HCC, Liver Transplantation, Oncological Outcomes
Conditions
Keywords
HOPE, randomised controlled trial, multicentre, hepatocellular carcinoma, liver transplantation
Brief summary
Liver transplantation is often performed to treat liver cancer, or hepatocellular carcinoma (HCC), in patients with impaired liver function due to cirrhosis. A shortcoming, however, is tumor recurrence after transplantation. Approximately 15 % of patients receiving livers develop recurrence and this depends on the quality of the liver received. Machine liver perfusion, for example, hypothermic oxygenated liver perfusion (HOPE), which means that the organ is perfused with an oxygen-rich fluid in a cold environment before transplantation, is a novel method to improve the quality of livers before implantation. The standard of care is cold storage without perfusion. The objective of this study is to compare the survival after tumor recurrence of patients after liver transplantation for HCC between perfused and not perfused livers. This study's hypothesis is that survival without tumor recurrence is improved when the liver is perfused before implantation. The study involves transplant centers worldwide, and adults with HCC waiting for liver transplantation are included. 220 Patients will be recruited within 12 months and then observed for at least 2 years after transplantation. To provide the most valid results, the patients will be randomly allocated to either the organ perfusion group or a control group with standard-of-care cold storage of the organ.
Interventions
PROCEDUREHypothermic oxygenated perfusion
All study centres will use either VitaSmart, Liver assist or Perlife devices for machine liver perfusion, with a pressure controlled hypothermic oxygenated liver perfusion through the portal vein (HOPE) or through the portal vein and the hepatic artery (DHOPE), targeting a flow rate between 200-250 ml/min at a pressure of 3 mmHg, and a perfusate temperature between 8-12°C. The perfusate consists of 3L re-circulating Belzer MPS® (Bridge to Life Ltd.) with an active oxygenation (70-110 kPa). The minimum perfusion duration is defined at 2 hours, while perfusion is generally continued until the recipient hepatectomy is completed. The perfusion will exclusively be performed in the recipient centre after initial cold storage and bench preparation of the liver for implantation. The perfusion devices are routinely used in all participating centres.
PROCEDUREConventional cold storage
Conventional cold storage at 4°C will be performed with precooled preservation solution according to local standard of care. For cold storage at the Swiss centres, IGL-1 (Institute George Lopez) is used for cold storage. Liver transplant centres in other European countries, use mainly three other storage solutions (Histidine trypophan-ketoglutarat, HTK and University of Wisconsin, UW solution, Celsior) in accordance to their national guidelines.
Sponsors
Philipp Dutkowski
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult recipients (\>18y), listed for liver transplantation with documented HCC (Liver Imaging Reporting and Data System (LIRADS) 5 lesion in magnetic resonance imaging or computer tomography of the liver or biopsy proven), * within up to seven criteria, i.e. HCC with seven as the sum of the diameter of the largest tumour (in cm) and the number of tumours at the time point of liver transplantation, * written informed consent for the trial. This also includes patients beyond the up to seven criteria after successful downsizing of the HCC
Exclusion criteria
* Donation after circulatory death (DCD) liver grafts * Combined liver transplants * Partial liver transplants * Combined or mixed hepatocellular cholangiocarcinoma (cHCC-CCC) or pure cholangiocarcinoma or other malignancies in histopathology of the liver explant * Systemic antitumoural medical treatment with checkpoint inhibitors or multikinase inhibitors * Post-transplant treatment with mTOR inhibitors * Acute and unexpected medical contraindications * Pregnancy * Cold storage time of \> 10 hours (both study arms)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recurrence free survival | 24 months | Post transplant HCC recurrence free survival, i.e. the time interval a patient is alive without HCC recurrence after transplantation, i.e., until either HCC recurrence is observed, or the patient dies from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HCC-related death | 24 months | Death related to HCC |
| Death from any other causes than HCC | 24 months | Death not related to HCC |
| Mean number of circulating tumour deoxyribonucleic acid (DNA) in blood | 6 months | This will be measured before transplantation (baseline), at discharge and at 6 months after transplantation. This endpoint will add information on the risk of tumour recurrence by seeding circulating cells. |
| HCC recurrence (while alive) | 24 months | Number of HCC recurrences |
| Median Rejection Activity Index | 6 months | The Rejection Activity Index (RAI) in liver histology (biopsy) is performed at 6 months after transplantation. This endpoint assessed in liver histology (biopsy) will show endothelial and T cell activation in implanted livers within the first months after 6 months. The RAI can be used to score liver allograft biopsies with acute rejection. The scale is from 1 to 9, higher scores mean more severe signs of rejection. |
| Liver related complications | 24 months | This endpoint will allow to assess the association between initial graft injury and liver specific complications in both study arms. |
| Mean number of high-mobility-group-protein B1 (HMGB-1) in blood | 1 week | This will be measured at the time of transplantation (baseline) and 1 week after transplantation. This endpoint will add information on danger signalling in both study arms during early and late reperfusion. |
Countries
Austria, Belgium, Czechia, Denmark, France, Germany, Italy, Lithuania, Netherlands, Norway, Poland, Portugal, Spain, Sweden, Switzerland, United Kingdom, United States
Contacts
Primary ContactPhilipp Dutkowski, Professor
Outcome results
None listed