 256-channel vest of electrodes.
      • Rudy Y.
      • Lindsay B.D.
      Electrocardiographic imaging of heart rhythm disorders: From bench to bedside.
      • Rudy Y.
      Noninvasive electrocardiographic imaging of arrhythmogenic substrates in humans.
      • Ramanathan C.
      • Ghanem R.N.
      • Jia P.
      • Ryu K.
      • Rudy Y.
      Noninvasive electrocardiographic imaging for cardiac electrophysiology and arrhythmia.

       Patient simulation and contouring

      Patients were immobilized and simulated with bridge abdominal compression, superior poles for overhead arm extension (CDR Systems, Calgary, Canada), and a body mold. Free-breathing CT simulation was performed using 1.5-mm slice thickness. The maximum compression tolerated by the patient was used. A respiratory phase–correlated 4-dimensional CT (4D-CT) was acquired and co-registered to the planning CT to assess target motion (cardiac and respiratory motion). CTs were performed with both oral and IV contrast if not contraindicated. PET-CT was co-registered to the simulation CT to aid in target delineation. Rigid co-registrations were used in all cases. The registration accuracy of the 4D-CT to the free breathing was maximized given the fact the scans were done immediately after each other in the same immobilization. Therefore, the uncertainty in the registration between the reference CT and 4D-CT based on the spine was kept ≤1 mm and was much smaller than the motion of the targets in the 4D-CT. However, the PET-CT was used as an aide for contouring and not contoured directly because the PET-CT registration to the reference CT inherently had more uncertainty owing to the scans taking place at different times, the spatial resolution of PET, and the positioning of the patient being different between the scans.
      The treatment target was delineated using conventional definitions. The gross “target” (in lieu of tumor) volume (GTV) was segmented through corroboration of all previously acquired imaging and electrocardiographic imaging data by the radiation oncologist and electrophysiologist. An internal target volume (ITV) was created from the phased-binned 4D-CT to account for the maximum range of motion. The combined effect of respiratory and cardiac motion was assessed by reviewing the playback of all the phases of the 4D-CT overlaid with the reference CT. Recent work describing cardiac motion for SBRT has estimated the magnitude of average displacements to be within 2 mm and maximum displacements to occur at 5-6 mm under breath-hold conditions, representing heart deformations during systole and diastole.
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      • Samson P.P.
      • Wazni O.
      • et al.
      Analysis of cardiac motion without respiratory motion for cardiac stereotactic body radiation therapy.
      • Bahig H.
      • de Guise J.
      • Vu T.
      • et al.
      Analysis of pulmonary vein antrums motion with cardiac contraction using dual-source computed tomography.
      Because patients would be treated under free breathing with compression, it was felt respiratory-gated 4DCT under the same conditions should be used to determine the maximum excursion of the gross target volume from respiratory and cardiac motion together to create the ITV. The maximum distance between GTV and ITV in the 3 Cartesian planes were recorded. No clinical target volume expansion was utilized. The planning target volume (PTV) was generated as a 5-mm volumetric expansion from the ITV. OARs including spinal cord, stomach, liver, total lung, esophagus, and heart minus PTV were contoured on the free-breathing CT.

       Treatment planning, evaluation, and quality assurance

      Patients were prescribed 25 Gy in 1 fraction to the PTV. A 6 MV beam energy was used, and the most recent plans used flattening-filter-free beams. VMAT was used via 3 arcs, each approximately 160 to 220 degrees in length.
      • Otto K.
      Volumetric modulated arc therapy: IMRT in a single gantry arc.
      Two of the arcs were noncoplanar (couch angle of ±15 degrees), and 1 had an axial arrangement. Plans were created in a commercial treatment-planning system (Eclipse v13.7, Varian Medical Systems, Inc, Palo Alto, CA). The coverage goal was for at least ≥95% of the PTV to be covered by at least 95% of prescription dose (25 Gy). Treatment plan constraints are listed in Table 1. Priority was always given to the spinal cord constraint; however, PTV coverage could take priority over other OAR constraints if deemed a higher priority by the physician. Beam geometry was optimized to avoid the ICD geometrically. Optimization was used to place prescription hotspots (areas receiving >100% of the prescription dose) within the ITV, allowing for the ITV to be covered by up to 35 Gy. Tuning structures (5-mm and 20-mm rings) were used to increase dose fall-off. The Normal Tissue Objective (NTO) function in Eclipse was used to aid in the sparing of normal tissues outside of the PTV. Conformity index (ratio of the volume of the 25-Gy isodose to the PTV), homogeneity index (ratio of the max dose to the prescription dose), R50 (ratio of the volume of the 12.5-Gy isodose to the PTV), monitor unit (MU) ratio (the total number of monitor units divided by 2500 cGy), total arc span, and gradient measure (GM; the average distance between the 12.5-Gy equivalent spherical volume and the 25-Gy equivalent spherical volume) were reviewed.
      Table 1Target and organ-at-risk constraints for cardiac stereotactic body radiation therapy treatment planning
      Target structureDose coveringCoverage goal
      PTV95% of 25 Gy (23.75 Gy)> 95%
      ITVUp to 35 Gy
      GTVUp to 35 Gy
      Serial tissuesVolume (cm3)Volume max (Gy)Max point dose (Gy)
      Max dose to 0.035 cm3.
      Spinal cord<0.35 cm3

      <1.2 cm3
      10 Gy

      8 Gy
      14 Gy
      Esophagus<5 cm311.9 Gy15.4 Gy
      Stomach<5 cm317.4 Gy22 Gy
      Parallel tissuesVolume (cm3)Volume max (Gy)
      Lung total (both)1500 cm37 Gy
      Liver700 cm311 Gy
      Abbreviations: GTV = gross target volume; ITV = internal target volume; PTV = planning target volume.
      Max dose to 0.035 cm3.
      Verification plans were created to measure point dose inside the target with an ionization chamber in a plastic water phantom, planar measurements (electronic portal imaging device–based dosimetry for all patients and additional film dosimetry for the first 8 patients), and treatment log file comparisons were completed for each treatment plan. Dose difference was used for point measurements, a 2-dimensional gamma analysis was used for planar measurements, and full analysis of the treatment plan parameters versus delivered parameters from the log files was completed using in-house software.
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      A technique for the quantitative evaluation of dose distributions.
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      The use of an aSi-based EPID for routine absolute dosimetric pre-treatment verification of dynamic IMRT fields.
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      • et al.
      Initial experience with TrueBeam trajectory log files for radiation therapy delivery verification.
      All plans had to meet the clinical criteria of the point-dose measurement being ±3% of expected, less than 10% of the planar measurements having a gamma value of (2%, 2 mm) > 1, and less than 5% of the planar measurements having a gamma value of (3%, 3 mm) > 1.

       Treatment delivery

      All patients received pretreatment ICD interrogation. Patients were treated using multimodality linear accelerator (Edge, Varian Medical Systems, Inc, Palo Alto, CA), with a 120-leaf high-definition multileaf collimator. After patient setup, a full trajectory cone beam CT scan was done. Couch corrections were applied with 6 degrees of freedom for the alignment of the cardiac silhouette on the reference simulation CT and cone beam CT. Fluoroscopy was used to confirm shifts and that the target motion was consistent with simulation, that is, that the targeted area of the cardiac silhouette did not leave the projection of the PTV. After treatment, ICD interrogation, and assessment of vital signs, the patient was discharged home.

       Heart substructures

      Cardiac substructure contours were delineated post hoc and included the pulmonary artery, aorta, aortic valve, pulmonic valve, left atrium, right atrium, left circumflex artery, coronary sinus, inferior vena cava, left anterior descending artery, left circumflex artery, right coronary artery, superior vena cava, left ventricle, right ventricle, and pericardium. For this analysis, we report the median doses to these substructures with the interquartile range (IQR) and equivalent dose in 2 Gy (EQD2; calculated with α/β = 3 Gy for cardiac tissue).

       Continual review and process improvement

      The processes detailed above were continually reviewed by the team during the trial. All dose-volume histogram (DVH) data for clinically significant structures for each patient were exported and analyzed using in-house software to be compared to previous participants. For target and OAR volumes, the median, first quartile, third quartile, IQR, and inner fence (first quartile – 1.5 IQR to third quartile + 1.5 IQR) dose values were calculated. Treatment data review included patient setup shift data, plan delivery times, and the time elapsed (in days) from simulation to treatment. Control charts were used to compare changes in PTV, GM, R50, and treatment time. Statistical process control using control charts to test for significant differences in treatment variables over time has been described extensively.
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      • Murray S.K.
      The run chart: A simple analytical tool for learning from variation in healthcare processes.
      We used Shewhart's 3-sigma method in Excel (Microsoft, 2010, Redmond, WA) to establish upper control limits and lower control limits to identify values that would be 3 standard deviations above or below the mean value, respectively.
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      • Lloyd R.C.
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      Results

       Treatment planning data

      For each of the 16 patients, the GTV, ITV, and PTV volumes were recorded. Target volumes varied in complexity and shape. Examples of 4 target volumes are shown in Figure 1A (i-iv). Median target volumes for the GTVs, ITVs, and PTVs were 25.1 cm3 (minimum: 11.5 cm3, maximum: 54.9 cm3), 30.1 cm3 (17.7, 81.6), and 97.9 cm3 (66, 208.5), respectively. The median maximum distance from the GTV to ITV in the axial, coronal, and sagittal planes across all patients was 4.4 mm (minimum: 3 mm, maximum: 11.3 mm), 4.65 mm (1.55, 12), and 3 mm (1, 7.2), respectively. In the control chart for PTVs (Fig. 1C), there was a significant decrease in volume in the more recent cohort of cases with 8 sequential data points below the mean volume, thereby establishing a new mean centerline. This was a direct result of smaller GTV volumes drawn because there was no change in motion management or margins used over time.
      Figure thumbnail gr1
      Fig. 1(A) Characteristic target shapes. (B) Gross target volume, internal target volume, and planning target volume for trial participants. (C) Process control chart for planning target volume shows a significant decrease in the more recent cohort of cases.
      The DVH data for all patients are shown in Figures 2A (PTV) and 2B-2G (OARs), along with the median values and the inner fences. In the plotting of each DVH, it was seen that 2 patients had significant portions of the PTV DVH lower than the inner fence (Fig. 2A). This was owing to limited coverage resulting from OAR constraints. One patient had a portion of their PTV DVH higher than the inner fence because this plan had a relatively larger portion of the GTV receiving higher than the prescription dose.
      Figure thumbnail gr2
      Fig. 2(A) Dose-volume histogram for each patient's planning target volume (red line), the median (black line), and inner fences (grey shaded area). Organ-at-risk DVH data for each participant's (B) heart minus planning target volume, (C) total lung contour, (D) stomach, (E) esophagus, (F) spinal cord, and (G) liver. The median DVH values are shown with thick solid black lines and the inner fences as the grey shaded area. Each red line demonstrates an individual patient's DVH for that organ at risk. Constraints are shown with the triangular markers if applicable. Abbreviation: DVH = dose-volume histogram.
      For distributions of OAR DVH data (Fig. 2B-2G), 2 patients had values higher than the inner fence, indicating comparatively higher doses for heart minus PTV, esophagus, and stomach. The spinal cord DVH data indicated 3 patients with values greater than the inner fence. In all cases, these deviations were considered clinically acceptable but were statistically outside of the inner fences of the distributions. These differences from the population DVHs often indicated (1) a subset of patients where the PTV was closer to a particular OAR than in other patients, (2) targets that were larger than other patients', or (3) differences were seen in doses much lower than the OAR constraints and were not optimized. In 1 case, the stomach constraints were not met; however, it was deemed increased target coverage paired with the patient fasting before the treatment was preferred. The maximum dose to the ICD for all patients ranged from 3.1 cGy to 60.3 cGy with a median of 13.1 cGy. For all patients, ICD dose was well below the 200-cGy limit recommended by the American Association of Physicists in Medicine.
      • Solan A.N.
      • Solan M.J.
      • Bednarz G.
      • Goodkin M.B.
      Treatment of patients with cardiac pacemakers and implantable cardioverter-defibrillators during radiotherapy.
      The MU ratio, R50, GM, conformity index, homogeneity index, treatment time (in minutes), and time from simulation to treatment (in days) for each patient are demonstrated in Figure 3 (A-C). A subjective decrease was seen in the R50, GM, homogeneity index, and treatment time from patient 1 to patient 16, but these decreasing values did not reach the threshold to establish a new mean baseline as they did for the PTV. The MU ratio, conformity index, and time from simulation to treatment did not exhibit any subjective or quantitative decrease in trend. However, this trend of a decrease in GM and R50 indicate a faster fall-off while maintaining the conformity index. In addition, we did see a trend toward reduction in treatment time by increasing the treatment dose rate from 600 MU/min to 1400 MU/min when 6 MV flattening-filter-free beams became clinically available for the last 3 patients treated. The days between simulation and treatment fluctuated, with a median of 13.5 days (minimum: 8, maximum: 33).
      Figure thumbnail gr3
      Fig. 3(A) Monitor unit ratio and R50. (B) Gradient measure, conformity index, and homogeneity index. (C) The total treatment time (in minutes and the number of days) from simulation to treatment.

       Quality assurance data

      All ionization chamber measurements were within 2.9% of the expected dose value. The median difference was 1.4% from the expected dose reading across all patients. All portal dosimetry measurements per field per patient had less than 8.0% of points with a gamma value of (2%, 2 mm) > 1 and less than 4.3% of points with a gamma value of (3%, 3 mm) > 1. The median number of points with gamma values >1 for (2%, 2 mm) and (3%, 3 mm) criteria was 3.0% and 0.8%, respectively. The film measurements completed for the first 8 patients show less than 4.3% of points had a gamma value of (2%, 2 mm) > 1. All treatment log files were confirmed to match the treatment plan file before each patient's treatment. These results are shown in the supplemental materials (Fig. E1, available at https://doi.org/10.1016/j.ijrobp.2019.04.005).

       Heart substructures

      For each patient, the median values, IQR, and EQD2 doses to the cardiac substructures are listed in Table 2. As expected based on the anatomy of the VT targets, the pulmonary artery and superior vena cava showed the lowest doses, whereas the left anterior descending artery and left ventricle demonstrated the highest dose exposure. A control chart for heart-minus-PTV mean dose (Fig. 4) demonstrated a significant decrease in the more recent cohort of cases, again with 8 sequential data points below the original mean, thereby establishing a new centerline. This coincides with a change in the planning process after patient 6, by ensuring planners directly optimized on the heart-minus-PTV structure in addition to ring structures and the NTO.
      Table 2Heart substructure median dose, IQR, and EQD2
      α/β = 3 Gy.
      StructureMedian dose (Gy)IQR (Gy)EQD2 of median dose (Gy)
      Pulmonary artery0.662.3-
      Aorta1.61.41.5
      Aortic valve3.57.14.5
      Left atrium3.63.14.7
      Right atrium2.90.73.4
      Circumflex artery9.26.322.4
      Coronary sinus4.17.35.9
      Inferior vena cava2.73.13.1
      Left anterior descending artery10.110.726.4
      Left main artery1.35.11.1
      Pericardium7.22.914.8
      Pulmonic valve1.89.71.8
      Right coronary artery3.23.94.1
      Superior vena cava0.91.3-
      Left ventricle11.35.932.6
      Right ventricle8.34.818.9
      Heart – PTV5.71.99.8
      Abbreviations: EQD2 = equivalent dose in 2 Gy fractions; IQR = interquartile range; PTV = planning target volume.
      α/β = 3 Gy.
      Figure thumbnail gr4
      Fig. 4Process control chart for heart-minus-PTV mean dose shows a significant decrease in the more recent cohort of cases.

      Discussion

      Early clinical results indicate single-fraction cardiac SBRT is a promising therapeutic modality for patients with refractory VT; however, much is yet to be learned in terms of targeting, optimal planning, dosing, and subsequent dose-volume predictors of toxicity and efficacy to improve the therapeutic index for future patients. Here, we present our experience with cardiac SBRT in terms of dosimetric evaluation of treatment volumes, OARs, heart substructures, and quality assurance. We also saw evidence of process improvement during the course of the trial, resulting in significantly smaller treatment volumes and a trend toward decreased R50, GM values, and treatment times.
      Cardiac SBRT for VT ablation includes integration of complex multimodality imaging, multidisciplinary collaboration for targeting, and the need to account for both cardiac and respiratory motion. These aspects of treatment planning and delivery have many similarities to other forms of SBRT.
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      Unique to cardiac SBRT is the fact that the target is within the heart itself, an organ that has traditionally been at the forefront of avoidance.
      Although the target for VT ablation is nonfunctional heart tissue with an abnormal conductive pathway, limiting radiation dose to the surrounding functional heart tissue is critical. Recent imaging studies in humans have demonstrated feasibility of real-time tracking and motion compensation for cardiac radioablation using MRI in the setting of atrial fibrillation.
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      However, MR gating does not negate the need for an ITV volume—either a respiratory ITV for free-breathing treatments (which would include cardiac movement), or, if using breath-hold techniques, a cardiac ITV. However, for clinical implementation, workflow adaptations and the increased treatment time of the patient would first need to be addressed.
      Previous work has defined specific cardiac constraints in the context of conventionally fractionated radiation to the lung, such as the relative volume of the heart receiving greater than or equal to 50 Gy exceeding 25% being associated with increased rates of cardiac toxicity and decreased overall survival.
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      The limits of normal tissue dose tolerance with hypofractionation is still uncertain, but a recent update of OAR toxicity in relation to lung SBRT dose constraints does provide some guidance.
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      In a review of dose to the great vessels, it did report 2 grade-5 events occurring after 5-fraction lung SBRT in the setting of a high Dmax (60-62 Gy) to the pulmonary artery.
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      Owing to tumor anatomy, some lung SBRT plans may have low volume but high dose cardiac exposure. Reshko and colleagues reported the range of doses given to cardiac substructures for over 70 patients treated with lung SBRT for early-stage lung cancer.
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      In that series, the median dose to the left ventricle (EQD2 adjusted) was 0.2 Gy, with a range from 0.02 Gy to 12 Gy. For the left anterior descending artery, the reported median EQD2 was 0.8 Gy, with a range from 0.02 Gy to 16 Gy. Patients experiencing cardiac complications after lung SBRT were more likely to have a prior cardiac history, but there was no association between either whole-heart dose or substructure dose and future cardiac events. In another institutional series of over 180 patients, the mean left ventricular dose was found to be 0.23 Gy (EQD2 adjusted = 0.25 Gy) with mean max doses of 10.2 Gy (EQD2 adjusted = 19.1 Gy).
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      Median values were not reported. The association between increasing bilateral ventricular dose and non-cancer-related death approached but did not reach significance. A third series reported the median maximum doses to the heart in a series of 100 lung SBRT patients: 14 Gy (EQD2 37.2 cGy), with a range from 0.34 cGy to 77 Gy.
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      Similar to Reshko's analysis, there was no association between cardiac dose and overall survival.
      Stam and colleagues also recently reported a large combined series of heart substructure doses from over 800 lung SBRT cases (60% treated with 54 Gy in 3 fractions and 40% 48 Gy in 4 fractions) that did find an independent association between increasing maximum dose to the left atrium and dose to 90% of the superior vena cava and increasing incidence of non-cancer-related death but did not find this association with dose to the lower heart region (right and left ventricles).
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      Dose to heart substructures is associated with non-cancer death after SBRT in stage I-II NSCLC patients.
      Our series of patients did have lower median EQD2s for the left atrium and superior vena cava compared to the series by Stam and colleagues, as expected from VT circuit anatomy. Although we have listed the EQD2 doses to the heart substructures in this manuscript, it should be recognized that the linear quadratic model may not accurately predict cell killing at high single fraction doses as the biological assumptions underlying this model are not entirely applicable to this clinical setting.
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      The tumor radiobiology of SRS and SBRT: Are more than the 5 Rs involved?.
      As expected, in our treatment plans, higher than previously reported doses were delivered to the left ventricle and left anterior descending artery. Clinical follow-up of the trial patients to monitor for the development of cardiac toxicity or exacerbation of other cardiac conditions will be instrumental as we define safe limits for this single-fraction ablative therapy and potentially identify heart substructures for optimization.
      For all patients, a comprehensive and strict quality assurance program was maintained. The use of multiple quality assurance methods during commissioning before treating patients was essential along with continuing quality assurance during the trial to ensure the radiation plan for this novel treatment modality was delivered as intended. The combination of planar measurements, point measurements, and log file analysis takes advantage of the strengths of each quality assurance method while not relying on any 1 method that would individually be subject to limitations.
      Owing to the novel nature of this treatment, there was a learning curve throughout all processes from simulation to treatment. Plan quality metrics in particular show a general trend of improvement with the more recent cohort of patients, including smaller GTV volumes and therefore PTV volumes, sharper dose gradients, and a reduction in treatment times while maintaining target coverage and conformity. The need for continued review is important to monitor for cases that are outliers and to investigate any potential causes.
      This methodology of continual review not only assures quality will not decrease but that the identification of outliers can be instructive. For example, in retrospect we were able to identify cases where the dose to the heart-minus-PTV DVH was outside of the inner fences of the population-based DVHs. Upon investigation, this was mostly likely in part owing to a reduction in target volumes seen with the later cases as the trial progressed; however, it also prompted us to standardize the practice of directly optimizing on the heart-minus-PTV structure, all other OARs, ring structures, and the NTO during planning. This ensured our plans remained highly conformal with sharp gradients and allowed for high levels of normal tissue sparing. Similarly, these review processes can be continued for future patients by adding new patient plans that can recompute the statistics and strengthen the overall population-based DVHs and process control metrics.

      Conclusions

      Noninvasive cardiac ablation for treatment-resistant VT is a coordinated team effort relying on multiple individuals from different disciplines. As this treatment is novel, more data will have to be collected and reviewed for both quality assurance and quality improvement. Future work will examine the possibility of further reduction of treatment volumes with motion gating, developing knowledge-based planning techniques, and potentially optimizing plans based on heart substructures.

      Supplementary Data

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