Mapping guided Stereotactic ablative Radiotherapy, Hybrid treatment for uncontrollable ventricular tachycardia

1.1 Ventricular tachycardia as an emerging clinical problem

Ventricular tachycardias (VT) are a medical emergency and require immediate
termination. VT typically occur in patients with a myocardial scar from
myocardial infarction or from non-ischemic cardiomyopathies. In patients with a
high risk for VT or who have survived a life-threatening VT an implantable
cardioverter defibrillator (ICD) device is recommended. The availability of
ICDs has resulted in a marked change in the survival of patients with VT.
Patients who formerly would have suffered sudden cardiac death now survive to
experience recurrent VT and ICD shocks. Within one year after implantation,
approximately 40% of patients will receive appropriate ICD therapy1, 2. This,
together with increasing utilization of ICDs (in the Netherlands >30000 ICD
recipients + approximately 4000 new implants/year) has resulted in an
increasing frequency of patients presenting with recurrent ICD shocks, and the
likelihood of a growing problem3. ICD therapy is considered as an adverse
event!
Although ICD therapy can be lifesaving it does not prevent VT. Patients with
very frequent VT are subject to increased risk of recurrent ICD shocks,
progressive heart failure and death4, 5.
Repeated VT and ICD shocks, as most frightening cardiac arrhythmia
presentation, result in (1) frequent re-admission to CCU and IC, (2)
psychological morbidity (PTSS)2, (3) loss of consciousness with the risk of
severe injury before VT is terminated by the device and most important (4)
progression of heart failure and increased mortality6. These adverse events
have dramatical consequences for the patient and the family in addition to the
impact on the costs of the health care system.
There are clinical VT presentations, which are associated with particularly
high morbidity and a high risk of (sudden) cardiac death despite the ICD
therapy7.
(1) Electrical storms (defined as >=3 ICD shocks within 24h), (2) VTs causing
recurrent (pre)syncope despite effective termination by ATP or ICD shocks, (3)
recurrent VT (high VT burden) leading to progressive heart failure or (4)
symptomatic, incessant VT not detected by the device or reinitiating after ICD
therapy. In particular, arrhythmia presentation 3 and 4 may preclude patients
with heart failure from LVAD implantation as destination therapy, as the right
ventricle is not supported by the assist device.
Despite escalated antiarrhythmic drug (AAD) therapy and advanced catheter
ablation technology, up to 50% of patients will experience recurrent VT8. New
drugs are not available and current catheter technologies have important and
well-recognized limitations in particular to reach deep intramural
arrhythmogenic substrates or areas protected by insulated fat or
calcification9-13. Despite the availability of state-of the art technology and
highly experienced operators in tertiary referral centers catheter ablation
acutely fails to eliminate the electrical storm causing VTs in 9-12% of the
patients7. Procedural failure has important prognostic implications during
short-term follow-up: sudden death occurs in up to 40% within 3 months despite
the ICD, and electrical storm, recurs in almost all7.
For these patients* therapeutic options to eliminate the VT sources
inaccessible by current catheter technologies are urgently needed.

1.2 Novel treatment option for no-option-patients

Non-invasive cardiac radiation, applying a single-fraction stereotactic body
radiotherapy (SBRT) has been recently reported as a very promising treatment
modality to abolish the source of VTs in patients with structural heart disease
and drug- and ablation refractory VT. In 3 series from two centers, including a
total of 31 patients, the VT burden could be significantly reduced in the
majority of patients with a reasonable safety profile. There was one grade 3
(pericarditis), probably related acute toxicity mentioned in the ENCORE-VT
trial, others did not found any acute toxicity 14-16.
The immediate and most important advantage of SBRT is the applicability to
reach VT substrates not accessible by any current catheter technologies. This
should therefore not be withheld in patients who have today no other
therapeutic option.

1.3 The importance of the accuracy and precision of radiotherapy for VT and
limitations of prior studies

Despite encouraging first results a significant number of treated patients
still had VT recurrence and 16% of these critically ill patients died with
recurrent VT in the setting of a worsening overall cardiac status15. It is
unclear if there is a lack of durable effect of radiation therapy or if the
applied technology is inaccurate. Worsening of the cardiac status can be due to
disease progression or late collateral damage to adjacent viable myocardium.
The method has great potential but a better understanding of the biological
effects is important and accuracy and precision need to be improved.

The major advantage of SBRT, in general, is to noninvasive target a
well-defined and demarcated volume of tissue minimizing collateral damage. For
efficacy and safety of stereotactic arrhythmia radio ablation (STAR) (1)
accurate definition of the part of the scar proven to participate in
arrhythmogenicity (accuracy of the method = correct identification, delineation
and registration of the source/substrate of VT referred to as target volume),
together with (2) optimal tracking of the radiation beam to follow the moving
target volume during the respiratory and cardiac cycle (precision of the
method), is mandatory.

The published methods to determine the target volume rely on
electrocardiographic imaging (ECGi) which uses multiple body surface
electrograms to project epicardial depolarization onto the CT derived surface
of the ventricles14, 15.
Noninvasive electrocardiographic mapping in conjunction with cardiac imaging to
identify the arrhythmogenic substrate has important limitations:
(1) It can only identify epicardial exits sites during VT of those VTs that are
inducible during non-invasive stimulation. However, in up to 35% of patients
VTs are not inducible at all and if a VT is induced, the majority of these
VT*s, are not clinically relevant or relevant at all17. (2) Recent
intraoperative simultaneous endo and epicardial mapping studies during VT in
post-MI patients could demonstrate that the epicardial exit site during VT and
the critical part of the scar, responsible to sustain VT are spatially distant
(mean distance 3.4cm) and discrepant18. The method is highly inaccurate for
septal, endocardial and intramural VT substrates and has a poor precision even
for epicardial VT sources (median distance from the VT source 3.3cm! (IQR 2.2
-4.6cm))19.

1.4 The rationale for the LUMC

1.4.1 Patient population
The department of cardiology, LUMC, is a national and international tertiary
referral centre for ablation of complex VT in structural heart disease. The
LUMC VT program is the largest in the Netherlands and among the 5 largest in
Europe. As last resort institute we are confronted (in contrast to other
institutes) with a high number of patients who have currently no other
treatment option to control VT. There is a need to apply and further develop
new technologies to reduce VT related morbidity and mortality in a growing
patient population.

1.4.2 Technical requirements
The current limitations of accurate substrate delineation and target volume
determination can be solved by combining current gold standards of catheter
mapping and ablation of scar related VT as a hybrid procedure to accurately
determine and potentially restrict the volume of interest to the area not
accessible by RFCA. As RFCA is the recommended treatment modality in the
described scenarios 1-4 this data is available from the clinically indicated
procedure.
Accurate delineation of a well-defined target volume and highly focused
radiation therapy allows to better determine and to improve the efficacy of the
novel treatment. We have developed a method of real-time registration of
electro anatomical mapping data (gold-standard to identify the VT source) and
cardiac imaging (CT and CE-CMR) and we are able to accurately define, delineate
and register the VT substrate, with a registration error of <0.3cm!12, 20, 21
The required knowledge and technologies to apply STAR with already higher
accuracy than previously described are available in the LUMC and we have
successfully treated the first two *no-option* patients in Leiden (April and
June, 2019).

1.5 Unsolved questions

1.5.1 The acute and long-term biological effects and the time-to-effect (acute
and long-term efficacy) are poorly understood.
The exact underlying mechanisms of the time-dependent effects of radiotherapy
on the VT substrate are unknown. Reported time-to-effect was highly variable
(from acute effects to weeks to months).
In many patients* immediate effects (within the blanking period) have been
described with no reported ICD shocks after one month following the
radiation15. Since scar formation/fibrosis due to radiotherapy normally takes
months/years, one hypothesis is that acute inflammatory responses may
contribute to the beneficial effect of radiotherapy on the VT substrate. To
evaluate the exact time-to-effect is very important. Acute effects would allow
the treatment of patients with arrhythmias only controllable in a clinical
setting (requiring i.v. drugs/ hemodynamic support). The exact mechanism and
type of tissue destruction is yet not clear. Based on limited animal studies
some biological effects require a longer period (gradual apoptosis, vascular
injury and fibrotic remodeling)22. The optimal effect in patients with
scar-related VT would be scar homogenization. However, if this can be achieved
and will be durable is unknown.


1.6 Summary of Rationale

There is an urgent need to demonstrate the clinical efficacy and safety of a
single dose stereotactic radiotherapy of an accurately determined substrate for
ventricular tachycardia, inaccessible by the current state of the art catheter
ablation techniques in the LUMC for several reasons:
(1) The number of patients who present with VT and without any other treatment
option to control these VTs is increasing.
(2) For these patients* therapeutic options to eliminate the VT sources
inaccessible by current catheter technologies are urgently and acutely needed.
(3) SBRT is an existing treatment modality which has the potential to reach VT
substrates not accessible by any current catheter technologies. The acute
toxicity is very low. The therapy should therefore not be withheld in patients
who have today no other therapeutic option.
(4) The knowledge and the technology required to apply SBRT with high accuracy
and precision is already available and can be further improved.
(5) The risk profile is low as these patients have a limited life expectancy
due to the underlying disease and co-morbidities and are unlikely to experience
potential late cardiac toxicity.
(6) The clinical efficacy in *no-option* patients and the time to effect needs
to be evaluated for optimal patient selection

Primary objective:
To evaluate the clinical efficacy and side effects (adverse events) of a single
dose stereotactic radiotherapy on the electro-anatomical arrhythmia substrate,
inaccessible by the current state of the art catheter ablation techniques, in
highly symptomatic patients with drug-refractory ventricular tachycardia.

Secondary objective:
To evaluate the efficacy and the time-to-effect of a single dose stereotactic
radiotherapy to control clinical VTs and to modify the electro-anatomical
arrhythmia substrate.
To evaluate formation and duration of an inflammatory response after a single
high dose radiation on the VT-substrate

The study is a single centre (Phase IIA) pre-post intervention, single arm (12
patients) pilot study using routinely acquired data of real-time integration of
electro-anatomical mapping data with cardiac imaging (including cardiac CT) to
determine the part of the VT substrate (target volume) inaccessible by catheter
ablation in highly symptomatic patients without any remaining established
treatment option. The identified volume will be targeted by precise
stereotactic radiotherapy. The study is designed to define the efficacy and
safety of this novel treatment option using mapping guided radiation and to
determine the time-to-effect and efficacy to abolish the delineated VT
substrate based on state of the art electro-anatomical mapping techniques with
real-time image integration.

According to our standard clinical protocol for mapping and ablation of complex
scar related VTs, (contrast) echo (right and left ventricular function,
valvular disease, intracardiac thrombus), CE-MRI and/or CT and coronary
angiogram if considered appropriate, is routinely performed prior to ablation,
followed by real-time image integration with electro-anatomical mapping data
during the clinically indicated procedure. Accordingly, determination of the
arrhythmogenic substrate, inaccessible by catheter ablation, which can be
post-procedurally extracted from the 3D mapping system is clinical standard and
not part of a study protocol.

The patient study duration will start after informed consent for STAR as a
bail-out strategy.
Additional assessment of safety endpoints includes a pulmonary function test.
Subsequently, patients will undergo a contrast enhanced 4D-CT-scan for
radiation treatment planning purposes. The radiation oncologist and the
cardiologist-electrophysiologist will in close cooperation delineate the target
area for treatment. After radiotherapy planning, the radiotherapy treatment
will be performed. After the treatment with radiotherapy patients will be
monitored for at least 24 hours. Afterwards the patient undergoes follow-up for
the primary and secondary efficacy and safety endpoints. Follow up will be
scheduled at 2, 4 and 12 weeks and at 3-months intervals thereafter. The
evaluation will include history, clinical examination, ECG and ICD
interrogation. For safety endpoints blood samples, transthoracic echo (at 3, 6
and 12 months) and a pulmonary function test (at 3 and 12 months) will be
performed. For evaluation of presence and duration of an inflammatory response
F18-FDG-PET/CT will be performed at 2 weeks and 6 months. For efficacy and time
to effect evaluation patients will be readmitted (one-to-two day admission) at
6 months for PES and endocardial electro-anatomical remapping of the target
area.

The endpoints are finalized at one year. Follow up will continue as a standard
of care thereafter which includes a minimum ICD interrogation every 6 months
and yearly clinical evaluation.

Patients are treated with a single radiotherapy fraction of 25 Gy targeting
specifically the part of the identified VT substrate, which was not accessible
by the current state of the art catheter ablation techniques (all maneuvers
that are known to enhance lesion depth). Substrate identification is performed
using the current state of the art techniques including real-time integration
of electro-anatomical mapping data with cardiac imaging, including cardiac CT.
This technique allows precise determination of the radiation volume by
extracting mapping data together with the anatomical location on CT which can
be used for the radiation planning

Possible disadvantages of participating in this study could be:
- The possible adverse effects that are related to the new treatment in both
the short and the long term (after 10-15 years)
- Possible inconveniences of the measurements
- Unexpected findings that may be detected in the additional investigations.
- Time investment
- Patient will undergo additional examinations
- Patient will be admitted for at least 24 hours.