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Page 2 of 12 Mathias-Machado et al. Hepatoma Res 2021;7:67 https://dx.doi.org/10.20517/2394-5079.2021.84

advanced stage. In these cases, patients are not candidates for curative intent local treatments such as
[1]
resection, percutaneous ablation, or liver transplantation .
In patients diagnosed with early-stage disease, especially cases detected during screening, curative
treatments are chosen in order to achieve a complete and durable remission. However, recurrence rates are
high, reaching up to 70% in five years . This scenario highlights the importance of strategies and treatments
[2]
able to reduce the risk of recurrence and, consequently, impact positively on mortality.

Currently, there are no established treatments in the adjuvant setting post resection, ablation, or
transplantation. The main treatment guidelines indicate that patients should remain under follow-up and
additional treatment is not recommended. Accordingly, no neoadjuvant therapy has proven to reduce the
[1,3]
risk of recurrence and is not part of treatment algorithms . The use of downstaging strategies for patients
beyond criteria for liver transplantation can be considered one of the only exceptions.

Some data suggest benefit with the use of interferon-alpha (IFNα), cytokine-induced killer cells, arterial
chemoembolization, and antiviral therapies. However, robust evidence of the efficacy of such therapies is
scarce.

Currently, new drugs have encouraging results in the treatment of advanced HCC, especially immune
checkpoint inhibitors. As a result, several clinical trials are ongoing aiming at the incorporation of such
agents to reduce risk of recurrence. The present review describes the rationale and available data on
adjuvant treatment after local treatments in HCC.

RATIONALE FOR (NEO)ADJUVANT TREATMENT
Conceptually, HCC recurrence can occur in different settings: (1) intrahepatic recurrence; (2) de novo HCC;
or (3) appearance of extrahepatic metastatic lesions with or without a liver tumor [Figure 1].

The first scenario occurs more frequently up to two years after local treatment, while the second scenario
has a later onset (more than two years) and is the result of risk factors that predispose to cirrhosis-induced
carcinogenesis. The third scenario, the appearance of extrahepatic metastatic lesions, is associated with poor
prognosis .
[4]
Some studies indicate that distinct genomic profiles between primary and recurrent HCC could explain
poor prognosis of recurrence. Transcriptomic reprogramming of tumor cells with acquired mutations in
specific genes, such as TP53 and ARID1A, are suggested to trigger clonal evolution and aggressive
phenotypes with invasion, metastasis, and epithelial-to-mesenchymal transition .
[5,6]
Recurrence prevention through adjuvant treatment is distinct in cases of de novo HCC. From this
standpoint, the management of cirrhosis complications, as well as measures to avoid liver function
deterioration through antiviral treatment, for example, are crucial. To reduce the risk of recurrence due to
intrahepatic and extrahepatic metastases, the use of systemic therapies is promising.

The rational for neoadjuvant therapeutic approaches before local treatment is based on an early control of
micrometastatic disease and the possibility of a tumor downsizing, which could improve the feasibility of
resection or ablation. The use of immunotherapy is being increasingly investigated in this scenario.