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Casolino et al. Hepatoma Res 2021;7:76 https://dx.doi.org/10.20517/2394-5079.2021.79 Page 3 of 23

[26]
(mOS 11.2 months vs. 7.7 months; HR = 0.69; 95%CI: 0.42-1.13; P = 0.139) . The meta-analysis of the two
trials confirmed significant improvement in progression-free survival (PFS) (HR = 0.64; 95%CI: 0.53-0.76; P
< 0.001) and OS (HR = 0.65; 95%CI: 0.54-0.78; P < 0.001) of CisGem over gemcitabine for intra-and extra-
hepatic cholangiocarcinomas (iCCA and eCCA) and gallbladder cancer, with most marked efficacy among
patients with good performance status (PS 0-1) (HR for PFS = 0.61; 95%CI: 0.51-0.74; P < 0.001; HR for OS
[27]
= 0.64; 95%CI: 0.53-0.77; P < 0.001) . Table 1 shows an overview of these three studies.
Subsequent studies explored the role of other compounds such as oxaliplatin and fluoropyrimidines.
Oxaliplatin showed a more favourable toxicity profile than cisplatin, with mOS reaching 12.4 months and
overall response rate (ORR) up to 50% [21,22] , but its activity has never been tested in a head-to-head
comparison with CisGem. Nonetheless, this agent may be adopted when cisplatin is contraindicated.
Fluoropyrimidines have also been shown to be active in aBTCs studies, but their precise role is still
controversial as a direct comparison with gemcitabine-based regimens is lacking [28,29] .

Another treatment option in the first-line setting is represented by gemcitabine plus S-1 (a fluoropyrimidine
derivative), as suggested by the FUGA-BT phase III trial showing non-inferiority of this regimen compared
[30]
with CisGem in the Japanese population .

Whether intensifying chemotherapy could improve oncological outcomes by maintaining a good quality of
life is still an unanswered question and is currently under clinical investigation. In the Japanese population,
the association of cisplatin, gemcitabine, and S1 could represent a treatment option on the basis of a phase
III trial, demonstrating an improved OS of the triplet compared with CisGem (13.5 months vs. 12.6 months;
[31]
HR = 0.791; 90%CI: 0.620-0.996; P = 0.046) .
Results from a phase II trial evaluating cisplatin, gemcitabine hydrochloride (salt of an analogue of the
antimetabolite nucleoside deoxycytidine with antineoplastic activity), and nab-paclitaxel demonstrated
median PFS (mPFS) of 11.8 months, mOS of 19.2 months, 45% response rate (RR) and 84% DCR with this
[13]
regimen . The ongoing phase III SWOG-1815 clinical trial will establish whether the triplet is more
efficacious than the standard CisGem (NCT03768414). Likewise, a phase III study comparing CisGem vs.
FOLFIRINOX (oxaliplatin, irinotecan, and 5-fluorouracil) has recently completed recruitment
(NCT02591030) and will define if non-gemcitabine regimes have a place in first-line. Furthermore, a phase
II study is exploring the activity of Nal-Iri in combination with 5-fluorouracil (5-FU)/leucovorin (LV) vs.
[12]
CisGem (NCT03044587) .
Second-line chemotherapy
Following a failure to first-line chemotherapy, 25%-40% of BTC patients are still fit to receive second-line
chemotherapy . The choice of second-line treatment is extremely limited, particularly in unselected
[32]
patients. In daily practice, 5-FU-based chemotherapy has been the most widely adopted regimen, despite
the absence of robust evidence and the poor clinical efficacy (mPFS of 2.5-5.5 months and a mOS of 7.5-13.5
[33]
months in published series) .

Only recently, the phase III ABC-06 study demonstrated the superiority of FOLFOX vs. active symptom
control (ASC, i.e., proactive detection of biliary obstruction, sepsis, and symptom management) in patients
progressing to CisGem . This study enrolled 162 patients with aBTC, including 72% of CCA following
[8]
progression on standard first-line CisGem. Patients were randomised to ASC (81 patients) or ASC plus
FOLFOX (81 patients). The ABC-06 trial demonstrated a benefit from second-line chemotherapy in terms
of OS (HR = 0.69; 95%CI: 0.50-0.97; P = 0.031). Even though absolute differences in mOS were modest (5.3