Liver Transplantation in Intrahepatic Cholangiocarcinoma

March 8, 2024 updated by: Keri E. Lunsford, Rutgers, The State University of New Jersey

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Research Significance:

Cholangiocarcinoma, which arises from biliary epithelium, can be anatomically subdivided into distal, hilar, and intrahepatic subgroups. Intrahepatic cholangiocarcinoma (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. At present, surgical resection is the only widely accepted potentially curative therapy for iCCA; however, 5-year survival rates for resectable disease are less than 25%. This high mortality is attributed to high tumor recurrence. Two-thirds of patients who undergo curative-intent resection for iCCA suffer from postoperative disease recurrence, most commonly in the remnant liver, followed by the peritoneum and abdominal lymph nodes. Approximately 83% of recurrences occur within the first 2 years after resection, suggesting inadequate local tumor control with resection in this highly infiltrative cancer.

Liver transplantation for intrahepatic cholangiocarcinoma:

While liver transplantation has been previously investigated for unresectable iCCA, the outcomes have been poor in comparison to the results for hepatocellular carcinoma, with 18-25% OS and RFS after 5 years; however, most studies evaluated patients with either incidental iCCA or iCCA misdiagnosed prior to transplant as hepatocellular carcinoma (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. Subsequently, several studies reported improved survival for hilar cholangiocarcinoma treated with neoadjuvant chemoradiation followed by liver transplantation. A multicenter study reported a 65% 5-year survival rate; liver transplantation has thus 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 (iCCA):

The published literature regarding liver transplantation (LT) for iCCA is mostly limited to incidental or misdiagnosed tumors identified on pathology, with most patients not receiving neoadjuvant therapy. Retrospective analysis including 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 investigated outcomes of liver transplantation in 48 iCCA patients who had not received neoadjuvant chemotherapy or locoregional 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 having received pre-transplant neoadjuvant therapy in this series were excluded. 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 tumor dimensions. These findings 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 experienced 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 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%. In regards to recurrence, 4 of 5 occurred within 12 months of transplant. Retrospective evaluation of the pre-transplant imaging demonstrated evidence of pre-transplant extrahepatic disease. More stringent 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. Therefore, the investigators 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 decision is made to list the patient, the patient will be assigned a subject identification number. All organ offers will be received as per UNOS regulations. When a matching donor liver becomes available, the inclusion and exclusion criteria will be re-verified.

Study Type

Observational

Enrollment (Estimated)

30

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • New Jersey
      • Newark, New Jersey, United States, 07103
      • Newark, New Jersey, United States, 07103
        • Recruiting
        • University Hospital
        • Contact:
        • Principal Investigator:
          • Keri E Lunsford, MD, PhD
        • Sub-Investigator:
          • James V Guarrera, MD
        • Sub-Investigator:
          • Arpit Amin, MD
        • Sub-Investigator:
          • Grace S Lee-Riddle, MD
        • Sub-Investigator:
          • Flavio Paterno, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

Patients with biologically responsive locally advanced non-metastatic intrahepatic cholangiocarcinoma (iCCA) treated with neoadjuvant systemic chemotherapy with a radiographic disease stability or regression.

Description

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.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status Scale score >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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Intrahepatic cholangiocarcinoma listed for liver transplant
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
Whole liver allotransplantation will be performed for patients on the liver transplant waiting list
Other Names:
  • Orthotopic liver transplantation

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
5-year Overall Survival Rate (ORS)
Time Frame: 5 years from the time of transplant or until death of patient, whichever came first
5-year ORS is the length of time that patients diagnosed with locally advanced non-metastatic intrahepatic cholangiocarcinoma (iCCA) treated with neoadjuvant systemic therapy followed by liver transplant (LT) are still alive post-LT.
5 years from the time of transplant or until death of patient, whichever came first

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Recurrence-free survival (RFS)
Time Frame: From date of transplant until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years
RFS is the length of time from liver transplantation (LT) to the time of disease recurrence, time of patient death, or time of study completion for patients with locally advanced non-metastatic intrahepatic cholangiocarcinoma treated with neoadjuvant systemic therapy followed by liver transplantation.
From date of transplant until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years
Intent-to-treat Overall Survival Rate (ITT ORS)
Time Frame: 5 years from time of waitlist or until death of patient, whichever came first
ITT ORS is the length of time that patients diagnosed with locally advanced non-metastatic intrahepatic cholangiocarcinoma (iCCA) treated with neoadjuvant systemic therapy and waitlisted for liver transplant for iCCA are still alive after being waitlisted for liver transplantation.
5 years from time of waitlist or until death of patient, whichever came first
Post-liver transplant functional assessments to identify postoperative complications, short-term morbidities, and long-term morbidities
Time Frame: From date of emergence of a post-transplant adverse event until the date the adverse event is designated as resolved by investigator or its effect on patient's condition stabilizes, whichever came first, assessed up to 5 years
All serious adverse events will be followed and documented, including bleeding requiring re-operation, hepatic artery or portal vein thrombosis, bile duct leak, bile duct stricture, primary non-function of the transplant liver, need for re-transplant of the liver.
From date of emergence of a post-transplant adverse event until the date the adverse event is designated as resolved by investigator or its effect on patient's condition stabilizes, whichever came first, assessed up to 5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Rutgers, The State University of New Jersey

Investigators

  • Principal Investigator: Keri E Lunsford, MD, PhD, Rutgers University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 15, 2023

Primary Completion (Estimated)

November 1, 2028

Study Completion (Estimated)

November 1, 2029

Study Registration Dates

First Submitted

October 2, 2023

First Submitted That Met QC Criteria

November 14, 2023

First Posted (Actual)

November 18, 2023

Study Record Updates

Last Update Posted (Actual)

March 12, 2024

Last Update Submitted That Met QC Criteria

March 8, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro2021000973

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual participant data that underlie the results reported in this study after deidentification (text, tables, figures and appendices)

IPD Sharing Time Frame

Following publication of study results

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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