Page 891 - Read Online

Cullen et al. Hepatoma Res 2020;6:76 I http://dx.doi.org/10.20517/2394-5079.2020.69 Page 9 of 14

Sixty-five percent of the patients underwent a protocol of bridging therapy, which led to significant
reductions in tumor burden and disease progression prior to transplant. A recurrence rate of 35% was
observed and 3-year survival was 56%, representing superior survival compared with palliative treatments.
[47]
Positive outcomes were also reported by Jeong et al. in their experience with 17 HCC patients with major
vascular invasion who underwent LDLT after combined treatment with transarterial chemo-embolization
and radiotherapy. The authors found that the 1- and 3-years DFS were 70.6% and 57.8% and the OS rates
at 1- and 3-years were 87.4% and 60.5%, respectively. Even though long-term results are not provided, the
authors concluded that acceptable oncologic outcomes can be achieved in select HCC patients with major
vascular invasion, and suggest that LDLT might be a therapeutic option for these patients if the tumors
are downstaged considering that 1-year survival rate for HCC patients with PVTT is less than 10%. Even
though it has been reported that the use of downstaging strategies in the presence of extended criteria of
HCC for LDLT has decreased in Asian countries, published experience among Asian institutions revealed
comparable 5-year overall survival rates in patients who received LDLT after downstaging versus those
[48]
without downstaging .

A benefit to pre-operative therapy is the additional time for proper surgical planning. Where the price of
DDLT might be a gap in planning, locoregional therapies create an ideal setting for LDLT in that it provides
better selection and timing, allowing for a set date for the surgery when it is most likely to succeed when
the disease response is most appropriate after locoregional therapy.

Adjuvant therapy
HCC recurrence remains the leading cause of death after liver transplantation, and patients with advanced
[49]
disease are at particular risk . Early recurrences are commonly seen in patients with associated negative
[45]
prognosis factors such as vascular invasion . In order to help decrease the incidence of HCC recurrence
post-transplantation, numerous strategies have been proposed as adjuvant therapy; however, none have
been able to provide enough support regarding prolonged recurrence-free survival and none have been
[50]
widely accepted . Other factors complicating the standardization of an adjuvant regimen for HCC is the
heterogeneity among HCC between different regions. Thus, targeting recurrence risk factors should be
analyzed in an individual manner. Currently published evidence include experience with systemic therapy
such as oral anti-HBV agents, tyrosine kinase inhibitors, IFN-alpha, TACE, anti-PD-1 antibodies (e.g.,
Nivolumab, pembrolizumab, atezolizumab), molecular-targeted agents, and chemotherapy agents (e.g.,
Oxaliplatin plus fluorouracil/leucovorin) .
[50]
Select immunosuppressive medications may portend an oncologic benefit, specifically mammalian target of
rapamycin (mTOR) inhibitors such as everolimus and sirolimus [51,52] . Inhibition of tumor growth mediated
by properties such as antiangiogenic and antiproliferative effects makes mTOR an extraordinary class
[53]
of immunosuppressants . In 2016, a prospective-randomized open-label international trial compared
recurrence-free survival in sirolimus-containing versus mTOR inhibitor-free immunosuppression patients
undergoing LT for HCC. The authors found that sirolimus in LT recipients with HCC did not improve
long-term recurrence free survival beyond 5 years. However, a benefit in the first 3 to 5 years for recurrence
free survival and OS was evident. Regarding adverse events, both groups reported similar frequencies [53,54] .

Clinicians should be aware of the increased risk of post-transplant HCC recurrence with calcineurin
inhibitors . In a systematic review of 42 publications, patients on everolimus had significantly lower
[54]
[52]
recurrence rates of HCC versus calcineurin inhibitors and sirolimus . Sorafenib, a multikinase inhibitor,
has also shown promise as an adjuvant therapy. In a study of 30 patients with HCC beyond Milan,
[55]
sorafenib reduced recurrence of post-transplant HCC compared with capecitabine . However, contrasting
experiences have been published. A recent publication evaluating the role of Sorafenib on HCC recurrence
and survival in 45 patients with advance HCC on explant pathology after LT found that adjuvant