Page 80 - Read Online

Page 10 of 21 Toniutto et al. Hepatoma Res 2020;6:50 I http://dx.doi.org/10.20517/2394-5079.2020.40

HCC response to anticancer treatments as a surrogate biological marker of tumor aggressiveness
Alongside the morphological, histological, and serological criteria used to predict the risk of HCC
recurrence after LT, an innovative and more flexible approach involves considering the response of HCC
to anticancer loco-regional treatments as a surrogate marker of the biological aggressiveness of the tumor
- and thus, of the risk of post-LT recurrence. This approach shifts the concept of selecting HCC patients
for LT from the characteristics of disease presentation to the final characteristics of the tumor after it has
undergone available treatment. Regarding this point, it is important to differentiate “bridge treatments”
from “downstaging treatments”. Bridge treatments refer to patients already on the waiting list for LT
that undergo HCC loco-regional treatments to reduce dropout rates from the waiting list. Downstaging
treatments refer to those initially applied to patients beyond the accepted criteria for LT (e.g., Milan,
[98]
UCSF, TTV-AFP, and others) to bring the tumor back within the accepted criteria for LT . The increasing
rate of applying the approach of merging HCC tumor stage and response to anticancer treatments in
[99]
European countries is justified by observations that post-LT survival outcomes in patients with HCC
exceeding the Milan criteria with objective and sustained response to pre-LT therapies are not significantly
different compared to those patients who meet conventional criteria at presentation [100] . In the US, the
UCSF downstaging protocol has recently been adopted as a national policy for granting priority listing
for LT [101] . This protocol implies that the initial selection criteria are single lesions ≤ 8 cm, or 2-3 lesions <
5 cm with total tumor diameter < 8 cm, or 4-5 nodules all < 3 cm with total tumor diameter < 8 cm. In a
retrospective analysis of the UNOS database of 3819 patients who underwent LT from 2012 to 2015, and
were classified as always within the Milan criteria or achieving UNOS downstaging criteria (UNOS-DS),
3-year post-LT survival was 83.2% for the Milan criteria and 79.1% for the UNOS-DS. The 3-year HCC
recurrence probability was 6.9% for Milan and 12.8% for UNOS-DS. Interestingly, AFP ≥ 100 ng/mL
was the only independent predictor of HCC recurrence in downstaging groups [102] . The application of
downstaging protocols involves a minimum observation period of 3 months of disease stability from
successful downstaging to LT [101,103] . This implies that liver transplant centers should adopt dynamic graft
allocation protocols to assure “on time” LT in those patients who can maximize the benefit of successful
[99]
downstaging . Thus, both AASLD and EASL guidelines recommended loco-regional treatments
in patients with HCC exceeding the Milan criteria and to consider those who underwent successful
downstaging as candidates for LT, when this status is maintained for at least 3-6 months [104-106] .

Although the rationale for supporting the application of downstaging strategies exists, it is much more
complex to evaluate the ways in which to obtain it. There are in fact multiple loco-regional therapies
applicable for the treatment of patients with HCC with both bridging and downstaging purposes. These
therapies include transarterial chemoembolization (TACE) and radioembolization, percutaneous ethanol
injection, radiofrequency ablation, and stereotactic body radiation. Liver resection may be a further part of
a multimodal downstaging strategy [107,108] . The long list of therapeutic strategies highlights how indications
to perform them can be varied between different transplant centers, thus results obtained are not always
comparable [107] . Since every treatment can negatively impact upon residual liver function, it has been
proposed that only patients with adequate liver function (Child Pugh class A/B) and with serum bilirubin ≤
3 mg/dL can be candidates for downstaging procedures [102,103] . TACE is the most commonly used treatment,
so it is recommended as first-line for downstaging [108] .

A further critical element relates to the method used in various studies to judge the response to loco-
regional treatments. In more recent studies, this has been done by applying the modified Response
Evaluation Criteria in Solid Tumors (mRECIST), which assesses both the change in tumor volume
and in arterial enhancement by means of contrast CT or MRI scan of the liver [109] . A very recent report
demonstrated that the addition of the mRECIST criteria into the Metroticket 2.0 framework improved
its predictive ability [110] . However, although sufficiently detailed, the mRECIST criteria may have
reproducibility limits between different transplant centers, such that the results obtained by loco-regional
therapies are not always reproducible.