Liver Transplant Combined With Neoadjuvant Chemo-radiotherapy in the Treatment of Unresectable Hilar Cholangiocarcinoma. A Prospective Multicenter Study.

Study Overview
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Brief Summary
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A prospective multicentre study which includes patients ≤ 70 years-old diagnosed of unresectable hilar cholangiocarcinoma (hCCA) ≤3cm in radial diameter, without evidence of lymph node or distant metastases. Liver transplantation preceded by neoadjuvant radio-chemotherapy will be performed in this selected group. The primary endpoint will be overall survival at 1, 3, and 5 years post-transplant. The secondary endpoints will be: 1) recurrence free survival at 1, 3 and 5 years post-transplant; 2) intention-to-treat survival of overall patients included in the study at 1,3 and 5 year; 3) the rate of patients included in the study who are finally transplanted.

Detailed Description
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A prospective multicentre pilot study which includes patients ≤ 70 years-old diagnosed of unresectable hilar cholangiocarcinoma (hCCA) ≤3cm in radial diameter, without evidence of lymph node or distant metastases. The number of subjects necessary is 34 patients to achieve a power of 82% with a significance level of 0.05 to detect a 40% difference between the estimated 50% survival of those patients who are transplanted and 10% of those patients with hCCA unresectable who are not transplanted. This corresponds to a hazard ratio of 3.3219. Estimated loss to follow-up of 10% of patients. RADIOLOGICAL EVALUATION It will be considered unresectable those lesions Bismuth IV with the following criteria (Jarnagin WR, et al. Ann Surg 2001; 234:507; Memorial Sloan Kettering Cancer Center Hilar Cholangiocarcinoma Classification): Bilateral extension to second order biliary Unilateral extension to second-order biliary radicals AND contralateral portal vein involvement OR contralateral hepatic lobar atrophy Main or bilateral portal vein involvement Insufficient future liver remnant even after portal embolization It will be performed the tumoral marker (CA 19.9), multiphase chest-abdomen CT scan, magnetic resonance cholangiopancreatography (MRCP) as well as positon emission tomography (PET)-scan if there is doubts of distant disease and upper endoscopic ultrasound (EUS) in order to rule out any obvious lymph node metastases. A biliary drainage will be placed by percutaneous transhepatic biliary drainage (PTBD) or endoscopic biliary drainage (EBD). NEOADJUVANT TREATMENT Patients will receive neoadjuvant radiotherapy (External - 50-54 grays) following by concomitant oral capecitabine (1,330mg/m2).Thereafter, gemcitabine iv (1000mg/m2) plus cisplatin iv will be administered the day 1 and 8 every 21 days until transplant. A staging laparotomy/laparoscopy is recommended before including the patient in waiting list for transplant to confirm the abscence of extra-hepatic disease, especially peritoneal seeding and lymph nodes involvement. A score exception will be allowed to optimized the treatment received and to be transplanted during the first 6 months. LIVER TRANSPLANT AND FOLLOW UP Regarding liver transplant technique, hepatic artery should be avoided for arterial reconstruction using the splenic artery or an iliac conduit. Biomarker analyses in the explant specimen will be performed. The patient will be monitored post-operatively at the clinical, biological and morphological levels every 3 months during the first 2 years and every 6 months thereafter in order to detect any recurrence and in the context of standard clinical care.

Official Title
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Liver Transplant Combined With Neoadjuvant Chemo-radiotherapy in the Treatment of Unresectable Hilar Cholangiocarcinoma. A Prospective Multicenter Study.

Conditions
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Unresectable Cholangiocarcinoma

Intervention / Treatment
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* Drug: Neoadjuvant Chemo-radiotherapy
* Procedure: Liver Transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written consent form Age ≤ 70 years-old ECOG 0 or 1 Unresectable hCCA ≤3cm in radial diameter Exclusion Criteria: Those patients who have received chemotherapy or radiotherapy previously out of protocol Liver, extrahepatic or lymph node metastases Previous intent of surgical resection or percutaneous biopsy Previous or concurrent cancer that is different in primary site or histology from adenocarcinoma, except cervical carcinoma in situ, localized prostate cancer, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis, T1). Any cancer curatively treated 5 years prior to entry is permitted. Infection no controlled

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Study group<br>Patients with unresectable hilar cholangiocarcinoma (hCCA) ≤3cm in radial diameter, without evidence of lymph node or distant metastases | Drug: Neoadjuvant Chemo-radiotherapy<br>* Patients will receive neoadjuvant radiotherapy (External - 50-54 grays) following by concomitant oral capecitabine (825mg/m2 bid).Thereafter, gemcitabine iv (1000mg/m2) plus cisplatin iv (25mg/m2) will be administered the day 1 and 8 every 21 days until transplant.<br>Procedure: Liver Transplantation<br>* If no spread disease is discovered after neoadjuvant treatment, the patient will be listed for liver transplantation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival at 1, 3, and 5 years post-transplant |  | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence free survival at 1, 3 and 5 years post-transplant |  | 5 years | 
| Intention-to-treat survival of overall patients included in the study at 1,3 and 5 year |  | 5 years | 
| The rate of patients included in the study who are finally transplanted. |  | 5 years |