Interim Report of a Japanese Phase II Trial for Cardiac Stereotactic Body Radiotherapy in Refractory Ventricular Tachycardia　― Focus on Target Determination ―

Mari Amino; Shigeto Kabuki; Etsuo Kunieda; Jun Hashimoto; Akitomo Sugawara; Tetsuri Sakai; Susumu Sakama; Kengo Ayabe; Yohei Ohno; Atsuhiko Yagishita; Yoshinori Kobayashi; Yuji Ikari; Koichiro Yoshioka

doi:10.1253/circrep.CR-23-0003

Abstract

Background: Cardiac radiotherapy using stereotactic body radiation therapy (SBRT) has attracted attention as a minimally invasive treatment for refractory ventricular tachycardia. However, a standardized protocol and software program for determining the irradiation target have not been established. Here, we report the first preclinical stereotactic radioregulation antiarrhythmic therapy trial in Japan, focused on the target-setting process.

Methods and Results: From 2019 onwards, 3 patients (age range 60–91 years) presenting with ischemic or non-ischemic cardiomyopathy were enrolled. Two patients were extremely serious and urgent, and were followed up for 6 and 30 months. To determine the irradiation targets, we aggregated electrophysiological, structural, and functional data and reflected them in an American Heart Association 17-segment model, as per the current recommendations. However, in all 3 patients, invasive electrophysiological study, phase-contrast computed tomography, and magnetic resonance imaging could not be performed; therefore, electrophysiological and structural information was limited. As alternatives, high-resolution ambulatory electrocardiography and nuclear medicine studies were useful in assessing arrhythmic substrates; however, concerns regarding test weighting and multiple scoring remain. Risks to surrounding organs were fully taken into account.

Conclusions: In patients requiring cardiac SBRT, the information needed for target planning is sometimes limited to minimally invasive tests. Although there are issues to be resolved, this is a promising option for the life-saving treatment of patients in critical situations.

External beam irradiation by stereotactic body radiation therapy (SBRT) is generally used to treat cancer. The first SBRT for ventricular tachycardia (VT) was performed at Stanford University in 2012 using a robotic radiosurgery system (CyberKnife^®; Accuray, Sunnyvale, CA, USA).¹ In 2015, a Linac (TrueBeam, Varian Medical Systems) was used to perform SBRT on 5 patients at Washington University; the reported VT reduction rate of 99% was robust.² Irradiation is completed in approximately 15 min without requiring surgery. Although currently not covered by insurance, it has shown great potential as the fourth treatment for lethal ventricular arrhythmias, especially in the US and Europe.³^–⁵

In June 2019, we obtained authorized approval to conduct a prospective clinical trial in Japan and treated 3 patients with SBRT for VT. However, there were no clear criteria for target setting, and electrophysiological studies (EPS) and phase-contrast computed tomography (CT)/magnetic resonance imaging (MRI) data were not available at the preliminary examination, which made determining the irradiation areas challenging. Hence, the aim of this study was to investigate the utility of high-resolution ambulatory electrocardiography (ECG)⁶ and cardiac nuclear medicine studies in evaluating arrhythmic substrates. These tests can be performed within the insurance reimbursement system in Japan; however, they are not common and have rarely been reported in other countries. We have previously published the effects of treatment in the first patient,⁷ but here we compare the 3 patients to clarify the process of target determination and discuss the possibility of alternative evaluation methods for patients in whom conventional examinations cannot be performed.

Methods

Participants

This is a Phase II interventional single-arm open-label asymmetric single-center study entitled “Stereotactic Radio-regulation Antiarrhythmic Therapy (SRAT) trial” that has been registered in the Japan Registry for Clinical Trials (JRCT) system (ID: jRCTs032190041; June 19, 2019). Based on the ENCORE-5 trial criteria,² eligible patients had more than 3 episodes of sustained monomorphic VT or cardiomyopathy (left ventricular ejection fraction <50%) related to monomorphic premature ventricular contraction (PVC >20% of total heart beats). An implantable cardioverter-defibrillator (ICD) was used.

Pretreatment Evaluation

The process of target determination is shown in Figure 1. In Step 1 (Figure 1, Left panel), an electrophysiologist estimated the VT substrate or lesion site. We followed the method used by the Washington University team.⁸ The areas with findings obtained from electrophysiological, structural, and functional information were virtual points plotted on a 17-segment model. Currently, the weighting of the 3 types of scores for each segment is not defined: the findings were converted to 1 point each, and the points calculated for each area were used as the total score.

Figure 1.

Study protocol. After registration with the Japan Registry for Clinical Trials, target and radiation planning comprised 3 steps. As part of Step 1, electrical, structural, and functional data were combined. Step 2 involved estimation of VT substrates and foci, as well as risk assessment of surrounding organs. Planning is repeated with targeting and contouring. Step 3 involves repeated calculation and determination of the optimal target volume, with permanent follow-up after radiotherapy. ECG, electrocardiogram; EPS, electrophysiological study; EVM, electroanatomic voltage mapping; ¹⁸F-FDG-PET, 18F-fluorodeoxyglucose positron emission tomography; HR, high resolution; ¹²³IMIBG, 123I-metaiodobenzylguanidine; MRI, magnetic resonance imaging; NSVT, non-sustained ventricular tachycardia; OAR, organ at risk; PVC, premature ventricular contraction; ^{99 m}Tc-TF, 99 m-technetium tetrofosmin; TCT, thoracic computer tomography; UCG, ultrasound cardiography; VT, ventricular tachycardia.

Electrophysiological assessment for predicting the origin of VT using 12-lead ECG during VT or non-sustained VT (NSVT) was based on the algorithm published by Andreu et al.⁹ EPS is useful for detecting VT-supporting channels considered potential substrates of scar-related VT, which were referenced by induced VT morphology, cut-off adjustment of the voltage map, and pace mapping during sinus rhythm.¹⁰

Structural substrate information was acquired from ultrasound cardiography (UCG), CT, MRI, and electroanatomic voltage mapping (EVM). Myocardial foci were noted on the basis of myocardial wall thinning, calcification, and areas of gadolinium-delayed contrast.

Single-photon emission CT (SPECT) and positron emission CT (PET) were used to obtain functional substrate information. Scintigraphy included 99 m-technetium tetrofosmin (^{99 m}Tc-TF), ¹²³I-metaiodobenzylguanidine (MIBG), and ¹²³I-β-methyl-p-iodophenyl pentadecanoic acid (BMIPP).¹¹ Arrhythmic substrates were assessed by calculating the area of poor perfusion and denervation, perfusion/innervation mismatch,¹²^,¹³ decreased heart-to-mediastinum (H/M) ratio,¹⁴ and increased regional washout in the myocardium.¹⁵

Target Selection and Dose Calculation

In Step 2 (Figure 1, Right panel), an electrophysiologist and radiation oncologist collaborated to select target areas based on the combined 17-segment model that was created in Step 1. Regions suspected to be the substrates or foci were designated as ON (red), unselected regions were designated as OFF (green), and organs at risk of failure were designated as OAR (yellow). OARs must be considered, including cardiac substructures (e.g., coronary arteries, valves, papillary muscles, and stimulatory conduction systems) and surrounding organs (e.g., the stomach wall, ribs, esophagus, trachea, and spinal cord). For the tentative target, the medical physicists used radiotherapy planning software (Eclipse ver. 13.7; Varian Medical Systems Inc., Palo Alto, CA, USA) to contour the cardiac substructures and target volume.¹⁶

In step 3, the irradiation volume and the dose distribution was estimated using an algorithm of Acuros XB (Varian Medical Systems Inc.). Adjustments were required if the dose calculation for critical organs exceeded the constraint. Targeting and contouring are mutually repeated many times to improve the accuracy of the treatment plan and to determine the final irradiated area. Considering heart rate and respiratory variability, as well as rotational errors,¹⁷ a margin of 2–5 mm was expanded to the clinical target volume (CTV), defined as the internal target volume and planning target volume (PTV). The amount for the PTV should be <100 mL, based on a previous report (mean 98.9 mL, range 60.9–298.8 mL).³

Cardiac Radiotherapy

Irradiation was performed with patients in the supine position on a vacuum-fixed cushion using a linear accelerator (TrueBeam STx; Varian Medical Systems Inc.). To avoid overexposure of surrounding OARs, a single 25-Gy dose was delivered for maximum coverage within the treatment volume. Immediately after confirming the position of the target by cone beam CT, volumetric-modulated arc therapy was used with the abdominal compression technique to reduce respiratory motion. The medical team was on standby in the radiation control room, with heart rate and respiratory monitored in case any sudden change in status or ICD malfunction occurred.

Outcome Evaluation

The primary endpoints were safety and efficacy. Acute to late myocardial impairment was defined as cardiac dysfunction (systolic and/or diastolic), pericarditis, pericardial effusion, myocardial ischemia, or heart failure. Safety was monitored by having patients visit the Cardiology and Radiation Oncology departments regularly for interviews, physical examinations, vital sign assessment, ICD checks, blood and biochemical data, ECG, high-resolution ambulatory ECG, UCG, and chest CT as appropriate. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.¹⁸ The arrhythmia suppression effect was assessed by antitachycardia pacing (ATP) events, ICD shocks, and manual direct current (DC) shocks. The blanking period was set for 90 days, as reported previously.²^–⁴ (More information about the methods is provided in the Supplementary File.)

Results

Patient Characteristics

The backgrounds of the 3 patients enrolled from July 2019 to October 2021 are presented in Table 1. The weight of Patient 2 was more than double that of Patient 1. Patient 1 had an old myocardial infarction with impaired cardiac function, but was living independently. ICD shock was effective for VT, and no transition to VT storm was observed. Patient 2 demonstrated reduced cardiac function due to ischemic cardiomyopathy (ICM) and was on home oxygen therapy for severe heart failure (New York Heart Association Class IV). He was frequently admitted to the emergency department because of exacerbation of acute heart failure, and ICD shocks for VT were frequently delivered 5–10 times during each admission. Patient 3 had a history of transcatheter aortic valve implantation (TAVI) for aortic valve stenosis and secondary hypertrophic cardiomyopathy (HCM), and was urgently admitted due to defecation-induced ICD shocks. The VT then transitioned to VT storms, a situation that necessitated the combination of manual DC shocks and ICD.

Table 1. Patient Characteristics

	Patient 1	Patient 2	Patient 3
Age (years), sex	71, female	60, male	91, female
Physical size	150 cm, 41 kg, BMI 18.2 kg/m²	180 cm, 97 kg, BMI 29.9 kg/m²	153 cm, 53 kg, BMI 22.6 kg/m²
Cardiac disease	Anterior OMI (LAD #7-CTO, PCI to RCA #2) ICM	Lateral OMI (PCI to LCx #14, #15) ICM, HT	AS (Post-TAVI in 2019) Secondary HCM, HT
LVEF; CHF	27%; HFrEF, NYHA II	20%; HFrEF, NYHA IV (with HOT)	65%; HFpEF, NYHA III
ADL	Walking with a cane	Walking with assistance	Wheelchair
Arrhythmia	VT, PAF	VT, PAF	VT, PAF
Spontaneous VT morphology (12-ECG documented)	CRBBB, inferior axis, 270 beats/min	CLBBB, anterior axis, 280 beats/min	CLBBB, anterior axis, 162 beats/min
Spontaneous VT morphology (12-ECG documented)	CRBBB, anterior axis, 270 beats/min		CLBBB, inferior axis, 119 beats/min
Antiarrhythmic drug	Bisoprolol	Bisoprolol	Bisoprolol
Antiarrhythmic drug	Amiodarone → discontinuation	Amiodarone → reduction	Amiodarone → discontinuation
Anticoagulant agent	+	+	+
No. prior EVM/RFCA	1 (EVM only)	RFCA; 2 times for AF, 1 time for VT (lateral endocardium)	0 (patient aging and frail)
EPS-induced VTs	VT-1, -2	VT-1, -2, -3,-4, -5, -6, -7	–
Other pre-existing conditions	–	CKD (Stage IV)	CKD (Stage IIIb)
		Allergy to contrast media	Stomach cancer (postoperation)
		Bronchial asthma	Cerebral aneurysm
		Sleep disordered breathing	Dyslipidemia
		Colon cancer (postoperation)
In-body metal	Coronary stent	Coronary stent	TAVI stent
	ICD (MRI unsafe)	CRT-D (MRI safe)	Metal clipping (MRI unsafe)
			ICD (MRI safe)
General condition at SBRT	Non-emergency	Emergency, ICU admission	Emergency, HCU admission
Time required for plan	300 h	50 h	30 h

ADL, activities of daily living; AF, atrial fibrillation; AS, aortic valve stenosis; BMI, body mass index; CHF, chronic heart failure; CKD, chronic kidney disease; CLBBB, complete left bundle branch block; CRBBB, complete right bundle branch block; CRT-D, cardiac resynchronization therapy device; CTO, chronic total occlusion; ECG, electrocardiogram; EPS, electrophysiological study; EVM, electroanatomic voltage mapping; HCM, hypertrophic cardiomyopathy; HCU, high-care unit; HFpEF, heart failure with preserved ejection function; HFrEF, heart failure with reduced ejection fraction; HOT, home oxygen therapy; HT, hypertension; ICD, implantable cardioverter-defibrillator; ICM, ischemic cardiomyopathy; ICU, intensive care unit; LAD, left anterior descending artery; LCx, left circumflex artery; LVEF, left ventricular ejection fraction; MRI, magnetic resonance image; NYHA, New York Heart Association; OMI, old myocardial infarction; PAF, paroxysmal atrial fibrillation; PCI, percutaneous coronary intervention; RCA, right coronary artery; RFCA, radiofrequency catheter ablation; SBRT, stereotactic body radiation therapy; TAVI, transcatheter aortic valve implantation; VF, ventricular fibrillation; VT, ventricular tachycardia.

Antiarrhythmic agents (bisoprolol and amiodarone) were prescribed for VT and paroxysmal atrial fibrillation (AF) in all 3 patients. However, owing to pulmonary toxicity, amiodarone was discontinued 10 years before SRAT in Patient 1, reduced 2 months before SRAT in Patient 2, and discontinued 6 months before SRAT in Patient 3. No changes were made in the pacing settings before and after cardiac SBRT.

Concerning invasive EPS, Patient 1 had a history of EVM and Patient 2 had a history of radiofrequency catheter ablation (RFCA). Patient 3 did not undergo invasive EPS because of advanced age. Comorbidities and examination limitations included an MRI-non-compatible ICD in Patient 1, renal dysfunction/contrast medium allergy in Patient 2, and renal dysfunction/intracranial clipping in Patient 3. Nonetheless, an SBRT irradiation plan was prepared for each patient, even with the limited information obtained from the examinations. Furthermore, Patients 2 and 3 were in a critical condition requiring immediate irradiation planning.

Target Determination

The target-setting process is shown in Figures 2–4 and summarized in Table 2. In Patient 1 (Figure 2; Table 2), electrophysiological information was found at the anterolateral wall (Segments 7, 12); however, the structural abnormality was far more widespread for Segments 1–4 and 7–17, except at the basal lateral wall. As a result, electrophysiological and structural findings were dissociated. ^{99 m}Tc-TF showed an extensive lower uptake consistent with EVM; however, 18F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG)-PET successfully rescued the viable myocardium in a section of the anterior wall. Although the inferior apex was highly thinning (Segments 15, 17) and calcification of the anterior apex (Segments 8, 14) could be a slow-conducting or circuit isthmus area, irradiation was avoided because the biological effects of radiation on the myocardium already showing complete fibrosis were not clear at this stage. Despite inconclusive data, a reduction in the irradiation volume may lower the risk of radiation-related cardiac complications (pericarditis, heart failure, or death). The final targets were Segments 7, 12, and 13, which excluded OARs from areas with >5 points (Table 2).

Figure 2.

Pre-examination for Patient 1. Information obtained from electrocardiography (ECG), high-resolution ambulatory ECG (HR-ambulatory ECG), electrophysiological study (EPS)/electroanatomic voltage mapping (EVM), ultrasound cardiography (UCG), thoracic computed tomography (TCT), 99 m-technetium-tetrofosmin (^{99 m}Tc-TF) and 123I-metaiodobenzylguanidine (¹²³I-MIBG) scintigraphy, and 18F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG-PET). LPO, left posterior oblique; NSVT, non-sustained ventricular tachycardia; OAR, organ at risk; RAO, right posterior oblique; VT, ventricular tachycardia.

Figure 3.

Pre-examination for Patient 2. Information obtained from electrocardiography (ECG), high-resolution ambulatory ECG (HR-ambulatory ECG), electrophysiological study (EPS)/electroanatomic voltage mapping (EVM), ultrasound cardiography (UCG), cardiac magnetic resonance imaging (CMR, T2 black blood star), and fusion images of planning computed tomography (CT) and 99 m-technetium-tetrofosmin (^{99 m}Tc-TF)/123I-metaiodobenzylguanidine (¹²³I-MIBG) scintigraphy. ABL, ablation; NSVT, nonsustained ventricular tachycardia; OAR, organ at risk; PVC, premature ventricular contraction; VT, ventricular tachycardia.

Figure 4.

Pre-examination for Patient 3. Information obtained from electrocardiography (ECG), high-resolution (HR) ambulatory ECG, ultrasound cardiography (UCG), and fusion images of planning computed tomography (CT) and 99 m-technetium tetrofosmin (^{99 m}Tc-TF)/¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy. OAR, organ at risk; PVC, premature ventricular contraction; VT, ventricular tachycardia.

Table 2. Target Determination Using the American Heart Association 17-Segment Model

	Patient 1	Patient 2	Patient 3
Step 1: Pre-examinations
Electrical information
ECG: clinical VT	Segments 7 or 8, 7 or 12	Segments 3 or 9	Segments 8 or 9, Segments 12
HR ambulatory ECG: initiated PVC of NSVT	Segments 1, 7	Segments 4, 10, 13, 16	Segments 15, 16
EPS: induced VT	Segments 7, 12, 13	Segments 11, 12, 16	N/A
EPS: pace map region	Segment 12	N/A	N/A
Anatomical information
EVM: low-voltage area	Segments 1–4, 7–10, 13–17	Segments 3, 4, 10, 11	N/A
UCG: akinesis/severe hypokinesis	Segments 7–17	Segments 3–5, 9–11, 13–17	No abnormality
TCT: wall thinning	Segments 7–17	N/A	No abnormality
MRI: wall thinning	N/A	Segments 5, 6, 11, 12	N/A
MRI: delayed enhancement	N/A	N/A	N/A
Functional information
^{99 m}Tc-TF: defect	Segments 1, 2, 7, 8, 13–15, 17	Segments 5, 6, 11, 12	No abnormality
^{99 m}Tc-TF: fill-in	No abnormality	Segments 3, 4, 9, 10	No abnormality
¹²³I-MIBG: defect	Segments 2, 7, 13, 17	Segments 3, 4, 9, 10, 15	No abnormality
¹²³I-MIBG: hyper-washout	Segments 11, 12, 16	Segments 11, 16	Segments 4, 10–17
^{99 m}Tc-TF/¹²³I-MIBG mismatch	No abnormality	Segments 3, 9, 15	Segments 4, 10–17
¹⁸F-FDG-PET: defect	Segments 13–15, 17	N/A	N/A
Summed points for above information
High (≥5 points)	Segments 7>13>12, 17>8, 14, 15	Segments 3, 11>4, 9, 10	N/A
Moderate (3–4 points)	Segments 16>1, 2, 9–11	Segments 16>5, 12, 15	Segments 12, 15, 16
Low (2 points)	N/A	Segments 6, 13	Segments 4, 10, 11, 13, 14, 17
Very low (1 point)	Segments 3, 4	Segments 14, 17	Segments 8, 9
Step 2: Target assessment
ON: red (suspected substrate segments)	Segments 7, 8, 12–15, 17	Segments 3, 4, 9–11	Segments 4, 10–17
OFF: green (region not marked by Step 1)	Segments 5, 6	Segments 1, 2, 7, 8	Segments 1–3, 5, 7
OAR: yellow (organ at risk)	Segments 15, 17 (wall thinning), Segments 8, 14 (calcification)	Segments 4, 10 (stomach attached)	Segments 4, 10 (stomach attached), Segments 11, 12 (rib attached)
Total of above information
Irradiation target	Segments 7, 12, 13	Segments 3, 9, 11	Segments 13–17
Step 3: Treatment plan
WHV (mL)	591.9	1,858.8	652.2
CTV (mL)	8.3	24.2	21.2
ITV (mL)	29.8	65.6	40.2
PTV (mL)	49.7	96.4	55.0
CTV/WHV ratio (%)	1.4	1.3	3.3
ITV/WHV ratio (%)	5.0	3.5	6.2
PTV/WHV ratio (%)	8.4	5.2	8.4
PTV/body weight ratio (%)	0.12	0.09	0.10
Internal margin^A (mm)	3	3	3
Setup margin^B (mm)	2	2	2
Cardiac radiotherapy
Entry to exit (min)	50	55	45
Beam-on time (min)	2.9	5.2	2.6
Estimated treatment time (min)	37	48	34

^AInternal margin: predicted organ movement range, such as respiration and heartbeat. ^BSetup margin: range of alignment and errors. CTV, clinical target volume; ¹⁸F-FDG-PET, 18F-fluorodeoxyglucose positron emission tomography; HR, high resolution; ¹²³IMIBG, 123I-metaiodobenzylguanidine; ITV, internal target volume; N/A, not available; NSVT, non-sustained ventricular tachycardia; OAR, organ at risk; PTV, planning target volume; PVC, premature ventricular contraction; ^{99 m}Tc-TF, 99 m technetium tetrofosmin; TCT, thoracic computer tomography; UCG, ultrasound cardiography; WHV, whole heart volume. Other abbreviations as in Table 1.

In Patient 2 (Figure 3; Table 2), 1 type of clinical VT on 12-lead ECG suggested an inferoseptum or posterior (Segments 3, 9) origin. The pseudo-12-lead ECG of the high-resolution ambulatory ECG showed 3 types of 12 PVC runs and NSVT originating from the inferior or anterolateral apex (Segments 4, 10, 13, 16). Induced VT in the EPS was centered on the lateral wall (Segments 11, 12, 16), and RFCA had been previously performed on it. Patient 2 differed from Patient 1 in terms of the distribution pattern; the plotting segment of the 3 kinds of information was generally consistent from the lateral to the posteroinferior wall. Because of the progressed electrical, structural, and sympathetic remodeling, extensive myocardial vulnerability was expected to contribute to the occurrence of VT. However, because of cardiac flattening, the inferior wall (Segments 4, 10) was in contact with the stomach wall and was excluded from the irradiation area. The final targets were Segments 3, 9, and 11, which excluded OARs from areas with >5 points (Table 2).

In Patient 3 (Figure 4; Table 2), unlike Patients 1 and 2, information was very limited; 2 types of clinical VT on 12-lead ECG suggested a septal or lateral (Segments 8, 9, 12) origin. However, the possibility of a right ventricular origin due to complete left bundle branch block-type VT and the possibility of scar-related VT around the aortic valve after TAVI could not be ruled out. The pseudo-12-lead ECG of the high-resolution ambulatory ECG showed that all 12 PVCs originated from the apex (Segments 15, 16). There were no significant findings that could indicate an anatomical substrate. However, nuclear medicine studies found that the region of dysfunction was wide; both the ^{99 m}Tc-TF/¹²³I-MIBG mismatch region and hyper-washout rate (WR) region shown by ¹²³I-MIBG scintigraphy were recognized in the inferolateral wall and apex (Segments 4, 10–17). The areas with the highest total scores were Segments 12, 15, and 16, followed by Segments 4, 10, 11, 13, and 14 (Table 2). We focused on the electrical instability assumed from ¹²³I-MIBG scintigraphy findings and targeted to apical PVCs. The posteroinferior wall in contact with the gastric body (Segments 4, 10) and the lateral wall with the adjacent left rib (Segments 11, 12) were excluded as OARs (Table 2).

Radiation Plan and Treatment

The lower part of Table 2 shows the dosimetric parameters based on dose calculations and the time required for treatment. CTV ranged from 8.3 to 24.2 mL, and PTV ranged from 49.7 to 96.4 mL. In case 2, whole-heart volume (WHV) was three times larger than those in the other two cases, however the CTV was reduced to 24.2 mL because the target was separated into two distant small areas owing to the OAR. The PTV/WHV ratio was minimal at 5.2. The final 3-dimensional images of the irradiated areas and dose distribution diagrams are shown in Supplementary Figures 1–3.

The time required for radiotherapy was 45–55 min from entry to exit, and 2.6–5.2 min for actual irradiation. The treatment time was 34–48 min, including immobilization, breathing instructions, cone beam CT imaging, verification of cardiac edge misalignment, and irradiation positioning by the laser beam. Patients were allowed to relax in the treatment room with music, without sedation or analgesics. Patient 2 had to be woken occasionally owing to an irregular respiratory pattern caused by sleep apnea. All 3 patients successfully completed the treatment without any changes in vital signs.

Safety and Efficacy

Patient 1 was discharged the day after cardiac SBRT. No adverse events were noted up to 30 months after the intervention. ICD checks showed no events (Figure 5A), and we judged the patient as “antiarrhythmic effective”. At 20 months, the patient was diagnosed with colon cancer and underwent partial colorectal resection. She remained stable without any cardiac events in the perioperative period.

Figure 5.

The number of implantable cardioverter-defibrillator (ICD), direct current (DC) shocks, and antitachycardia pacing (ATP) events in Patients 1 (A), 2 (B1), and 3 (C) before and after cardiac stereotactic body radiation therapy. (B2) An electrocardiogram (ECG) strip from the ICD record with atrial fibrillation (AF)-triggered ventricular tachycardia (VT) in Patient 2. The lower-left panel shows the atrial tachycardia (AT)/AF burden and the right panel shows the premature ventricular contraction (PVC) count. CHF, congestive heart failure; Pre, before treatment; M, months; Tx, treatment; RV, right ventricle; W, weeks.

Patient 2 was discharged 5 days after cardiac SBRT. Three months after irradiation, UCG showed mild pericardial effusion; however, there were no findings suggestive of radiation pericarditis, and steroids and anti-inflammatory analgesics were not administered (CTCAE, Grade II). During the 6-month postirradiation period, the patient had 4 short hospitalizations for acute exacerbation of heart failure, all of which improved with diuretics (Figure 5B1; Days 53, 110, 122, and 156; mean (±SD) hospital stay 9±5 days; Grade III). In the 6-month pre-irradiation period, this patient also had 4 hospitalizations due to heart failure. ICD events were concentrated between Days 110 and 128 (Figure 5B1), and we judged the antiarrhythmic effect as “poor”. All events were ATP/ICD activations for VT triggered by rapid AF (Figure 5B2). According to the ICD records, the AF burden 6 months before treatment was <1%, suggesting that the reduction in the amiodarone dose may have been a risk factor for AF. Contrastingly, PVCs decreased by 78% at 6 months before and after treatment.

Patient 3 was discharged 8 days after cardiac SBRT; she complained of mild heartburn at 14 days, which resolved without medication (Grade I). At 30 days, UCG showed a mild pericardial effusion, which improved with diuretics (Grade II). According to device checks, 108 shocks/ATP events occurred during the 6-month pre-irradiation period, compared with 4 events during the 6-month postirradiation period (1 ICD shock on Day 5 and 3 ATP events on Day 21; Figure 5C). Because all events occurred within the blanking period and no further events occurred, we judged that “there was an antiarrhythmic effect”.

Non-Invasive Parameters Over Time

The time series data obtained from high-resolution ambulatory ECG, 12-lead ECG, and ¹²³I-MIBG scintigraphy are presented in Table 3. High-resolution ambulatory ECG analysis revealed decreased PVCs and NSVT, and improved ventricular delay potential (LP) owing to decreased duration of the low-amplitude filtered QRS signal after the voltage decreased to <40 μV (LAS40μV) and increased root-mean-square voltage of the signals in the final 40 ms of filtered QRS wave (RMS40ms) in Patient 1. The high frequency component (HF) reflecting parasympathetic activity in the heart rate variability analysis increased 3.2-fold after 2 years. Patient 2 showed no change in PVC or NSVT count. LP was not evaluable due to noise; however, the HF component increased 32.9-fold after 6 months. In Patient 3, pre- and postirradiation PVC frequencies were low and not comparable. LP showed no change, except for a reduction in filtered-QRS wave duration; however, the HF component increased 3.8-fold after 6 months. There were no significant changes in the ECG and ¹²³I-MIBG scintigraphy in any of the 3 patients.

Table 3. Follow-up

	Patient 1			Patient 2		Patient 3
	Before	1 year after	2 years after	Before	6 months after	Before	6 months after
HR ambulatory ECG
THB (beats/24 h)	100,392	87,537	97,092	90,978	85,574	97,451	88,588
PVC (count/24 h)	3,530	940	463	25,633	28,285	12	10
NSVT (time/24 h)	3	0	1	3	2	0	0
Maximum run	20	N/A	4	6	4	N/A	N/A
LP^A (average during sleep)
f-QRSd (ms)	149.3	151.2	147	241^B	230^B	256.7	200.9
LAS40μV (ms)	31.6	17.0	13.8	90^B	85^B	92.0	83.2
RMS40ms (μV)	29.8	49.9	83.9	9^B	14^B	7.0	12.1
Heart rate variability (24 h)
HF (ms²)	240	213	764	10	329	5	19
LF/HF	0.79	1.52	0.65	0.80	1.02	0.18	0.36
ECG
QRS width (ms)	148	146	140	196	192	230	225
QT interval (ms)	464	478	464	524	532	534	526
¹²³I-MIBG
H/M (early)	1.77	2.17	1.74	2.22	2.01	3.91	3.49^C
H/M (delay)	1.78	1.99	1.53	2.09	1.97	2.97	2.63^C
WR (%)	38.2	30.7	37.6	25.9	21.3	39.1	31.6^C

^AThe 3 parameters of ventricular late potential were calculated during sleeping hours. ^BIn the pre-examination of Patient 2, only a single point measurement was possible due to significant noise. Post-examination values are for the same time period as the pre-examination, along with the average during sleeping hours. ^CIn the post-examination of Patient 3, ¹²³I-MIBG was performed at 3 month after treatment. f-QRSd, filtered QRS wave duration; H/M, heart to mediastinum ratio; HF, high frequency; LAS40μV, duration of the low amplitude filtered QRS signal after the voltage decreased to <40 μV; LF/HF, low frequency to high frequency ratio; LP, late potential; RMS40ms, root-mean-square voltage of the signals in the final 40 ms of the filtered QRS wave; THB, total heart beats; WR, washout ratio. Other abbreviations as in Tables 1,2.

Discussion

This is the first prospective clinical trial of radiotherapy for VT in Japan. The target-setting process was described in 3 steps. During Step 1, in which electrophysiological, structural, and functional information were acquired, the data obtained were biased due to the presence of invasive EPS and cardiac organic changes. Alternatively, we estimated the arrhythmic substrate and instability by PVC origin using pseudo-12-lead ECG with high-resolution ambulatory ECG and mismatch regions and sympathetic hyper-washout area using nuclear cardiology medicine studies.

Role of Non-Invasive Assessment

In RFCA, the isthmus, exit, and substrate (e.g., low-potential areas) are targeted in re-entrant arrhythmias,¹⁹ and these are also considered effective therapeutic targets in cardiac SBRT. However, in cases where EPS is difficult to perform, the isthmus and exit cannot be identified; hence, substrates are inferred using spontaneous VT ECG and cardiac image tests. High-resolution ambulatory ECG can capture spontaneous PVCs and NSVT under physiological conditions, including during exertion and sleep. The clinical significance of these arrhythmias depends on the underlying cardiac disease and cardiac function, but their usefulness as risk indicators in ischemic heart disease, HCM, coronary artery disease, and hypertrophic cardiomyopathy is high.²⁰ In ischemic heart disease, the level of evidence is higher for consecutive PVCs compared with PVC total counts, with sudden cardiac death rates significantly increased with a hazard ratio of 2.3–2.8 for 4 or more consecutive PVCs.²¹ In patient 1, consecutive PVCs were significantly reduced, which may have led to risk aversion.

¹²³I-MIBG scintigraphy provides essential information on triggers and substrate modifiers.¹² Animal studies using MIBG imaging have shown that impaired catecholamine uptake and storage in the reperfused region after porcine myocardial infarction are associated with VT.¹³ In rabbit models of denervation without blood flow injury, the moderately denervated regions generate repolarization heterogeneity²² and VT vulnerability related to the nerve sprouting and sympathetic hyperinnervation at the remote area.²³ In clinical cases, a decreased H/M ratio,¹⁴ increased regional WR,¹⁵ and increased whole-heart WR²⁴^,²⁵ on ¹²³I-MIBG scintigraphy are decisive prognostic factors in patients with heart failure. The perfusion/innervation mismatch provides helpful information for arrhythmia risk and prognosis prediction in patients with ICD implantation²⁶^,²⁷ and HCM.²⁸^,²⁹ In the present study, we focused on the region of higher WR and perfusion/innervation mismatch and considered the possibility that local sympathetic functional properties of the myocardium may contribute to substrate instability. Follow-up after SBRT did not lead to WR normalization, but high-resolution ambulatory ECG analysis showed recovery of parasympathetic tone, which is analogous to irradiation-associated modifications in the cardiac autonomic nervous system.

Future Issues in Target Definition

RFCA and cardiac SBRT differ in terms of imaging modalities for substrate visualization, the extent of lesion, and collateral damage. The risk to healthy myocardium and surrounding organs that should be excluded from irradiation must also be considered.

The advantage of diverting the AHA 17-segment model for target setting is that it is a reasonable and excellent method that allows for the integration of information from many modalities, facilitating understanding of the localization.⁸ It serves as a common language between cardiologists who are not familiar with treatment planning and radiation oncologists who are not familiar with electrophysiology. It also facilitates sharing of understanding between different hospitals. However, there are problems with weighting the scores of imaging tests and the multiple scoring of several findings from a single test. It cannot be ruled out that multiple imaging examinations may increase the number of scores assigned to structural and functional assessment models and may lead to an underestimation of the electrical assessment index.

The optimal evaluation modality may also change as the underlying disease or condition progresses. For example, in HCM, the risk of sudden death may be predicted by fragmented QRS or LP. In the presence of a reduction in regional wall motion, myocardial densification and fibrosis are of interest as risk lesions and should be evaluated using CT and MRI. If there is an overall decrease in myocardial contractility, myocardial strain can be examined by echocardiography. In EPS, the arrhythmogenic substrate is more abundant in the epicardium or mid-myocardium during the diastolic phase of HCM.³⁰ Therefore, arrhythmogenic substrate analysis of these results may not always be consistent, even among skilled electrophysiologists. Uniformity in target setting will continue to be the most important issue to address.

Late Adverse Effects and Persistence of Effects

Caridiac-SBRT has a short history and limited evidence from long-term studies on adverse events. Severe complications are not common after a short observation period of 6 months to 1 year; however, gastric-epicardium fistula development and delayed mitral regurgitation have been reported in cases after 2 years.³¹ In general, radiation-induced late cardiac effects are known to cause coronary artery stenosis and conduction defects over a period of 10–15 years.

The duration of antiarrhythmic effects is also uncertain. In a study of 18 patients, VT suppression was 75% at 2 years after treatment.³ Conversely, VT recurred in all patients (5/5) after 12 months.³² In one study of 8 patients, 1 case worsened at 12 months later than at baseline.³³ SBRT is also less effective for VT suppression in non-ICM compared with ICM.³⁴ Indications for cardiac SBRT should be carefully assessed taking into account the risk of VT-related death and radiation-induced late injury. Because anticoagulant therapy is recommended for approximately 1 month after SBRT,³ bleeding tendencies and renal function should also be carefully considered.

It has been reported that the early antiarrhythmic mechanism cannot be explained by fibrosis-induced conduction block, because post-SBRT VT suppression is confirmed as early as the next day.³⁴^,³⁵ In the chronic phase, SBRT is believed to have an antiarrhythmic mechanism comparable to RFCA-induced fibrosis formation. However, the use of 25-Gy X-ray cannot induce transmural tissue fibrosis of the left ventricle (17–478 days after SBRT).³⁶

It may be controversial to view radiation arrhythmia treatment as a “cardiomyocyte ablation” concept. Cardiomyocytes may display variable radiation dose- and time-dependent changes in ion channels, protein expression, and histological morphology after irradiation. Many issues remain to be resolved to elucidate the mechanisms in this fascinating research area.

Study Limitations

This study has several limitations. First, ¹²³I-MIBG, the most established neurotracer, is commonly used for neuroimaging and research. However, it is less common than blood flow scintigraphy. Therefore, some technical problems remain to be solved. Cardiac axis misalignment occurs when fusing MIBG images to irradiation planning CT. We performed simultaneous CT examinations during ¹²³I-MIBG studies to reduce image rotation errors, but ¹²³I-MIBG images are limited by the spatial resolution of the SPECT camera technology (10–12 mm), and image registration from low-resolution images to high-resolution images requires accuracy and experience. Second, this was a single-center study that involved a small number of patients. Thus, it is not known whether these findings can be applied to other patients with VT. Further, the background factors and underlying comorbidities of the patients were very different, and it is unclear whether the findings obtained can be generalized in other cases. In addition, the nature of lethal arrhythmias may require formulation of an associate urgent irradiation plan; however, there is no system to ensure the accuracy and reproducibility of the plan. Third, there is a lack of clarity on the appropriate dose limits, volume, and frequency. When the target is the inferior wall, the gastric body is often included as an OAR; currently, the entire subject area cannot be selected for safety reasons. To obtain a sufficient antiarrhythmic effect, accumulating data on low-dose irradiation or fractionated irradiation within the range of the dose regulation is necessary.

Conclusions

Cardiac SBRT for patients with catheter ablation-resistant lethal arrhythmias may require minimally invasive evaluation methods not only for radiotherapy, but also for the treatment planning process. Although certain issues (e.g., examination weighting and accuracy control) need to be resolved, cardiac SBRT is a promising alternative treatment option for refractory VT compared with conventional therapy. To widely and safely apply this attractive treatment as a life-saving therapy in critical situations, developing complementary programs that will ensure accuracy and reproducibility of the targeting process is urgently needed.

Acknowledgments

The authors thank their colleagues for their support of this study, specifically: Yutaka Imai (Department of Diagnostic Radiology, Tokai University); Sadaki Inokuchi, Seiji Morita, Yoshihide Nakagawa (Department of Emergency Care Medicine, Tokai University); Tsuyoshi Fukuzawa, Toshihisa Kuroki, Tatsuya Mikami, Ryuta Nagao (Department of Radiation Oncology, Tokai University); Tomoyuki Hiroki, Akira Kamiya, Takashi Yamashita, Toshiki Saito, Kenji Soda, Susumu Takano, Hideharu Todaka (Department of Radiation Technology, Tokai University); Asako Horikawa (Department of Nursing, Tokai University); Kyong Hee Lee, Marie Yoshikawa, Tsutomu Murakami, Teruhisa Tanabe (Department of Cardiology, Tokai University); Akari Takahashi, Misako Shirasu, Goichi Nagata, Yu Kojima (Department of Clinical Engineering Technology, Tokai University); Yukiko Fujiwara (Clinical Research Coordinator, Tokai University); Keiko Yamaguchi, Hiromichi Fukushi (Electrocardiography Analysis, Tokai University); Itsuo Kodama (Nagoya University); and Phillip S. Cuculich, Clifford G. Robinson, Geoffrey D. Hugo, Yoram Rudy (Washington University in St. Louis Center for Noninvasive Cardiac Radioablation). The authors also thank Editage (www.editage.com) for English language editing this manuscript.

Sources of Funding

This work was supported by the JSPS KAKENHI (Grant no. 20K084599) and the Tokai University School of Medicine Research Fund (2020).

Disclosures

K.Y. has received a research grant from Accuray Japan K.K. Y.I. is a member of Circulation Reports’ Editorial Board. The remaining authors have nothing to disclose.

IRB Information

This study was registered by the Japan Registry of Clinical Trials (JRCT) system defined by the Ministry of Health, Labour and Welfare (ID: jRCTs032190041; June 19, 2019). The study design was approved by National Institutes for Quantum Science and Technology Certified Review Board. All study participants provided informed consent, and the identity of the patients has been protected.

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-23-0003

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