Liver Resection Versus Radio-chemotherapy-Transplantation for Hilar Cholangiocarcinoma

Study Overview
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Brief Summary
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A prospective, open-label, randomised, multicentre, comparative study in two parallel groups comparing an interventional group with liver transplantation preceded by neoadjuvant radio-chemotherapy and a control group receiving conventional liver and bile duct resection. The primary endpoint will be overall survival at 5 years in the intent-to-treat population. The secondary endpoint will be recurrence-free survival at 3 years evaluated by CT-scan and tumoral markers (Carcinoembryonic antigen (CAE) and cancer antigen (CA19.9)) in the intent-to-treat population. The number of subjects necessary is 54 patients (27 x 2): this population will enable the demonstration of a significant difference is 5-year survival rates between the transplanted group and the resected group with a power of 80% and a first-species risk of 5%, under the hypothesis that these survival rates are 70% in the transplanted group and 30% in the resected group.

Detailed Description
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The protocol will comprise a phase 1 during which the potential eligibility of patients (presenting with a resectable Klatskin - Excepted Type 1of Bismuth) will be assessed, based on clinical, biological and morphological data. After phases 1, the eligibility of the patient will be confirmed or not. In the context of the study, phase 2 will include the collection of blood samples as well as positon emission tomography (PET)-scan and upper endoscopic ultrasound (EUS) in order to rule out any obvious lymph node metastases. A short exploratory laparoscopy will also be performed in phase 2 to eliminate infra-clinic subcapsular liver metastases and peritoneal carcinomatosis. The randomization process will take place at the end of the phase 2, patients will be assigned into the transplantation arm (OLT) or the resection arm (RSX). During phase 3, patient will receive nutritional support and, if not done previously, a biliary drainage will be placed endoscopically. In the RSX arm (phase 3A), patients will undergo radical resection of the tumor (refer below technical details). Preoperative portal vein embolization may be necessary at this stage depending on the expected remnant liver volume, assessed by CT-scan volumetry. In the OLT arm (phase 3A), patients will receive neoadjuvant radiochemotherapy (External - 50 grays) following by liver transplantation (phase 4B). Before the fifth week after completion of radiochemotherapy, a staging laparotomy with local lymphadenectomy will be performed and patients will be put on the national waiting list in the absence of extra-hepatic disease, especially peritoneal seeding and lymph nodes involvement. A score exception will allowed a liver transplantation in the 3 months after staging laparotomy. During phase 5 the patient will be monitored postoperatively at the clinical, biological and morphological levels for 3 months. During phase 6, the patient will be followed clinically, biologically and morphologically for 5 years in order to detect any recurrence and in the context of standard clinical care.

Official Title
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Randomized Prospective Multicentric Study: Radio-chemotherapy and Liver Transplantation Versus Liver Resection to Treat Respectable Hilar Cholangiocarcinoma

Conditions
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Cholangiocarcinoma

Intervention / Treatment
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* Procedure: CAPECITABINE-Radiotherapy -Liver Transplantation
* Procedure: RESECTION


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients (male or female) aged from 18 to 68 year-old, French Hilar cholangiocarcinoma histologically proved and/or highly suspected on hilar stenosis with mass syndrome from 0.1 cm to 3 cm Hilar cholangiocarcinoma type 2, type 3A, type 3B, type 4 Patients considered as resectable (R0 resection) by liver resection including segment 1 and biliary confluence with or without vascular resection Patient potentially transplantable Patient affiliated to French Health Insurance Patient who had sign an informed consent Exclusion Criteria: Pregnant or breastfeeding woman Women of childbearing potential without an effective contraception method Radiotherapy contraindication Positive dosage of ImmunoglobulinsG4 (IgG4) dihydro-pyrimidine-dehydrogenase (DPD) total deficit Personal history of cancer in the last 5 five years (exclusion basocellular cellular carcinoma) Personal history of fluoropyrimidine hypersensibility Personal history of capecitabine hypersensibility Personal history of dihydro-pyrimidine-dehydrogenase deficit Polynuclear neutrophil < 1500 / ml Platelet rate < 100 000 / ml Severe leucopenia < 2000 / ml Severe liver failure (Factor V < 50%) Severe renal failure (Creatin clearance < 30 ml/min) Treatment by Sorivudine or its analogue as Brivudine Non controled diabetes mellitus and/or others severe co-morbidities (renal failure, severe and instable coronaropathy, severe risk factor of stroke, body mass index superior to 35) Proved histological cirrhosis Sclerosing cholangitis Intra and/or extra-hepatic metastases Hypereosinophilia and/or wirsung dilatation and/or mass of the pancreas head Hilar mass superior to 3 cm Duodenal invasion Patient under guardianship

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 68 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CAPECITABINE-Radiotherapy -Liver Transplantation<br>Neoadjuvant Radio-Chemotherapy (RC) and Liver Transplantation (LT) | Procedure: CAPECITABINE-Radiotherapy -Liver Transplantation<br>* CAPECITABINE (800 mg/m2 twice a day during 5 weeks) + External Radiotherapy (50 grays during 5 weeks) then Liver transplantation<br>* Other names: Neoadjuvant Radio-Chemotherapy and Liver Transplantation;|
| Active Comparator: RESECTION<br>Liver resection | Procedure: RESECTION<br>* Intent-to-treat R0 liver resection<br>* Other names: Liver Resection;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | To demonstrate the superiority, in terms of 5-year survival, of liver transplantation (TH) preceded by neoadjuvant chemoradiotherapy on the radical resection of Klatskin tumors considered resectable | At 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence free survival | 3-year recurrence-free survival assessed by CT and markers | At 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hilar cholangiocarcinoma, Liver transplantation, Radiochemotherapy