Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04107324 |
| Other study ID # |
ARAPS |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2020 |
| Est. completion date |
May 1, 2023 |
Study information
| Verified date |
November 2020 |
| Source |
University of Aarhus |
| Contact |
Anders Knudsen, PhD |
| Phone |
004530595123 |
| Email |
andeknud[@]rm.dk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Liver resection is the golden standard in the treatment of hepatic malignancies. The size and
function of the remnant liver is a major concern. If the future liver remnant (FLR) is below
30 % of the initial liver volume, the risk of post hepatectomy liver insufficiency rises.
Several techniques have been developed to increase the size of FLR before liver resection. In
this study a new technique ARAPS (portal vein embolization with radio frequency ablation) is
compared to portal vein embolization alone for accelerated liver growth in the FLR. This is
done in a randomized controlled trial.
Description:
Curative intent liver resection is the gold standard for treatment of hepatic malignancies,
including metastases from colorectal cancer (CRLM), but liver resection can only be performed
if future liver remnant (FLR) volume is at least 25 %. Unfortunately, many cancer patients
have multiple liver lesions at the time of diagnosis, rendering radical resection impossible
due to a marginal FLR, thereby increasing the risk of posthepatectomy liver failure and
subsequent death.
Several techniques have been designed to increase the size of the FLR, allowing more patients
to undergo surgery. These techniques include portal vein embolization (PVE), portal vein
ligation (PVL), two-stage partial hepatectomy, and the associating liver partition with PVL
for staged hepatectomy (ALPPS). The ALPPS procedure seems to be superior to the other
techniques for achieving increased size and accelerated growth of the FLR. Especially the
kinetic growth rate (KGR) is superior to what has been previously described. The major
drawback of ALPPS is, however, that the patient is subjected to two open procedures that are
associated with high morbidity and mortality.
In a previous experimental study on rats, The investigators have shown that PVE combined with
radiofrequency ablation (RFA), hereafter called Associated Radiofrequency Ablation and Portal
Vein Ligation for Staged Hepatectomy (ARAPS), can induce accelerated growth of the FLR as
potent as that seen after ALPPS. In humans, the ARAPS procedure can (the first step), in
contrast to the two-stage ALPPS procedure, be performed percutaneously, and the investigators
expect this to reduce the high morbidity and mortality associated with the ALPPS. In the
present study, the investigators want to examine the effect of ARAPS compared with PVE alone
on liver regeneration and function of the FLR.
Study rationale In order to allow more patients to undergo radical surgery for CRLM,
implementation of new methods to enhance liver regeneration is vital.
Aim In the present study, the investigators test the hypothesis that the ARAPS approach is
superior to PVE alone in achieving growth of the FLR in patients with CRLM.
Hypothesis the investigators expect to see higher growth of the FLR in the ARAPS arm compared
with the PVE arm one week after intervention.
Study design The study is an investigator-initiated prospective, randomized study. Any
patient eligible for this study will be offered enrollment. Patients enrolled in the study
will be randomized (1:1) to either the intervention (ARAPS) or control (PVE) as
Recruitment of study subjects Potential study subjects will be given the option to
participate after the study is presented during their first visit to the outpatient clinic.
The visit will take place in a consultation room, where the surgeon will provide verbal and
written information regarding the study prior to enrollment. Patients are allowed a companion
for this interview. At least 24 hours are given before an informed consent is obtained.
Patient consent can be withdrawn at any time, and all data collected for the project, will be
destroyed without any consequence for their subsequent treatment.
Data analysis plan Power calculations Total liver volume is ~1500 mL. Assuming that FLR is 20
% of the total liver volume, FLR comprises 300 mL. Based on previous literature, the
investigators expect a growth in the FLR of 10 % (30 mL, KGR ≈ 4.3 ml/day) in the PVE arm and
50 % (150 mL, KGR ≈ 21.4 ml/day) in the ARAPS arm. At alpha=0.05, power 80 %, and a standard
deviation of 200 mL, 12 patients in each arm is needed to show a statistically significant
difference between the two interventions. In order to be able to deal with potential dropout
of up to 20%, the investigators aim to include 15 patients in each arm; 30 patients in total.
Statistical methods Liver regeneration will be measured as the increase in anatomical (CT)
and functional (PET) liver volume seven and thirteen days following intervention (quantified
in milliliters). Further, the KGR will be calculated as volume increase per day (ml/day).
Differences in the two arms will be expressed as means or medians with associated standard
deviations or interquartile ranges (depending on the distribution of data). Differences
between the two arms will be analyzed using a t-test or non-parametric test where
appropriate. P<0.05 will be considered statistically significant.
Data on patients Data on age, diagnosis, comorbidity, and tumor imaging material will be
passed on from the medical records in order to assess if the patient is eligible for
inclusion in the study. Information on sex, tumor size, tumor histology, number and size of
metastases, medications, tobacco/alcohol exposure, and blood sample results will be retrieved
on from the patient's medical records. Radiological, biochemical, and pathological reports
will also be retrieved for use in the statistical analyses.
Study procedures Intervention Portal vein embolization The standard-of-care procedure, which
would be offered to the patients regardless of this study, is PVE. PVE will be used to
redirect portal flow to segments of the FLR: The portal venous system is assessed through the
tumor-bearing part of the liver (i.e. the part that is later going to be removed). The portal
vein is assessed under guidance by ultrasonography, and a catheter is then advanced under
fluoroscopic guidance for subsequent embolization. In the case of a planned extended right
hepatectomy, the portal branches to segment 4 should be selectively embolized. As
embolization material plugs are preferred.
Radio-frequency ablation Under guidance of ultrasonography a single-electrode RFA-needle is
placed in the part of the liver that has just been deportalized. The needle is placed in
normal parenchyma, and within a period of ten minutes a necrosis of approx. 3 cm is created.
In literature, complication rates following RFA treatment are low, making it a feasible
procedure.
Both treatments will be performed in general anesthesia. Patients will be equipped with two
bandages, which they have to wear until after the second PET/CT scan in order to blind them
to the treatment received.
PET/CT scanning Accurate liver volume estimation relies on precise segmentation of the liver
by multi-phase CT images according to the Couinaud classification. A thicknesses of ≥ 1 mm
will be used to ensure accurate results. Total liver volume, volume of the deportalized part
of the liver, and volume of the FLR will be estimated before and after intervention. Positron
emission tomography (PET) with the radioactively labelled galactose analogue
2-[18F]fluoro-2-deoxy-D-galactose (FDGal) can be used to quantify whole-liver and regional
hepatic metabolic function as well as to measure functional liver volume. The method is
validated, simple and with insignificant day-to-day variation. The PET scan is performed
after a 4h fast, but the patient is allowed to drink water. In Aarhus, the scanner is a
64-slice Siemens Biograph TruePoint PET/CT camera (Siemens AG, Erlangen, Germany). FDGal (100
MBq) is injected intravenously and a low-dose CT scan (50 effective mAs with CAREDose4D, 120
kV, pitch 0.8, slice thickness 5 mm) is performed for attenuation correction of the PET data
and anatomical co-registration. A static PET scan of the mean tissue radioactivity
concentration is performed from 10-20 minutes after tracer injection (12). The PET data are
corrected for radioactive decay back to injection time and reconstructed with resolution
modeling (4 iterations, 21 subsets and 2 mm (18F-FDGal) or 3 mm (18F-FDG) Gaussian filter)
and 336 x 336 matrix. The standardized uptake value (SUV; unit-less) is calculated dividing
tissue radioactivity concentration (kBq/mL tissue) with the ratio between injected dose (kBq)
and body weight (mL tissue, assuming an average tissue density of 1 g/mL tissue). Whole-liver
and regional hepatic FDGal-SUVs as well as the functional liver volume are estimated.
Potential benefits, risks, and side-effects Potential benefits As the potential impact of
this study is extensive, including the possibility for more patients with CRLM to undergo
curative-intent resection, it is our opinion that the benefits by far outweigh the few
potential side effects. Only two PET and two CT scans with minimal radiation will be
conducted. The blood samples drawn is part of the standard work-up procedure. No additional
blood samples will be drawn on the basis of participation in this study.
Radiation dose from PET/CT scans Patients participating in the present study are not
sustained to more radiation from imaging modalities than patients not participating. From the
low-dose CT-scans, the patient receives an irradiation dose of up to 1 mSv. For FDGal the
effective radiation dose is 0.032 mSv/MBq, the administration of 100 MBq FDGal thus gives a
dose of 3.2 mSv. The total irradiation dose that each patient receives from two PET and two
CT scans is approximately 8.4 mSv which equals three times the average yearly background dose
in Denmark. This presents an estimated risk of 1:10.000 for cancer development due to
participation in the study. These doses should be seen in connection with the potential
benefit for the patient in participating in the study, as mentioned above.
Interventions Potential risks related to the RFA treatment are extremely sparse, and include
bleeding, hepatic abscesses, hepatic infarcts, and bile duct injuries. PVE is a safe
procedure that causes few adverse effects and can be performed in an outpatient setting. Most
large series report 0 % procedure related mortality. Risks include bleeding, infection and
displacement of the embolization material. Especially the latest is extremely rare.
Further patient treatment Following calculation of KGR and increase in FLR, patients are
re-evaluated with regard to the timing of the second-stage partial hepatectomy. Some
patients, especially in the PVE arm, are expected to need further liver hypertrophy before
advancing to the partial hepatectomy. Further hypertrophy in a period of 1-3 weeks and a new
CT evaluation might be necessary. In some patients, the hypertrophy might be impaired or
absent. These patients will be evaluated with regard to other treatment options including
salvage ALPPS, which have previously been used in patients with impaired hypertrophy
following PVE. The resection rate in each arm will be reported as a secondary endpoint.
Time schedule This study will commence on 1. November 2019. Total study duration is expected
to be 24 months for subject recruitment, and an additional six months for data analysis. The
investigators expect to finalize the data analysis and present our findings during 2021. The
project will begin at Aarhus University Hospital, while the other participating centers will
be enrolled as appropriate.
Publications Both positive, negative, and inconclusive results will be published, and
presented at scientific meetings. Results will be presented at international scientific
congresses, and the investigators will aim for publications in high-impact journals with
focus on oncology, radiology, and liver surgery. The study will be registered at
www.clinicaltrials.gov.
Financial aspects This study is investigator-initiated, and supported by several Danish
foundations (Vissing Fonden [322.000 DKK (Danish Kroner)], Knud & Edith Eriksens Mindefond
[50.000 DKK], Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis' Legat [148.000 DKK],
Familien Erichsens Mindefond [98.000 DKK], Tømmerhandler Vilhelm Bangs Fond [98.000 DKK],
Riisfort Fonden [198.000 DKK], and Neye Fonden [98.000 DKK]). Grants from these foundations
are given to the principal investigator Prof. Frank Viborg Mortensen, and are administered by
Aarhus University Hospital. The grants support running costs related to the project (CT/PET
scans, blood samples, RFA needles, etc). The researchers participating in this study are
independent from any financial interests. No fee will be paid to the study subjects. Salaries
for the scientific staff are already financed by their respective employers.
Ethical considerations The study will be conducted according to the Helsinki Declaration, and
following approval by the local ethics committee. The project is registered at the Danish
Data Protection Agency in accordance with the Central Denmark Region common registration
system. No patient will be included before these permissions are granted. All information
involving patients will be handled according to national law on personal data information.
The study is covered by the Danish Patient Compensation Authority.
