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Page 6 of 15 Allen et al. Hepatoma Res 2021;7:73 https://dx.doi.org/10.20517/2394-5079.2021.98

(capecitabine) vs. 36.0 months (adjusted HR = 0.75, 95%CI: 0.58-0.97, P = 0.028) and the median DFS 25.9
months vs. 17.4 months, respectively (adjusted HR = 0.70, 95%CI: 0.54-0.92, P = 0.0093). No OS benefit was
observed with adjuvant capecitabine compared to surveillance in patients with an R1 resection (HR = 0.90,
95%CI: 0.63-1.29) in the intention-to-treat analysis, while R0 had an HR = 0.73 (95%CI: 0.51-1.04). Fifty-five
percent of patients receiving capecitabine completed eight cycles, and 46% of those who commenced
treatment had at least one dose reduction. It was argued that despite the intention-to-treat analysis not
achieving statistical significance regarding OS, the secondary analyses suggested that capecitabine improved
survival outcomes. Adjuvant capecitabine is today accepted as a standard of care in many countries and
guidelines and has become the control arm on most newer randomized trials.
[44]

The phase II trial SWOG S0809 investigated gemcitabine plus capecitabine followed by chemoradiotherapy
[45]
with capecitabine, and while only a single arm has been influential . Seventy-nine patients received
chemotherapy, with 69 completing the subsequent chemoradiotherapy. The median OS was 34 months for
R0 and 35 months for R1, with the 2-year OS 67% and 60%, respectively. Median DFS was 26 months for R0
and 23 months for R1, with the 2-year DFS 54% and 48%, respectively. Thus, this trial suggested that
survival outcomes of the poor prognostic R1 disease group may be improved in-line with R0 survival
outcomes with the addition of chemoradiotherapy. Unfortunately, a search of clinicaltrials.gov and
clinicaltrialsregister.eu using the search terms “cholangiocarcinoma” or “biliary” and “adjuvant” did not
identify this specific trial design has progressed to an active or completed phase III clinical trial.

Ongoing adjuvant clinical trials
There are presently 15 ongoing clinical trials investigating adjuvant chemotherapy in biliary tract cancers
[Table 2]. Four separate trials are comparing cisplatin plus gemcitabine to capecitabine [NCT02778308
(India), NCT02548195 (China), NCT02170090/EudraCT 2012-005078-70 (ACTICCA-1) (global), and
NCT03079427 (Korea)]. These trials compare cisplatin plus gemcitabine, the current standard-of-care
treatment in advanced/metastatic biliary tract cancers, as per ABC-02 to capecitabine. ACTICCA-1also
includes a second randomization in R1 patients whereby chemoradiation is introduced to the treatment,
replacing the final two (of eight) cycles of chemotherapy. This design has the potential to answer the
chemo-intensification question and whether more tailored treatment for R1 cases improves outcomes. It
has the distinction of being the largest adjuvant trial planned in biliary cancers and should give us clear
answers. Also ongoing is a single phase II study investigating gemcitabine plus nab-paclitaxel
(NCT04077983), a phase III study comparing gemcitabine plus capecitabine to single-agent capecitabine
(NCT03779035), a Japanese trial is investigating adjuvant S-1 (UMIN000011688), and a trial investigating
the benefit of adjuvant gemcitabine following liver transplantation is being performed in Germany
(EudraCT 2010-020480-21). Additionally, following the observed results from SWOG S0809, a phase III
clinical trial is proposed in China comparing adjuvant gemcitabine plus capecitabine with or without
chemoradiotherapy in perihilar/distal CCA and GBC (NCT02798510). However, it is unclear if this trial has
proceeded to recruitment. Three trials are investigating the combination of an anti-PD-1/PD-L1
monoclonal antibody with chemotherapy(s) (NCT04333927, NCT04782804, and NCT04295317). Clarity on
the best approach awaits the completion and review of several of these important trials.

NEOADJUVANT AND DOWNSTAGING THERAPY
There has been a steady shift to neoadjuvant and perioperative chemotherapy in some gastrointestinal
[47]
malignancies, including gastric and locally advanced rectal carcinoma . While improved OS is yet to be
[46]
determined with neoadjuvant chemotherapy in pancreatic adenocarcinoma, an improved R0 rate, DFS, and
locoregional failure-free interval have been observed with neoadjuvant FOLFIRINOX in borderline
resectable pancreatic cancer . Evidence supporting neoadjuvant chemotherapy as opposed to adjuvant
[48]