The LIVERATION project
LIVERATION is a comprehensive, practical, and multinational clinical trial spanning seven countries, in the order to investigating if the enlargement of the ablated margin through radiofrequency can reduce the recurrence of Colorectal Cancer Liver Metastasis and enhance patient longevity in both, Colorectal Cancer Liver Metastasis, as well as in Liver Cancer patients.
Colorectal cancer is the third most common tumour in men and the second in women, with an forecast of 1.9 million new cases worldwide (450K in Europe) and approximately 900,000 deaths in 2020. Hepatic metastases develop in around 50% of colorectal cancer cases.
Furthermore, the liver is the first and only area of spread in 30–40% of patients. Surgery is considered the gold standard treatment and the only potentially curative option for colorectal liver metastases.
Liver cancer is the fifth most common cancer and the second leading cause of cancer-related deaths in the world (830.000 deaths in 2020), with men being more likely to develop it than women (2,8:1).
Patients who are diagnosed at an early stage without metastasis of the disease are candidates for treatments including surgical resection, ablation, trans-arterial chemoembolization and liver transplantation, and have a 5-year overall survival between 50-70%.
However, when hepatocellular carcinoma hepatocellular carcinoma is diagnosed at an advanced stage, the prognosis is poor and an overall survival of less than 6 months is expected.
Furthermore, even after radical resections, hepatocellular carcinoma still shows a high recurrence rate (five-year recurrence rates ~70% postresection, with 2/3 of recurrences occurring within 2 years related to intrahepatic spread and a rate of local recurrence about 20%).
On the other hand, the major proportion of patients who present with hepatocellular carcinoma are initially not appropriate candidates for surgical resection (is recommended only for patients with a single lesion without clinically significant portal hypertension and with a future liver remnant greater than 40% to maintain adequate liver function).
LIVERATION aims at decreasing the rate of tumour recurrence after resection and increase the number of patients with hepatocellular carcinoma who can undergo surgery.
LIVERATION leverages a prospective pragmatic clinical trial coordinated by expert clinicians and surgeons on liver cancer that had achieved promising preliminary results: a reduction of cancer local recurrence by adding an additional coagulation of the margin (ACM) with radiofrequency (RF) ablation devices compared to conventional hemostatic techniques in a retrospective clinical trial.
Figure 1. Schematic showing the liver metastasis cascade of Colorectal Cancer (CRC)
The main aim of LIVERATION is to evaluate if an additional coagulation of the margin coagulation (ACM) provided by specific radiofrequency devices will deliver a reduction in local recurrence in colorectal liver metastases and hepatocellular carcinoma patients when compared to conventional (no ablative) methods of haemostatic resection.
1) the portal vein system directly connects the colorectal region and liver, which is associated with abundant blood supply.
2) location and histological type of primary tumour.
The liver metastatic cascade of CRC is a complex multi-factor and multi-step biological process, wherein a small subset of CRC cells acquire a capacity to evade from the primary CRC, in part by morphological changes such as epithelial-to-mesenchymal transition (EMT), migration through the extracellular matrix (ECM), invasion into the neighbouring tissues, intravasation, survival in the circulation, extravasation and finally, colonization to distant liver forming more aggressive secondary CRLM.
In the arm 1 of the clinical study, conventional (no ablative) methods of haemostatic resection (such as Conventional crush-clamp or finger fracture technique, Ultrasonic dissector (e.g CUSA) or Ultrasonic mediated devices, Water jet dissectors, Argon beam coagulator and Bipolar forceps) will be used. These technologies aimed for arm 1, might be used by the chosen centres at their preference after accurate randomization of the patients between arm 1 and arm 2 methodology will be used causing a specific additional coagulation of the tumour margins with a radiofrequency-assisted device (Coolingbis or Aquamantys) in the liver after resection and transection of the tumour.
Figure 2. In the arm 2, the Additional Coagulation of the margin (ACM) will be researched
LIVERATION WORKING PACKAGES (WPs)
The goals of WP1 are.
1) To establish and guarantee full synergy, motivation, and effective interactions among LIVERATION participants, coordinate their action towards full successful execution of the Project tasks in a timely fashion and within the budget and quality limits as defined by the Grant Agreement signed with the EC and the Consortium Agreement signed among the beneficiaries and those participating as sites.
2) Ensure efficient operational management including that of administrative, financial and legal issues. The Project coordinator is Patricia Sánchez Velázquez and the Hospital del Mar/IMIM institute.
The final goal of this WP2 is to obtain the approval of the clinical trial by the regulatory body in each of the countries and to sign the agreements with each of the sites that would allow clinical trial initiation. WP2 will focus on the ethical and legal governance of the Project, ensuring that full account is taken of the legal and ethical issues at stake. WP2 tasks will aim at protecting the rights of patients in the LIVERATION project and in particular ensure that the patients’ perspective on data sharing, consent and data privacy are considered in all project steps in full compliance with the new General Data Protection Regulation (GDPR).
To evaluate the hypothesis that less local recurrence can occur after ACM within liver resection and narrow margins, previously demonstrated by the coordinators in a small retrospective study. A new prospective, multicentric randomised clinical trial will be carried out. The trial has been designed following pragmatic clinical trial principles and will consist of a multicenter single-blind, randomized, parallel groups, controlled clinical trial including a total of 720 patients scheduled for either conventional or additional margin coagulation of liver transection in order to assess oncological outcomes.
The overall objective of WP4 is to provide a comprehensive evaluation of the trial, including the social impact and the comparative efficacy with other competing interventions. This Work package will integrate a comprehensive evaluation of the social perspective of patients. It will also include a systematic review of the literature with the aim to synthesise the eligible studies, including the pragmatic trial of the project, through a network meta-analysis model.
This package focuses on promoting the project’s findings, leveraging its results, and facilitating effective communication. It includes the development and implementation of strategic dissemination plans to share the results with a broad audience, including the medical & scientific community, patients, and the public. The exploitation component is committed to maximizing the project’s impact by integrating its findings into clinical practice and health policies. Lastly, the communication aspect ensures a two-way interaction with all stakeholders, fostering an open dialogue about the project’s progress, challenges, and outcomes.