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Hewitt et al. Hepatoma Res 2021;7:75 https://dx.doi.org/10.20517/2394-5079.2021.83 Page 11 of 19

BCAT
The BCAT trial was a randomized controlled multi-institutional phase III Japanese trial that investigated
[130]
adjuvant gemcitabine compared to observation in patients with resected bile duct cancer . The primary
endpoint was OS. Secondary endpoints included relapse-free survival, subgroup analysis, and toxicity. Two
hundred and twenty-five patients were included: 45% had PCCA while 55% had DCCA. Gemcitabine
provided no difference in OS or RFS.

TOSBIC01 (Tokyo Study Group for Biliary Cancer)
The TOSBIC01 was a phase II study that examined S-1, an oral fluoropyrimidine derivative, in 46 patients
with resected biliary malignancies. The regimen consisted of S-1 given within 10 weeks post-surgery and
continued up to 1-year post-surgery. Of the 46 patients that met inclusion criteria, 19 had ECCA, 10 had
gallbladder carcinoma, 9 had ampullary carcinoma, and 8 had ICCA. There was a 54.3% completion rate,
while the completion rate without recurrence during the 1-year administration was 62.5%. OS and DFS rates
at 1 year were 91.2% and 80.0%, and 84.3% and 77.2% at 2 years, respectively .
[131]

Chemoradiotherapy - SWOG0809
The SWOG0809 trial is the only clinical trial utilizing chemoradiotherapy for ECCA or gallbladder cancer.
In this study, 54 of 79 patients had ECCA, while the remainder had gallbladder cancer. Results were similar
for gallbladder and ECCA. The two-year OS was 68% (95%CI: 54%-79%) for ECCA and 56% (95%CI: 35%-
73%) for gallbladder cancer patients (P = 0.87). The two-year DFS was 54% (95%CI: 39%-66%) for ECCA
[132]
and 48% (95%CI: 28%-66%) for gallbladder cancer (P = 0.71) .

LOCOREGIONAL OPTIONS
Unfortunately, most patients with cholangiocarcinoma present with advanced disease and are not
candidates for surgical resection. Locoregional therapies may improve outcomes in patients with advanced
disease. Intra-arterial therapy (IAT) options such as TACE, TAE, drug-eluting beads, or Y-90
radioembolization were found to be safe and effective in patients with ICCA. In a retrospective review of
five major hepatobiliary institutions, IAT produced a partial or complete response in 25.5% of patients and
stable disease in 61.5%, while 13.0% had progressive disease . In addition to treating patients with
[133]
advanced disease, locoregional therapies have been used in an attempt to downstage patients to render the
tumor resectable . Patients with locally advanced cholangiocarcinoma who underwent neoadjuvant
[119]
therapy followed by resection after tumor downstaging were found to have similar short and long-term
[79]
results compared to patients with initially resectable cholangiocarcinoma . This highlights the importance
of surgical resection in the treatment of cholangiocarcinoma.

The concept of liver-directed arterial infusion therapy was initially developed in the 1950s for the treatment
of primary and secondary liver cancers. The concept of liver regional therapy was conceived by the
landmark study from Sullivan et al. , which described their experience with placement of a catheter in the
[134]
common hepatic artery and directly infusing chemotherapy for one to two months to treat primary and
secondary liver cancer. Hepatic artery infusion therapy has gained a foothold in the treatment of patients
with colorectal liver metastasis . However, the application of HAI therapy to other primary or secondary
[135]
liver tumors, such as ICCA, is under investigation.

A phase II clinical trial included 34 patients with unresectable primary liver cancer (26 ICCA and 8 HCC)
treated with hepatic artery infusion with floxuridine (HAI-FUDR). Sixteen patients had a partial response,
14 patients had stable disease, and three patients had progressive disease. Patients who responded to therapy
had a median disease-specific survival of 29.5 months. The patients with ICCA had a greater response rate
[136]
than HCC (53.8% vs. 25%, respectively) . A retrospective review analyzed 104 patients with unresectable