Page 20 - Read Online

Allen et al. Hepatoma Res 2021;7:73 https://dx.doi.org/10.20517/2394-5079.2021.98 Page 3 of 15

significantly increased median OS compared to a positive microscopic margin (R1) [36,37] .

The rationale for adjuvant therapy, whether it be chemotherapy, chemoradiotherapy, or radiation therapy
[38]
alone, has been presented in a metanalysis by Horgan et al. , which reported a significant benefit with any
adjuvant therapy in R1 and N+ disease, of which the majority received chemotherapy. Meanwhile,
neoadjuvant therapy has the potential benefit of improving the R0 resection rate, increasing the rate of
receipt of systemic chemotherapy given the potential challenges of adjuvant chemotherapy, enhancing
patient selection for major surgery, and facilitating in vivo assessment of chemotherapy efficacy .
[20]
Preoperative or “downstaging” therapy can also potentially downstage locally advanced inoperable tumors
to enable resection to occur.

This review aims to report on the current evidence for adjuvant and neoadjuvant systemic therapy in biliary
tract cancers and discuss ongoing clinical research.

ADJUVANT THERAPY
Due to the relative rarity of biliary tract cancers, most of the evidence regarding adjuvant therapy is from
phase II clinical trials and retrospective analyses, which are detailed in Table 1 with just five phase III
randomized-control clinical trials reported.

One of the earliest studies by Takada et al. (2002) compared adjuvant mitomycin C plus fluorouracil
[39]
followed by oral fluorouracil until recurrence to surveillance. Patients with stage II-IV adenocarcinoma of
the pancreas, gallbladder, biliary tract, or ampulla of Vater were included. The primary outcome was OS.
One hundred and eighteen (of 508) patients with CCA were included in the analysis, with 58 randomized to
adjuvant chemotherapy and 60 to surveillance. One hundred and twelve patients with GBC were included.
Sixty-nine received adjuvant chemotherapy, and 43 were randomized to surveillance. Seventy-two (61%)
patients with CCA and 51 (46%) with GBC underwent curative surgery. There was no observed 5-year OS
benefit in CCA patients with chemotherapy (26.7% vs. 24.1%) or disease-free survival (DFS). The 5-year OS
in GBC was 26.0% vs. 14.4% (P = 0.0367) and the 5-year DFS 20.3% vs. 11.6% (P = 0.021). When stratified for
curative surgery, the 5-year OS in GBC was not improved with adjuvant chemotherapy. This suggests that
the observed OS benefit may result from chemotherapy administration in patients with advanced disease.
This study was not powered to determine the standard of care specifically in respect to biliary tract cancers.

ESPAC-3 (2012; NCT00058201) compared fluorouracil to gemcitabine and surveillance . Ninety-six of 434
[40]
patients included in this study had distal CCA, in what was a predominantly pancreatic cancer adjuvant trial
conducted in Europe. The median OS with surveillance (n = 31) was 27.2 months (95%CI: 15.4-31.9), 18.3
months (95%CI: 12.9-28.7) in those who received fluorouracil (n = 31), and 19.5 months (95%CI: 16.2-36.1)
in those who received gemcitabine (n = 34). No biliary-specific DFS data was presented. Multivariate
regression analysis indicated a survival benefit with chemotherapy (fluorouracil and gemcitabine combined)
compared to surveillance [hazard ratio (HR) = 0.75, 95%CI: 0.57-0.98, P = 0.03], although this did not
differentiate based on tumor subtype. This trial was not powered to draw specific conclusions regarding
survival benefits for biliary tract cancers alone and could not offer recommendations regarding the standard
of care.

The Bile Duct Cancer Adjuvant Trial [BCAT (2017; UMIN000000820)] was a Japanese study comparing
gemcitabine to surveillance . Patients with stage I-III perihilar and distal CCA with either an R0 or R1
[41]
resection were included. The primary endpoint was OS. Two hundred and twenty-five patients were
included in the analysis, with 117 patients randomized to gemcitabine and 108 to surveillance. Seventy-eight