Liver transplant is emerging as a treatment option in patients with unresectable hilar or intrahepatic cholangiocarcinoma (CCA), with accumulating data supporting transplant protocols in patients with early-stage CCA.
A protocol for liver transplant in patients with unresectable hilar CCA was developed by the Mayo Clinic, explained John Fung, MD, PhD, Director, Transplantation Institute, University of Chicago, IL, who spoke at the 2020 Cholangiocarcinoma Summit.
This protocol combines neoadjuvant radiation and chemotherapy, in the form of external beam radiotherapy with bolus 5-fluorouracil, followed by brachytherapy and oral capecitabine, a formal staging operation to rule out metastases or local extension of the tumor, which would preclude complete resection, followed by orthotopic liver transplant. The staging laparotomy is important to detect peritoneal disease and rule out node-positive disease.
To be eligible for liver transplant at the Mayo Clinic, patients must have either malignant cytology or histology, an elevated CA 19-9 level without cholangitis, or polysomy on fluorescence in situ hybridization, and the cancer should be primarily located above the cystic duct. Patients are ineligible if they have a mass extending >3 cm into the parenchyma, have undergone previous attempted resection with violation of the tumor plane, and have had a transperitoneal biopsy.
“Presence of lymph-node metastases is a contraindication in this setting,” said Dr Fung. “All patients undergo, during the staging laparotomy, lymph-node biopsies and/or EUS [endoscopic ultrasound] biopsy of suspicious lymph nodes.”
Results from 214 patients who underwent transplant at the Mayo clinic showed a 65% survival rate at 5 years and a 60% survival rate at 10 years after transplant.
A retrospective study assessing outcomes after liver transplant in patients with small intrahepatic CCA tumors reported a 5-year survival rate of more than 60% compared with 45% in patients with larger intrahepatic CCA tumors.
“As you would expect, the patients that had larger tumors had more risks for tumor recurrence, with a 5-year recurrence rate of about 50%, compared to less than 20% in the smaller tumors,” Dr Fung said.
According to the M.D. Anderson Cancer Center protocol, a 6-month duration of stability while receiving neoadjuvant therapy is an appropriate basis for the selection of patients with biologically favorable intrahepatic CCA for transplant. With this protocol, imaging is repeated every 3 months and must demonstrate stable or regressing disease. In 6 patients with intrahepatic CCA who had a transplant there, the 1-year survival rate was 100%, and the 5-year rate was 83%. The 5-year disease-free survival was 50%.
And at the University of California, Los Angeles, survival rates were evaluated in 37 patients with intrahepatic CCA and 20 patients with hilar CCA who underwent either resection or orthotopic liver transplant. Approximately 66% of the patients received adjunctive therapy. The hazard ratio for recurrence was 4 times higher in the patients who had resection than in those who had orthotopic transplant.
In the group that underwent resection, hilar CCA was associated with a 3-fold increased risk for recurrence compared with intrahepatic CCA. Perineural involvement, multifocality, and larger tumor size also increased the risk for recurrence. A trend toward better disease-free survival with transplant was observed, but the difference was not significant, because of the small number of patients.
Although the population of patients eligible for resection is expanding as a result of the novel techniques and neoadjuvant therapies that are improving resection rates, patients who have intrinsic liver disease and early-stage CCA should be considered for transplant, suggested Dr Fung. Patients with larger CCA tumors are also candidates for liver transplant.
Combining the experience from multiple centers will help to identify candidates for liver transplant, perhaps through the use of tumor markers and genomic mutations, explained Dr Fung.
He emphasized the importance of a multidisciplinary team to apply the newest tools (ie, imaging, immunosuppression) to prepare patients for transplant and to provide proper management afterward, and stressed the potential of targeted therapies in addressing disease recurrence.
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