Perivascular and peribiliary colorectal liver metastases (0-5 cm): irreversible electroporation versus stereotactic body radiotherapy.

Colorectal carcinoma is one of the most common malignancies in the Western
world, where 40-60% of the patients develop liver metastases in the course of
the disease. Surgical resection is still the treatment of choice, but
unfortunately up to 70% of the patients are not eligible for resection.
Selected patients are offered other local treatment modalities like
radiofrequency ablation (RFA) and microwave ablation (MWA). The suitability of
these modalities can be limited for perivascular and peribiliary colorectal
liver metastases (CRLM), when used in close vicinity to these tubular
structures. The heat can damage the bile ducts and vessels, leading to biliary
and vascular complications. Also, when used in the vicinity of large vessels it
can lead to inadequate tumor destruction due to a *heat-sink* effect (where
blood flow in adjacent large vessels carries away the heat, thereby causing an
inadequate temperature rise, leaving vital tumor cells in situ), which causes a
higher percentage of local recurrences. Similarly, thermal ablation is
contra-indicated for unresectable CRLM in close vicinity to other thermally
sensitive structures such as the bowel (e.g. due to adhesions). Therefore, the
search for new local treatment therapies is ongoing.

Irreversible electroporation (IRE) is an ablation technique that takes
advantage of the electric potential gradient that exists across cell membranes.
The application of a pulsating electric field across the cells alters the
transmembrane potential. By reaching a sufficiently high voltage, the
phospholipid bilayer structure of the cell membranes is permanently
permeabilized, causing intracellular homeostasis to be disrupted, and inducing
apoptosis. Recent findings resulting from animal studies using IRE on healthy
(liver) tissue show a sharply demarcated treatment area, with preservation of
the - acellular - connective tissue architecture and major blood vessels in the
ablated area. This contrasts with thermal ablation techniques, where
denaturation of proteins causes disruption of the connective tissue, destroying
the anatomical framework. Electroporation leaves supporting tissue largely
unaffected so the structural integrity of the walls of large blood vessels and
bile ducts and bowel wall is preserved. IRE relies on electrical energy, not
thermal energy, for achievement of cell death and appears to be unaffected by
heat-sink. This suggests a potentially more effective treatment of an area with
tumor cells near large vessels, such as centrally located liver lesions.

With these distinctive characteristics, IRE has the potential to become a
successful ablation method for solid tumors in areas around large blood vessels
and bile ducts, such as centrally located colorectal liver metastases (CRLM),
other secondary liver tumors or early-stage hepatocellular carcinoma (HCC) that
are not amenable for surgical resection or thermal ablation due to the
anatomical location. Clinical trials investigating the safety of IRE in
different organs have shown a safe use of this method, including the
prospective VUmc pilot-study of IRE in the liver (COLDFIRE-I) and phase II
trial (COLDFIRE-II).

Stereotactic body radiotherapy (SBRT) is gaining interest as another potential
ablative technique to treat CRLM. Especially for solitary or a limited number
of CRLM the potential to induce long-term local tumor control has been
established with acceptable toxicity. Major complications that involve damage
to blood vessels and bile ducts seem to occur only infrequently. Furthermore,
the effectiveness of SBRT is, in contrast to RFA or MWA, not impaired by the
blood flow in the vessels or the bile accumulated in the gallbladder. However,
solely looking at primary local control rates following an ablative procedure
seems unjust when comparing an easily repeatable technique with a one-shot
treatment method (SBRT).

As the gold standard for perivascular and peribiliary CRLM (0-5 cm) is
currently undetermined, we have designed a two-arm phase-IIb/III randomized
trial comparing IRE to SBRT for perivascular and peribiliary CRLM (0-5 cm).

The primary objective of this study is to compare efficacy of IRE to the
efficacy of SBRT regarding the primary endpoint (local control at 2 years) in
patients with perivascular and peribiliary CRLM (0-5 cm). The CRLM are
unsuitable for surgery and thermal ablation due to either comorbidities, a
history of extensive abdominal surgery, a poor performance status or due to an
unfavorable perivascular of peribiliary location of the tumor.

COLDFIRE III is a prospective single-center phase-IIb/III randomized trial. The
primary conducting center will be the Amsterdam UMC, location VUmc.

Patients will be randomized into one of two arms, arm A (IRE) and arm B (SBRT).
The expert panel, consisting of at least two interventional radiologists, two
radiation oncologists and two hepatobiliary surgeons, will appoint lesions that
are ineligible for surgery of thermal ablation, and suitable for both IRE and
SBRT, as target lesions.

Over the last decades, technical developments in SBRT have allowed a more
precise delivery of high radiation doses per treatment fraction to the tumor.
Furthermore, in some hospitals it is possible to visualize the tumor during
radiation treatment to deliver gated treatment (beam-on only when the tumor is
in the predetermined position) using small uncertainty margins and thereby
limiting the dose delivered to surrounding healthy tissue, likely resulting in
decreased toxicity. Disadvantages include the need to be positioned within a
MRI bore during radiation delivery, and a prolonged time per treatment
fraction. Local tumor control of SBRT for liver malignancies ranges between
50-95% after one year. A recent systematic review showed a one-year local
control rate of 67% and a two-year local control rate of 59.3%; however, this
systematic review also included older studies and in the last few years SBRT
techniques have substantially improved. Grade I-II toxicity occurred in 23-78%
of patients receiving SBRT, grade III toxicity or higher only occurred in 0-10%
of patients.
IRE is a non-thermal ablation modality based on delivering pulsed electrical
fields, created between needle electrodes placed in and around the tumor, that
alter the existing cellular transmembrane which eventually results in cell
death. IRE has the potential to become a successful alternative ablation method
for solid tumors, especially in areas around large blood vessels and vulnerable
structures, such as centrally located CRLM. Prospective trials using IRE for
malignancies in the liver show 1-year local tumor control of 74%, and a 1-year
local recurrence free survival of 59,5%. Preclinical as well as clinical
studies show a low complication profile in comparison to other local treatment
modalities in these specific locations in the liver, with an overall
complication rate of 40%. Because of the high voltage used with IRE, the
procedure carries a small risk of inducing cardiac arrhythmias, although with
the Accusync ECG gating device, which enables synchronized pulsing, no
clinically significant arrhythmias have been observed within the registry.
Because of the primarily non-thermal treatment effect IRE causes little damage
to adjacent or inlaying vital structures. The NanoKnife IRE system is CE marked
and FDA approved for image-guided ablation of soft tissue in humans.
By participating in the study, patients agree to undergo either IRE or SBRT.
For each participant, the method of treatment will be decided upon by
randomization. Pre-treatment screening will not be different from the standard
screening for these techniques and will not be an extra burden. Both IRE and
SBRT are considered safe and established treatment options for the target
population.