LIver TrAnspLantation for Non-resectable Peri-HIlar cholangioCArcinoma (LITALHICA)

Study Overview
=================
Brief Summary
-----------------
LITALHICA is a prospective non-randomized study aimed at exploring the outcome of liver transplantation in selected patients with unresectable perihilar cholangiocarcinoma (pCCA) after treatment 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-MRI, especially in relation to lymph node locations, by correlating the results with histological examination after hilar lymphadenectomy.

Official Title
-----------------
LIver TrAnspLantation for Non-resectable Peri-HIlar cholangioCArcinoma (LITALHICA)

Conditions
-----------------
Perihilar Cholangiocarcinoma

Intervention / Treatment
-----------------
* Procedure: Liver transplantation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of pCCA (transcatheter biopsy or brush cytology, CA 19-9 > 100 mg/mL and/or a mass on cross-sectional imaging with a malignant appearing stricture on cholangiography, or biliary ploidy with a malignant appearing stricture on cholangiography) 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) Unresectable tumor above cystic duct (pancreatoduodenectomy for microscopic involvement of CBD) or resectable pCCA arising in PSC Radial tumor diameter <3 cm At least six months have passed since the first diagnosis of pCCA to the date of inclusion on the liver transplant waiting list The patient has received at least six months of standard of care (SOC) chemotherapy, achieving disease stability or partial response (according to RECIST criteria version 1.1) at the time of listing for transplantation Absence of medical or surgical contraindication to liver transplantation 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: Diagnosis of intrahepatic cholangiocarcinoma (iCCA) Uncontrollable infection Prior radiotherapy or chemotherapy Prior biliary surgical resection or attempted surgical resection Diameter of tumor >3cm Presence of intra-hepatic metastases Present or past evidence of extrahepatic metastatic disease Transperitoneal biopsy (including percutaneous ecography-guided FNA) Prior neoplasms, except those treated curatively for more than 5 years without recurrence 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study population<br>Candidates will be evaluated by the Multidisciplinary Group after routine radiological studies (CT, MRI, PET-MRI/CT). Patients will receive 6 months of standard of care chemotherapy and undergo PET-MRI 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<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | 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 |
| --- | --- | --- |
| Overall survival comparison with chemotherapy alone | Comparison of 3-year survival between patients enrolled in the LITALHICA study and survival of a population balanced for prognostic factors and disease characteristics from the database of the Veneto Oncological Institute (IOV) | 3 years | 
| Progression-Free Survival (PFS) | Survival from time of transplantation to time of death or first evidence of progression of 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 | 
| Progression-free survival comparison with chemotherapy alone | Comparison of 3-year progression-free survival between patients enrolled in the LITALHICA study and progression-free survival of a population balanced for prognostic factors and disease characteristics from the database of the Veneto Oncological Institute (IOV) | 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 | 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/MRI staging | Asses if lymph nodes described as suspicious at the preoperative PET-MRI confirm to be pathological at the histological evaluation after lymphadenectomy of the hepatic hilum and exploratory laparotomy | 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 QLQ 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Liver transplantation