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Early experiences with liver transplantation for the treatment of perihilar cholangiocarcinoma (CCA) uniformly reported high rates of disease recurrence and poor patient survival.1,2 Results were poor, even for patients with incidental early-stage cancers detected in explanted livers of patients that underwent transplantation for primary sclerosing cholangitis (PSC).3,4

The transplant teams at the University of Nebraska and Mayo Clinic pioneered the concept of aggressive neoadjuvant radiotherapy prior to liver transplantation and achieved early success. The new paradigm included (1) careful patient selection, (2) high-dose radiotherapy with chemosensitization, (3) operative staging. and (4) liver transplantation.5 Careful selection was designed to choose patients with early-stage disease without lymph node involvement and/or metastases. High-dose radiotherapy with chemosensitization was known to be effective in slowing progression of CCA and thought to be absolutely necessary in order to improve on the poor results observed with liver transplantation alone. Administration of neoadjuvant therapy prior to staging and transplantation was done to reduce tumor burden and the risk of dissemination of cancer while waiting for transplantation and potentially also during those operations. Operative staging was done to avoid transplantation for patients with regional lymph node and/or peritoneal metastases or locally extensive disease with direct invasion of surrounding structures. Liver transplantation achieves a radical resection, avoids future liver problems due to high-dose radiotherapy, and treats underlying liver disease such as PSC.

The Mayo Clinic protocol was designed in 1993 with an aim to treat patients with early-stage unresectable CCA arising de novo and patients with CCA arising in the setting of PSC. Early results were promising and led to widespread adoption of the protocol.6,7 Eventually, the United Network for Organ Sharing (UNOS) adopted the Mayo Clinic inclusion/exclusion guidelines and protocol guidelines (requiring neoadjuvant therapy and operative staging along with protocol review) to enable appropriate prioritization for CCA patients awaiting deceased-donor liver transplantation. The effectiveness of this combined-modality treatment is now well recognized by the transplant and hepatobiliary surgeons and the oncology community. Many transplant centers that have adopted this paradigm and the Center for Medicare and Medicaid Services and other commercial insurance companies now provide coverage for this treatment.

Neoadjuvant therapy and liver transplantation achieves results comparable to or better than those achieved with resection and palliation. Current Mayo Clinic results with over 270 patients enrolled in the neoadjuvant therapy protocol demonstrate overall 5-year survival rates of 61% for patients with underlying PSC and 37% for those with CCA arising de novo. Five-year survival rates after transplantation are 79% for patients with underlying PSC and 54% for those with CCA arising de novo (Fig. 66-1).


Patient survival after unresectable perihilar cholangiocarcinoma protocol. (A) All patients included in the protocol up to March 2015, (B) intention to treat survival, and (C) posttransplant survival.



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