LIver Transplantation for Non-Resectable Intrahepatic CholAngiocarcinoma (LIRICA) (LIRICA)

LIRICA is a prospective non-randomized study aimed at exploring the outcome of liver transplantation in selected patients with unresectable iCCA after a downstaging/disease control protocol with standard of care chemotherapy, in terms of overall survival and quality of life. Additionally, the study aims to identify pre-transplant biological markers and clinical factors that can stratify patients with the best post-transplant prognosis. Finally, the study aims to investigate the role of preoperative PET-MR, especially in relation to lymph node locations, by correlating the results with histological examination after iliac lymphadenectomy.

Study Overview

• Status: Recruiting
• Conditions: Intrahepatic Cholangiocarcinoma
• Intervention / Treatment: Procedure: Liver transplantation

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Enrico Gringeri, Prof.; Phone Number: +39 0498218547; Email: enrico.gringeri@unipd.it

Study Locations

• Italy
  • Padova, Italy, 35128
    • Recruiting
    • Azienda Ospedale Universita Di Padova
    • Contact: Enrico Gringeri, Prof.; Phone Number: +39 0498218547; Email: enrico.gringeri@unipd.it
    • Principal Investigator: Enrico Gringeri, Prof.
    • Sub-Investigator: Umberto Cillo, Prof.
    • Sub-Investigator: Domenico Bassi, Dr.
    • Sub-Investigator: Alessandra Bertacco, Dr.
    • Sub-Investigator: Riccardo Boetto, Dr.
    • Sub-Investigator: Francesco Enrico D'Amico, Prof
    • Sub-Investigator: Annalisa Dolcet, Dr.
    • Sub-Investigator: Jacopo Lanari, Dr.
    • Sub-Investigator: Alessandro Vitale, Prof.
    • Sub-Investigator: Alessandro Furlanetto, Dr.
    • Sub-Investigator: Sara Lonardi, Dr.
    • Sub-Investigator: Francesca Bergamo, Dr.
    • Sub-Investigator: Caterina Solda', Dr.
    • Sub-Investigator: Mario D Rizzato, Dr.
    • Sub-Investigator: Martina Gambato, Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed diagnosis of iCCA
• First diagnosis of iCCA
• Recurrence after R0 hepatic resection, N0, M0 without macrovascular invasion
• Disease considered unsuitable for hepatic resection based on tumor location and extent or underlying liver dysfunction
• Absence of major vascular invasion, extrahepatic disease, or involvement of regional lymph nodes detected on radiological study
• No evidence of extrahepatic metastatic disease after chest-abdomen-pelvis CT and PET-MR (or PET-CT)
• At least six months have passed since the first diagnosis of iCCA (or recurrence) to the date of inclusion on the liver transplant waiting list
• The patient has received at least six months of SOC chemotherapy, achieving disease stability or partial response (according to RECIST version 1.1) at the time of listing for transplantation
• Hematochemical evaluation: Hb ≥ 9 g/dL, Leukocytes ≥ 3.0 X 109/L, Neutrophils ≥ 1.5 X 109/L, Platelets ≥ 100,000/mm3 (≥ 10 X 109/L), Total Bilirubin ≤ 3 mg/dL (≤ 51 umol/L), AST or ALT ≤ 5 times the upper limit of normal, Serum Creatinine and Urea < 1.5 times the upper limit of normal
• ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1
• Patient's BMI ≥ 18 and ≤ 30 kg/m2
• Signed informed consent, and expected patient cooperation for treatment and follow-up, must be obtained and documented according to good clinical practice and national/local regulations

Exclusion Criteria:

• Tumor involving nearby extrahepatic structures (including involvement of major hepatic vessels) by direct invasion (T4 per AJCC 8th edition)
• Tumor penetrating the visceral peritoneum (T3 per AJCC 8th edition)
• Previous extrahepatic metastatic disease
• Prior neoplasms, except those treated curatively for more than 5 years without recurrence
• Known history of human immunodeficiency virus (HIV) infection
• Known history of solid organ or bone marrow transplantation
• Substance abuse and medical, psychological, or social conditions that may interfere with the patient's participation in the study or with the evaluation of study outcomes
• Pregnant or breastfeeding women
• Medical-surgical contraindications for liver transplantation
• Any reason for which, in the investigator's judgment, the patient should not participate in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Study population; Candidates will be evaluated by theMultidisciplinary Group after routine radiological studies (CT, MRI, PET-MR/CT). Patients will receive 6 months of standard of care chemotherapy and undergo PET-MR with FDG to exclude the presence of extrahepatic disease. Following completion of therapy, patients will undergo radiological restaging. If the disease is resectable, the patient will be considered for curative-intent surgical resection; if not, the patients will be evaluated by the Center's Multidisciplinary Transplantation Group. Patients will continue chemotherapy until a compatible liver becomes available. If there are no further contraindications, exploratory laparotomy and surgical nodal staging of the tumor will be performed at the time of transplantation. If there are no signs of extrahepatic disease, transplantation will be conducted according to institutional protocols.

Procedure: Liver transplantation; Patients will undergo liver transplantation according to the standard procedures of the institutional Center's protocol (cadaveric or living donor transplantation, whole or partial liver). Liver transplantation is preceded by an exploratory laparotomy with clinical evaluation and frozen section examination of lymph nodes in the hepatoduodenal ligament and along the common hepatic artery/celiac axis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Survival from time of transplantation to time of death or last follow up	3 and 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
OS comparison with chemotherapy alone	Comparison of 3-year survival between patients enrolled in the LIRICA study and survival of a population balanced for prognostic factors and disease characteristics from the database of the Veneto Oncological Institute (IOV)	3 years
Disease-Free Survival (DFS)	Survival from time of transplantation to time of death or first evidence of recurrence fo disease	3 and 5 years
Overall survival from the time of recurrence	Survival from time of recurrence to time of death or last follow up	5 years
PFS comparison with chemotherapy alone	Comparison of 3-year Progression-Free Survival (PFS) between the per-protocol population of patients enrolled in the LIRICA study and the PFS of the population from the Veneto Oncological Institute (IOV) database	3 years
Biological markers	Correlation of overall survival and recurrence with tissue and circulating biological markers (immunohistochemistry, proteomics, circulating tumor cells, circulating tumor DNA, new molecular markers)	5 years
Morbidity	Morbidity at 90 days (according to Clavien-Dindo and Comprehensive Complication Index, CCI)	90 days
Cancer-related mortality	Risk of mortality with sole relation to death by tumor progression and	3 and 5 years
Drop out	Percentage of patients who do not complete the procedure (drop-out) stratified by cause	5 years
Concordance of surgical and PET_RM staging (number, size, location)	Asses if suspicious lymph nodes described at the preoperative PET-RM confirm to be pathological at the histological evaluation after lymphadenectomy of the hepatic hilum and exploratory laparotomy. Lymph nodes will we evaluated by number, size and location	Perioperative
Quality of life assessed using EORTC QLQ-C30	Quality of life assessed using EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer QLG Core Questionnaire) 30 items questionnaire (scale 1-4 or 1-7, 1 being the lowest and 4 or 7 the highest, accordingly)	5 years
Quality of life assessed using FACT-Hep questionnaire	Quality of life assessed using FACT-Hep questionnaire (Functional Assessment of Cancer Therapy - Hepatobiliary) questionnaire about quality of life in the last 7 days (scale 0-4, 0 being the lowest and 4 the highest)	5 years

Collaborators and Investigators

• Sponsor: Azienda Sanitaria Ospedaliera
• Collaborators: Istituto Oncologico Veneto IRCCS
• Investigators: Principal Investigator: Enrico Gringeri, Prof., Azienda Ospedale Universita Di Padova

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2024
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): November 1, 2033

Study Registration Dates

• First Submitted: October 18, 2023
• First Submitted That Met QC Criteria: October 21, 2023
• First Posted (Actual): October 24, 2023

Study Record Updates

• Last Update Posted (Estimated): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 23, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Liver transplantation
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Cholangiocarcinoma
• Other Study ID Numbers: AOP 3006; LIRICA (Other Identifier: University of Padova)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No