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Page 2 of 20 Gim et al. Hepatoma Res 2023;9:51 https://dx.doi.org/10.20517/2394-5079.2023.90

INTRODUCTION
Biliary tract cancer (BTC) is a heterogeneous group of biliary cancers that occur at various locations along
the biliary tree, representing approximately 3% of gastrointestinal malignancies. BTC is divided into several
main subtypes based on its location: intrahepatic cholangiocarcinoma (iCCA), perihilar
cholangiocarcinoma (pCCA), and distal cholangiocarcinoma (dCCA). These subtypes represent different
locations along the biliary tree and contribute to the heterogeneity of BTC [Figure 1]. The incidence of BTC
[1]
is steadily increasing worldwide . Unfortunately, the prognosis for BTC remains grim due to delayed
detection and the limited number of patients (approximately 30% or less) who qualify for curative
surgery . Furthermore, while several study results support the use of neoadjuvant therapy to potentially
[2]
enhance survival and achieve a higher R0 resection rate, there is no unanimous consensus on its necessity .
[3]
Additionally, most patients are diagnosed at advanced stages with distant metastasis and extensive liver
involvement. The rarity of the disease and the lack of effective treatments intensify the urgency to explore
novel strategies for managing this devastating condition. The treatment of advanced BTC poses a significant
challenge because the condition remains incurable and alternative treatment options are limited. As a result,
the current approach focuses primarily on supportive care and systemic therapy to improve overall survival
(OS) and enhance quality of life. Despite efforts, the prognosis for advanced BTC patients varies
considerably, with reported median OS ranging from 4 to 12 months in different studies . Therefore, the
[4-6]
ongoing challenges in treating advanced or recurrent BTC underscore the necessity for further
advancements in therapeutic interventions.

The gemcitabine and cisplatin combination regimen has long been the standard systemic therapy for
advanced BTC, based on the findings of the ABC-02 study . This phase 3 trial compared the efficacy of
[6]
gemcitabine alone versus gemcitabine plus cisplatin and showed better OS and progression-free survival
(PFS) with the combined therapy. Patients received gemcitabine plus cisplatin for approximately 8 cycles,
followed by close surveillance. It also showed a better response rate (RR) in the combination regimen group
than in the gemcitabine monotherapy group (26.1 % and 15.5 %, respectively). Subgroup analysis revealed
the benefits of the combination therapy across different tumor locations, including intrahepatic,
extrahepatic, and gallbladder. These findings established the gemcitabine and cisplatin therapy as the
standard systemic treatment for advanced BTC.

In the pursuit of enhancing treatment outcomes, the TOPAZ-1 study investigated the addition of
immunotherapy to chemotherapy for advanced BTC . The study included patients who received up to 8
[7]
cycles of gemcitabine/cisplatin plus durvalumab, followed by durvalumab maintenance, compared to those
who received gemcitabine/cisplatin followed by placebo. The results demonstrated a positive outcome with
durvalumab, showing a median OS of 12.8 months compared to 11.5 months with placebo (hazard ratio
[HR] of 0.80; 95% confidence interval [CI]: 0.66-0.97 months; P = 0.021). The study also showed a higher RR
in the durvalumab group compared to the placebo group [26.7% and 18.7%, respectively, odds ratio of 1.60,
(95%CI: 1.11-2.31)]. Subgroup analyses based on sex, PD-L1 expression, tumor location (intrahepatic vs.
extrahepatic or gallbladder), and Asian vs. non-Asian populations all showed benefits from the combination
therapy. Additionally, the PFS was improved in durvalumab group. Consequently, the combination of
gemcitabine/cisplatin plus durvalumab has emerged as a new frontline standard of treatment for advanced
BTC, presenting a promising advancement in treatment options.

Despite the advancements made in systemic treatment over time, the prognosis of the disease remains
unfavorable as it continues to worsen despite undergoing initial treatment. Unfortunately, only a limited
number of patients with BTC who experience disease progression following their first-line therapy are
eligible to undergo second-line chemotherapy, further limiting their treatment opportunities. According to