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Alqahtani et al. Hepatoma Res 2020;6:70 I http://dx.doi.org/10.20517/2394-5079.2020.65 Page 3 of 15

CCA patients, adjuvant treatment strategies have been explored, including chemotherapy, radiotherapy, and
combination chemoradiotherapy.

A systematic review and meta-analysis of data of 6,712 patients with CCA of the gallbladder or biliary ducts
who received adjuvant therapy with either chemotherapy, radiotherapy, or chemoradiotherapy after surgery
[16]
revealed a non-significant OS improvement compared to OS with surgery alone (P = 0.06) . Patients
who received chemo- or chemoradiotherapy had a significantly greater survival benefit than patients who
[16]
received adjuvant radiotherapy alone (OR = 0.39, 0.61, and 0.98, respectively, P = 0.02) . A second meta-
[22]
analysis, reported by Ghidini et al. also found a survival benefit from adjuvant chemo(radio)therapy in
patients with resected biliary tract cancers; in that analysis (n = 22,499), adjuvant therapy was associated
with a significant (4.3 months) prolongation in median OS. Compared with surgery alone, adjuvant chemo
(radio)therapy was associated with a 41% reduced risk of death (HR = 0.59, 95%CI: 0.49-0.71, P < 0.001)
[22] . More recently, however, two prospective, randomized phase III trials of CCA patients found no clinical
benefit from adjuvant chemotherapy. The PRODIGE-12 trial randomized 196 patients with localized biliary
tract cancer to observation or adjuvant chemotherapy with the GEMOX regimen (gemcitabine 1000 mg/
2
m on Day 1 and oxaliplatin 85 mg/m infused on Day 2 of a two-week cycle for 12 cycles). Patients who
2
received adjuvant GEMOX had a median recurrence-free survival of 30.4 months compared with 18.5
months for patients randomized to the control arm. However, this numerical difference did not meet the
threshold for statistical significance (HR = 0.88, 95%CI: 0.62-1.25, P = 0.48). In addition, there was no
significant difference in OS (median OS: 75.8 months vs. 50.8 months; HR = 1.08, 95%CI: 0.70-1.66, P = 0.74)
[12] . Similarly, a randomized phase III trial comparing adjuvant gemcitabine alone to observation in 225
patients with resected bile duct cancer found no difference in OS (median OS: 62.3 months vs. 63.8 months;
HR = 1.01, 95%CI: 0.70-1.15, P = 0.96) or recurrence-free survival (median: 36.0 months vs. 39.9 months;
[13]
HR = 0.93, 95%CI: 0.66-1.32, P = 0.69) .

In the phase III BILCAP trial, 447 patients with histologically confirmed CCA or muscle-invasive
gallbladder cancer who underwent a complete resection were randomized to receive oral capecitabine
2
(1250 mg/m BID on Days 1-14 of a 21-day cycle, for eight cycles) or observation. After a median follow-
up of 60 months, the median OS for patients in the adjuvant chemotherapy arm was 51.1 months, which
was almost 15 months longer than the 36.4 median OS in the observation arm. In a protocol-specified
sensitivity analysis, this difference in OS was statistically significant, with an HR of 0.71 (95%CI: 0.55-0.92,
[14]
P = 0.010) . Although the trial failed to meet the primary endpoint of improving OS in the intention-
to-treat population, the prespecified sensitivity and per-protocol analyses showed signals of capecitabine
efficacy and could be considered for adjuvant care. Based on these results, capecitabine has become the
preferred adjuvant chemotherapy regimen in patients with resected CCA. In addition, the American
Society of Clinical Oncology endorsed this adjuvant chemotherapy regimen in its 2019 practice guidelines
[23]
update . In line with endorsement, the ongoing ACTICCA-1 trial, evaluating adjuvant gemcitabine-
cisplatin in patients with resected CCA or muscle-invasive gallbladder cancer, amended its protocol and
[15]
changed its control arm from observation to capecitabine . The results of this trial are awaited.
CHEMOTHERAPY FOR UNRESECTABLE OR METASTATIC CCA
First-line therapy
As long ago as 1996, it was established that chemotherapy could improve the survival rate and quality
[24]
of life of patients with advanced biliary tract cancer . In the early 2000s, gemcitabine monotherapy
was often used as a frontline regimen for patients with advanced CCA. In a phase II trial (n = 23),
2
gemcitabine (1000 mg/m over 60 min once a week in a two-weeks on/one-week off schedule) resulted in
[25]
a median progression-free survival (PFS) of 8.1 months with a median OS of 13.1 months . However,
in a retrospective case series of 100 patients with advanced CCA, the results obtained with gemcitabine
monotherapy did not match the results of this phase II trial, with a median OS of only 7.3 months, and only
[26]
one, out of five patients, was alive after one year .