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Page 8 of 12 Ruff et al. Hepatoma Res 2023;9:17 https://dx.doi.org/10.20517/2394-5079.2023.18

RECURRENT DISEASE
Even after curative-intent resection of ICCA, the risk of recurrence is high ranging from 30-70%. Risk
factors for recurrence include underlying liver disease (e.g., cirrhosis, primary sclerosing cholangitis), large
tumor size, multifocal disease, positive surgical margin, vascular or perineural invasion, and metastatic
[59]
regional lymph nodes . In one study of 685 patients with ICCA who developed a recurrence, patients were
divided into two cohorts based on the timing of recurrence: early (< 24 months) versus late (≥ 24
[60]
months) . Individuals with early recurrence were more likely to have extrahepatic disease and worse
overall survival. On a multivariable analysis, increased tumor size and the presence of satellite lesions were
associated with an increased risk of early intrahepatic recurrence, whereas underlying liver cirrhosis was
associated with late intrahepatic recurrence. Early recurrences may be due to occult residual disease at the
time of the operation, while the late recurrences may have been related to background liver disease and de
novo disease rather than a recurrence of the original tumor .
[60]
In another multi-institutional study of 920 patients with ICCA who underwent curative-intent resection,
[61]
607 (66%) developed a recurrence . Among these patients, 24% recurred at the resection margin, 29% had
an intrahepatic recurrence away from the margin, 15% had only extrahepatic recurrence, and 32% had both
intra and extrahepatic recurrence. Intrahepatic margin recurrence and extrahepatic only recurrence
commonly occurred within 6 months of resection, while distant intrahepatic recurrence occurred later
within 2 years . In turn, the authors speculated that early recurrence may be related to surgical technique
[61]
(e.g., positive margin) or poor tumor biology (extrahepatic disease only).

In the setting of recurrent disease, additional systemic therapy, non-surgical liver-directed therapy (e.g.,
transarterial chemoembolization, Yttrium-90 radioembolization), or re-resection may be employed. Given
that most recurrences are intrahepatic, re-resection may be a reasonable option in a subset of individuals.
The selection of patients for repeat surgery depends on the size of the liver remnant, patient co-morbidities,
and the anatomic location of the recurrent disease; in addition, the underlying biology (i.e., timing, location,
and number) needs to be considered. In a study of 400 patients with ICCA recurrence, patients who
underwent a re-resection had a better median survival (26.1 months) compared with individuals who
received non-surgical locoregional therapy (9.6 months) or systemic chemotherapy (16.8 months). Among
41 patients who underwent re-resection, more than half developed additional recurrences within a median
time of 11.5 months . In a separate study of 156 patients with recurrent ICCA, 113 patients underwent re-
[62]
resection and had a median survival of 65.2 months . For patients who are not candidates for re-resection,
[63]
Yttrium-90 radioembolization or other locoregional therapies may help to slow disease progression or
palliate symptoms. In the setting of recurrence, treatment should be discussed in a multidisciplinary setting
and clinical trials should be explored.

FUTURE DIRECTIONS FOR SYSTEMIC TREATMENT
Given the poor prognosis of ICCA, ongoing efforts are needed to identify effective systemic therapies to
prevent disease recurrence and metastasis. Over the past few decades, immunotherapy has come to the
forefront of cancer care with promising results. In order to successfully utilize immunotherapy, the tumor
microenvironment needs to be characterized further to identify potential therapeutic targets. For example,
Gani et al. demonstrated that some cells in the ICCA invasive tumor front and ICCA tumor macrophages
stain positive for programmed death ligand 1 (PD-L1) expression and that PD-L1 expression was associated
with worse survival, nodal metastases, and multifocal disease . These data suggest that the PD-L1 pathway
[64]
may be suppressing the host immune response in patients with ICCA. The TOPAZ-1 phase III trial
evaluated whether the addition of durvalumab (a PD-L1 inhibitor) could improve survival when added to
[65]
the cisplatin/gemcitabine regimen among patients with locally advanced or metastatic ICCA . Indeed, the