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Page 6 of 8 Gavriilidis et al. Hepatoma Res 2023;9:23 https://dx.doi.org/10.20517/2394-5079.2023.26

study were chosen based on data obtained from the ABC-02 and BILCAP trials [22,25] . The trial is currently
underway and has finished recruitment. Additional adjuvant therapy for biliary tract cancer has also been
investigated in the JCOG1202 study. This randomized phase 3 trial was conducted in Japan to examine the
efficacy of adjuvant S-1, which was previously studied in other cancers. In this study, patients treated with
S-1 had a better 3-year survival (77.1%) compared with patients treated with placebo (67.6%). Although
long-term clinical benefits still need to be defined, adjuvant S-1 may be a reasonable adjuvant option for
Asian patients following resection of biliary tract cancer .
[27]

Role of liver transplantation and LND
The use of liver transplantation in the management of iCCA remains controversial. Recently, there has
[28]
been growing interest in transplant oncology for a variety of cancer indications, including iCCA . A recent
meta-analysis conducted by Ziogas et al. reported that cirrhotic patients with very early iCCA or select
[29]
patients with advanced iCCA following neoadjuvant therapy may benefit from transplantation . In a
prospective case series, Lundsford et al. reported on transplantation of patients with locally advanced
unresectable iCCA without extrahepatic disease or vascular involvement who had six months of
radiographic disease response or stability following neoadjuvant gemcitabine. Six out of 21 patients
eventually underwent transplantation and 1-, 3-, and 5-year OS was 100%, 83.3%, and 83.3%, respectively.
Three patients developed recurrent disease after transplantation (median 7.6 months). Given the current
scarcity of organs and the indeterminate long-term benefit, transplant for unresectable iCCA should be
done on a per-protocol basis for highly selected patients (i.e., no extrahepatic disease, nodal disease, vascular
invasion, etc.) [28,30-32] .

Limitations
Data in the current review need to be interpreted in light of several strengths and limitations. While we
provided an overview of the role of LND for iCCA in light of the recently published data, the field of
medicine related to iCCA continues to evolve quickly. In particular, a rapidly emerging understanding of
the molecular pathogenesis and the varied mutational profile of iCCA has ushered in an era of targeted
precision medicine. Multiple studies have recently examined the impact of targeted therapy among patients
with and without actionable mutations relative to long-term survival [33,34] . In the future, the relative
importance of LND and the presence of LNM may change in the future as these therapies are introduced
into the treatment paradigm of patients with iCCA.

CONCLUSIONS
iCCA is an aggressive biliary tract malignancy generally with a poor 5-year survival of 20%-30% even after
curative-intent surgical resection. For this reason, additional data regarding staging and prognosis is critical
to help risk stratify patients and guide adjuvant chemotherapy. The role of LND in iCCA continues to
evolve with more data supporting the use of routine LND with the goal of obtaining at least six lymph nodes
and examination of nodes beyond station 12. Important attention to the sidedness of the primary tumor
dictates the extent and location of LND. An increased number of lymph node metastases portends more
aggressive disease. In general, patients with LNM may benefit the most from adjuvant chemotherapy based
on data from the BILCAP trial. In the future, translational studies are needed to clarify the mechanisms
involved in lymphatic spread. iCCA has a rich stroma consisting of cancer-associated fibroblasts that
promote early metastatic spread. Pre-clinical studies have demonstrated that lymphatic spread may be
mitigated through the targeting of fibroblasts and lymphatic endothelial cells via PDGFR pathway
inhibition. Therefore, the inhibition of fibroblasts or PDGF-induced signals may represent an effective
method to block tumor-associated lymphangiogenesis [35,36] .