HOPE to Reduce Tumour Recurrence After LT In Patients With HCC

Hepatocellular Carcinoma Clinical Trial

— POTERE  

Official title:

Hypothermic Oxygenated Perfusion To Reduce Tumour Recurrence After Liver Transplantation In Patients With Hepatocarcinoma

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05876052
• Other study ID #: POTERE
• Status: Not yet recruiting
• Phase: N/A
• Start date: May 2023
• Est. completion date: May 2025

Study information

• Verified date: May 2023
• Source: University of Bologna
• Contact: Matteo Ravaioli, Professor
• Phone: 0512144810
• Email: matteo.ravaioli6[@]unibo.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Hypothermic oxygenated ex-situ machine perfusion (HOPE) is a dynamic preservation method that has been developed to reduce the incidence and severity of ischaemia-reperfusion injury and to improve outcomes after liver transplantation. Whit this study Pi and collaborators hypothesize that the application of ex-situ liver perfusion before LT in HCC recipients leads to an optimization of graft function, with a decrease in ischaemia-reperfusion injury and a possible decrease in tumor cell growth. This is multicentre, prospective, two-arm, randomized, controlled, clinical trial, that will will involve patients with HCC candidate to LT. The liver grafts will be randomized in two groups to compare HOPE and static cold storage (SCS) preservation before transplantation. For each group evaluation of clinical outcomes, graft function tests, histologic findings, perfusate, tumor characteristics, and recurrence will be done.

Description:

Tumor recurrence after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC) is a major complication leading to decreased long-term survival of patients. However, the mechanisms leading to tumor emergence and growth remain incompletely understood. Several factors, can promote cancer growth or recurrence. Ischemia-reperfusion injury (IRI) has been recognized as an important early driver of microvascular dysfunction resulting in tissue hypoxia and inflammation, which promotes tumor cell growth.

A recent therapeutic strategy used to reduce the incidence and severity of IRI and to improve outcomes after transplantation is ex vivo HOPE. Which allows to redirect anaerobic metabolism to aerobic metabolism under hypothermic conditions, protect grafts from oxidative species-related damage, improve graft function and may potentially reduce cancer recurrence after liver transplantation.

A multicentre, prospective, two-arm, randomized, controlled, clinical trial will be performed; four Italian centres (Bologna, Palermo, Pisa e Torino) will be involved. A total of 192 patients with a history of HCC or active HCC, already present or about to be placed in the liver transplantation waiting list of the four transplantation center will be enroll. The liver grafts will be randomized in two groups to compare HOPE and SCS preservation before transplantation. For each group evaluation of clinical outcomes, graft function tests, histologic findings, perfusate, tumor characteristics, and recurrence will be done during follow up visit; 1-3-6 and 12 months after transplantation.

Livers assigned to HOPE group will be perfused by machine perfusion with cold Belzer solution (4°-10°C) and with continuous oxygenation (partial pressure of oxygen = 500-600 mmHg). Organs will be perfused from the start of the back-table procedure until implantation, without increasing cold ischemia time (CIT).

In the control group livers undergoing SCS will be steeped in cold Celsior or Belzer solutions and stored in ice. Presence of bacterial and/or fungal contamination will be tested by setting up microbiological cultures from the preservation fluid, before and after treatment in both groups.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 192
• Est. completion date: May 2025
• Est. primary completion date: May 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• all patients with HCC medical history or active HCC

• Donation after circulatory death (DBD) donor with standard or extended criteria

Exclusion Criteria:

• Living transplantation

• Split Transplantation

• Combined Transplantation

• Donation after cardiac death (DCD)Transplantation

• Re-transplantation

• Patient whose liver graft will undergo ex-vivo machine perfusion for medical decision, regardless the study

Related Conditions & MeSH terms

• Hepatocellular Carcinoma
• Hypothermia
• Liver Cancer
• Liver Transplantation
• Recurrence
• Tumor Recurrence

Intervention

Device:
• Hypothermic oxygenated Perfusion - HOPE
HOPE will start by flushing the organ at low flow values (30 ml/min) with new oxygenated perfusion fluid during back-table preparation. Organ will be treated with continuous HOPE until transplant. Organ perfusion will be continuously monitored. Minimal perfusion time will be 1 hour for livers.

Locations

Country	Name	City	State
Italy	IRCCS Azienda Ospedaliero-Universitaria di Bologna	Bologna

Sponsors (5)

Lead Sponsor	Collaborator
University of Bologna	Azienda Ospedaliera Città della Salute e della Scienza di Torino, Azienda Ospedaliero, Universitaria Pisana, IRCCS Azienda Ospedaliero-Universitaria di Bologna, The Mediterranean Institute for Transplantation and Advanced Specialized Therapies

Country where clinical trial is conducted

Italy, 

References & Publications (10)

Belzer FO, Southard JH. Principles of solid-organ preservation by cold storage. Transplantation. 1988 Apr;45(4):673-6. doi: 10.1097/00007890-198804000-00001. No abstract available. — View Citation

Bodzin AS, Lunsford KE, Markovic D, Harlander-Locke MP, Busuttil RW, Agopian VG. Predicting Mortality in Patients Developing Recurrent Hepatocellular Carcinoma After Liver Transplantation: Impact of Treatment Modality and Recurrence Characteristics. Ann Surg. 2017 Jul;266(1):118-125. doi: 10.1097/SLA.0000000000001894. — View Citation

Boteon YL, Afford SC. Machine perfusion of the liver: Which is the best technique to mitigate ischaemia-reperfusion injury? World J Transplant. 2019 Jan 16;9(1):14-20. doi: 10.5500/wjt.v9.i1.14. — View Citation

Czigany Z, Schoning W, Ulmer TF, Bednarsch J, Amygdalos I, Cramer T, Rogiers X, Popescu I, Botea F, Fronek J, Kroy D, Koch A, Tacke F, Trautwein C, Tolba RH, Hein M, Koek GH, Dejong CHC, Neumann UP, Lurje G. Hypothermic oxygenated machine perfusion (HOPE) for orthotopic liver transplantation of human liver allografts from extended criteria donors (ECD) in donation after brain death (DBD): a prospective multicentre randomised controlled trial (HOPE ECD-DBD). BMJ Open. 2017 Oct 10;7(10):e017558. doi: 10.1136/bmjopen-2017-017558. — View Citation

Dutkowski P, Polak WG, Muiesan P, Schlegel A, Verhoeven CJ, Scalera I, DeOliveira ML, Kron P, Clavien PA. First Comparison of Hypothermic Oxygenated PErfusion Versus Static Cold Storage of Human Donation After Cardiac Death Liver Transplants: An International-matched Case Analysis. Ann Surg. 2015 Nov;262(5):764-70; discussion 770-1. doi: 10.1097/SLA.0000000000001473. — View Citation

Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, Shaked A, Christie JD. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl. 2010 Aug;16(8):943-9. doi: 10.1002/lt.22091. — View Citation

Ravaioli M, De Pace V, Angeletti A, Comai G, Vasuri F, Baldassarre M, Maroni L, Odaldi F, Fallani G, Caraceni P, Germinario G, Donadei C, Malvi D, Del Gaudio M, Bertuzzo VR, Siniscalchi A, Ranieri VM, D'Errico A, Pasquinelli G, Morelli MC, Pinna AD, Cescon M, La Manna G. Hypothermic Oxygenated New Machine Perfusion System in Liver and Kidney Transplantation of Extended Criteria Donors:First Italian Clinical Trial. Sci Rep. 2020 Apr 8;10(1):6063. doi: 10.1038/s41598-020-62979-9. Erratum In: Sci Rep. 2020 Sep 1;10(1):14658. — View Citation

Ravaioli M, Germinario G, Dajti G, Sessa M, Vasuri F, Siniscalchi A, Morelli MC, Serenari M, Del Gaudio M, Zanfi C, Odaldi F, Bertuzzo VR, Maroni L, Laurenzi A, Cescon M. Hypothermic oxygenated perfusion in extended criteria donor liver transplantation-A randomized clinical trial. Am J Transplant. 2022 Oct;22(10):2401-2408. doi: 10.1111/ajt.17115. Epub 2022 Jun 21. — View Citation

Schlegel A, Muller X, Dutkowski P. Hypothermic Machine Preservation of the Liver: State of the Art. Curr Transplant Rep. 2018;5(1):93-102. doi: 10.1007/s40472-018-0183-z. Epub 2018 Jan 22. Erratum In: Curr Transplant Rep. 2018;5(1):103. — View Citation

Schlegel A, Muller X, Dutkowski P. Machine perfusion strategies in liver transplantation. Hepatobiliary Surg Nutr. 2019 Oct;8(5):490-501. doi: 10.21037/hbsn.2019.04.04. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in circulating tumor DNA (ctDNA) level	Blood and tissue samples collection, ctDNA extraction and quantification via Next Generation Sequencing (NGS)	1 day before LT/ until 12 months after LT
Primary	Incidence of liver recurrence	Present/Non present; Diagnosis with abdominal ultrasound and serum tumor markers analysis Date of recurrence and location	1 year after LT
Secondary	Incidence of early allograft disfunction (EAD)	Present/Non present; Diagnosis with analysis of serum values of : Aspartate transaminase (AST), Alanine transaminase (ALT), Bilirubin and International Normalised Ratio (INR)	starting 24 hours after LT until 7 days after LT