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Page 8 of 12 An et al. Hepatoma Res 2023;9:43 https://dx.doi.org/10.20517/2394-5079.2023.60

systemic chemotherapy is a viable first-line treatment option for unresectable intrahepatic
cholangiocarcinoma.

A phase three clinical trial comparing TARE preceding gemcitabine/cisplatin with gemcitabine/cisplatin
[71]
alone (SIRCCA) was closed in 2022; however, preliminary results are not yet available . Further
prospective, randomized controlled clinical trials should be performed to define the clinical benefit of TARE
and systemic chemotherapy in the context of intrahepatic cholangiocarcinoma.

TARE and TACE in the neoadjuvant setting
TARE and TACE for intrahepatic cholangiocarcinoma are most often utilized in the palliative setting.
However, several retrospective studies have demonstrated a small percentage of patients initially with
unresectable diseases that were able to be down-staged to resectability following locoregional therapy with
TARE and TACE . Burger et al. performed a retrospective analysis of 17 patients with unresectable
[72]
intrahepatic cholangiocarcinoma who underwent TACE with cisplatin, doxorubicin, and mitomycin-C.
[50]
Two patients (12%) were able to undergo tumor resection following downstaging post-TACE therapy .
Similarly, Mouli et al. conducted a retrospective analysis involving 60 patients who underwent TARE for
unresectable intrahepatic cholangiocarcinoma and found that 5 patients (8%) underwent R0 resection
following down-staging post-TARE . However, downstaging to surgical resection post TACE/TARE
[34]
appears to be an uncommon occurrence overall based on available retrospective data. Future clinical trials
are warranted to help clarify the role of locoregional therapies such as TACE and TARE in the neoadjuvant
setting.

Hepatic artery infusion therapy
Hepatic artery infusion pump therapy is another form of locoregional therapy that has a role in unresectable
intrahepatic cholangiocarcinoma. Hepatic artery infusion pumps are surgically implanted catheters that
deliver high-dose chemotherapy directly to the hepatic arterial circulation while reducing systemic effects
and toxicity. Hepatic artery infusion therapy for cholangiocarcinoma is most commonly performed with
floxuridine, a precursor of the chemotherapeutic agent fluorouracil.

A meta-analysis of nine studies with 478 patients with intrahepatic cholangiocarcinoma who underwent
hepatic artery infusion therapy demonstrated a three-year overall survival of 39.5%, which outperformed
[73]
systemic chemotherapy . An additional study by Franssen et al. comparing 141 patients who underwent
hepatic arterial infusion with 178 patients who underwent surgical resection demonstrated similar overall
[74]
survival between groups (20.3 vs. 18.9 months, respectively) . These findings suggest that hepatic arterial
infusion with floxuridine may also be considered an effective locoregional therapy option.

Locoregional therapy with immunotherapy
Immunotherapy has an increasing role in the treatment of unresectable intrahepatic cholangiocarcinoma.
The TOPAZ-1 trial demonstrated improved survival and response rates for patients who received
[75]
durvalumab plus gemcitabine/cisplatin compared to placebo plus gemcitabine/cisplatin . This study has
led to durvalumab being the first immunotherapy to be FDA-approved for the treatment of intrahepatic
cholangiocarcinoma. However, limited data are available for TACE and TARE combined with
immunotherapy in the context of intrahepatic cholangiocarcinoma. A single retrospective study with 49
patients who underwent DEB-TACE combined with immune checkpoint inhibitors demonstrated
improved objective response rate and overall survival compared to patients who received gemcitabine/
cisplatin alone . Additional studies are necessary to assess the potential additional benefit that TACE and
[76]
TARE may provide in combination with immunotherapy.