Liver Transplantation for Cholangiocarcinoma
Liver Transplantation for Cholangiocarcinoma
Today, available therapies for hilar cholangiocarcinomas (CCA) are not satisfactory. Although
 these tumors are rare, their study is important because of the high death rates in afflicted
 patients, rivaling that of pancreatic cancer. Surgical resection offers the only current hope
 for long-term survival, averaging only 20% in major series1. The reality is such that for the
 majority of patients, CCA is a diagnosis of despair.

 Although surgery has offered the only hope of cure, one of the major limiting factors in
 achieving long-term survival following surgical resection of CCA is the technical ability to
 achieve negative resection margins. The presence of malignant cells at the surgical margins
 following resection is a major prognostic factor predicting recurrence and death.
 Theoretically, the likelihood of achieving negative margins can be increased with total
 hepatectomy and orthotopic liver transplantation (OLT). Previous experience with OLT
 performed in isolation for hilar CCA's has been discouraging with dismal survival rates.
 However, a recent report has demonstrated that long-term survival can occur in carefully
 selected patients by combining the benefits of radiotherapy, chemosensitization, and OLT.
 With this strategy, patients survival rates of 92%, 82%, and 82% at 1, 3, and 5 years after
 transplantation have been achieved. It is not clear that these preliminary results can be
 confirmed at other centers, nor is it clear what selection criteria should optimally be used
 for this treatment strategy.

 Our hypothesis is that select patients undergoing liver transplantation for CCA in the
 context of multi-modality neoadjuvant therapy exhibit survival equivalent to other
 established indications for liver transplantation as previously demonstrated. We will also
 attempt to extend previously published criteria for liver transplantation in the setting of
 CCA by offering this protocol to patients with evidence of intrahepatic disease and regional
 nodal disease. Patients undergoing transplantation for CCA will be followed longitudinally
 for their entire post-transplant course and compared with a matched cohort of liver
 transplant recipients in regard to post-transplant survival, survival on the waiting list, as
 well as complications pre-and post-transplantation. Explanted livers will be examined for the
 presence of residual tumor.

 Data will be collected on the rate of regional lymph node metastasis, invasion of adjacent
 organs and tissues, and the rate of peritoneal metastases. The rate of tumor recurrence,
 site, and time to recurrence will also be assessed.
Objectives Specific Aim #1: Determine whether results obtained in select patients with
 American Joint Commission on Cancer (AJCC) Staging System Stage I or II CCA are transferable
 to select patients with T3 or N1 disease.

 Specific Aim #2: To determine whether success achieved with the only published protocol
 currently in use is directly transferable to the University of Utah's liver transplant
 program.

 Liver Transplant Protocol:

 The surgical protocol will initially be offered to liver transplant candidates with de novo
 hilar CCA or CCA arising in the setting of PSC. Diagnosis of CCA will be established by
 intraluminal brush cytology, intraluminal biopsy, or a carcinoma antigen (CA) 19.9 level
 greater than 100 ng / mL in the setting of a radiographic malignant stricture. Biliary
 aneuploidy demonstrated with DIA and FISH will be considered equivalent to cytology.

 All patients with CCA will be evaluated by the liver transplant team which includes
 experienced hepatobiliary and liver transplant surgeons. Patients will be presented at the
 weekly liver transplant selection conference to assess their candidacy as well as the weekly
 GI Multidisciplinary Tumor Conference at the Huntsman Cancer Institute. Clinical staging
 prior to neoadjuvant therapy will include chest and abdominal computed tomography, liver
 ultrasound, and bone scan. Patients will also undergo endoscopic ultrasound with fine needle
 aspiration of suspicious lymph nodes. Exclusion criteria will include previous chemotherapy
 or radiotherapy, uncontrolled infection, a previous malignance other than non-melanoma skin
 cancer or in situ cervical cancer within the last five years, medical conditions precluding
 transplantation, metastatic disease (including N2 disease), and patients with hilar tumors
 extending below the cystic duct.

 All patients will undergo staging laparoscopy to rule out the presence of peritoneal disease
 followed by staging laparotomy. Patients with extrahepatic metastases, local spread of
 disease to adjacent organs, and N2 nodal disease (metastasis to peripancreatic, periduodenal,
 periportal, celiac, superior mesenteric, and / or posterior pancreaticoduodenal nodes) will
 be excluded as will patients with extension of tumor into the main portal vein. Patients with
 N1 disease (metastasis to lymph nodes within hepatoduodenal ligament) will remain eligible
 for the protocol. Tumor size will not be included in the exclusion criteria. Patients with
 evidence of disease progression beyond study criteria will not be eligible to continue on to
 liver transplantation.
The surgical protocol will initially be offered to liver transplant candidates with de novo
 hilar CCA or CCA arising in the setting of PSC. Diagnosis of CCA will be established by
 intraluminal brush cytology, intraluminal biopsy, or a carcinoma antigen (CA) 19.9 level
 greater than 100 ng / mL in the setting of a radiographic malignant stricture.

 Biliary aneuploidy demonstrated with DIA and FISH will be considered equivalent to
 cytology.

 All patients with CCA will be evaluated by the liver transplant team which includes
 experienced hepatobiliary and liver transplant surgeons. Patients will be presented at the
 weekly liver transplant selection conference to assess their candidacy as well as the
 weekly GI Multidisciplinary Tumor Conference at the Huntsman Cancer Institute. Clinical
 staging prior to neoadjuvant therapy will include chest and abdominal computed tomography,
 liver ultrasound, and bone scan. Patients will also undergo endoscopic ultrasound with fine
 needle aspiration of suspicious lymph nodes.

 All patients will undergo staging laparoscopy to rule out the presence of peritoneal
 disease followed by staging laparotomy.

 Patients with N1 disease (metastasis to lymph nodes within hepatoduodenal ligament) will
 remain eligible for the protocol.

 Tumor size will not be included in the exclusion criteria. Patients with evidence of
 disease progression beyond study criteria will not be eligible to continue on to liver
 transplantation.

 ** Patients with metastatic disease are not eligible for this trial **

 Exclusion criteria will include:

 -  previous chemotherapy or radiotherapy,

 -  uncontrolled infection,

 -  a previous malignance other than non-melanoma skin cancer or in situ cervical cancer
 within the last five years,

 -  medical conditions precluding transplantation,

 -  metastatic disease (including N2 disease), and

 -  patients with hilar tumors extending below the cystic duct.

 Patients with extrahepatic metastases, local spread of disease to adjacent organs, and N2
 nodal disease (metastasis to peripancreatic, periduodenal, periportal, celiac, superior
 mesenteric, and / or posterior pancreaticoduodenal nodes) will be excluded as will patients
 with extension of tumor into the main portal vein.