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Page 12 of 19 Hewitt et al. Hepatoma Res 2021;7:75 https://dx.doi.org/10.20517/2394-5079.2021.83

ICCA confined to the liver who were treated with combined HAI and systemic therapy (gemcitabine-based)
[81]
or systemic therapy alone . The HAI combination therapy demonstrated a greater response rate than
[81]
systemic therapy alone .
Systemic gemcitabine and oxaliplatin was then investigated in combination with FUDR via HAI. The study
included patients with unresectable ICCA and also allowed for resectable regional lymphadenopathy.
Eighty-four percent of patients achieved disease control at 6 months, with 58% of patients showing a partial
response. The 6-month PFS was 67% for pretreated patients and 89% for chemotherapy-naïve patients. The
median OS was 25 months. Similar to prior studies, nodal disease did not alter OS or PFS. Four patients
experienced a significant enough response to undergo resection of their tumor . Although there is a
[82]
limitation in the number of studies, the use of HAI pump therapy, particularly in ICCA, is gaining interest,
and a randomized controlled trial is needed to establish the role of this therapy for ICCA.

TRANSPLANT
Liver transplantation (LT) is a widely accepted treatment modality for HCC. HCC typically occurs in
patients with underlying liver disease, which may hinder a patient’s ability to undergo resection. In these
patients, LT has the advantage of not only addressing the HCC but also the underlying liver disease.
Similarly, patients with CCA may experience limitations for resection secondary to chronic liver disease and
[137]
inadequate future liver remnant . The use of LT for CCA is becoming more widely accepted, specifically
for early-stage non-resectable PCCA, while the role of LT in patients with ICCA is currently debated.

Initial series investigating LT for patients with ICCA resulted in poor outcomes with an 18%-25% OS and
RFS at 5 years and is considered by most centers a contraindication for LT [138-141] . There is limited, largely
retrospective data to support LT for ICCA. A 2016 retrospective study suggested LT may be a viable
treatment option for patients with small (< 2 cm), solitary ICCA in patients who did not receive
[142]
neoadjuvant chemotherapy . Lunsford et al. investigated the utility of LT in patients with locally
[140]
advanced, unresectable ICCA without vascular involvement or extrahepatic disease who received
neoadjuvant chemotherapy in a prospective case series. Patients received gemcitabine-based chemotherapy
and were required to have a minimum of six months of stable disease prior to listing for transplantation.
Twenty-one patients were evaluated, and twelve patients were listed for transplant. Nine patients were not
listed for transplant because seven had extrahepatic disease or disease progression, and two were
downstaged to resectable disease. Six of the twelve patients listed for LT underwent transplantation, three of
the six not transplanted were still on the transplant list, two did not receive a transplant because of severe
adhesions, and the remaining patient was found to have resectable disease on exploration. In patients who
underwent LT, OS at 1 year was 100% with a 3 and 5 year OS of 83.3%. Three patients developed recurrent
[140]
disease at a median of 7.6 months with a 50% recurrence-free survival at 1, 3, and 5 years . Liver
transplant for ICCA remains controversial and, as of this writing, has not made its way into the National
[47]
Comprehensive Cancer Network (NCCN) guidelines for the treatment of ICCA .

Unlike patients with ICCA, LT is more widely accepted for the treatment of PCCA. In patients with PCCA,
LT highly focuses on patient selection. The NCCN guidelines recommend LT in highly selected patients
[47]
with tumors < 3 cm in radial diameter, no intrahepatic or extrahepatic metastasis, and no nodal disease .
Protocols for LT of PCCA often test underlying tumor biology with neoadjuvant therapy followed by repeat
staging [143-145] . The Mayo Clinic Protocol utilizes external beam radiation (45 Gy in 30 fractions) with
continuous infusion of 5 FU over 3 weeks followed by brachytherapy administered 2 weeks following
[145]
completion of external beam radiation therapy and then capecitabine until the time of LT . Diagnostic
laparoscopy is essential in these patients to look for metastatic disease, or lymph node involvement as up to