CROSSFIRE trial: Crossatlantic Randomized controlled trial comparing Outcome in Survival after Systemic plus Focal therapy for Inoperable pancreatic carcinoma: Radiotherapy versus irreversible Electroporation

Pancreatic adenocarcinoma is one of the most aggressive forms of cancer, for
which survival hardly improved over the past 40 years. It is the 4th leading
cause of cancer-related death in Europe and the United States. Pancreatic
cancer has the highest mortality rate of all major cancers; 94% of pancreatic
cancer patients will die within five years of diagnosis, 74% within the first
year of diagnosis; only 6% will survive for more than five years. Surgical
resection is the only curative option. However, about 40% present with
non-metastatic locally advanced pancreatic carcinoma (LAPC; AJCC stage III).
These patients are not eligible for surgical resection because the tumor
involves major blood vessels such as the superior mesenteric artery, celiac
axis, common hepatic artery and/or portal vein. These patients are currently
treated with palliative chemotherapy as first line therapy. Focal therapy using
external beam radiation therapy (EBRT) may further improve survival, but
outcome remains poor. Stereotactic ablative radiotherapy (SABR) is a form of
EBRT that has important advantages over conventional radiotherapy such as a
more precise and greater biological dose delivery and hence less toxicity and
presumably better outcome.
For patients diagnosed with LAPC, a combination of chemotherapy plus local
tumor destruction using irreversible electroporation (IRE), a novel tumor
ablation technique, has recently shown great promise. IRE is based on
permeabilization of the cell membrane through electrical pulses leading to
apoptosis. Theoretically, IRE only affects viable tumor tissue, leaving
surrounding vital structures relatively intact. It is therefore considered to
cause less morbidity than thermal ablative strategies. Several studies have
investigated the safety and efficacy of IRE for LAPC. However, up until now no
randomized controlled trial has been conducted.
Although for now the primary aim remains macroscopically complete tumor
destruction, preliminary data, obtained at the VUmc immuno-oncology research
institute in Amsterdam, suggests the induction of a T-cell mediated systemic
immune response. This may represent a so-called *abscopal effect*, referring to
the phenomenon where localized treatment of the primary tumor induces a
forceful immune response, targeting occult distant micrometastases which could
have an additional positive effect on recurrence-free and overall survival.

The objective of this study is to compare the efficacy of chemotherapy and IRE
(experimental arm) to the efficacy of chemotherapy and radiation (control arm)
in patients with locally advanced, non-resectable, non-metastasized, pancreatic
cancer.

Amsterdam UMC, location VU University Medical Center and location AMC
(Amsterdam, the Netherlands), Radboud University Medical Center (Nijmegen, The
Netherlands) and the Miami Miller School of Medicine (Miami, Florida, USA) will
participate in this phase II/III study to define the efficacy of systemic
chemotherapy followed by IRE versus systemic chemotherapy followed by SABR. All
patients with radiologically and histopathologically proven LAPC <5 cm in
largest diameter will be discussed at the weekly multidisciplinary meeting. If
they meet the inclusion criteria and formally consent, they will be randomized
into one of the two arms. Patients in both arms will receive 4 cycles of
FOLFIRINOX followed by either percutaneous CT-guided IRE (experimental arm, n =
69) or SABR (control arm, n = 69). After patient recovery (>6 weeks post-
procedure), FOLFIRINOX will be continued. To examine the immunologic response
before and after SABR and IRE, venous blood sampling will be performed.

AMENDMENT (14-05-2020):
The CROSSFIRE-study is a single center, randomised, prospective phase II/III
efficacy study. Participating hospital is the Amsterdam UMC, location VUmc.

Irreversible electroporation (IRE) is a novel image-guided tumor ablation
technique in which the mechanism of cell destruction is primarily based on a
non-thermal effect. The application of multiple short high-voltage electrical
pulses leads to the formation of microscopic perforations of the cellular
membrane of 100-150 nanometer. As a result, the cells lose their homeostatic
capabilities and will go into the process of apoptosis. The * mostly theoretic
- advantage over other local ablative techniques is that IRE selectively
destroys all cells within the ablation zone, whilst the extracellular matrix
structures remains intact. As a result, the anatomical framework to which
vulnerable structures such as bile ducts, blood vessels, ureters and nerves
derive their strength, is presumed to remain intact during IRE. For this
reason, tumors in the proximity of these critical structures can be ablated
safely. Although long-term follow-up results are still unknown, the future of
IRE for the minimally-invasive destruction of difficult-to-reach tumors, seems
promising.

A recent advancement in radiation therapy is SABR delivering higher doses of
radiation per treatment fraction more precisely to the tumor. Visualization of
the pancreatic tumour and its surrounding normal organs prior to and during
radiation delivery can be used to deliver *gated* treatment (beam-on only when
the tumour is in the predetermined position) using small uncertainty margins
and thereby limiting the dose delivered to normal organs, likely resulting in
decreased toxicity. Disadvantages for patients include the need to be
positioned within the MRI bore during radiation delivery, and a prolonged time
per treatment fraction (estimated at 30-60 minutes per fraction), which has to
be weighed against the use of a total of only five fractions.
Several studies have investigated the safety and efficacy of open and
percutaneous IRE for locally advanced disease, with an overall complication
rate of 10-37% and an overall survival time from IRE ranging from 16.0 to 24.9
months. One trial compared the results to a matched group of patients treated
with chemoradiation alone which showed a potential survival benefit of 9 months
in favor of the IRE group. Clinically relevant complications are expected in up
to 17% of procedures with a 1-2% mortality rate.