Liver Transplantation in Patients With Unresectable Colorectal Liver Metastases Treated by Chemotherapy

Study Overview
=================
Brief Summary
-----------------
This is a multicentric randomized parallel group open trial comparing 5-year survival of chemotherapy followed by LT (Group LT+C) versus chemotherapy alone (Group C) in patients with confirmed unresectable liver-only metastases, well controlled by chemotherapy (no progression) and extensively explored by modern imaging techniques. The primary objective of the trial is to validate in a large multicentric cohort of selected patients the possibility to obtain at least 50% 5-years survival with LT combined to chemotherapy compared to around 10% with chemotherapy alone.

Detailed Description
-----------------
Liver transplantation (LT) has recently been proposed as alternative treatment for definitively unresectable colorectal liver metastases in selected patients with a 60% estimated survival at 5 years in a recent prospective Norwegian study. However, disease free survival (DFS) in this preliminary study has been poor with 90% of recurrence after LT. The objective of our study is to validate LT as a therapeutic option on a large multicentric scale throughout a highly strict policy selection in term of survival, disease free survival and quality of life. In order to reduce selection bias, unresectability criteria and theorical indication to LT will be confirmed by an independent Steering Committee including HPB surgeons, oncologists, radiologists and hepatologists.

Official Title
-----------------
Curative Potential of Liver Transplantation in Patients With Definitively Unresectable Colorectal Liver Metastases (CLM) Treated by Chemotherapy: a Prospective Multicentric Randomized Trial

Conditions
-----------------
Liver Metastasis, Colorectal Cancer, Metastasis

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ≥ 18 and ≤ 65 years Good performance status, ECOG 0 or 1 (39). Histologically proved adenocarcinoma in colon or rectum BRAF wild-type CRC on primary tumor or liver metastases High standard oncological surgical resection of the primary defined by : Safe margin of resection Curative resection of primary tumor according to oncological principles TNM adequate staging Absence of local recurrence on colonoscopy performed in the 12 months prior to inclusion (except in case of primary tumor resection < 12 months ) Confirmed non resectable colorectal liver metastases by the validation committee ≥ 3 months of tumor control during the last chemotherapy line: Stable or Partial Response on RECIST criteria (40) ≤ 2 lines of chemotherapy for metastatic disease CEA < 80 microg/L or a decrease ≥ 50% of the highest serum CEA levels observed during the disease Absence of extrahepatic tumor localisation according to CT scan and PET-CT Renal function should be within the normal limits No need for extra-renal purification procedure, hemodialysis or kidney transplantation associated (nephrologist assessment) A platelet count> 80,000 / mm3 White blood cell count> 2500 / mm3 Eligible for both treatments groups Signed informed consent and expected cooperation of the patient for the treatment and follow up Exclusion Criteria: Participation refusal No health insurance facilities General contraindication to LT (Severe cardiopulmonary disease or other life-limiting coexisting medical conditions, extrahepatic malignancy, active alcohol or substance abuse, active infection or uncontrolled sepsis, lack of psychosocial support or inability to comply with medical treatment) Other malignancies either concomitant or within 5 years before liver transplantation Patients not having received standard treatment for the primary CRC according to recommended guidelines Prior extra hepatic metastatic disease or local relapse Pregnancy at the time of inclusion

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

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

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

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

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liver Transplantation<br>Arm LT+C: patients will be treated by experimental liver transplantation preceding the non experimental standard chemotherapy (according to usual practices). | Procedure: Liver Transplantation<br>* The patient of the arm LT+C are treated by experimental liver transplantation preceding the Non experimental standard chemotherapy (according to usual practices) .<br>* Other names: Experimental LT+Non Experimental Usual Chimiotherapy;|
| No Intervention: No intervention<br>Arm C: patients will receive non experimental standard chemotherapy according to usual practices in the context of definitively unresectable CLM. | |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5 years overall survival (OS) |  | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-years overall survival (OS) |  | 3 years | 
| Disease free survival (DFS) (Arm LT+C) or Progression free survival (PFS) (Arm C) |  | 3 and 5 years | 
| Recurrence rate at 3 and 5 years | Radiological assessment will be performed according to the RECIST criteria and confirmed by 2 local radiologists. | 3 and 5 years | 
| Quality of life (QOL) of patients using the European Organization for Research and Treatment of Cancer (EORTC) questionnaires.: QLQ-C30 | QLQ-C30 covers general aspects of health-related quality of life | year 5 | 
| Quality of life (QOL) of patients using the European Organization for Research and Treatment of Cancer (EORTC) questionnaires.: QLQ-LMC21 | QLQ-LMC21 is valid and reliable questionnaire module to use with the QLQ-C30 in assessing in hepatectomy or palliative treatment for colorectal liver metastases | year 5 | 
| Quality of life (QOL) of patients of Group LT followed by chemotherapy, using the NIDDK questionnaire of Liver Transplantation Database |  | year 5 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Liver, Metastasis, Colorectal cancer, Liver transplantation