Page 49 - Read Online

Page 4 of 9 Akabane et al. Hepatoma Res 2023;9:29 https://dx.doi.org/10.20517/2394-5079.2023.45

combined with oxaliplatin) chemotherapy was the recommended treatment for cholangiocarcinoma
patients, its response rate was 21.4%, with the median recurrence-free survival (RFS) and OS time of 2.5 and
[37]
14.5 months, respectively . Data on chemotherapy for iCCA are limited, derived from case series and
retrospective studies with varied results due to the restricted sample size and absence of control groups. The
effectiveness and appropriateness of these treatments are largely dictated by factors such as the patient’s
overall health status, tumor characteristics, and response to therapy. Additionally, patients with iCCA
confront additional challenges regarding chemotherapy due to the heightened risk of treatment-related
[38]
toxicity and reduced OS .
Recently, immunotherapies, particularly immune checkpoint inhibitors, have shown promise in treating
advanced iCCA. Checkpoint inhibitors, such as pembrolizumab and nivolumab, have exhibited durable
[39]
responses and enhanced survival outcomes in patients with unresectable or recurrent biliary tract cancer .
These agents may offer a potential bridge to transplantation or even serve as adjuvant therapy in
combination with liver transplantation. Recent studies have reported successful liver transplantation cases
following neoadjuvant immunotherapy in patients with advanced iCCA, suggesting a potential role for this
[40]
approach in the management of selected patients .

Beyond immune checkpoint inhibitors, adoptive cell therapies such as natural killer (NK) cells and chimeric
antigen receptor T (CAR-T) cells have emerged as promising immunotherapeutic strategies for advanced
iCCA. Combing liver transplantation with adoptive cell therapies may improve patient outcomes by
augmenting immune surveillance and targeting residual cancer cells [41,42] . Additional research is required to
ascertain the safety and efficacy of this combined approach in advanced iCCA patients .
[43]
Meanwhile, therapies that target the local region, such as radiofrequency ablation (RFA), transarterial
chemoembolization (TACE), and stereotactic body radiation therapy (SBRT), have demonstrated some
promise in the treatment of unresectable iCCA [44,45] . A multi-center retrospective study revealed that 25% of
patients with advanced iCCA achieved complete or partial response after intra-arterial embolization therapy
(IAET), and 61% achieved disease stability . The median survival duration for this cohort was 13.2 months,
[29]
with 1, 3, and 5-year OS of 54.0%, 22.2%, and 16.2%, respectively. Meanwhile, a study that compared
outcomes in incidental iCCA patients who underwent either IAET or RFA to those who did not indicates
[46]
that locoregional therapies developed for HCC are not significantly effective treatments for iCCA .
Retrospective studies suggest that tumor size is a key determinant of RFA effectiveness and patient
outcomes in iCCA, as one study found RFA ineffective on lesions larger than 4 cm [47,48] . A significant
proportion of iCCA-related deaths occur due to local and locoregional progression rather than distant
metastases. Despite their potential to provide local tumor control and extend survival in selected cases, they
are not curative and might be associated with significant complications. Unresectable iCCA patients who
are not suitable for chemotherapy or locoregional therapies may be managed with palliative care . The
[49]
current treatment strategy for iCCA is depicted in Graphical Abstract.

LIVER TRANSPLANTATION FOR VERY EARLY ICCA IN PATIENTS WITH CIRRHOSIS
Liver transplantation has been demonstrated to provide survival benefits for patients with early-stage iCCA
in the setting of cirrhosis . A recent investigation identified that a subset of cirrhotic patients with very
[40]
early iCCA, denoted by a single tumor ≤ 2 cm, attained an impressive 5-year survival rate of up to 73%
following liver transplantation . The recurrence rate of these early-stage iCCAs over five years was as low
[50]
as 18%, in contrast to 65% for advanced iCCAs comprising multiple or larger tumors (> 2 cm) .
[8]
Consequently, liver transplantation should not be ruled out for patients with a single iCCA less than 2 cm,
as their long-term prognosis may align with that of HCC patients. However, the current criteria for