Hilar Cholangiocarcinoma and Liver Transplantation

Cholangiocarcinoma (CCA) is a malignant neoplasm with features of bile duct epithelial cell differentiation. This cancer, whose incidence is increasing, has a grim prognosis and unfortunately survival rates have not substantially changed over the past 10 years (¹). There is no established medical therapy, and although the primary treatment is surgical resection, many patients present with unresectable disease. Even with a complete resection (possible in 70%–80% of attempted surgical resections), most centers have reported 5-year survival for hilar lesions of 20% to 40% (^2–6).

Because of the limitations of surgical resection, orthotopic liver transplantation (OLT) was initially proposed as an optimal solution. Complete hepatectomy followed by transplantation addressed all relevant margins of resection and treatment of underlying liver disease, such as that occurs with primary sclerosing cholangitis, a primary risk factor. Unfortunately, the experience with liver transplantation alone for CCA was uniformly disappointing because of a high incidence of disease recurrence and subsequent mortality. Thus, OLT in the setting of hilar CCA is controversial and generally considered to be contraindicated (^7–9).

In this issue of Transplantation, Schwartz et al. (¹⁰) present a detailed analysis of the available literature related to OLT for hilar CCA, with an emphasis of the successful application of neoadjuvant chemoradiotherapy followed by OLT for selected patients with early stage hilar CCA. The center’s own experience with four patients who received neoadjuvant therapy followed by OLT and outcomes from other centers are described. Although the current report offers a limited amount of new data, the authors thoughtfully discuss the pertinent issues, which involve the need for a standardized protocol and rigorous patient selection, as well as the challenges surrounding organ allocation and determination of the appropriate model for end-stage liver disease (MELD) exception score.

As additional evidence of the effectiveness neoadjuvant therapy followed by OLT for selected patients with hilar CCA becomes available, the question is no longer whether to consider this therapy for unresectable patients with no other viable treatment options (clearly yes) but whom to transplant and how. The current available evidence is in support of neoadjuvant therapy followed by OLT for hilar lesions that have remained confined to the liver, as determined by operative staging in addition to standard radiographic staging. Once the tumor has metastasized, a localized therapy such as chemoradiotherapy followed by OLT is destined to fail. Clearly, for advanced tumors, novel systemic therapies are needed.

How to transplant these patients is an important question given the critical shortage of donor organs as well as the intensity of the resources required to provide appropriate support for the protocol (dedicated staff within radiation oncology, medical oncology, hepatology, transplant surgery, endoscopy, or interventional radiology). Transplantation using a living donor is an option though the radiation injury to the hilar vessels and the location of the tumor presents a challenge given the short vessels of a living donor allograft. Additionally, as only a limited number of potential living donors are found to be suitable, many recipients are left without this option.

Granting a standardized MELD exception, as for hepatocellular carcinoma, was recommended by the United Network for Organ Sharing consensus conference for patients with early stage hilar CCA treated with neoadjuvant therapy (¹¹). As Schwartz et al. identify, an MELD exception is being granted in a few of the regions across the United States, although the approach is inconsistent. To determine the appropriate MELD exception score, information regarding pre- and posttransplant mortality and the risk of disease progression while waiting is needed to determine the appropriate initial exception and subsequent upgrades (currently available from a handful of small single-center reports).

Aligning the centers currently performing this procedure for a multicenter retrospective review may provide insight, but given the small numbers involved and wide variation in access to transplant and other issues, it is unlikely that such a study would allow us to definitively set organ allocation policy. Creating a national MELD exception policy including standardized diagnostic criteria, data reporting, and neoadjuvant treatment protocols would mandate that this data be gathered and prospectively analyzed. Challenges in determining the appropriate initial MELD score exception are best illustrated by the hepatocellular carcinoma exception policy that has required revision three times since the initiation of the MELD system despite the vast amounts of data available. However, without a consistent national policy that requires data collection and a standardized approach, questions regarding appropriate organ allocation policy and the overall effectiveness of the protocol will remain essentially unanswerable. The knowledge gained from such an approach will allow for a far more equitable allocation policy, better prediction of posttransplant survival, and potentially even more effective neoadjuvant therapy.