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Page 4 of 11 Calderon Novoa et al. Hepatoma Res 2023;9:33 https://dx.doi.org/10.20517/2394-5079.2023.36

[49]
published a follow-up international study for external validation . Now, with a total of 48 patients with
iCCA, 15 with “very-early” and 33 with advanced iCCA. With a follow-up time of almost 5 years for the
“very-early” group and over 2 years for the advanced iCCA group, tumor recurrence was seen in 13% of
very early iCCA, while in 54% of the advanced iCCA (P < 0.05). The 5-year survival for the “very-early”
group was indeed a staggering 65% compared to 45% in the advanced iCCA group. These values are above
[54]
the arbitrarily stipulated threshold of 50% at 5 years suggested for oncological LT , and favor LT over LR as
well. These findings clearly support LT as a viable and effective alternative for a select group of patients with
iCCA. However, the low frequency of this tumor, difficulties in preoperative diagnosis and its
contraindication for LT, as well as the limited organs available for allocation to patients without ESLD,
make prospective trials for early iCCA a true challenge. These last findings have led transplant societies to
include and consider iCCA as a potential indication for LT, given the correct scenario . Table 1
[55]
summarizes the most important studies regarding iCCA in LT in the past 10 years. Currently, a single-
armed clinical trial to determine the usefulness of transplantation in very early iCCA is ongoing
(NCT0287847) .
[56]
A 2021 meta-analysis by Ziogas et. al. recollected and analyzed data from 18 studies and 355 patients with
iCCA. The 1, 3 and 5-year OS rates were 75%, 56% and 42 %, respectively, coincident with previous
[57]
reports . RFS at 1, 3 and 5-years was 70%, 49% and 38%, meaning that over 60% of patients recur after 5
years. Subgroup analysis of very early stage (n = 29) and advanced stage (n = 79) showed relevant
differences, with 5-year OS in the very-early group of 71% vs. 48% in the advanced iCCA group. However,
the 5-year OS did not reach statistically significant differences, most likely due to the small sample size. RFS
was also significantly higher in the very early group (67% vs. 34%), with an overall recurrence rate of 15%
compared to 51% in the advanced group.

Tumor burden and nodal status
As described thus far, there are mainly two factors that have been shown to negatively affect survival after
LT in iCCA: tumor size and the presence of nodal status.

Notwithstanding the encouraging results by Sapisochin et al., preoperative diagnosis of iCCA continues to
preclude LT in most centers worldwide, making large prospective analysis of the risk factors involved with
survival and recurrence challenging, to say the least [48,49] . Small-sized tumors may be adequately treated by
LT alone without previous or posterior adjuvant treatment. However, encouraging results such as those
shown by the Methodist group with large 10 cm tumors adequately treated preoperatively appear to have
similar results to smaller tumors. Perhaps, although size does matter and has been shown by several series to
predict worse outcomes, The beneficial effect of neoadjuvant therapies may negate this. The authors believe
that strict criteria such as tumor burden may potentially preclude many patients from receiving curative
treatment in spite of their “unresectable” condition. Following the experience with HCC, there are many
groups that no longer abide by the Milan criteria and have shown great results with patients using UCSF
criteria. Such rules may also eventually apply to iCCA, and rather than only abide by tumor size, transplant
groups should evaluate tumor biology by its response to neoadjuvant therapies in larger tumors.

Another key aspect is lymph node compromise. Lymph node assessment is, without a doubt, mandatory for
LT in iCCA. Lymph node invasion has been shown to be an independent risk factor for worse DFS and OS
in large LR series such as Kim et al. . This can translate into LT, especially if we consider LT a form of
[33]
extreme LR, in which one can achieve the best possible margins and cure underlying disease in the same
procedure. Lymph node involvement can predict early recurrence and distant metastases, and should be
ruled out either preoperatively by adequate imaging studies or intraoperatively by performing routine