Trial Title:
Liver Transplantation in Intrahepatic Cholangiocarcinoma
NCT ID:
NCT06140134
Condition:
Intrahepatic Cholangiocarcinoma
Cholangiocarcinoma, Intrahepatic
Conditions: Official terms:
Cholangiocarcinoma
Liver Extracts
Conditions: Keywords:
liver transplantation
neoadjuvant systemic therapy
intrahepatic cholangiocarcinoma
iCCA
locally advanced non-metastatic iCCA
non-metastatic intrahepatic cholangiocarcinoma
liver transplant
unresectable intrahepatic cholangiocarcinoma
locally advanced intrahepatic cholangiocarcinoma
Study type:
Observational [Patient Registry]
Overall status:
Recruiting
Study design:
Time perspective:
Prospective
Intervention:
Intervention type:
Procedure
Intervention name:
Liver Transplant
Description:
Whole liver allotransplantation will be performed for patients on the liver transplant
waiting list
Arm group label:
Intrahepatic cholangiocarcinoma listed for liver transplant
Other name:
Orthotopic liver transplantation
Summary:
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:
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.
Criteria for eligibility:
Study pop:
Patients with biologically responsive locally advanced non-metastatic intrahepatic
cholangiocarcinoma (iCCA) treated with neoadjuvant systemic chemotherapy with a
radiographic disease stability or regression.
Sampling method:
Probability Sample
Criteria:
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
Gender:
All
Minimum age:
18 Years
Maximum age:
89 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Rutgers New Jersey Medical School
Address:
City:
Newark
Zip:
07103
Country:
United States
Status:
Recruiting
Contact:
Last name:
Keri E Lunsford, MD, PhD
Email:
keri.lunsford@rutgers.edu
Facility:
Name:
University Hospital
Address:
City:
Newark
Zip:
07103
Country:
United States
Status:
Recruiting
Contact:
Last name:
Keri E Lunsford, MD, PhD
Email:
keri.lunsford@rutgers.edu
Investigator:
Last name:
Keri E Lunsford, MD, PhD
Email:
Principal Investigator
Investigator:
Last name:
James V Guarrera, MD
Email:
Sub-Investigator
Investigator:
Last name:
Flavio Paterno, MD
Email:
Sub-Investigator
Investigator:
Last name:
Arpit Amin, MD
Email:
Sub-Investigator
Investigator:
Last name:
Grace S Lee-Riddle, MD
Email:
Sub-Investigator
Start date:
December 15, 2023
Completion date:
November 2029
Lead sponsor:
Agency:
Rutgers, The State University of New Jersey
Agency class:
Other
Source:
Rutgers, The State University of New Jersey
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06140134
