Liver Transplantation in Intrahepatic Cholangiocarcinoma

Study Overview
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Brief Summary
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The aim of the current study is to determine the potential efficacy of liver transplantation in the form of patients' overall survival (OS) after neoadjuvant systemic therapy in patients with biologically responsive locally advanced non-metastatic intrahepatic cholangiocarcinoma (iCCA) in comparison to patients historically treated with chemotherapy alone.

Detailed Description
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Research Significance: Cholangiocarcinoma, which arises from biliary epithelium, can be anatomically subdivided into distal, hilar, and intrahepatic subgroups. iCCA constitutes the second most common primary liver cancer after hepatocellular carcinoma, with a rising incidence but without parallel advances in treatment or patient outcome [1]. Nowadays, surgical resection is the only widely accepted potentially curative therapy for iCCA; however, 5-year survival rates for resectable disease are less than 25%.[2] This high mortality is attributed to high tumor recurrence. Two-thirds of patients who undergo curative-intent resection, suffer from postoperative disease recurrence, most commonly in the remnant liver, followed by the peritoneum and abdominal lymph nodes [3-7]. Approximately, 83% of recurrences occurring within the first 2 years after resection [8], suggesting inadequate local tumor control with resection in this highly infiltrative cancer. Liver transplantation for intrahepatic cholangiocarcinoma: Liver transplantation has been previously investigated for unresectable iCCA[9-11]; however, the outcomes have been poor compared with the promising results for hepatocellular carcinoma, with 18-25% OS and RFS after 5 years [12-14]; however, most studies evaluated patients with either incidental iCCA or iCCA misdiagnosed prior to transplant as HCC. Thus, iCCA is considered by most centers to be a formal contraindication to liver transplantation. Neoadjuvant therapy with subsequent Liver transplantation for perihilar cholangiocarcinoma: Similar to iCCA, liver transplantation outcomes for perihilar cholangiocarcinoma were initially poor; however, an analysis of the United Network of Organ Sharing (UNOS) database found a significant survival benefit for patients with perihilar cholangiocarcinoma who received pre-transplant neoadjuvant systemic therapy compared with patients who transplanted for incident disease [14]. Subsequently, several studies [15-20] reported improved survival for hilar cholangiocarcinoma treated with neoadjuvant chemoradiation followed by liver transplantation. A multicenter study[15] reported 65% 5-year survival rate, thus liver transplantation has become the preferred treatment for patients with locally advanced unresectable hilar cholangiocarcinoma. Response to neoadjuvant therapy probably offers a means to select patients with hilar cholangiocarcinoma who might benefit from transplantation. Neoadjuvant therapy with subsequent liver transplantation for intrahepatic cholangiocarcinoma: The published literature regarding liver transplantation for iCCA is mostly limited to incidental or misdiagnosed tumors identified on pathology [21, 22], with most patients not receiving neoadjuvant therapy. Retrospective analysis [18, 23] included a small cohort of patients receiving neoadjuvant therapy showed that pre-transplant therapy appeared to decrease disease recurrence; however, reports did not distinguish between hilar cholangiocarcinoma and iCCA. In 2016, a multi-center, international, retrospective study [11] investigated outcomes of liver transplantation in 48 iCCA patients who had not received neoadjuvant chemotherapy or loco-regional therapy. In that study, 5-year OS was 65% for iCCA ≤2 cm and 45% for advanced larger lesions. Survival outcomes for locally advanced iCCA were worse, but patients in this series were excluded if they received pre-transplant neoadjuvant therapy. The effect of neoadjuvant chemotherapy in patients with larger and multifocal tumors remains largely undefined. In 2020, another multicenter study compared the outcomes of patients with cirrhosis undergoing liver transplantation or liver resection who had iCCA or combined hepatocellular-cholangiocarcinoma (cHCC-CCA). The retrospective study analyzed a total of 49 LT and 26 liver resected patients with cirrhosis and histologically confirmed iCCA/ cHCC-CCA ≤5 cm. Results suggested that liver transplanted patients had a significantly lower tumor recurrence (diameter of largest nodule and tumor differentiation were independently predictive) and had a significantly higher 5-year recurrence-free survival. The effects of liver transplantation may provide a benefit for highly selected patients with cirrhosis and unresectable iCCA/cHCC-CCA with specific tumors dimensions [28]. These finding suggests that liver transplantation might be a viable option for small, solitary iCCA in the absence of pre-transplant therapy or with locoregional therapy alone. A subset of patients with iCCA experience sustained response to neoadjuvant therapy, and it has been postulated that response duration might be an appropriate surrogate marker for the selection of patients for liver transplantation. Through the Methodist-MD Anderson Joint Cholangiocarcinoma Collaborative Committee, a recent prospective case-series [24] of 6 patients with locally advanced unresectable iCCA without extrahepatic disease or vascular involvement was performed. Patients treated with neoadjuvant systemic chemotherapy with a minimum of 6 months radiographic disease stability or regression received liver transplantation. The median post-transplant follow-up duration was 36 months (range; 29-51). The OS rate was 100% (95% Confidence interval [CI]; 100-100) at 1-year, 83·3% (95% CI; 27·3-97·5) at 3 years, and 83·3% (95% CI; 27·3-97·5) at 5 years. Three patients developed post-transplant recurrence at a median of 7·6 months with 50% (95% CI; 11·1-80·4) RFS at 1-, 3-, and 5-years. Since publication, an additional 5 patients have been transplanted, and all patients have been followed for an additional 24 months. More recent data indicates a 5-year OS of 79.5% with RFS of 42.4%. Of recurrence, 4 of 5 occurred within 12 months of transplant. Retrospective evaluation of the pre-transplant imagining demonstrated evidence of pre-transplant extrahepatic disease. More careful patient selection, such as the addition of a PET CT scan, would likely avoid early recurrence in the majority of patients. Adverse events have been reported including grade 3 postoperative ileus in one patient and grade 4 acute kidney injury requiring temporary dialysis in another patient. Both adverse events were among those commonly occurring with liver transplantation for any indication. No post-operative complications could be directly related to this protocol. We, therefore, anticipate that selected patients with locally advanced non-metastatic iCCA who show pre-transplant disease stability on neoadjuvant therapy might benefit from liver transplantation. Research Design and Methods: This is a Single-center phase II study. Patients with locally advanced unresectable iCCA with no evidence of vascular invasion or extrahepatic disease who have at least 6 months of disease stability or regression on neoadjuvant systemic therapy will be enrolled. Eligible patients who also meet center-specific medical criteria for transplant listing will be listed in the United Network of Organ Sharing (UNOS) national registry. When a final decision is made to list, the candidate will be assigned a subject identification number. All patients will receive organ offers as per UNOS regulations. When a matching donor liver becomes available, the inclusion and exclusion criteria will be re-verified.

Official Title
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A Single-Arm Nonrandomized Phase II Study of Liver Transplantation in Locally Advanced Unresectable Non-Metastatic Intrahepatic Cholangiocarcinoma Treated With Neoadjuvant Systemic Therapy

Conditions
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Locally Advanced Non-metastatic Intrahepatic Cholangiocarcinoma, Determine Efficacy of Liver Transplantation After Neoadjuvant Systemic Therapy in Patients With Locally Advanced Non-metastatic Intrahepatic Cholangiocarcinoma

Intervention / Treatment
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* Procedure: Liver Transplant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years of age on the day of consenting to the study. Patients must have histologically confirmed diagnosis of locally advanced intrahepatic cholangiocarcinoma Confirmed diagnosis of locally advanced unresectable iCCA with no vascular invasion, lymph node, or extrahepatic disease. Unresectable disease based on tumor location or underlying liver disease Patients must have ≥ 6 months of disease stability or tumor regression on neoadjuvant therapy. In cases in which patients had received second-line therapy, disease must also have been controlled for ≥ 6 months on that regimen. Patients who had previous surgical resection for iCCA are eligible if surgery occurred more than 6 months prior to listing, and patients have had ≥ 6 months of disease stability or response on therapy. ECOG performance status ≤1 (Karnofsky ≥70%, see Appendix A). Patients must have organ and marrow function acceptable for liver transplantation per institutional protocol: If history of chronic hepatitis B virus (HBV) infection, viral load should be undetectable on suppressive therapy. If history of chronic hepatitis C virus (HCV) infection, patients should have undetectable HCV viral load. Women of child-bearing years must have contraception plan in place from the time of study enrollment until at least one year following liver transplant. Ability to understand and the willingness to sign a written informed consent document Meets all other medical and psychosocial criteria for liver transplant Demonstrate ability to comply with study procedures Exclusion Criteria: Age <18 years of age on the day of consenting to the study. Patients who have extrahepatic metastases, lymph node involvement, invasion or encasement of major hepatic vascular structures, perforation of the visceral peritoneum, invasion of extrahepatic structures, invasion of perihilar fat, periductular invasion, concurrent hepatoma or mixed hepatocellular cholangiocarcinoma. Concurrent severe and/or uncontrolled concurrent illness including, but not limited to, ongoing or active infection, acute fulminant liver failure, symptomatic congestive heart failure, unstable angina pectoris, severe uncorrected coronary artery disease, severe cerebrovascular disease, severe pulmonary disease, or psychiatric illness/social situations that would limit compliance with study requirements and that would exclude the patient from eligibility for liver transplantation per institutional protocol. Prior solid organ or bone marrow transplant Dependent on ≥2 IV inotropic support to maintain hemodynamics Previous (within the past 5 years) or concurrent presence of other cancer, except non-melanoma skin cancer and in situ carcinomas. ECOG performance status >1 (Karnofsky <70%, see Appendix A). Unable to understand and sign a written informed consent document Untreated viral hepatitis Pregnant or breast-feeding women HIV-infected patients

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 89 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 |
| --- | --- |
| Intrahepatic cholangiocarcinoma listed for liver transplant<br>Listed patients enrolled with diagnosis of intrahepatic cholangiocarcinoma will be enrolled on an intent to treat basis with comparison between patients receiving transplant versus those who expire or are removed from the waitlist. | Procedure: Liver Transplant<br>* Whole liver allotransplantation will be performed for patients on the liver transplant waiting list<br>* Other names: Orthotopic liver transplantation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Endpoint | The primary endpoint of the current study is to compare 5-year OS of patients with biologically responsive locally advanced non-metastatic intrahepatic cholangiocarcinoma (iCCA) undergoing liver transplantation after neoadjuvant systemic therapy to patients historically treated with chemotherapy alone. | 5 years or through study completion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Outcome: Recurrence-free survival (RFS) | To determine recurrence-free survival (RFS) among locally advanced none metastatic iCCA treated with neoadjuvant system therapy followed by liver transplantation. | 5 years or through study completion | 
| Secondary Outcome: Intent-to-treat Overall Survival | All patients enrolled in the study will be assessed for survival from the time of enrollment for survival from enrollment through 5 years or study completion. | 5 years or through study completion | 
| Secondary Outcome: Postoperative Complication | To identify postoperative complications, short-term and long-term morbidities with liver transplantation after neoadjuvant systemic therapy in patients with biologically responsive locally advanced non-metastatic iCCA. | 5 years or through study completion | 
| Secondary Outcome: Molecular Analysis to Identify Biomarkers | To perform molecular profiling assays on malignant and normal tissues using next-generation sequencing in order to identify potential predictive and prognostic biomarkers beyond any genomic alteration by which treatment may be assigned. | 5 years or through study completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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liver transplantation, neoadjuvant systemic therapy, intrahepatic cholangiocarcinoma, iCCA, locally advanced non-metastatic iCCA, Locally advanced non-metastatic intrahepatic cholangiocarcinoma, liver transplant