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Fonseca et al. Hepatoma Res 2023;9:27 https://dx.doi.org/10.20517/2394-5079.2023.63 Page 3 of 5

Table 1. Summary of american association for the study of liver diseases guidelines
First line Level Recommendation
Indication: patients with preserved liver function (Child-Turcotte-Pugh A or well-selected Child-Turcotte-Pugh B 1 Strong
cirrhosis), ECOG PS 0-1, who have BCLC Stage C HCC, or BCLC Stage B HCC not amenable to or progressing after
locoregional therapy
Atezolizumab plus bevacizumab or durvalumab plus tremelimumab are preferred first-line therapy options 2 Strong
Patients considered for atezolizumab plus bevacizumab should undergo an EGD to assess for risk of variceal or 5 Strong
other gastrointestinal bleeding
The optimal treatment of large varices prior to atezolizumab plus bevacizumab initiation is unknown, although 5 Weak
AASLD recommends at least one session of banding. Carvedilol may be considered as an alternative prior to
atezolizumab and bevacizumab
Patients with recent bleeding within 6 months and those with high-risk stigmata for bleeding on EGD should have 5 Strong
varices adequately treated prior to atezolizumab plus bevacizumab initiation, or these patients may be considered
for durvalumab and tremelimumab
First-line sorafenib or lenvatinib should be offered to patients with contraindications to atezolizumab plus 1 Strong
bevacizumab or durvalumab plus tremelimumab
Second-line
Indication: patients with preserved liver function (Child-Turcotte-Pugh A or well-selected Child-Turcotte-Pugh B 1 Strong
cirrhosis), ECOG PS 0-1, who develop HCC progression or intolerance with first-line systemic therapy
Sorafenib or lenvatinib as preferred agents after first-line if patients are not eligible for clinical trials 5 Weak
Cabozantinib, regorafenib, or ipilimumab plus nivolumab may be alternatives after immunotherapy-based regimens 5 Weak
AASLD advises cabozantinib or regorafenib (or ramucirumab in patients with AFP ≥ 400 ng/ml) as preferred 1 Strong
agents after sorafenib or lenvatinib if patients are not eligible for clinical trials
AASLD advises against the use of immunotherapy after liver transplantation 4 Strong
HCC: Hepatocellular carcinoma; ECOG-PS: eastern cooperative oncology group performance status; BCLC: barcelona clinic liver cancer; EGD:
esophagogastroduodenoscopy; AFP: alpha-fetoprotein; AASLD: American Association for the study of liver diseases

[16]
evidence to support the indication of immunotherapy in HCC patients with relevant liver dysfunction .

Global real-world data reported that sorafenib is safe in Child-Pugh B patients, but survival outcomes are
[17]
worse compared to Child-Pugh A . Additionally, an Italian multicentric randomized trial was designed to
explore the benefit of sorafenib in Child-B7-9 patients. The trial was planned to include 320 patients, but
only 35 patients were enrolled. Although not statistically powered, a median overall survival of 3.5 months
was observed .
[18]

Solid organ transplantation is a formal contraindication to immunotherapy because of its potential risk of
inducing allograft rejection, and therefore this subgroup was also excluded from the pivotal trials. Although
small series have reported cases of transplanted patients safely treated with immune checkpoint inhibitors,
the standard systemic therapy for these patients is still based on tyrosine kinase inhibitors .
[19]

The use of systemic treatment in early stages is currently under active research. Adjuvant treatment with
atezolizumab plus bevacizumab has been shown to delay recurrence after surgery or ablation in patients at
high risk of recurrence, but no positive impact on survival has been demonstrated . In intermediate stage
[20]
(BCLC-B) HCC, systemic treatment is preferable for patients with high tumor burden. In a propensity-
matched study, lenvatinib was shown to provide better survival and lower liver alteration compared to
[21]
transarterial chemoembolization, in patients with BCLC-B and beyond up-to-seven criteria . In addition,
several trials are testing combinations of immune checkpoint inhibitors plus transarterial treatments such as
transarterial chemoembolization or radioembolization. The rationale for this approach is to harness the
immune boost provided by tumor cell death with local treatments and to optimize systemic antitumor
activity with immune checkpoint inhibitors.