The Clinical Problem

With earlier reperfusion after myocardial infarction, better medical and mechanical support for heart failure (HF), and more widespread use of implantable cardioverter-defibrillators (ICDs), patients with cardiomyopathies are living longer. As a result, there is a growing group of patients with advanced cardiomyopathy who are surviving after multiple ICD shocks. For this growing group of patients, we have turned sudden cardiac arrest into a chronic disease.

Increasingly, catheter ablation (CA) is being used to minimize ICD shocks and prevent ventricular tachycardia (VT).¹ However, CA comes at the price of subjecting patients to a time-consuming (typically >6 hours) procedure with serious potential toxicity and substantial rates of recurrence. These risks are further elevated in patients with high-risk features such as extensive cardiomyopathy, severe HF symptoms, increased age, and prior failed CA, where peri-procedural mortality may exceed 5%, survival at 1 year is <70%, and recurrence rates exceed 50%.² The myocardial scar substrates are larger, and the patients are sicker. As such, a method for safer, more comprehensive ablation of VT is desperately needed for high-risk patients with refractory VT.

A Novel Solution: Noninvasive Cardiac Radioablation

As part of a multidisciplinary collaboration between electrophysiology and radiation oncology at Washington University in St. Louis, we developed a completely noninvasive method for treatment of VT: EP-Guided Noninvasive Cardiac Radioablation (ENCORE) (Figure 1). This method combines modern noninvasive multimodality imaging to identify the arrhythmia target with a single dose of radiotherapy. The ENCORE procedure is delivered in the ambulatory setting over an average of 15 minutes using the same precision stereotactic body radiotherapy (SBRT) used to treat cancer.

The procedure's benefits for patients include the following:

• Mapping and targeting are done noninvasively. We use standard noninvasive cardiac images or previously obtained invasive catheter maps.
• Imaging and treatment are entirely noninvasive.
• Unlike CA, treatment is across the entire thickness of abnormal myocardium.
• Unlike CA, treatment is not restricted by anatomical access.
• Treatment is done in a single treatment that lasts only minutes while the patient is awake (no general anesthesia).
• Patients can go home immediately after the treatment.

Figure 1: Example of ENCORE Workflow

Learning From the History of Radiotherapy While Writing a New Chapter

Radiotherapy is an indispensable tool in the management of patients with cancer. However, when healthy organs are exposed to radiotherapy, some of the most severe toxicities may not manifest until many years after treatment.^3,4 Of particular relevance to ENCORE are late cardiac toxicities that are most well-described in patients treated with radiotherapy for lymphoma and breast cancer. In younger patients treated several decades ago using outdated techniques that exposed large portions of the heart to high doses of radiation, a significant increase in rates of coronary artery disease, valvular disease, pericardial disease, conduction abnormalities, and cardiomyopathy has been described. Modern computerized treatment planning, coupled with more advanced delivery techniques to minimize unintended dose to the heart, is expected to significantly reduce the risk of cardiac toxicity, though proof of this will take decades to bear out.⁵

ENCORE employs a particularly advanced form of radiotherapy called SBRT, which allows for high precision, high-dose treatment to discrete targets anywhere in the body, typically in 1-5 sessions.⁶ Use of SBRT has increased dramatically in the past decade due in large part to unprecedented tumor control rates in the setting of low rates of toxicity. Importantly, a key feature of SBRT is leveraging advanced treatment planning and delivery systems to give those high doses to tumors that are often within or immediately adjacent to critical structures, such as the brain and lung. Within the ENCORE workflow, we adhere to the same philosophy: Attempt to deliver the full radiotherapy dose to the diseased myocardium harboring the VT circuit(s) while sparing as much of the surrounding healthy cardiac tissue as possible.

Preclinical dose-finding studies in porcine models have demonstrated that large (25 to 35 Gy), single doses of SBRT can be accurately delivered to discrete targets in the heart, resulting in fibrosis and electrical isolation similar to that found with CA.^7,8 Histologic analysis demonstrates effects consistent with radiotherapy confined to the targeted areas with no evidence of damage outside the heart. Dose-finding across multiple studies suggests that 25 Gy was a minimum dose needed to produce an electrophysiologic effect, and this was consistently observed by 90 days. Based on these data and a seminal publication by Loo and Zei describing a first-in-man treatment using SBRT to 25 Gy to control refractory VT, we chose 25 Gy for our current clinical studies.⁹

Early Clinical Results of ENCORE Are Promising

Our initial report of using ENCORE included 5 patients with end-stage, treatment-refractory VT who had no other reasonable options and had high burden of VT nearly every day.¹⁰ Ablation volumes ranged from 17 to 81 cc; for comparison, a golf ball has a volume of 40 cc. Mean noninvasive VT ablation time was 14 minutes (range 11-18), performed awake. In total, there was a >99% reduction in total VT burden (6,577 ICD therapies in the 3 months before treatment to 4 ICD therapies in the 12 months after treatment). Reduction in VT burden was achieved in all patients (mean 1,315 per-patient ICD therapies [range 5-4312] to 1 [range 0-2]) despite stopping antiarrhythmic medication. Left ventricular ejection fraction did not adversely change over time, and mild adjacent lung inflammatory changes were observed at 3 months, which resolved by 1 year. These results were better than expected.

Following up on these positive results, we recently completed ENCORE-VT (Phase I/II Study of EP-guided Noninvasive Cardiac Radioablation for Treatment of Ventricular Tachycardia) (NCT02919618).¹¹ A total of 19 subjects was enrolled from August 2016 to December 2017. Median age was 66 years (range 49-81); 89.5% were male, and 42.1% had nonischemic cardiomyopathy. Most patients had New York Heart Association Class III/IV HF (73.7%), and median left ventricular ejection fraction was 25% (range 15-58%). Subjects previously underwent a median of 1 VT CA procedures (range 0-4), and at the time of ENCORE treatment, 52.6% presented with VT storm (>3 VT treatments in 24 hours), and 10.5% were in incessant VT. Median number of induced VTs during noninvasive mapping was 2 (range 1-5). Mean gross target volume for ablation was 25.4 cc (range 6.4-88.6). Treatment was delivered in a single treatment with median duration of 15.3 minutes (range 5.4-32.3) while the patient was awake.

Overall number of VT events (Figure 2) comparing the 6 months before and after ENCORE (with a 6-week blanking period) was substantially reduced (1782 vs. 111 VT events, 94% reduction). Median number of VT events per patient before and after ENCORE was 119 versus 3 (p < 0.001). For the primary efficacy endpoint, 18/19 (94%) had any reduction in VT or premature ventricular complex (PVC). Overall survival at 6 and 12 months was 89% and 72%, respectively. In addition to improvements in VT/PVC, use of dual antiarrhythmic medication decreased from 59% to 12% (p = 0.008), and significant improvements were observed in perceived health change and social functioning on the SF-36 quality-of-life measures. Two (10.5%) patients developed a serious adverse event within 90 days: One patient was admitted for a HF exacerbation, and another developed pericarditis that responded to conservative management. Another patient died from an accident at a nursing facility that was unrelated to treatment and attributed to his overall debilitated state. For a group of patients with end-stage, treatment-refractory VT, achieving 89% survival at 6 months was an unexpected achievement.

Figure 2: Efficacy of ENCORE in the ENCORE-VT Trial

Putting ENCORE-VT Results Into Context

Preliminary results from our initial 5-patient cohort and subsequent 19-patient ENCORE-VT trial support a strong and consistent early safety and efficacy profile with ENCORE for high-risk patients with treatment-refractory VT. In short, this treatment appears to be highly effective in the first 6-12 months. However, because radiation can have effects that may not manifest for years, the full risk profile for this procedure has not yet been discovered. It may very well be that we are trading short-term risks for a complication that can occur much later. As such, it makes sense to temper enthusiasm until our field has learned more about best uses for this technique. Previous lessons learned from therapeutic radiation should be respected and remembered, and we should proceed forward only in the context of careful clinical trials. What do these clinical trials look like?

Patient Selection

To start, we advocate for very careful patient selection for this technique, limiting access for treating only select patients who have failed traditional therapies for VT. These patients often have limited longevity without effective treatment, and the benefits of VT suppression with ENCORE may outweigh the risks that are likely to occur in several years. For patients with non-life-threatening arrhythmias (atrial fibrillation) and for young patients with symptomatic PVCs who are likely to live long lives, we strongly recommend against cardiac radioablation at this time. Unfortunately, we have already seen several submitted case reports for cardiac radiation being used for such patients.

In addition to a warning against using cardiac radiation for patients who are "too well," we also caution against having too high hopes for the effect of cardiac radioablation in patients who may be "too sick." We have been referred a number of patients for consideration of an ENCORE procedure who have died of non-arrhythmia-related diseases, namely cardiogenic shock, before we could even treat the VT. Had we treated these patients, it is unlikely that the heart function would have improved, and their early deaths would have been attributed to the cardiac radiation. Similar parallels can be made to early clinical trials for transcatheter aortic valve replacement for high-risk, surgically inoperable patients with severe aortic stenosis. Despite transcatheter aortic valve replacement, 1-year mortality rates exceeded 30%, demonstrating a very high burden of co-morbid diseases and competing causes of death.

Consistent Treatment Standards

To effectively treat a tumor, radiation oncologists rely on imaging to identify the target. Identifying the critical components of a VT circuit without catheters is not as obvious. The process of noninvasively targeting a VT is in evolution, and it relies heavily on combining various forms of cardiac imaging (anatomic scar imaging, metabolic imaging, functional imaging, 12-lead electrocardiograms of VT, and noninvasive electrocardiographic imaging). As the field of noninvasive ablation moves forward, it is imperative that the processes for noninvasive targeting become reproducible among centers.¹² Software solutions and learned algorithms can play an important role toward this goal. Without consistency, the size and locations of ablation targets will vary tremendously, and it will become impossible to determine the reasons for successes and failures of cardiac SBRT.

Similarly, we must develop consistency in delivery of treatment. Radiation oncologists have developed numerous ways to treat moving tumors in the lung. However, there is longstanding dogma in the field to avoid radiation dose to the heart, so there is little comfort with the overall concept of cardiac SBRT for VT. As this concept gains traction within the radiation oncology community, opportunities exist to further improve the motion management strategies that incorporate cardiac motion into the treatment plans.

Prospective Clinical Trials: It's Now or Never

We are personally aware of many sites starting to perform noninvasive cardiac radioablation off-label, with several case reports recently published^9,13,14 and more to follow soon. However, without rigorous standards for treatment and robust evaluation of the short- and long-term safety and efficacy of this treatment, uncertainty will linger as to the true benefit or harm of such a treatment and the ideal group of patients in which to deliver it. With rapid uptake of this treatment will come loss of clinical equipoise in the community, and the opportunity to definitively answer the necessary questions will be lost. This is of particular importance to regulatory bodies such as the US Food and Drug Administration that wishes to have oversight over the development of this nascent technique and have made its stance abundantly clear: Any further study of this treatment is considered investigational and must be performed under an Investigational Device Exemption.

We have proposed a multi-institutional expansion of our current trial as well as a prospective randomized trial to definitively assess the safety and efficacy of ENCORE for patients who have had recurrent VT despite at least one CA procedure. The population being examined will be uniform, such that reported toxicity and efficacy should be more clearly related to the modality and not the patient population. It will be performed with standardized ways to target the VT and treat the diseased myocardium. Such trials will provide invaluable opportunities to explore the scalability of the current ENCORE workflow to other centers and provide these same centers with experience in the technique that would be necessary for subsequent participation in future prospective comparisons.

We are excited by the potential for ENCORE to fill a gap for patients with refractory VT for which few options exist. We look forward to working with groups around the world to study this with care and scientific rigor.

References

1. Cronin EM, Bogun FM, Maury P, et al. 2019 HRS/EHRA/APHRS/LAHRS expert consensus statement on catheter ablation of ventricular arrhythmias. Heart Rhythm 2019;May 8:[Epub ahead of print].
2. Vergara P, Tzou WS, Tung R, et al. Predictive Score for Identifying Survival and Recurrence Risk Profiles in Patients Undergoing Ventricular Tachycardia Ablation. Circ Arrhythm Electrophysiol 2018;11:e006730.
3. Curigliano G, Cardinale D, Dent S, et al. Cardiotoxicity of anticancer treatments: Epidemiology, detection, and management. CA Cancer J Clin 2016;66:309-25.
4. Yusuf SW, Sami S, Daher IN. Radiation-induced heart disease: a clinical update. Cardiol Rese Pract 2011;2011:317659.
5. Hurkmans CW, Cho BC, Damen E, Zijp L, Mijnheer BJ. Reduction of cardiac and lung complication probabilities after breast irradiation using conformal radiotherapy with or without intensity modulation. Radiother Oncol 2002;62:163-71.
6. Benedict SH, Yenice KM, Followill D, et al. Stereotactic body radiation therapy: the report of AAPM Task Group 101. Med Phys 2010;37:4078-101.
7. Blanck O, Bode F, Gebhard M, et al. Dose-escalation study for cardiac radiosurgery in a porcine model. Int J Radiat Oncol Biol Phys 2014;89:590-8.
8. 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.
9. 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.
10. Cuculich PS, Schill MR, Kashani R, et al. Noninvasive Cardiac Radiation for Ablation of Ventricular Tachycardia. N Engl J Med 2017;377:2325-36.
11. 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.
12. Knutson NC, Samson PP, Hugo GD, et al. Radiation Therapy Workflow and Dosimetric Analysis from a Phase 1/2 Trial of Noninvasive Cardiac Radioablation for Ventricular Tachycardia. Int J Radiat Oncol Biol Phys 2019;Apr 16:[Epub ahead of print].
13. Cvek J, Neuwirth R, Knybel L, et al. Cardiac Radiosurgery for Malignant Ventricular Tachycardia. Cureus 2014;6:e190.
14. 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.

Keywords: Arrhythmias, Cardiac, Algorithms, Anesthesia, Atrial Fibrillation, Biological Products, Aortic Valve Stenosis, Cardiotoxicity, Cardiotoxins, Catheter Ablation, Cardiomyopathies, Cohort Studies, Chronic Disease, Cicatrix, Coronary Artery Disease, Cause of Death, Defibrillators, Implantable, Electrocardiography, Electrophysiology, Heart Failure, Death, Sudden, Cardiac, Lymphoma, Myocardial Infarction, Myocardium, Pericarditis, Polyvinyl Chloride, Prospective Studies, Radiation Dosage, Radiation Oncology, Radiosurgery, Shock, Cardiogenic, Quality of Life, Stroke Volume, Tachycardia, Ventricular, Transcatheter Aortic Valve Replacement, United States Food and Drug Administration, Ventricular Premature Complexes

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