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Page 4 of 15 Alqahtani et al. Hepatoma Res 2020;6:70 I http://dx.doi.org/10.20517/2394-5079.2020.65

Table 1. Chemotherapy in the first-line treatment of patients with advanced CCA: an overview of pivotal clinical trials
Median OS
Trial Phase Regimen N Response rate
[HR (95%CI)]
ABC-02 [29] III Gem-Cis vs. Gem 410 11.7 months vs. 8.1 months DCR: 81.4% vs. 71.8%
0.640 (52-0.80)
Okusaka et al. [30] II Gem-Cis vs. Gem 83 11.2 months vs. 7.7 months ORR: 19.5% vs. 11.9%
0.69 (0.42-1.13) DCR: 68.3% vs. 50.0%
FUGA-BT [32] III Gem-Cis vs. Gem-S1 354 13.4 months vs. 15.1 months ORR: 29.8% vs. 32.4%
0.945 (0.78-1.15)*
GERCOR [33]# II GEMOX 33 15.4 months ORR: 36%
Kim et al. [34] III GEMOX vs. XELOX 222 10.4 months vs. 10.6 months ORR: 24.6% vs. 15.7%
NR DCR: 63.2% vs. 58.3%
Shroff et al. [36] II Gem-Cis + nab-paclitaxel 60 19.2 months ORR: 45%
DCR: 84%
KHBO1401-MITSUBA [37] III Gem-Cis vs. Gem-Cis-S1 246 13.5 months vs. 12.6 months ORR: 41.5% vs. 15%
0.79 (0.60-1.04)
#
*90% confidence interval. Study met threshold for non-inferiority; only data for Group A (good performance status) are listed here.
CCA: cholangiocarcinoma; DCR: disease control rate; ORR: overall response rate; OS: overall survival

Table 1 lists the pivotal clinical trials which study various chemotherapy options in the first-line treatment
of patients with advanced CCA.

Gemcitabine-based doublet chemotherapy
To improve on these outcomes, numerous gemcitabine-based combination regimens have been tested.
The most prominent consists of the gemcitabine-cisplatin (Gem-Cis) doublet. Two phase-II trials of
the combination produced efficacy signals in patients with advanced CCA and had a favorable toxicity
profile [27,28] . These encouraging findings formed the rationale for comparing the Gem-Cis doublet to
gemcitabine alone in a randomized phase III trial: In the ABC-02 study, 410 patients with locally advanced
or metastatic CCA, gallbladder cancer, or ampullary cancer were randomly assigned to receive cisplatin
2
2
(25 mg/m ) followed by gemcitabine (1000 mg/m on Days 1 and 8, every three weeks for eight cycles) or
gemcitabine alone (1000 mg/m on Days 1, 8, and 15, every four weeks for six cycles) for a total of 24 weeks.
2
Study patients who received the combination treatment had a median OS of 11.7 months, which was
significantly longer than 8.1 months in the gemcitabine-treated cohort (HR = 0.64, 95%CI: 0.52-0.80, P <
0.001); the PFS also was significantly longer (median PFS: 8 months vs. 5 months; P < 0.001) in patients
treated with the chemotherapy doublet, and the tumor was controlled in significantly more patients (81.4%
[29]
vs. 71.8%; P = 0.049) . Toxicity was similar with the two treatments, but the addition of cisplatin to the
regimen resulted in more Grade 3/4 neutropenia (25% vs. 17%) and a higher incidence of Grade 3/4 liver
[29]
abnormalities (27% vs. 17%) . A similar efficacy benefit of Gem-Cis over gemcitabine alone was reported
[30]
by Okusaka et al. , with a median OS of 11.2 months with the combination compared with 7.7 months
with gemcitabine alone (HR = 0.69, 95%CI: 0.42-1.13); at the one-year mark, this difference translated into
[30]
an absolute survival difference of 8% . A subsequent meta-analysis of these two studies indicated that,
compared to gemcitabine alone, Gem-Cis was associated with a 35% reduced death risk (HR = 0.65, 95%CI:
0.54-0.78, P < 0.001) and a 36% reduced risk for disease progression (HR = 0.64, 95%CI: 0.53-0.76, P <
0.001). The benefit of Gem-Cis over gemcitabine monotherapy was present irrespective of the location of
the primary tumor (i.e., gallbladder or CCA). These findings established Gem-Cis as the reference first-line
treatment for patients with advanced CCA. However, a subgroup analysis of the performance status found
that the superiority of Gem-Cis over gemcitabine alone was mainly in patients with good performance
status, whereas patients with a European Cooperative Oncology Group (ECOG) performance status of 2 or
more benefited less .
[31]
A second gemcitabine-based doublet regimen that has gained momentum in recent years is the
combination of gemcitabine and S-1, an oral fluoropyrimidine that includes three agents (tegafur, gimeracil,