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

A second interesting treatment-intensification study in patients with biliary tract cancer is the phase
III KHBO1401-MITSUBA trial. In that, 246 chemotherapy-naïve patients with advanced biliary tract
adenocarcinoma were randomly assigned to treatment with Gem-Cis or a triple combination of Gem-Cis
and S-1 (GCS). The addition of S-1 to Gem-Cis resulted in a lengthening of the median OS from 12.6 months
to 13.5 months (HR = 0.79, 95%CI: 0.60-1.04, P = 0.046). At the one-year mark, this translated into an
absolute survival difference of 5.7% in favor of GCS (59.4% vs. 53.7%). In addition, the median PFS was
significantly longer with GCS than with Gem-Cis (7.4 months vs. 5.5 months; HR = 0.75, 95%CI: 0.58-0.97,
[37]
P = 0.0015), and the rate of patients who had a treatment response was almost tripled (41.5% vs. 15.0%) .
Based on these results, the authors concluded that GCS could become a new standard treatment for
patients with advanced biliary tract cancer.

Patients with poor performance status: can we do good enough with a little bit less?
As indicated above, poor performance status seemed to be associated with a lower likelihood of treatment
benefit from a Gem-Cis doublet. For these patients, gemcitabine monotherapy can be considered.
5-fluorouracil (5-FU) monotherapy is not recommended in patients with biliary tract cancer because of
[38]
the low response rate (ORR: 20%) , but response rates were slightly higher when leucovorin was used in
combination with 5-FU: in 28 patients with biliary tract cancer, leucovorin-modulated 5-FU resulted in an
[40]
[39]
ORR of 32.1%, with a median OS of six months . Similar results were reported by Chen et al. in a series
of 19 biliary tract cancer patients (ORR: 33%, median OS 7.0 months).
A second alternative for gemcitabine monotherapy in CCA patients with a poor performance status could
be capecitabine monotherapy. In a study from the MD Anderson Cancer Center , 63 patients with
[41]
advanced hepatocellular carcinoma (n = 37), gallbladder cancer (n = 8), or CCA (n = 18) were treated with
2
capecitabine monotherapy (1000 mg/m BID for 14 days, in 21-day cycles). Among the CCA patients in
this trial, a median OS of 8.1 months was reported. Although the response rate in this trial was modest,
[41]
CCA patients have been reported to survive long term with capecitabine monotherapy .
Second-line therapy
Few studies have been conducted in patients with advanced CCA and progression after first-line therapy, so
there is no established standard of care for these persons. There are also few data on selecting patients who
might benefit from second-line therapy; the available studies consistently required good performance status
to initiate second-line therapy [42-45] . Other prognostic factors are the treatment effect in first-line therapy
(disease control or not), a low CA19-9 level, and the absence of peritoneal carcinomatosis [44,45] .

[46]
In 2014, Lamarca et al. published a systematic review of clinical studies that evaluated second-line
chemotherapy (fluoropyrimidine, irinotecan, docetaxel, and gemcitabine) in patients with advanced biliary
tract cancer. A platinum compound was often used in second-line therapy in patients who received a
fluoropyrimidine in first-line treatment; the median OS in this analysis was 7.2 months, with a median
[46]
PFS of 3.2 months. The response rate to second-line chemotherapy was only 7.7% . Currently, the most
frequently used second-line treatment for patients with advanced CCA, who have failed first-line Gem-Cis,
is the FOLFOX regimen (oxaliplatin plus 5-FU). This practice is based on the results of the randomized,
phase III ABC-06 trial. One hundred and sixty-two patients with locally advanced or metastatic biliary
tract cancer, who were previously treated with Gem-Cis, were randomly assigned to active symptom
control with or without modified FOLFOX (mFOLFOX) regimen, containing L-folinic acid (175 mg) (or
2
2
2
folinic acid 350 mg), 5-FU (400 mg/m bolus and 2400 mg/m infusion), and oxaliplatin (85 mg/m ) (all
every 14 days, up to 12 cycles) . Only patients with an ECOG performance status of 0-1 were eligible for
[47]
the study, and 72% of patients in the study cohort had advanced CCA. The use of mFOLFOX led to only a
modest prolongation in the median OS, from 5.3 to 6.2 months (HR: 0.69). However, the absolute OS rates
at 6 and 12 months were more impressive: at 6 and 12 months, the OS rate for patients in the mFOLFOX