DRAGON 2 - An international multicenter randomized controlled trial to compare combined Portal and Hepatic Vein Embolization (PVE/HVE) with PVE alone in patients with Colorectal Liver Cancer Metastases (CRLM) and a small Future Liver Remnant (FLR).

The current standard treatment for patients at risk of developing PHLF is
performing a PVE prior to the (major) liver resection. In cases where tumors
are located in the FLR, a two-stage hepatectomy may be the best option to
prevent tumor growth due to possible growth stimulus in the FLR after PVE. In
the first stage, tumors in the FLR are removed (the FLR is *cleaned*).
Afterwards, PVE is performed and after 4 weeks, the volume growth of the FLR is
assessed by volumetry. Once the volume of the FLR is sufficient (>30% of total
liver volume, or >40%in case of a chemotherapy damaged liver), a second stage
resection can be scheduled. This technique is well established in many liver
surgery centers.
This protocol proposes to study superiority of combined PVE/HVE over PVE alone
in an international multicenter randomized controlled trial (1:1). The novel
combined PVE/HVE technique has the potential to replace the current standard
PVE. For the reason that PVE/HVE is more efficient, ALPPS will be less of a
treatment option to consider and there will perhaps be no need for two staged
hepatectomies because the time in which potential tumor progression can take
place will be reduced. Participating centers in the DRAGON trials collaborative
who safely performed 3 cases of combined PVE/HVE within a year in the DRAGON
trial 1 or DRAGON registry are eligible for the DRAGON trial 2.

The primary objective of DRAGON 2 is to demonstrate the superiority of combined
PVE/HVE over PVE alone in either the resectability of the patients within 3
weeks after intervention defined as FLR sufficient for resection on week 3 and
the 5-year overall survival.

Secondary Objectives
Secondary objectives of the study are volume and function changes of the FLR,
complications, time to surgery/ waiting time, surgical details (e.g. bloodloss,
operation duration), number of oncological co-interventions, quality of life,
economical evaluation, etc.

An international multicenter randomized controlled trial (approximately 40
centers) in which patients will be randomized (1:1) in center-stratified blocks
into two arms: combined PVE/HVE and PVE alone. In total 348 patients will be
included (n=174 patients per arm)

Combined PVE/HVE is the occlusion of the portal vein branch of one side of the
liver complemented by the embolization of the hepatic veins draining the same
area, to induce hypertrophy on the contralateral side.

In most cases, the embolization of the portal vein branch is achieved by PVE. A
micro-puncture set either from the side that will be embolized or from the
contralateral side (both techniques are used by interventional radiologists).
PVE is a standard interventional radiology technique that is performed in most
medical centers. Technical modifications are common between centers, but in
this trial, PVE involves filling the portal vein system with glue consisting of
a mixture of iodized oil (Lipiodol), cyanoacrylate and sometimes additional
particles like coils or plugs can be placed centrally. We advise, if possible,
to always embolize segment 4 during the PVE procedures. After the procedure,
the access sheath is pulled back and the track occluded. The used technique is
recorded, and the report with blacked identifiers is uploaded onto the
electronic case report form (CRF). In the Work Instruction *PVE and PVE/HVE
procedure* the PVE procedure is explained in more detail.

Subsequently, HVE is performed in the same session. Only in exceptional cases a
staged procedure with up to 48 hours between PVE and HVE is accepted, but the
reason must be filled out in the CRF. In HVE the right or left hepatic vein is
accessed through a trans jugular approach. Through a sheath, an appropriately
sized Amplatzer Vascular Plug device is introduced into the hepatic vein.
Injection of contrast is then used to confirm placement of the vascular plug.
Additional embolization of small vessels with glue is not allowed in the DRAGON
2 trial. If applicable the middle hepatic vein is plugged as well. The HVE
procedure is displayed in more detail in the WI *PVE an PVE/HVE*.

The decision on how many hepatic veins should be embolized is also left to the
judgement of the local principal investigators, since it depends on the
individual anatomy of the liver. We do advise to plug as much separate vein
branches as possible. If required, cases can always be discussed upfront within
the DRAGON trial study collaborative.

Based on the currently available literature, the performance of PVE/HVE is
completely safe with no complications occurring more frequently compared to the
gold standard PVE. Theoretically, because of the HVE in PVE/HVE, there is a
risk of local bleeding (at the puncture site in the neck or groin),
inflammation or plug migration into the hepatic vein, however, this has not yet
been described in the literature and we have never seen this either.
The PVE/HVE procedure takes twice as long as the PVE procedure. Radiation is
used during the procedures. Compared to PVE, the radiation exposure by PVE/HVE
is twice as high (32mSv compared to 16 mSv). However, this has been approved by
the radiation protection committee of the MUMC+.

With regard to the burden:
The regular care is followed in this trial, however, in the first year the
patient is asked to fill out 5x a quality of life form.


Benefits of the interventional proccedure (PVE/HVE) could be more and faster
Futurel Liver Remnant hypertrophy, which could lead to a higher resection rate
in this arm. this could also improve the oncological outcomes in these
patients.