Introduction

Stereotactic body radiotherapy (SBRT) was introduced in the 1950s using the Leksell Gamma Knife system (Elekta AB; Stockholm, Sweden) that involved a spherical dose of radiation from multiple cobalt-60 sources that focused on a target volume of tissue. The initial system was limited to target tissues in the brain. Linear accelerator-based radiotherapy was introduced in the 1980s. Linear accelerator-mounted kilovoltage cone-beam computer tomography generates X-rays instead of gamma rays that are present in the Gamma Knife system. In the 1990s, CyberKnife (Accuray; Sunnyvale, CA) was created and allowed for submillimeter accuracy and the eventual ability to target extracranial lesions.¹

Stereotactic Body Radiotherapy

High dose per fraction is delivered using SBRT, usually in the 25-40 Gray (Gy) range. The dose is targeted to a specific area of tissue and results in local tissue destruction. On a cellular level, radiation induces double-stranded DNA breaks that lead to apoptosis and vascular damage that leads to ischemia. These effects were mainly studied in dividing cells. The effects of radiation in SBRT can take several weeks to become evident by noninvasive full thickness gap-free ablation via cardiac fibrosis, though immediate effects/early response are seen in some cases likely via electrical substrate remodeling, increased levels of cardiac conduction proteins, and activated electrical reprogramming pathways to prevent ventricular tachycardia (VT) reentry.

Standard cardiac ablation is not successful in some cases when the substrate is not easily ablated or accessible. SBRT has its own challenges in that it must account for respiratory and cardiac motion. Techniques have been developed to account for both of these with the aim of creating an internal target volume. The radiation dose is not uniform, though, with a decrease in the radiation dose at the edge of the target and collateral tissues receiving radiation dose. Studies have initially been performed on swine models to assess feasibility of SBRT in creating electrical disturbances in the heart. One group of researchers targeted different areas on the heart including the cavotricuspid isthmus, atrioventricular (AV) node, junction of the pulmonary vein and left atrium, and left atrial ablation. In many cases, the dose of radiation required to achieve success exceeded 25 Gy that is used clinically. SBRT produced histologic changes including vacuolation, fibrosis, and calcifications without damage to nearby tissue structure. Lehmann et al. demonstrated dose-dependent fibrotic changes caused by increasing doses of radiation to different areas of the heart in 17 swine with successful decrease in cardiac impulse propagation in all cases.³ Linear accelerator-based SBRT was tested on 7 swine AV nodes, and 6 of these pigs had successful interruption of AV nodal conduction at doses ranging from 25 to 55 Gy without any short-term side effects. Additionally, histologic studies of surrounding tissues did not show any effects of radiation outside the target volume.⁴

Outline of SBRT Procedure

For VT, the first step is to locate the ventricular scar that is thought to be the substrate of the VT. There are several imaging modalities that can be used to identify scar; these include magnetic resonance imaging (MRI), computed tomography (CT), and nuclear imaging/viability scans. Electroanatomic or electrocardiogram (ECG) mapping can also be done to create a three-dimensional (3D) map and help locate scar tissue and VT circuit (Figure 1). The 12-lead ECG and programmed electrical stimulation also help in the location of the VT exit site. A clinical target volume is thus created. Imaging fiducial markers for respiratory tracking include existing implantable cardioverter defibrillator (ICD) leads and temporary pacing wires. An internal target volume is then created with respiratory and cardiac motion compensation. A radiation treatment plan with a planning target volume is then created to target the ventricular scar (Figure 2). The patient is positioned in the immobilization cradle and aligned with the use of imaging, and treatment with a single-fraction ablative dose of radiation is applied to the planning target volume in a shielded room. The patient is monitored closely on telemetry during and immediately after the procedure in the recovery area before going home (Table 1).

Figure 1: 3D Electroanatomical Map Identifying the Arrhythmogenic Scar Substrate

Figure 2: Developed Radiation Treatment Plan

Table 1: Steps Followed in Noninvasive Ablation of VT

1.	Anatomic scar imaging by cardiac MRI with late gadolinium enhancement (with wideband inversion pulse in patients with ICDs to limit the artifact), CT, and echocardiography.
2.	Scintillography/nuclear imaging (thallium-201 single photon emission CT rest redistribution, rubidium-82/fluorodeoxyglucose positron emission tomography).
3.	Electrophysiology mapping: 3D electroanatomical catheter-derived map (Figure 1) or ECG imaging map and fusion with the anatomic map.
4.	Scar contouring/delineation with creation of a clinical target volume identifying arrhythmogenic scar substrate. In some patients, noninvasive program stimulation is pursued to induce VT from the ICD and access the circuit location and VT exit site. The induced VT by noninvasive program stimulation is compared to the clinical VT by assessing the near field morphology, far field morphology, and cycle length.
5.	Imaging fiducial marker for respiratory tracking: existing ICD lead or insertion of a temporary pacing wire.
6.	Creation of an internal target volume with respiratory motion compensation and with cardiac motion compensation during phases of the cardiac cycle (systole and diastole).
7.	Development of a radiation treatment plan/target contour with a planning target volume heat map targeting the ventricular segments with scar and arrhythmia zone/exit site of the clinical VT based on the 12-lead ECG, noninvasive program stimulation, echocardiography, and MRI/CT/nuclear imaging that might include positron emission tomography (Figure 1).
8.	Positioning, simulation with imaging, segmentation, and aligning of the patient.
9.	Arc treatment delivery with a single-fraction ablative dose of X-ray radiation energy of 25 Gy on the targeted area from a linear accelerator in a shielded room (usually takes less than 10 minutes) in free-breathing or breath-hold state.
10.	Patient monitoring with ECG via a closed-circuit television.

SBRT in VT

SBRT is emerging in its clinical use in VT. When used for cardiac arrhythmias, SBRT is termed stereotactic arrhythmia radioablation or stereotactic ablative radiotherapy. Because ventricular arrhythmias often arise from regions of myocardial scar, imaging is performed to identify these areas as targets for stereotactic arrhythmia radioablation. Areas of scar are generally mapped using electroanatomic mapping systems during routine invasive cardiac ablations as areas of low voltage. With the emergence of noninvasive ablation, noninvasive imaging modalities are also used in identifying areas of scar. These include CT, echocardiography, nuclear perfusion imaging, positron emission topography scan, or contrast-enhanced MRI.⁵ Additionally, noninvasive electroanatomic mapping can be performed with electrocardiographic imaging to identify origin of VT.^6,7

The first use of stereotactic arrhythmia radioablation for VT in humans was performed by Loo et al. in 2015. VT scar substrate was localized to the left ventricular (LV) myocardium in a 71-year-old man with a history of ischemic heart disease. A dose of 33 Gy of radiation was targeted to the center of this scar. A significant decrease in the burden of VT was seen after the procedure, but recurrence was seen after 9 months; this was thought to be because of underdosing of radiation. There were no acute or long-term complications from the procedure.⁸ Cvek et al. applied a dose of 25 Gy using the CyberKnife system to a patient with VT, which resulted in no episodes of VT within the 120-day follow-up period with no clinical side effects.⁹ Robinson et al. performed SBRT in 19 patients with either treatment-refractory VT or premature ventricular contraction-related cardiomyopathy. A dose of 25 Gy was also used in this study. There was an 11% serious adverse event rate and a 94% reduction in VT episodes, with 89% overall survival at 6 months. Three deaths were related to recurrent VT. Use of dual antiarrhythmic medication also decreased significantly.¹⁰ Cuculich et al. performed SBRT on 5 patients with refractory VT by delivering a dose of 25 Gy to target tissue. During the 3-month pretreatment period, these 5 patients had 6,577 episodes of VT combined. During the 6-week period after ablation, when arrhythmias are thought to occur due to post-ablation inflammation, there were 680 episodes of VT. After that, the reduction of VT burden was 99.9%. Adjacent lung opacities consistent with inflammatory changes at 3 months had resolved by 1 year.¹¹ Cuculich et al. additionally assessed global myocardial function a year after noninvasive ablation and showed preservation of function, with some cases of improvement in LV ejection fraction (likely because of reduced burden of VT).¹²

Krug et al. performed the first SBRT treatment for VT in Germany and were successful in significantly reducing VT burden from 5 to 1.6 episodes per week. Long-term effect was not studied because the patient died 57 days after the procedure from severe sepsis.¹³ Martí-Almor et al. performed SBRT in a patient with arrhythmogenic right ventricular cardiomyopathy and refractory VT. Absence of ventricular arrhythmias was seen at 4 months, and MRI showed a new dense transmural scar at the site of radiation. The right ventricular ejection fraction did not significantly change after radiation.¹⁴

Cuculich et al. recently reported longer-term results from SBRT performed in 19 patients (median LV ejection fraction 25%; 74% had New York Heart Association Class 3 or 4; 53% had VT storm despite antiarrhythmic medication [median = 2] and catheter ablation [median = 1]) with either treatment-refractory VT or premature ventricular contraction-related cardiomyopathy. A single-fraction dose of 25 Gy was used in this study, and the median follow-up was 34 months (7.9-60.1 months). Overall survival at 1, 2, and 3 years was 74%, 53%, and 46%, respectively. Nine deaths occurred, with 4 possibly related to the treatment. Late serious adverse events (>6 months) were rare. The markedly reduced VT burden persisted through the first 3 years, but complete freedom from VT was uncommon.¹⁸ Table 2 lists studies and reports of SBRT for VT.

Table 2: Summary of SBRT Studies in VT

Author (Year)Ref	Sample/Target	Dose (Gy)	Result
Loo et al. (2015)8	VT with ventricular scar	33	Significant decrease in VT burden but recurrence after 9 months
Cvek et al. (2014)9	VT with ventricular scar	25	No episode after 120 days
Robinson et al. (2019)10	Nineteen patients with refractory VT or premature ventricular contracts	25	Significant decrease in VT or premature ventricular contraction burden in 89% of patients
Cuculich et al. (2017)11	Five patients with refractory VT	25	Significant decrease in VT burden in all patients
Krug et al. (2019)13	Patient with refractory VT	25	Significant reduction in VT episodes from 5 to 1.6 episodes per week
Martí-Almor et al. (2020)14	Patient with arrhythmogenic right ventricular cardiomyopathy and sustained VT	25	Absence of ventricular arrhythmias at 4 months
Zeng et al. (2019)15	VT secondary to cardiac lipoma	24	No episode after 2 months
Haskova et al. (2018)16	VT associated with cardiac fibroma	25	Within 8 months follow-up, episodes gradually disappeared
Jumeau et al. (2018)17	Electrical storm due to incessant VT	25	Free of electrical storm within 4 months
Cuculich et al. (2020)18	Nineteen patients with refractory VT or premature ventricular contracts	25	Significant decrease in VT burden that persisted for 2 years in most patients

Collateral Damage in SBRT

As seen in clinical experiments, radiotherapy has delayed effect on cardiac structures. Knowledge about these delayed effects, often decades after radiation, comes from the cardiotoxic effects after radiation of lymphomas. These effects have been seen on coronary arteries, the conduction system, valves, myocardium, and pericardium. Although SBRT aims to avoid toxic effects on adjacent tissues, there still exists respiratory and cardiac motion that can increase the risk of delivery of radiation out of target despite the strategies to limit their effect. These risks are particularly important in patients who have longer expected survival than in patients for whom this is used as a palliative measure. Collateral radiation in SBRT was studied in a patient who received 25 Gy to a target volume of myocardium. The maximal dose that reached the spinal cord was 3.9 Gy (acceptable limit = 13.7 Gy), the maximal dose that reached the lung was 2.2 Gy (acceptable limit <18 Gy), and maximal esophageal dose was 13.9 Gy (acceptable limit = 15.4 Gy).¹⁹ The normal myocardium also receives a dose of radiation, especially nearby coronary arteries. It is thought that the coronary artery nearest the myocardial scar is most likely already occluded, so radiation will unlikely have any major effects.⁵ Neuwirth et al. studied the side effects of radiation in 10 patients who received SBRT for VT related to structural heart disease. They note nausea as an acute toxicity in 40% of patients, and these patients had received target radiation to the inferior wall of the LV, which is close to the stomach. These patients responded well to antiemetics. One patient who had baseline mitral regurgitation had worsening regurgitation and valvular morphology changes 17 months after the procedure that was thought to be a possible late effect of radiation toxicity. No effects were observed either acutely or in the long-term follow-up period in these patients.²⁰

Conclusion

SBRT is proving to be a promising alternative for refractory VT with what has so far been shown to be a low side effect profile. However, continued improvement in strategies to compensate for cardiac and respiratory cycle motion in SBRT is needed, as are more long-term efficacy and long-term recurrence data. Furthermore, the toxic effects of radiation to both cardiac structures and adjacent organs need to be assessed, and more multicenter studies are needed with randomized controlled trials comparing radioablation to repeated catheter ablation.

References

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2. Sharma A, Wong D, Weidlich G, et al. Noninvasive Stereotactic Radiosurgery (CyberHeart) for Creation of Ablation Lesions in the Atrium. Heart Rhythm 2010;7:802-10.
3. Lehmann HI, Graeff C, Simoniello P, et al. Feasibility Study on Cardiac Arrhythmia Ablation Using High-Energy Heavy Ion Beams. Sci Rep 2016;6:38895.
4. Refaat MM, Ballout JA, Zakka P, et al. Swine Atrioventricular Node Ablation Using Stereotactic Radiosurgery: Methods and In Vivo Feasibility Investigation for Catheter-Free Ablation of Cardiac Arrhythmias. J Am Heart Assoc 2017;6:e007193.
5. John RM, Shinohara ET, Price M, Stevenson WG. Radiotherapy for Ablation of Ventricular Tachycardia: Assessing Collateral Dosing. Comput Biol Med 2018;102:376-80.
6. Wang Y, Cuculich PS, Zhang J, et al. Noninvasive Electroanatomic Mapping of Human Ventricular Arrhythmias With Electrocardiographic Imaging. Sci Transl Med 2011;3:98ra84.
7. Zhang J, Cooper DH, Desouza KA, et al. Electrophysiologic Scar Substrate in Relation to VT: Noninvasive High-Resolution Mapping and Risk Assessment With ECGI. Pacing Clin Electrophysiol 2016;39:781-91.
8. Loo BW Jr, Soltys SG, Wang L, et al. Stereotactic Ablative Radiotherapy for the Treatment of Refractory Cardiac Ventricular Arrhythmia. Circ Arrhythm Electrophysiol 2015;8:748-50.
9. Cvek J, Neuwirth R, Knybel K, et al. Cardiac Radiosurgery for Malignant Ventricular Tachycardia. Cureus 2014;6:e190.
10. Robinson CG, Samson PP, Moore KMS, et al. Phase I/II Trial of Electrophysiology-Guided Noninvasive Cardiac Radioablation for Ventricular Tachycardia. Circulation 2019;139:313-21.
11. Cuculich PS, Schill MR, Kashani R, et al. Noninvasive Cardiac Radiation for Ablation of Ventricular Tachycardia. N Engl J Med 2017;377:2325-36.
12. Cuculich P, Kashani R, Mutic S, Hallahan DE, Robinson CG. Myocardial Performance After EP-Guided Noninvasive Cardiac Radioablation (ENCORE) for Ventricular Tachycardia (VT). Int J Radiat Oncol Biol Phys 2017;99:e511-e512.
13. Krug D, Blanck O, Demming T, et al. Stereotactic Body Radiotherapy for Ventricular Tachycardia (Cardiac Radiosurgery) : First-in-patient Treatment in Germany. Strahlenther Onkol 2020;196:23-30.
14. Martí-Almor J, Jiménez-López J, Rodríguez de Dios N, Tizón H, Vallés E, Algara M. Noninvasive Ablation of Ventricular Tachycardia With Stereotactic Radiotherapy in a Patient With Arrhythmogenic Right Ventricular Cardiomyopathy. Rev Esp Cardiol (Engl Ed) 2020;73:97-9.
15. Zeng LJ, Huang LH, Tan H, et al. Stereotactic Body Radiation Therapy for Refractory Ventricular Tachycardia Secondary to Cardiac Lipoma: A Case Report. Pacing Clin Electrophysiol 2019;42:1276-9.
16. Haskova J, Peichl P, Pirk J, Cvek J, Neuwirth R, Kautzner J. Stereotactic Radiosurgery as a Treatment for Recurrent Ventricular Tachycardia Associated With Cardiac Fibroma. HeartRhythm Case Rep 2018;5:44-7.
17. Jumeau R, Ozsahin M, Schwitter J, et al. Rescue Procedure for an Electrical Storm Using Robotic Non-Invasive Cardiac Radio-Ablation. Radiother Oncol 2018;128:189-91.
18. Cuculich P. Longer Term Results From A Phase I/II Study Of EP-guided Noninvasive Cardiac Radioablation For Treatment Of Ventricular Tachycardia (ENCORE-VT). Presented at the Heart Rhythm Society 2020 virtual meeting. May 8, 2020.
19. Grimm J, LaCouture T, Croce R, Yeo I, Zhu Y, Xue J. Dose Tolerance Limits and Dose Volume Histogram Evaluation for Stereotactic Body Radiotherapy. J Appl Clin Med Phys 2011;12:3368.
20. Neuwirth R, Cvek J, Knybel L, et al. Stereotactic Radiosurgery for Ablation of Ventricular Tachycardia. Europace 2019;21:1088-95.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Valvular Heart Disease, Implantable Devices, EP Basic Science, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Mitral Regurgitation

Keywords: Arrhythmias, Cardiac, Antiemetics, Arrhythmogenic Right Ventricular Dysplasia, Stroke Volume, Electrons, Radiosurgery, Mitral Valve Insufficiency, Coronary Vessels, Ventricular Premature Complexes, Electrocardiography, Atrioventricular Node, DNA Breaks, Double-Stranded, X-Rays, Pulmonary Veins, Atrial Fibrillation, Cobalt Radioisotopes, Fibrosis, Particle Accelerators, Myocardium, Gamma Rays, Ventricular Function, Right, Feasibility Studies, Cicatrix, Follow-Up Studies, Tachycardia, Ventricular

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