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Page 2 of 23 Casolino et al. Hepatoma Res 2021;7:76 https://dx.doi.org/10.20517/2394-5079.2021.79

INTRODUCTION
Advanced stage is the most common clinical presentation of biliary tract cancers (BTCs). Given the paucity
of specific early symptoms and the lack of early-detection programs, up to 80% of patients are diagnosed
with unresectable tumours . In addition, recurrence rate after surgery ranges between 50% and 79%, even
[1,2]
[3-5]
for those patients diagnosed with early-stage cancer . Advanced disease at presentation or relapse after
local treatment, along with the scarce availability of active treatments and the significant chemo-resistance,
[6]
make BTCs one of the deadliest solid tumours with a global five-year survival rate of 10% . In this scenario,
untreated patients have an overall survival (OS) of 3-4 months, while those receiving active treatment can
reach up to 18-20 months with two therapeutic lines [7-10] . Systemic approach represents the standard of care
of advanced biliary tract cancers (aBTCs) and aims at increasing survival, delaying disease progression,
relieving symptoms, and improving/maintaining the quality of life. Historically, cytotoxic chemotherapy
was the only available option and was associated with marginal improvements in oncological outcomes.
More recently, emerging compounds targeting isocitrate dehydrogenase (IDH) 1 mutations and fibroblast
growth factor receptor (FGFR) 2 fusions, as well as immune checkpoint inhibitors (ICIs), showed promising
results in molecularly selected patients . Thanks to advances in molecular biology, many other therapeutic
[11]
vulnerabilities have recently been identified both in the tumour and in the surrounding microenvironment,
providing a plethora of novel potential strategies to be further investigated for the treatment of BTCs .
[12]

In this paragraph, we aim to offer an overview of the current therapeutic approaches for the management of
patients with aBTCs, and to discuss the novel opportunities on the near horizon.

UNSELECTED TREATMENT APPROACH: PAST, PRESENT AND FUTURE
The history of the therapeutic development in BTCs has been characterised by “all-comers” design of
clinical trials exploring the efficacy of cytotoxic agents and targeted therapies. This “one size fits all” model
has shown clinical benefit from chemotherapy, allowing the identification of current standard first and
second-line regimens . Chemotherapeutic drugs combination is demonstrated to increase efficacy by
[7,8]
using different mechanisms of cytotoxic action. The two chemotherapy combinations regimens approved
following positive results of phase III clinical trials include cisplatin and gemcitabine (CisGem) for frontline
treatment and 5-fluorouracil plus oxaliplatin (FOLFOX) after first-line progression. More recently, two
combinatorial regimens showed promising results in phase II studies for the first-line (cisplatin,
gemcitabine, and nab-paclitaxel) and second-line (5-fluorouracil and liposomal irinotecan; Nal-Iri)
[13]
[14]
setting . Clinical studies investigating targeted therapies and ICIs have been widely unsuccessful in
unselected patients instead [15-24] .

First-line chemotherapy
Limited data supported effective management of aBTCs before 2010. A pooled analysis of 104 small and
nonrandomised trials, including 2810 patients conducted in 2007, showed combination chemotherapy with
CisGem or oxaliplatin being the most active strategy . The first evidence of superior regimen from
[11]
randomised phase II study was reported in 2007, when CisGem demonstrated better time to progression
compared to gemcitabine alone (8 months vs. 4 months, respectively) and improved disease control rate
(DCR) . This association became the standard first-line treatment for patients with metastatic BTCs since
[25]
2010, when the Advanced Biliary Tract Cancer (ABC-02) phase III trial demonstrated the superiority of
CisGem vs. gemcitabine alone . The median overall survival (mOS) resulted superior for the experimental
[7]
arm compared to gemcitabine [11.7 months vs. 8.1 months, respectively; hazard ratio (HR) = 0.64; 95%
confidence interval (CI): 0.52-0.8; P < 0.001]. The combination also demonstrated a better rate of partial
response (PR) compared to the gemcitabine (26% vs. 16%, respectively) . Similar results were reported in
[7]
the Japanese BT22 randomised phase II trial that investigated the antitumour activity of the same agents