Page 32 - Read Online

Allen et al. Hepatoma Res 2021;7:73 https://dx.doi.org/10.20517/2394-5079.2021.98 Page 11 of 15

colorectal trials highlighting the potential changed pharmacokinetics and chemotherapy tolerance following
[58]
partial hepatectomy . BILCAP included all biliary tract cancers except ampullary carcinomas and mucosal
GBC, with this heterogenicity again potentially blunting the observed effect of adjuvant capecitabine. While
there was an equal distribution between treatment arms, there are relative differences in biliary subtypes
compared to some other trials, as detailed in Table 1 that may be important. Pending further data, adjuvant
capecitabine has been adopted as the standard of care in many guidelines. With the current standard of care
in metastatic biliary tract cancers cisplatin plus gemcitabine, the outcomes of large trials comparing cisplatin
plus gemcitabine to capecitabine are eagerly awaited.

In all described adjuvant trials, anatomical subtypes were combined for analysis. BILCAP and BCAT had a
relatively even distribution amongst all eligible anatomical subtypes, whereas PRODIGE 12-ACCORD 18
was predominately intrahepatic CCA, with 20% GBC. Subgroup analysis in these trials demonstrated
differences in survival relative to anatomical subtype, particularly in PRODIGE 12-ACCORD 18, in which
GBC exhibited a poorer survival with chemotherapy than surveillance. Therefore, it is likely that the mixing
of distinctly different histological and genetic subtypes limits the interpretation of survival benefits with
adjuvant chemotherapy.

Consistently across all trials, patients with R1 resections were observed to have poorer survival outcomes. In
PRODIGE 12-ACCORD 18, the DFS and OS hazard ratios for R1 patients who received GEMOX were
similar to that of surveillance, an observation reiterated for OS in BILCAP. SWOG S0809 demonstrated that
with the addition of chemoradiotherapy, R1 tumors could potentially achieve comparable DFS and OS to
that in R0 tumors. This suggests that R1 tumors specifically may benefit from adjuvant chemoradiotherapy
in addition to chemotherapy. The ACTICCA-1 trial, which is currently recruiting with an estimated study
completion early 2023, may go some way to answer this.

In respect to neoadjuvant chemotherapy, current evidence is sourced from retrospective analyses and three
phase II trials. The population is highly selected in these analyses and is generally considered unresectable at
diagnosis. With satisfactory R0 resection rates reported, there is a suggestion that systemic chemotherapy
may have a role in downstaging a tumor to enable an attempt at curative resection. However, completion of
the neoadjuvant trials currently underway is required to draw any further conclusions. The benefit of
neoadjuvant chemotherapy on survival outcomes in those considered resectable at diagnoses remains less
clear.

The survival benefits of anti-PD-1 and PD-L1 monoclonal antibodies in both adjuvant and neoadjuvant
treatment remain unanswered. While there is minimal evidence of a significant ORR in metastatic biliary
tract cancers, particularly with single agent treatment, the IMbrave150 clinical trial demonstrated a
significantly improved OS in hepatocellular carcinoma with atezolizumab plus bevacizumab, offering hope
that immunotherapy, particularly in combination with other targeted agents or chemotherapy may improve
outcomes [59,60] . Furthermore, at this point, while targeted therapies such as FGFR inhibitors show promise in
[61]
metastatic intrahepatic CCA , evidence is lacking to support their use in either adjuvant or neoadjuvant
treatment. Targeted treatment is attractive but establishing the optimal standard of care with chemotherapy
remains an unanswered and more pertinent question. Chemotherapy should then also serve as the
backbone on which to add or compare with targeted agents.

CONCLUSION
Biliary tract cancers are a heterogenous group of cancers. Few phase III adjuvant trials have been completed,
with only BILCAP suggesting a survival benefit with capecitabine. Several trials are ongoing, including