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Gim et al. Hepatoma Res 2023;9:51 https://dx.doi.org/10.20517/2394-5079.2023.90 Page 3 of 20

Figure 1. Illustration of the anatomical sites of BTC includes intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma
(pCCA), and distal cholangiocarcinoma (dCCA). iCCA refers to malignancies located in the periphery of the second-order bile ducts,
while pCCA originates in the right or left hepatic duct and/or at their junction. On the other hand, dCCA involves the common bile duct.
Each subtype of BTC occupies a distinct anatomical position within the biliary tract. The collective term extrahepatic
cholangiocarcinoma (eCCA) is used to encompass both pCCA and dCCA.

the TOPAZ-1 trial, 42.5% of patients received subsequent anticancer therapy following immune-
[7]
chemotherapy . There are several factors that contribute to the limitation of advancing beyond the first line
of treatment. One such factor is the insufficient remaining healthy liver parenchyma, which significantly
restricts the feasibility of receiving cytotoxic systemic treatments, often resulting in poor outcomes.
Additionally, the overall performance status of patients with advanced or metastatic BTC tends to be
generally poor, further complicating treatment decisions and options. Infection poses another significant
barrier to overcome, as advanced BTC is often complicated by cholangitis, sepsis, and other issues
associated with the biliary tree.

When patients with BTC experience disease progression on the first line of therapy and are able to proceed
to second-line systemic treatment, the decision regarding the subsequent line of therapy becomes complex.
This complexity arises from the absence of a well-defined global treatment standard for this stage. The
ABC-06 trial has shown improved survival in patients who received second-line therapy with folinic acid,
fluorouracil, and oxaliplatin (FOLFOX) in combination with active symptom control (ASC) compared to
ASC alone . However, despite these advancements, the efficacy and prognosis remain discouraging, with
[4]
median OS at 6.2 months with FOLFOX.

Due to the discouraging prognosis and limited treatment options in BTC, advancements in molecular
techniques like next-generation sequencing (NGS) have paved the way for alternative approaches.
Moreover, patients with BTC display significant variations in their molecular characteristics and genetic
abnormalities, which can vary depending on their specific anatomic locations [Table 1]. This diversity in
molecular features makes BTC a potential candidate for targeted therapy. As a result, molecular analysis has
now become a routine part of diagnostic testing for advanced BTC cases, providing valuable insights for
treatment decisions and enhancing treatment efficacy. In the upcoming section, we will delve into diverse
targeted therapies for BTC, exploring their effectiveness and research findings in the context of this
challenging cancer.