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Ruff et al. Hepatoma Res 2023;9:17 https://dx.doi.org/10.20517/2394-5079.2023.18 Page 9 of 12

addition of durvalumab improved overall survival and progression-free survival among patients with
metastatic or unresectable biliary tract cancers, including ICCA. As a result, durvalumab was recently
approved in combination with gemcitabine/cisplatin for this patient population.

Recent research has also focused on identifying effective targeted therapies for ICCA. Through genetic
analysis and molecular profiling, specific genetic aberrations within ICCA can be targeted [66,67] . Studies have
identified common genetic aberrations in CCA, including isocitrate dehydrogenase (IDH), AT-rich
interactive domain-containing protein 1A (ARID1A), BRCA1-associated protein (BAP1), tumor protein 53
(TP53), cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B), and fibroblast growth factor receptor
(FGFR) [68,69] . Targeted therapy with IDH and FGFR inhibitors has had promising results in early clinical
trials, but there is still much that is unknown about which patient populations will respond to these drugs
and how to overcome mechanisms of resistance.

CONCLUSIONS
ICCA is an aggressive primary liver cancer. When feasible, surgical resection should be pursued as this
therapeutic modality offers the best potential for long-term survival. Preoperative planning with volumetric
analysis of the FLR and medical optimization is crucial to ensuring that patients will be able to tolerate
surgery and minimize complications. In addition, high-risk tumor features may result in early recurrence
and should therefore be used to select patients who may benefit from preoperative systemic chemotherapy
prior to resection. In particular, patients with locally advanced or high-risk tumors (e.g., extrahepatic
lymphadenopathy, poor differentiation, vascular invasion, multifocal disease) should be strongly considered
for chemotherapy with gemcitabine/cisplatin (+/- durvalumab) with re-staging scans and delayed resection.
For patients with favorable biology and resectable disease, upfront surgery with adjuvant capecitabine based
on the BILCAP data should be considered.

At the time of surgery, staging laparoscopy should be considered to evaluate for occult metastatic disease
and laparoscopic ultrasound can be used to better evaluate the liver parenchyma. Resection with the goal of
achieving an R0 margin, along with lymphadenectomy to adequately stage patients, should be the standard
operative approach. Unfortunately, the surgical technique cannot overcome poor tumor biology and ICCA
has a high incidence of recurrence, with many patients developing metastatic disease. Therefore, future
endeavors should strive to identify more effective systemic and targeted therapies, which will hopefully
improve survival for patients with ICCA.

DECLARATIONS
Authors’ contributions
Conceptualization, drafting, and critical revision of the manuscript: Ruff SM, Pawlik TM

Availability of data and materials
Not applicable.

Financial support and sponsorship
There was no financial support for this work.

Conflicts of interest
The authors do not have any potential conflicts of interest to declare.