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Liver transplantation for cholangiocarcinoma

Past, present, and the future

Begum, Saleema; Khan, Muhammad R; Chang, Stephen

doi: 10.4103/ijssr.ijssr_3_18
Review Article

Management of hilar cholangiocarcinoma (CCA) remains a major challenge incorporating complex diagnostic and therapeutic modalities. The management has evolved over the decades in pursuit of optimal therapeutic outcome for this challenging pathology. The only curative therapeutic option for CCA is complete (R0) surgical resection with negative margins. Curative resection for hilar CCA (HCCA) remains a surgical challenge due to its high propensity for invasion into liver parenchyma, encasement of portal vessels, and metastasis to regional lymph nodes. Liver transplantation (LT) was proposed as an alternative therapeutic option, but the initial results were extremely disappointing due to high rate of recurrence. The management has evolved over decades with introduction of neoadjuvant treatment options followed by LT resulting in optimal outcomes for an otherwise lethal disease. The current review outlines the changing trends in the management of HCCA over the years.

Department of Surgery, Aga Khan University and Hospital, Karachi 74800, Pakistan

Department of Surgery, Aga Khan University and Hospital, Karachi 74800, Pakistan

Mt Elizabeth Liver Transplant Program, GLAD Clinic, Mount Elizabeth Hospital, Singapore

Address for correspondence:Muhammad Khan, Department of Surgery, Aga Khan University and Hospital, Karachi 74800, Pakistan

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Cholangiocarcinoma (CCA) is an aggressive tumor arising from epithelial cells of biliary tract, usually classified as intrahepatic, hilar, and distal CCA depending on the location. The most common type of CCA is hilar (60%–70%) followed by distal CCA (20%–30%). Intrahepatic CCA is the least common variety (5%–10%), but it is the second most frequent primary liver malignancy after hepatocellular carcinoma (HCC). 1 Management of CCA remains a major challenge incorporating complex diagnostic and therapeutic modalities. The only curative therapeutic option for CCA is complete (R 0) surgical resection with negative margins, 2 and unfortunately, only 50%–70% of patients who undergo surgery are the candidates for curative resection. 3 Various innovative perioperative strategies such as portal vein embolization, neoadjuvant chemoradiation, and extended liver resection techniques with vascular reconstruction have improved the chances of curative resection and thus survival in patients with CCA in the recent years. 4 Hilar and intrahepatic CCA usually require complex hepatic resection or liver transplantation (LT), and changing trends in its management over the decades form the basis of the current review.

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Resection for Cholangiocarcinoma… a Surgical Challenge

Curative resection for hilar CCA (HCCA) is a surgical challenge due to its high propensity for invasion into liver parenchyma, encasement of portal vessels, and metastasis to regional lymph nodes. Locally advanced disease at presentation usually results in poor patient survival. Despite advances in surgical techniques, most of the patients may not be candidates for extended surgical resection. Extensive surgical resection is poorly tolerated in patients with underlying primary sclerosing cholangitis (PSC) and those with cirrhosis and concomitant hepatocellular carcinoma. 5 Extensive resection in such patients may result in postoperative liver failure and high mortality rates due to small future liver remnant. Even with resectable disease, 5-year survival rates vary between 25% and 40% after tumor resection 6 and may improve to 50% with more radical surgery including extended liver resection and vascular reconstruction. 7

Due to limitations of curative hepatic resection in patients with CCA, extensive search has focused on alternative treatment options. Various palliative modalities such as biliary drainage, photodynamic therapy, chemotherapy, and radiation result in median survival of <12 months for unresectable tumors. 8 Such dismal outcomes prompted the application of advanced procedures such as LT in patients with CCA. Theoretically speaking, patients with locally unresectable tumors with central vascular encasement, bilobar involvement, and CCA arising in the background of PSC with insufficient hepatic reserves should be good candidates for total hepatectomy, regional lymphadenectomy, and liver transplant. Liver transplant offers the only surgical option in such patients to achieve negative margin resection as well as treatment of underlying parenchymal disease.

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The Past… Disappointing Results of Transplantation for Cholangiocarcinoma

Orthotopic LT has been established since 1990s for end-stage liver disease and HCC. LT resulted in significant survival benefit in these patients with widest possible tumor-free margins after total hepatectomy and replacement of underlying parenchymal disease with a healthy liver graft. 9 After promising results for HCC, LT was proposed as optimal management for unresectable CCA. However, the early experience of LT for CCA was disappointing due to unacceptably high tumor recurrence rates under immunosuppression. Results from Hannover in 1996 reported a 5-year survival rate of only 17% for CCA after LT, which was no higher than survival after resection. Table 1 depicts historical studies and survival rates after LT in early reported data.{Table 1}

The most common reason for death after LT was recurrence. Lifetime immunosuppression, intraoperative tumor cell seeding, and microscopic metastases accounted for posttransplantation failure. 18 In addition, organ allocation for a patient with 5-year survival <50% and increasing donor organ shortage prompted preferential allocation to those who had the best chance of long-term survival. 19 Based on these discouraging results and donor organ shortage, the role of LT was not very well established and CCA was regarded as contraindication to LT.

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The Evolution… Era of Neoadjuvant Therapy

After initial poor outcomes after LT for CCA, the search for effective systemic therapy continued at many fronts. The efficacy of neoadjuvant therapy for CCA was demonstrated by several studies but often limited by dose-related hepatotoxicity. Reversing the hepatotoxicity with safe use of high doses of chemotherapeutic agents was considered as the potential advantage of LT in such cases.

Two American groups devised this new concept, which improved the outcomes after LT for CCA. The University of Nebraska introduced the concept of use of neoadjuvant therapy before LT. 15 Patients included in LT protocol for CCA had percutaneous biliary drains placed. Apart from relieving jaundice, these catheters provided access for the placement of iridium-192 wires for tumor irradiation. Total dose of 6000 Gy was delivered over 55–60 h, and at the same time, daily continuous dose of 5-flurouracil (FU: 300 mg/m 2) was started. Patient while on waiting list underwent exploratory laparotomy and lymphadenectomy to rule out extrahepatic involvement before LT. They published their results of 17 patients in 2002 which showed 3-year survival rate of 45% which was higher than the comparative studies without neoadjuvant treatment. 15

Mayo hospital in 2004 published their modified neoadjuvant protocol. They established a diagnosis of CCA by cytology, histology, or CA 19–9 >100 U/ml in the presence of a radiologically suggestive malignant stricture. Patients were considered candidates for LT if a HCCA or extrahepatic CCA arouse in the background of PSC or lesion was unresectable in the absence of PSC. It consisted of external beam radiation therapy administered with a target dose of 4500 Gy in 30 fractions, delivered over a 3-week period. Intravenous fluorouracil was given at 500 mg/m 2at a daily bolus for the first 3 days at the initiation of the external beam radiotherapy. At 2–3 weeks after completion of the external beam radiation, transluminal boost of radiation was delivered using a catheter with iridium-192 seeds, with the dose of 2000–3000 Gy. Thereafter, patients were targeted with oral capecitabine at a dose of approximately 3 g/day for 2 out of every 3 weeks while awaiting LT. Routine exploratory laparotomy was performed to rule out extrahepatic spread before transplant and only patients with confirmed Stage I and II disease were eligible for transplantation. Posttransplant patients received standard immunosuppression including tacrolimus, mycophenolate, and prednisone. Between 1993 and 2006, 65 patients with CCA underwent LT. According to the published results, survival at 1, 3, and 5 years was 91%, 82%, and 76%, respectively. Their results with neoadjuvant therapy and LT for unresectable HCCA were comparable with those for early HCC and end-stage liver disease. 20 At the last follow-up, 17% patients had developed recurrence 7–64 months after LT. These results had a positive impact on the neoadjuvant approach, and further groups reported promising results, which changed the perspective of CCA being a contraindication to LT. Table 2 depicts the results of neoadjuvant era.{Table 2}

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The Present… Liver Transplantation for Cholangiocarcinoma

The dismal prognosis in 1990s and donor organ shortage were the limiting factors against the establishment of LT as the standard procedure for unresectable CCA in the North American and European centers. However, it is critical to understand the fact that the disappointing results were based on rather a generous patient selection. It is worthwhile to reevaluate patients for LT under specified circumstances. In recent years, studies have proven that careful patient selection with use of neoadjuvant therapy can prolong the survival after LT with outcomes comparable to the classical standard indications of LT such as HCC and end-stage liver disease Table 2.

It seems that liver transplant for CCA may represent as an acceptable procedure today in some centers with a highly strict selection process and with neoadjuvant chemoradiation. Despite lack of standard guidelines in this regard, there are a number of centers performing liver transplant for CCA within and outside clinical trials. Several studies are currently underway to scrutinize the worth of LT for CCA. The trials are registered in the central database, and some of them are given below.

  1. Study NCT00301379 is a prospective registry study of neoadjuvant chemoradiation and LT for CCA patients, initiated at Washington University. The objective is to evaluate the treatment of patients with unresectable CCA and how many of them receive LT and 2-year survival
  2. Study NCT01549795 from Padua, Italy, has started recruitment in 2012. Unresectable CCA patients are considered for LT after pretreatment with external beam radiation (45 Gy) and endoluminal bile duct brachytherapy (20 Gy) combined with capecitabine. Before LT, a laparoscopic hand-assisted evaluation of the abdominal cavity is performed. This is a single-arm trial without control group
  3. Study NCT02178280 from Nanjing University Medical School, China, was started in June 2014. This nonrandomized single-arm study also combines neoadjuvant brachytherapy with external beam radiation and capecitabine before LT
  4. Study NCT02232932 from Paris, France, was initiated in 2014 and aims to include 60 individuals until 2021. This prospective, open-label, randomized, multicenter comparative study compares LT for CCA preceded by neoadjuvant radiochemotherapy to conventional hepatic and bile duct resection. Treatment in the LT group consists of external beam radiation and capecitabine.

The outcomes of the similar trials might help develop guidelines and protocols for the standardized application of LT in patients with CCA.

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The Future…

Review of the available literature suggests that unresectable CCA is emerging into focus as an indication for LT. The criteria for unresectable tumors need to be standardized in all centers. Extended hepatic resection should be considered in resectable tumors with comparable outcomes to LT in specialized centers that would try to overcome the shortage of donor grafts. Study by Paris group is currently working on the comparison of advantages between resection and transplant for CCA, but the results are not available yet as the recruitment is scheduled until 2021.

For LT, patients may be divided into two categories: patients with CCA associated with and without PSC. For PSC-associated patients where there is early detection of tumor due to constant medical surveillance, LT is the best option. Due to underlying parenchymal disease and chances of bile leak after partial hepatectomy, resection is not a suitable option for these patients. Studies demonstrate encouraging long-term survival results after LT in carefully selected patients. 35 For CCA without PSC, resection is the treatment of choice. Chances of significant long-term survival have been observed even in patients with positive lymph nodes or incomplete surgical resection with adjuvant protocols.

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Liver transplant for HCCA has undergone a transformation over the last few decades. In view of the recent available literature, neoadjuvant therapy followed by LT as devised by the Mayo group has shown promising results in prolonging the 5-year survival. For patients with unresectable hilar and intrahepatic CCA, LT may be justified under strict protocols. Careful patient selection is critical in allocating liver grafts for patients before transplantation. Candidates must have tumor size smaller than 3 cm on cross-sectional imaging; computed tomography/magnetic resonance imaging must be performed 3 monthly while on neoadjuvant therapy and waiting for LT for staging of any intrahepatic or extrahepatic metastasis, and staging laparotomy must be performed after neoadjuvant therapy and before LT to rule out lymph node involvement and metastasis. Various multicenter studies are underway which will further clarify the definitive role of LT for CCA and the most effective perioperative regimen.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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36. . .;:

    Cholangiocarcinoma; resection; transplantation

    © 2018 President and Fellows of Harvard College