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Liver transplantation for the treatment of unresectable colorectal cancer liver metastases

Liver transplantation

CRISTINA DOPAZO, MD/PhD

CRISTINA DOPAZO

Cristina Dopazo, PhD/MD

Ramón Charco

Elena Elez

Cristina Dopazo

Ernest Hidalgo

Itxarone Bilbao

Concepción Gómez-Gavara

Mireia Caralt

Javier Ros

Francesc Salva

Isabel Campos-Varela

Lluis Castells

The patients with non-resectable colorectal liver metastases (CRLM) have always being considered a particular subgroup of CRLM in which the therapeutic approach, is focused on strategies that allow a potential surgery like neoadjuvant systemic treatments. But, the underlying biology that causes this particular profile of spread in a proportion of patients that always recur and progress in the liver has not been properly characterized from a biological point of view. Unfortunately, these patients finally develop liver metastasis not amenable for local treatments and become refractory to systemic treatments even without developing extrahepatic liver metastases. As a result, liver transplantation (LT) is a potential for patients without extrahepatic involvement and nonresectable CRLM. There are several studies that aims to evaluate if LT increases overall survival compared to best alternative care. To our knowledge, none of these studies incorporate objectives focused on the underlying tumor biology of this particular population and the development of focused strategies including a dynamic disease monitoring and targeted treatments for this particular population.The METLIVER trial will permit to expand the genetic studies to the whole complexity of metastatic lesions and a more precise evaluation of their genetic heterogeneity. Moreover, it will help to precise the type of genetic analyses on liquid biopsies that can be designed for patients that will unfortunately relapse mostly with lung metastases after LT. Our proposal will maximize the opportunity to produce an unprecedented knowledge on CRLM evolution and will provide new opportunities for relapsed patients.

A prospective multicenter Spanish clinical phase II trial is proposed. The study population will consist of male and female with non-resectable CRLM, who are 18 to 70 years old, inclusive, at the time of providing informed consent. Patients will be identified, treated and followed by the clinical investigators within the different centers included in the present study. Those patients deemed unresectable CRLM by consensus in multidisciplinary meeting will be pre-screened for eligibility to be included in the study. After receiving the corresponding chemotherapy and if the patient meets the inclusion criteria and none of the exclusion criteria will sign the informed consent and will be evaluated for liver transplantation according to institutional protocols at the transplant unit. Patients eligible for liver transplantation will continue chemotherapy until the time of an organ is available. However, patients receiving treatment with bevacizumab or aflibercept will discontinue this treatment at time of inclusion in waiting list. If there are no further contraindications at the time of transplantation, laparotomy including tumor staging will be performed and if there is no sign of extrahepatic disease, liver transplantation will continue according to institutional protocols. Participants will be followed for 5 years and monitored for safety, survival and disease recurrence.

Regarding the translational research:

* The metastatic liver removed on day of transplant will be analysed using high-throughput single-cell RNA sequencing (scRNA-seq) which will allow deep phenotyping of cells for detection of rare and common cell populations and determination of developmental trajectories of distinct cell lineages.
* RAS allele fraction will be monitored by BEAMing and it will be performed before chemotherapy treatment, before LT, post-transplantation, and every 3 months until the patient relapses if relapses.

Liver Transplantation for Non-resectable Colorectal Liver Metastases: Translational Research

Clinical Impact of Molecular Biomarkers in Liver Transplantation for Non-resectable Colorectal Liver Metastases: Translational Research

High-throughput single-cell RNA sequencing (scRNA-seq) will allow deep phenotyping of cells, allowing detection of rare and common cell populations and determination of developmental trajectories of distinct cell lineages from the metastatic liver removed to the recurrence (hepatic or extrahepatic).

ctDNA monitorization will be performed pre-chemotherapy, pre-transplantation and every three months after transplantation

Percentage of subject who reach the endpoint of overall survival from the inclusion in waiting list until death or last follow-up

Percentage of subjects who reach the endpoint of overall survival from the inclusion in waiting list until death or last follow-up

Percentage or patients who did not progress from transplantation until death or last follow-up analysed using Kaplan-Meier and the log-rank test.

Percentage of patients that drop-out of the study prior to liver transplantation

Defined as porcentage of patients with hepatic recurrence, extrahepatic recurrence or both

These questions allowed categorizing patients into whether they exhibited a clinically important symptom/functional impairment for each scale from 1 (not at all) to 4 (very much). It would be assessed pretransplantation and every 6 months after transplantation.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Liver Transplantation for Non-resectable Colorectal Liver Metastases: Translational Research	NCT05398380	Colorectal Canc... Liver Metastase... Genetic Change	Liver transplan...	18 Years - 70 Years	Hospital Vall d'Hebron
Liver Transplantation for Non-resectable Colorectal Liver Metastases: Translational Research	NCT05398380	Colorectal Canc... Liver Metastase... Genetic Change	Liver transplan...	18 Years - 70 Years	Hospital Vall d'Hebron

Spots Global Cancer Trial Database for tumoral biomarkers