1 9/14/2019 Survival benefit is absent in VT ablation clinical - - PDF document

9/14/2019 1

Stereotactic Body Radiotherapy (SBRT) for Treatment of Refractory VT

Phillip Cuculich, MD

Washington University in St. Louis Associate Professor of Medicine (Cardiology) Associate Professor of Radiation Oncology Co-Director, Center for Noninvasive Cardiac Radioablation (CNCR)

Financial Disclosures: Medtronic: Consultant Varian Medical Systems: Consultant Cardialogica: Intellectual Property Your patient with structural heart disease has sustained VT and an ICD shock. If (s)he undergoes a catheter ablation procedure, what is the expected improvement in 1-year mortality?

• A. 3.5% improvement
• B. 10% improvement
• C. 25% improvement
• D. 40% improvement
• E. Other

Question #1: Survival

Survival benefit is absent in VT ablation clinical trials

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Survival benefit is absent in VT ablation clinical trials “Outcomes” associated with clinical & substrate features

31-day mortality for all structural VT catheter ablation:

5%

(1 in 20 die)

Need More Comprehensive Treatment Need it to be LESS risky

Surgery SBRT

Stereotactic Body Radiotherapy (SBRT)

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Maguire et al. Cureus, 2011, Sharma, et al., Heart Rhythm, 2010; Song, et al., Heart Rhythm, 2014; Wong et al, The CyberKnife Society Meeting 2008; Blanck, et al, Int J Radiat Oncol Biol Phys, 2014; Lehmann et al, Circ Arrhythm Electrophysiol, 2015

Doses from 25 Gy/1 – 50 Gy/1

• 25 Gy minimum dose to produce

electrophysiologic effect by 3 mo

• 3-6 mo transmural fibrosis (25-32.5 Gy?)
• No clear toxicity in non-target heart or
• verall heart function

Radiotherapy induces fibrosis (dose-dependent)

Assumption: The EP effect is closely related to cell death & fibrosis

Workup / Targeting Imaging / Simulation Segmentation Treatment Planning Delivery Patient selection

NIPS Imaging

Workup / Targeting Imaging / Simulation Segmentation Treatment Planning Delivery Patient selection

NIPS Imaging

Noninvasive Cardiac Radioablation

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5 patients recurrent VT treated in 2015 (published 2017) Arrhythmogenic scar targeted by combining anatomic imaging and ECGI SBRT delivered to target, 25Gy/1 (no fiducial needed) Mean noninvasive ablation time 14 min (11-18) 3 month pre treatment = 6577 6 week blanking = 680 Next 10.5 months = 4 10 patients recurrent VT treated in 2014-2017 (published 2019) Arrhythmogenic scar targeted with invasive CARTO maps SBRT delivered to target, 25Gy/1 (ICD lead as fiducial) Mean noninvasive ablation time 68 min (45-80) 19 patients recurrent VT treated in 2017-2018 (NCT02919618, published 2018) Arrhythmogenic scar targeted by combining anatomic imaging and ECGI SBRT delivered to target, 25Gy/1 (no fiducial needed) Mean noninvasive ablation time 15 min (5-32)

• Baseline characteristics

Median Age = 66 y/o (49-81) 89.5% Male 89.5% Caucasian Ischemic (57.9%) NHYA Class III (52.6%), IV (21.1%) Median LVEF = 25% (15-58) VT storm (52.6%) PVC cardiomyopathy (10.5%) Meds >1 AAD (57.9%) >300 mg amio (57.9%)

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19 patients recurrent VT treated in 2017-2018 (NCT02919618, published 2018) Arrhythmogenic scar targeted by combining anatomic imaging and ECGI SBRT delivered to target, 25Gy, 1 fraction Mean noninvasive ablation time 15 min (5-32)

• Primary Endpoint: Any G5/G4/Hospitalized G3

possibly/probably/definitely related to treatment within 90 days:

• n=2 (10.5%)
• Possible: Grade 3 heart failure admission (day 65)

– treated with diuretics

• Probable: Grade 3 pericarditis (day 80)

– resolved with prednisone

• Unlikely: One patient death in first 90 days (day 17)

– accidental, not related to treatment

Median 119 Median 3 p < 0.001

19 patients recurrent VT treated in 2017-2018 (NCT02919618, published 2018) Arrhythmogenic scar targeted by combining anatomic imaging and ECGI SBRT delivered to target, 25Gy, 1 fraction Mean noninvasive ablation time 15 min (5-32) 6 months BEFORE 6 week BLANKING 4.5 months AFTER 1778 VT episodes 149 VT episodes 111 VT episodes

18 of 19 (94%) patients met primary endpoint of reduction in VT burden

ICD shocks decreased from 4 to 0 (p = 0.002) Anti-tachycardia pacing decreased from 81 to 3 (p = 0.001) 19 patients recurrent VT treated in 2017-2018 (NCT02919618, published 2018) Arrhythmogenic scar targeted by combining anatomic imaging and ECGI SBRT delivered to target, 25Gy, 1 fraction Mean noninvasive ablation time 15 min (5-32)

5 10 15 20 25 30 35

Baseline 6 Months

Class I Agents Class III Agents Low-Dose Amiodarone High-Dose Amiodarone

Nine SF-36 modules: 5 improved 4 maintained 0 worsened

Secondary Endpoints: Medication Usage and Quality of Life

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Where do we go from here? Next steps…

These results for noninvasive ablation look encouraging. What should we do next?

A. Isn’t radiation dangerous? You need to understand the biology of how radiation affects the heart better – do more animal studies B. Wait, how do you treat a moving target? Figure out the motion management first. C. Whoa, how do you know where to ablate if you didn’t use catheters? Figure out the targeting first. D. Radiation can have lasting, late effects. Follow your treated patients for 25 years, then revisit. E. Giddy-up! Let’s do a RCT!

Question #2: Next Steps

Center for Noninvasive Cardiac Radioablation (CNCR) Biology Clinical Population Imaging Process

Murine (SAARP) Human explant

How is SBRT antiarrhythmic? How should SBRT be delivered?

ENCORE-RCT ENCORE-MULTI Global Registry ENCORE-VT

Can SBRT extend access to care?

Democratize VT Ablation How can we improve & standardize the processes? How to determine critical arrhythmia sites? Scar architecture Metabolism Electrical In silico modeling Augmented targeting tools Motion management Automation of feature analysis Augmented decision tools Scalable & Sharable

Longer T erm Results from a Phase I/II Study of EP- guided Noninvasive Cardiac Radioablationfor Treatment of Ventricular T achycardia (ENCORE-VT)

• C. G. Robinson, P. Samson, K. M. S. Moore, G. D. Hugo, N. Knutson, S.

Mutic, S. M. Goddu, D. H. Cooper, M. Faddis, A. Noheria, T. W. Smith, P. K. Woodard, R. J. Gropler, D. E. Hallahan, Y. Rudy, and P. S. Cuculich Washington University School of Medicine in St. Louis

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95.5 3.5 1 3.5 20 40 60 80 100 120 6 mo PRE 0-6 mo 6-12 mo 12-18 mo 18-24 mo

Per-Patient VT Episodes by 6-month time periods

Median VT burden

At risk 18 18 17 14 12

VT Episodes

Pha hase II – Effic ficacy Ov Over Tim ime

CONFIDENTIAL NIH 1 R01 HL148210-01 “Novel imaging and treatment technologies for image-guided noninvasive stereotactic cardiac radiosurgery.” (PI: Yang/Gach)

MRI guidance

Targeting End-to-end testing Plan quality / Plan automation

Towards quality and reproducibility

Collaborative Sciences Award (PI: Robinson/ Cuculich)

Clinical Decision Support Tools

CNCR Outreach: Helping Patients Together

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Next Steps: Symposium for Noninvasive Radioablation

Global impact

Caution Clinical trials (avoid hype & bias, choose appropriate endpoints) Accessibility (CNCR) Mutual learning

Key takeaways. . .

Take a picture to be directed to the Center for Noninvasive Cardiac Radioablation

Moving the field forward together:

Center for Noninvasive Cardiac Radioablation (CNCR)

Contact: Kaitlin Moore (314) 273-0830 sites.wustl.edu/cncr/

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Direct tissue effects

• DNA (ds breaks)
• RNA, mitochondria

proteins, lipids

• Damage response

Off- target effects

• Inflammation /

Fibrosis (TGF-B)

• Vascular effects
• “Bystander effect"

Immune

• Local
• Systemic

Seconds to minutes Days to weeks Months to years

Survival Vs. Function Tumor Vs. “Normal”

Intensity of tissue damage:

Dose (higher dose=greater injury) Speed of dose delivered (faster

delivery=more injurious effect)

Size of exposed body (the

bigger part of the body, the more severe injury)

Sensitivity of tissue to radiation

Age, Health status, Genetic differences

• Meta-analysis of 8

cooperative RT studies

• Median 32% rate of

protocol deviations

Ohri et al (JCNI, 2013)

X

1.74

Mortality X

1.79

Recurrence

Quality and reproducibility

• Protocol deviations

associated with ~2x increased risk of treatment failure and

• verall mortality