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Page 6 of 11 Calderon Novoa et al. Hepatoma Res 2023;9:33 https://dx.doi.org/10.20517/2394-5079.2023.36

locoregional treatments used to control local progression before transplant (transarterial
chemoembolization, radioembolization, radiofrequency ablation, or even LR), while “ downstaging” refers
to the same therapies used to bring a patient from a higher BCLC score (usually BCLC B) to be considered
for LT.

One of the questions related to iCCA and LT is if these therapies can be taken from the experience with
HCC and reproduced for iCCA. As mentioned, prospective trials regarding NAT and LT in iCCA are
limited due to low prevalence and exclusion from transplant when preoperative assessment identifies large
iCCA-compatible masses in most centers. Takahashi et al. analyzed results for 13 patients with incidental
iCCA in the specimen of LT, and were matched to patients with HCC in the explant specimen . Four
[60]
patients underwent TACE and one RFA. However, NAT before LT showed no benefit, with the RFS rate for
these patients being worse than those without locoregional treatment (14 months vs. 24.6 months, P = 0.91).
Recent publications have also studied neoadjuvant therapies. De Martin et al. recently published a study on
14 years of cirrhotic patients who underwent LT with specimen findings of iCCA previously interpreted as
HCC . 49 patients had an iCCA in the LT, and 31 of these (63%) had received some kind of preoperative
[61]
treatment (mainly TACE). Almost a third of the patients with iCCA or mixed iCCA-HCC had vascular
invasion or satellite nodules. Overall survival for the LT with iCCA population was 67% at 5 years, with a
75% DFS at 5 years, significantly better than the matched LR patients for this study. A trend favoring
preoperative therapies as a protective factor for tumor recurrence was identified in the univariate analysis
(HR 0.67, P = 0.06), but failed to reach statistical significance in the multivariate (P = 0.12). This study
reaffirmed that tumor burden was the most important predictor of recurrence, and failed to find a
significant protective value of preoperative TACE treatment over OS or DFS.

Rayar et al. have shown promise for both for treatment while on waitlist and downstaging using
radioembolization with Yttrium-90 [62,63] . However, as far as this review is concerned, there are only two
centers that have published prospective results with standardized neoadjuvant protocols in patients with
preoperatively confirmed iCCA: UCLA and the Houston Methodist-MD Anderson.

The first results presented by Hong et al. from UCLA in 2011 showed encouraging results of 25 locally
advanced iCCA undergoing LT. This group was compared to 12 iCCA with LR . Nine of these received
[64]
NAT and adjuvant therapy, while 7 received only adjuvant after the LT. NAT consisted of stereotactic body
radiation with a total of 40 Gy, delivered shortly in 7-12 days within five sessions. Following SBRT, patients
continued with Capecitabine, Fluoracil or Gemcitabine-based regimes until the time of transplant. For those
patients with iCCA larger than 3.5 cm, the locoregional therapy of choice was TACE instead of SRBT.
Survival rates were significantly improved in patients who received combined adjuvant and NAT compared
to no therapy or adjuvant therapy alone (8% recurrence vs. 40% and 50%, respectively). The same group has
recently published their follow-up on these patients until 2019 . 31 patients were now enrolled, 23 of these
[65]
received NAT, and 29 received adjuvant therapy. OS for the 31 patients was 49% at 5 years, with a DFS at 5
years of 42%. There was a trend for better survival in those patients who were transplanted in the “new era”
(after 2007), and the best survival rates were associated with patients receiving both NAT and adjuvant
therapies, independently of the era or tumor size. This may suggest that the use of perioperative therapies
may level the field for patients with more advanced stages, and may make LT an option for a larger number
of patients with significantly higher tumor burden.

In 2018, Lunsford et al. from Houston Methodist-MD Anderson published a prospective case series of
[66]
gemcitabine-cisplatin based NAT followed by LT in 12 patients with biopsy-proven unresectable iCCA .
Using livers that would have been discarded (extended criteria donors or domino living donors), 6 patients