PROspective Multi-center study to Evaluate the correlation between safety margin and local recurrence after THErmal ablation USing image co-registration in patients with hepatocellular carcinoma (PROMETHEUS-study)

Compared to thermal ablation, the complication rate in surgically treated HCC
patients is much higher with an odds ratio of 8.24 (95% CI: 2.12-31.95). Yet,
surgical resection yields better results regarding local recurrence (HR 0.38
(95% CI: 0.17-0.84)). Therefore, surgical resection remains the treatment of
choice for most patients with BCLC 0/A HCC, despite higher morbidity and
mortality rates. For thermal ablation to become truly competitive with
surgical resection, the issue of local recurrence needs to be addressed.
Ablation systems have predefined algorithms, based on in vitro experiments, to
predict size and shape of the ablation. In general, ablations setting are
chosen that would result in complete tumor ablation with a safety margin of
>5mm, but the actual ablation zone may be smaller than expected and deformed as
a result of factors such as inhomogeneous tissue density, liver cirrhosis and
heat-sink.
After surgical resection, a pathologist examines the resected specimen to
confirm complete resection. After ablation, confirmation of successful ablation
can only be obtained using imaging modalities. Currently there is no validated,
standardized method to accurately determine safety margins. Most commonly, the
interventional radiologist performing the procedure estimates the safety
margins by visual qualitative assessment of pre- and post-ablation
contrast-enhanced CT (CECT). This method is associated with high interobserver
variability and lacks accuracy. There is a need for a method that allows more
accurate assessment of safety margins after ablation.

Over recent years, post-processing software has become available that allows
co-registration of pre- and post-ablation CECT. This allows three-dimensional
quantitative assessment of ablation margins. Such quantification of ablation
margin would allow immediate evaluation of ablation margins and reablation
during the same treatment session if margins are deemed to be insufficient. It
would potentially be the equivalent of the frozen section that is used for
real-time margin control during surgery.
Retrospective studies have demonstrated the potential value of quantitative
assessment of ablation margins after thermal ablation, but this has neither
been validated in prospective studies nor in larger patient groups. In a
prospective, multi-center, non-experimental study in patients undergoing
ablation for BCLC 0/A/B HCC, safety margins will be quantitatively assessed
using dedicated co-registration software.
The aim of this project is to correlate ablation margins with outcome to
determine the relationship between ablation margins and local recurrence and
set the optimal threshold for minimal ablation margin.

Multicentre study in patients with early stage HCC (BCLC 0 / A) undergoing
ablation. All patients receive one
treatment according to the applicable standard of the participating center.
Patients are treated under overall
anesthesia or under deep sedation. During the procedure, a CT is performed both
before and after the ablation. The treating
The doctor determines in a standard manner whether the treatment has been
successful (in most centers a visual estimate is made
made whether the tumor has burned away sufficiently widely). After the
procedure, the scans are sent to the Leiden University
University Medical Center (LUMC). The scans are used to determine the safety
margin for each patient
was achieved with the help of the deLIVERed computer program developed by the
LUMC. Patients will be over time
continued, collecting data on, among other things, the occurrence /
non-occurrence of a local recurrence and survival.
LUMC, Radboud MC, Erasmus MC, Amsterdam MC, UMCU, MUMC +, UMCG and HMC are
participating in the research. It
research is supported by the Dutch Liver Patient Association, the Dutch
hepatocellular Carcinoma Group,
Dutch oncology Research Platform and the Dutch Association for Intervention
Radiology.

This study is considered an intermediate risk trial. Patients may undergo an
additional CT of the upper abdomen (in same centers this is standard of care as
the pre-ablation CT is used for needle placement). The additional CT carries a
low risk of additional radiation and increased dose of contrast medium.
The additional CT will be performed during the ablation procedure with the
patient under general anesthesia or conscious sedation. Besides the additional
CT, patients will receive standard of care. Thermal ablation and follow-up will
be performed according to the standard protocol of the participating center.
We expect that this project will result in a clear understanding of the
correlation between ablation margins and local recurrence. Using
co-registration software, we will then, in future patients, be able to estimate
the risk of local recurrence in patients undergoing ablation for HCC. Immediate
re-ablation may be performed in patients with insufficient margins. The
long-term objective is to reduce local recurrence rates after thermal ablation.