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Alqahtani et al. Hepatoma Res 2020;6:70 I http://dx.doi.org/10.20517/2394-5079.2020.65 Page 5 of 15

and oteracil) (Gem-S). In the Japanese FUGA-BT trial, 354 chemotherapy-naïve patients with recurrent or
unresectable biliary tract cancer and an ECOG performance status of 0-1 were randomized to treatment
2
with gemcitabine (1000 mg/m on Days 1 and 8) in combination with either S-1 (60, 80, or 100 mg per day
2
on Days 1-14 of a 21-day cycle) or cisplatin (25 mg/m IV on Days 1 and 8). In this study, Gem-S was non-
inferior to Gem-Cis, with a median OS of 15.1 and 13.4 months, respectively (HR = 0.945, 90%CI: 0.78-1.15,
[32]
non-inferiority P = 0.046) . In addition, Gem-Cis and Gem-S yielded similar results in PFS (median PFS:
5.8 months vs. 6.8 months; HR = 0.86, 95%CI: 0.70-1.07) and overall response rate (ORR): 32.4% vs. 29.8%.
Clinically significant adverse events (AEs) were reported by 35.1% of patients enrolled in the Gem-Cis
compared with 29.9% in the Gem-S arm. Based on these findings, Gem-S, when available, is a feasible first-
line alternative to Gem-Cis in patients with advanced CCA.

Other gemcitabine-based doublets have also been evaluated in patients with advanced CCA. In the phase
II GERCOR trial, 33 patients with newly diagnosed advanced biliary tract cancer and good performance
2
status were treated with a combination of gemcitabine (1000 mg/m as a 10 mg/m /min infusion on Day 1)
2
2
and oxaliplatin (100 mg/m as a 2-h infusion on Day 2), every two weeks (GEMOX). The GEMOX regimen
[33]
induced an ORR of 36% and had a median PFS and OS of 5.7 months and 15.4 months, respectively .
Recently, the GEMOX regimen was evaluated in a phase III setting, where it was compared to a combination
2
2
of capecitabine (1000 mg/m BID on Days 1-14) and oxaliplatin (130 mg/m on Day 1) (XELOX). In that
non-inferiority trial, with 222 patients with advanced biliary cancer, GEMOX and XELOX were given every
three weeks for eight cycles . The median PFS for GEMOX and XELOX was 5.3 months and 5.8 months,
[34]
respectively, translating to a five-month PFS rate of 44.5% with GEMOX and 46.7% with XELOX. OS was
not significantly different in the two arms, with a median OS of 10.4 and 10.6 months for GEMOX and
[34]
XELOX, respectively . These two studies established the clinical efficacy of GEMOX in the frontline
treatment of patients with advanced biliary tract cancer, and the drug has become widely used in the
treatment of patients with advanced CCA. This practice was fueled by oxaliplatin having a more favorable
toxicity profile than that of cisplatin. However, whether GEMOX is non-inferior or superior to Gem-Cis
has not been established (no head-to-head comparisons).

A final gemcitabine-based doublet that was explored in patients with advanced CCA is gemcitabine plus
[35]
nab-paclitaxel. In 2018, Sahai et al. reported the results of a multicenter phase II trial in which 74 patients
2
2
with advanced CCA were treated with nab-paclitaxel (125 mg/m IV) followed by gemcitabine (1000 mg/m
on Days 1, 8, and 15) in 28-day treatment cycles . The regimen was effective, with an ORR of 30% and
[35]
a median OS of 12.4 months. The most common high-grade AEs with the gemcitabine nab-paclitaxel
combination were neutropenia (43% Grade ≥ 3) and fatigue (14% Grade ≥ 3). These findings are promising,
but validation in a randomized comparison with the current standard of care (Gem-Cis or Gem-S) is
required before this regimen can be used routinely.

Treatment intensification: the more, the merrier?
Several clinical trials have evaluated whether a more intensive treatment strategy would result in better
treatment outcomes than those of the current two-drug standard in the frontline treatment of advanced
biliary tract cancer. A phase II trial, conducted at the MD Anderson Cancer Center and the Mayo Clinic,
tested a triple regimen of gemcitabine, cisplatin, and nab-paclitaxel (initially 1000, 25, and 125 mg/m ,
2
2
respectively, on Days 1 and 8 of 21-day cycles, with a later reduction to 800, 25, and 100 mg/m , respectively,
[36]
to mitigate the hematological toxicity) in 60 patients with advanced biliary tract cancer (78% CCA) .
The results with the triplet regimen were promising, with a median PFS of 11.8 months and a median OS of
19.2 months. Forty-five percent of patients obtained a partial response, and 39% had disease stabilization.
As could be expected, this benefit came with the cost of substantial toxicity, with 58% of patients
experiencing Grade ≥ 3 AEs (Grade ≥ 3 AE neutropenia was most common, present in 33% of patients).
[36]
Sixteen percent of patients withdrew from the treatment because of toxicity . This regimen will be
evaluated further in a phase III randomized trial (NCT03768414).