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Page 2 of 15 Alqahtani et al. Hepatoma Res 2020;6:70 I http://dx.doi.org/10.20517/2394-5079.2020.65

INTRODUCTION
Cholangiocarcinoma (CCA) refers to a group of malignancies that arise from epithelial cells along the
[1]
[1]
biliary tree . It is a rare tumor type that accounts for less than 1% of all human cancers . Based on the
location of the tumor, CCAs are divided into three categories: Intrahepatic CCAs (iCCAs) are within
the liver parenchyma (i.e., proximal to the second-degree bile ducts), whereas perihilar CCAs (pCCAs)
and distal CAAs (dCCAs) are outside the liver, with the cystic duct as the boundary between the two
[2,3]
[1]
types . Most CCAs are extrahepatic; iCCAs account for only 10%-20% of cases . CCAs are classified
[4]
histopathologically as adenocarcinomas, but rare histologic subtypes can be encountered .
[3]
Over the last decades, the incidence of CCA has increased in Western countries , which is the basis
[5,6]
for large studies that have looked into risk factors for cancer development . The most prominent risk
factors identified in these analyses are liver cirrhosis, viral hepatitis, metabolic syndrome, and diabetes
[5-8]
mellitus . However, the best-known risk factors for CCA are pre-existing conditions, such as choledochal
cysts, inflammatory bowel disease, and primary sclerosing cholangitis [9,10] .The incidence of CCA is highest
in Southeast Asia, where there is a strong relationship between infections with the hepatobiliary flukes
[10]
Opisthorchis viverrini and Clonorchis sinensis and CCA .

The only potentially curative treatment for patients with CCA is radical surgical resection of the lesion
combined with lymphadenectomy . Unfortunately, however, surgical resection is feasible in only about
[3]
30% of patients [3,11] , and recurrence after surgery is frequent; thus the prospects of long-term survival after
resection are poor [2,3,11] . To counter the high rates of local and distant recurrence after surgery for CCA,
several adjuvant treatment strategies have been explored, with mixed results [3,12-16] . In about 70% of patients,
[1]
the disease is unresectable or metastatic at the time of diagnosis . For these patients, the treatment
[1,3]
options are usually limited to systemic therapies . Only in a minority of advanced CCA patients are
palliative loco-regional therapies beneficial, and the use of this approach is restricted mainly to patients
with iCCA whose disease spread is limited to the liver. In this setting, small studies have demonstrated
that transarterial chemo- or radioembolization can provide local disease control, with a survival benefit
comparable to that of supportive care [17-21] . More recently, insight into the molecular basis of CCA and
understanding of the interplay between tumor cells and the immune system have led to the development of
targeted treatments. The most promising results in this area have come from studies evaluating inhibitors
of mutated forms of the FGFR or isocitrate dehydrogenase (IDH) and from studies evaluating immune
checkpoint inhibitors.

This review provides an overview of the systemic treatment options for patients with advanced CCA. Data
from the use of chemotherapy regimens in initial treatment and of recurrent disease, as well as a summary
of the clinical trials evaluating molecularly targeted agents or immunotherapy, are presented.

IS THERE A PLACE FOR ADJUVANT CHEMOTHERAPY IN PATIENTS WITH SURGICALLY
RESECTED CCA?
As discussed above, surgical resection of CCA is associated with a high rate of disease recurrence and a
poor long-term survival rate. In a series of 564 CCA patients who were operated on between 1973 and
2004, the five-year overall survival (OS) rate was only 18% (30% in patients in whom an R0 resection was
possible; median OS 15 months for all patients, 28 months for R0 patients) . The survival rate was better in
[2]
patients with more proximal tumors (i.e., five-year OS rates for R0 patients with iCCA, pCCA, and dCCA
of 63%, 30%, and 27%, respectively) . Data from the Memorial Sloan-Kettering Cancer Center confirm the
[2]
high risk of disease recurrence after surgical resection of CCAs; in their series, the median disease-specific
survival of patients with resected CCA was only 36 months, and almost two-thirds of patients had disease
[11]
relapse during a median follow-up of 26 months .In attempts to improve the dismal prognosis of resected