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Page 4 of 12 Mathias-Machado et al. Hepatoma Res 2021;7:67 https://dx.doi.org/10.20517/2394-5079.2021.84

virus infection who underwent surgical resection, the use of IFNα at five million units three times a week
was associated with better overall survival (63.8 months vs. 38.8 months for the control group) and better
[9]
recurrence-free survival (31.2 months vs. 17.7 months) . In addition, a meta-analysis including 14 studies (9
randomized trials and 5 cohort studies) showed that IFNα is associated with a reduction in recurrence and
mortality in patients infected with hepatitis C virus, while in patients with hepatitis B virus there was a
[10]
reduction in mortality, but no impact on HCC recurrence was demonstrated . Despite the mentioned data,
the results with IFNα have not been globally reproduced, and this treatment is not considered a standard-of-
[1,3]
care according to recommendation guidelines .
Antiviral drugs
The use of nucleotide/nucleoside analogs is recommended in patients with HCC and active hepatitis B virus
infection. The effect of nucleotide/nucleoside analogs as an adjuvant therapy was evaluated in a longitudinal
study with patients with chronic hepatitis B infection. This study showed lower rates of recurrence and
deaths related to HCC, as well as higher probability of preserved liver function at six months after
surgery . The use of antiviral drugs is recommended for patients with chronic hepatitis B with detectable
[11]
HBV-DNA and HCC.

Intra-arterial treatment
The use of transarterial chemoembolization (TACE) is the recommended treatment for patients with
intermediate stage BCLC-B . The rationale for using this modality as an adjuvant treatment stems from
[1,3]
the potential benefit in detecting residual disease by angiography and early embolization of the residual
tumor focus.

Two randomized studies with a limited number of patients suggest the role of TACE in the adjuvant setting.
In the first study, patients with HCC associated with hepatitis B virus infection who underwent TACE after
resection had favorable recurrence rates (56% vs. 42.1%) and three-year survival rates (85.2% vs. 77.4%)
compared to the control group . In another study, including patients with resected tumors larger than
[12]
5 cm or presenting microvascular invasion, the use of adjuvant TACE resulted in better overall survival
(44.29 months vs. 22.37 months) when compared to the control arm . However, randomized trials with a
[13]
larger number of patients are warranted to refine the role of TACE after resection.

Target therapies: tyrosine kinase inhibitors
TKIs are essential tools for managing advanced HCC. Sorafenib, an inhibitor with activity against RAF and
receptors for vascular growth factor-2 (VEGFR-2) and platelet-derived growth factor, was the first drug able
to demonstrate a survival improvement with advanced HCC according to phase III placebo-controlled
[14]
trial .
The use of sorafenib in the adjuvant setting was evaluated in the phase III STORM trial. In this study, 1114
patients who had undergone complete resection or ablation were randomized to sorafenib 400 mg twice
daily or placebo for up to four years. According to the final analysis, no difference in recurrence-free
survival between the groups was demonstrated, with a median to time to recurrence of 33.3 months in the
[15]
sorafenib group and 33.7 months in the placebo group (HR = 0.94, P = 0.26) . Thus, the positive results
obtained with sorafenib in advanced disease have not been reproduced in the adjuvant context post
resection or ablation. A possible explanation for the negative result of the STORM trial is the absence risk
stratification in the inclusion criteria, defining patients at high risk of recurrence. Additionally, adverse
events of sorafenib (diarrhea, dermatological reactions, fatigue, etc.) which determined dose reduction or
early therapy discontinuation may have impaired efficacy.