Cardiology and Radiation Oncology working together—a new ‘STAR’ on the horizon?

Until recently, most cardiologists associated radiation exposure to the heart with potential adverse effects, such as pericarditis, late coronary artery disease or potential damage to cardiac implantable devices. The landmark publication of 2017 reporting a case series of just five patients with recurrent ventricular tachycardia (VT) treated with stereotactic arrhythmia radioablation (STAR) changed this perception and introduced a new area for both cardiac electrophysiology and radiation oncology

Andratschke, Nicolaus

Kovacs, Boldizsar

Mayinger, Michael

Saguner, Ardan M

English

ZENODO

Stereotactic arrhythmia radioablation: competitor or adjunct to catheter ablation?

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Zurich Open Repository andArchiveUniversity of ZurichUniversity LibraryStrickhofstrasse 39CH-8057 Zurichwww.zora.uzh.chYear: 2022Stereotactic arrhythmia radioablation: competitor or adjunct to catheter ablation?Kovacs, Boldizsar ; Mayinger, Michael ; Andratschke, Nicolaus ; Saguner, Ardan MDOI: https://doi.org/10.1093/eurheartj/ehac435Posted at the Zurich Open Repository and Archive, University of ZurichZORA URL: https://doi.org/10.5167/uzh-220966Journal ArticleAccepted VersionOriginally published at:Kovacs, Boldizsar; Mayinger, Michael; Andratschke, Nicolaus; Saguner, Ardan M (2022). Stereotactic arrhythmiaradioablation: competitor or adjunct to catheter ablation? European Heart Journal, 43(35):3279-3281.DOI: https://doi.org/10.1093/eurheartj/ehac435Stereotactic Arrhythmia Radioablation – Competitor or Adjunct to Catheter Ablation? Boldizsar Kovacs1,2, Michael Mayinger3, Nicolaus Andratschke3, Ardan M Saguner1 1 University Heart Center, University Hospital Zurich, Zurich, Switzerland 2 Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA  3 Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland  Cardiology and Radiation Oncology working together - a new ‘STAR’ on the horizon? Until recently, most cardiologists associated radiation exposure to the heart with adverse effects, such as pericarditis, late coronary artery disease or potential damage to cardiac implantable devices. The landmark publication of 2017 reporting a case series of just five patients with recurrent ventricular tachycardia (VT) treated with stereotactic arrhythmia radioablation (STAR) changed this perception and introduced a new area for both cardiac electrophysiology and radiation oncology1. Monomorphic VT in cardiomyopathy usually arises because heterogeneous (i.e. partially viable) myocardial scar tissue enables electrical reentry circuits. Current treatment consists of optimal guideline-directed medical heart failure therapy, ICD implantation to interrupt VT episodes and ultimately radiofrequency catheter ablation (CA) to modify the arrhythmogenic substrate (i.e. creating non-viable myocardial tissue). Several randomized controlled trials have demonstrated the efficacy of CA for sustained VT in structural heart disease and hence it is an established intervention with its place in the most recent guidelines2,3. Still, not all patients requiring and potentially benefiting from this procedure are eventually eligible for RFA. Therefore, non-invasive local ablative methods are highly desirable for these patients and stereotactic ablative radiotherapy has been sought as one such possible alternative by directly exploiting one side-effect of this treatment, namely tissue fibrosis. Stereotactic radiotherapy is a form of high-precision radiotherapy in which high energy x-rays are used to deliver a high single fraction dose to a well circumscribed tissue area using modern linear accelerator technology (LINAC). This beam can accurately and reliably be focused on a target, usually macroscopic cancerous tissue and causes tissue necrosis (cancer tissue, short-term) and fibrosis (normal mesenchymal tissue, long-term). The latter effect is similar  to CA and would be in the case of VT ablation the desired consequence of such a treatment. In theory, this non-invasive therapy with short treatment duration is highly attractive for this patient population with high morbidity and mortality.  Since the publication by Cuculich et al, numerous case reports/series and non-randomized clinical trials have been published. In a recent publication, we have systematically reviewed these publications reporting on the use of STAR in human subjects4. While all reported patients (n = 55) had an immediate and impressive reduction in sustained VT burden, 75% ultimately recurred during a mean follow-up of 410 days. Clinically significant adverse events were seldom reported. Currently, several prospective observational studies investigating the efficacy and safety of STAR are ongoing or planned as demonstrated on clinicaltrials.gov reflecting the high interest in thoroughly evaluating this innovative, but still experimental treatment indication (table 1).  Most importantly, up to date the mode of action of STAR remains to be elucidated: 1) the demonstrated effects happens on a time scale of hours to days which is well below the time course for the development of tissue fibrosis (i.e. months), 2) experimental studies claim a significant higher radiation dose for scar formation as currently used (> 30 Gy single fraction), 3) the desired transmural fibrosis could only partially be detected either by histopathology or imaging (67%) in examined patient specimen as demonstrated in a recent systematic review. Recently, enhanced conduction properties of myocardial cells have been proposed by increased expression of critical gap junction proteins induced by radiation5.  Patterns-of-failure data mapping the recurring VT and correlating them to the STAR target volume and dose received are highly needed to address the questions of the high recurrence rate beyond 12 months. As fundamental questions still need to be answered regarding STAR, an emerging therapeutic modality, the following sections discuss the pertinent questions, when considering patients for STAR.  When should STAR be considered? Currently, the most common indication for STAR is recurrent, often incessant monomorphic VT caused by reentry in structural heart disease (either ischemic or non-ischemic). Among these, three common clinical scenarios must be differentiated: (1) primary treatment before any CA, (2) treatment for recurrent VT after CA or (3) last resort and “palliation”. Based on the vast experience with CA for monomorphic VT and uncertainty of long-term safety and limited mid-term efficacy of STAR, this novel approach seems reasonable in this population only if there is a contraindication for CA (e.g. mechanical valves in both aortic and mitral positions or difficulty to gain epicardial access). All other patients should primarily be referred for CA until there is more data showing similar efficacy and safety. If CA ablation fails, there is uncertainty, whether STAR is the right approach. Repeat CA (endocardial and/or epicardial) for recurrent VT are commonly performed at experienced centers, however not always with improved outcomes as compared to a single intervention6. This patient group in our opinion should be the main focus of research and patients would ideally all be included in clinical trials. Lastly, patients who have failed all interventions and remain in incessant VT or have ongoing electrical storms represent a group with high mortality. In these patients STAR seems to offer at least short term palliation and could be offered on a compassionate basis.   What should be irradiated? The major source of heterogeneity in the use of STAR is the actual target volume definition. Firstly, the electrophysiologic substrate has to be defined (i.e. electrophysiology - EP target) and secondly this has to be transferred to a treatment planning software (i.e. radiation oncology - RAO target). When defining the arrhythmogenic substrate (EP target), numerous approaches have been used. This included the use of 12-lead ECG, non-invasive electroanatomic mapping (EAM), non-invasive imaging such as computed tomography (CT), magnetic resonance imaging and invasive (catheter-based) EAM. Many randomized and non-randomized trials have investigated these approaches, with heterogeneous results. In general, it is at the discretion of the treating electrophysiologist to define the substrate on the modality of his choice. This also explains the large variation in target volume sizes as discussed in the literature (reference). Transfer of the EP target to a designated stereotactic radiation software is highly susceptible to error and can result in a large difference between the EP and RAO target. The axis of images in cardiology is dependent on the position of the heart (e.g. short axis, long axis, apical), whereas in radiology it conventionally is axial, sagittal or coronal. To tackle this issue, a wide range of approaches has been implemented, including the use of the American Heart Association 17 segment model, which has been validated on axial CT images7, several different designated transfer softwares (Figure 1) and manual transfer based on anatomy.  How much should be irradiated? Several methods also exist for the compensation of cardiac and respiratory movement of the finally selected target volume. Respiratory tracking can be done by tracking clearly visible structures which move with the heart, like an ICD-lead or by simulating the movement of the target volume during the whole respiratory cycle and only applying radiation when the target volume is in a certain position (usually end-inspiratory; also called respiratory gating) or by tracking soft tissue when using a magnetic resonance based LINAC. Naturally, the different respiratory gating or tracking methods may again result in significant differences in irradiated volumes. Additionally, the complex movement of the beating heart is currently not compensated for when defining the final target volume, as the technology to do so is currently being developed and evaluated8.  STOPSTORM consortium The outspoken heterogeneity in several of the critical steps in the process of preparation and delivery of STAR launched “The Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entry tachycardia by a Multidisciplinary” consortium. STOPSTORM is a HORIZON 2020 funded European collaborative effort to bring STAR in a coordinated fashion into European clinical practice9. The ultimate goal is to harmonize each previously mentioned step and ultimately provide reliable and reproducible data on the efficacy and safety of STAR.  Conclusions With the birth of the novel and exciting collaboration between cardiac electrophysiologists and radiation oncologists, patients with therapy-refractory VT now have a novel and innovative treatment option with impressive acute-term, but yet disappointing mid-term success. Thus, until results of well-conducted prospective randomized clinical trials suggest otherwise, STAR should be reserved as a last-resort adjunct therapy for appropriate patients or for patients recruited in approved prospective clinical trials.  Figure 1: Illustration of target identification, manual target volume delineation, and verification with automated fusion.  Table 1: Ongoing or planned clinical trials of STAR for the treatment of VT N (%) Randomized Non-randomized Total Number of trials 2 (12.5) 14 (87.5) 16 Number of patients 344 (55.9) 271 (44.1) 615 Intervention: Radioablation 2 (12.5) 14 (87.5) 16 Control: Catheter ablation 2 (100) n/a 2 Location    North America 1 (11) 8 (99) 9 Europe 1 (16.7) 5 (83.7) 6 South America 0 (0) 1 (100) 1 Table 1: Systematic search of clinicaltrials.gov on June 1st, 2022 using variations of the terms “ventricular tachycardia” and “radioablation”, excluding trials listed as completed or withdrawn. The outcome measures were a heterogenous combination of efficacy (VT burden reduction) and safety.  References 1.  Cuculich PS, Schill MR, Kashani R, Mutic S, Lang A, Cooper D, Faddis M, Gleva M, Noheria A, Smith TW, Hallahan D, Rudy Y, Robinson CG. Noninvasive Cardiac Radiation for Ablation of Ventricular Tachycardia. N Engl J Med 2017;377:2325–2336.  2.  Anderson RD, Ariyarathna N, Lee G, Virk S, Trivic I, Campbell T, Chow CK, Kalman J, Kumar S. Catheter ablation versus medical therapy for treatment of ventricular tachycardia associated with structural heart disease: Systematic review and meta-analysis of randomized controlled trials and comparison with observational studies. Hear Rhythm Elsevier Inc.; 2019;16:1484–1491.  3.  Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck K-H, Hernandez-Madrid A, Nikolaou N, Norekvål TM, Spaulding C, Veldhuisen DJ Van, ESC Scientific Document Group. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the Europe. Eur Heart J 2015;36:2793–2867.  4.  Kovacs B, Mayinger M, Schindler M, Steffel J, Andratschke N, Saguner AM. Stereotactic radioablation of ventricular arrhythmias in patients with structural heart disease – A systematic review. Radiother Oncol Elsevier Ireland Ltd; 2021;162:132–139.  5.  Zhang DM, Navara R, Yin T, Szymanski J, Goldsztejn U, Kenkel C, Lang A, Mpoy C, Lipovsky CE, Qiao Y, Hicks S, Li G, Moore KMS, Bergom C, Rogers BE, Robinson CG, Cuculich PS, Schwarz JK, Rentschler SL. Cardiac radiotherapy induces electrical conduction reprogramming in the absence of transmural fibrosis. Nat Commun Springer US; 2021;12:5558.  6.  Tzou WS, Tung R, Frankel DS, Biase L Di, Santangeli P, Vaseghi M, Bunch TJ, Weiss JP, Tholakanahalli VN, Lakkireddy D, Vunnam R, Dickfeld T, Mathuria N, Tedrow U, Vergara P, Vakil K, Nakahara S, Burkhardt JD, Stevenson WG, Callans DJ, Bella P Della, Natale A, Shivkumar K, Marchlinski FE, Sauer WH. Outcomes after repeat ablation of ventricular tachycardia in structural heart disease: An analysis from the International VT Ablation Center Collaborative Group. Hear Rhythm Elsevier Inc.; 2017;14:991–997.  7.  Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, Pennell DJ, Rumberger JA, Ryan TJ, Verani MS. Standardized Myocardial Segmentation and Nomenclature for Tomographic Imaging of the Heart. J Cardiovasc Magn Reson 2002;4:203–210.  8.  Mayinger M, Kovacs B, Tanadini-Lang S, Ehrbar S, Wilke L, Chamberlain M, Moreira A, Weitkamp N, Brunckhorst C, Duru F, Steffel J, Breitenstein A, Alkadhi H, Garcia Schueler HI, Manka R, Ruschitzka F, Guckenberger M, Saguner AM, Andratschke N. First magnetic resonance imaging-guided cardiac radioablation of sustained ventricular tachycardia. Radiother Oncol Elsevier B.V.; 2020;152:203–207.  9.  STOPSTORM Consortium. https://stopstorm.eu  

Stereotactic arrhythmia radioablation: competitor or adjunct to catheter ablation?

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