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Page 6 of 12 Mathias-Machado et al. Hepatoma Res 2021;7:67 https://dx.doi.org/10.20517/2394-5079.2021.84

[24]
Takayama et al. conducted a randomized study in which patients previously treated with surgical
resection were allocated to receive adoptive autologous lymphocytes stimulated with interleukin-2 and anti-
CD3 antibody in five infusions for 6 months or observation. The experimental treatment resulted in a risk
reduction of 18% in 4.4 years and a longer time to recurrence (48% vs. 33% at three years). There was no
difference in survival between the groups.

[25]
Lee et al. evaluated the use of this modality in a phase III randomized multicenter study that enrolled 230
patients with HCC treated with surgery, ablation, or percutaneous ethanol injection. Patients were
randomized to receive a cytokine-induced cell injection 16 times for 60 weeks or observation. Recurrence-
free survival was 44 months in the experimental group vs. 30 months in the observation group [HR = 0.63,
(95% confidence interval: 0.43-0.94)]. There was also a significant reduction in overall mortality and cancer-
specific mortality. Adverse events were greater in the group that received treatment (62% vs. 41%), especially
chills, pyrexia, and productive cough .
[25]

A Chinese phase II study involving 46 patients showed favorable results with the use of an autologous
tumor peptide vaccine after HCC resection, demonstrating an 81% reduction in recurrence risk . Other
[26]
studies with similar techniques have not reproduced the same results and neither cell therapies nor vaccines
are used routinely.

In advanced stage HCC, therapies based on immune checkpoint inhibitors are well-established. The main
drugs in this class are intended to block the PD1/PD-L1 interaction, which inhibits antitumor action of
cytotoxic lymphocytes against tumor cells. The use of treatment combination based on atezolizumab (anti-
[27]
PDL1 antibody) and bevacizumab is considered to be the standard first-line treatment . The combination
of nivolumab (anti-PD1) and ipilimumab (anti-CTLA4) is also an option for the treatment of advanced
[28]
HCC . Pembrolizumab (anti-PD1) produces durable response rates in up to 20% of patients with advanced
disease .
[29]
Adjuvant therapies are often inspired by positive strategies in the setting of advanced disease. Both
nivolumab (CHECKMATE-9DX trial) and pembrolizumab (KEYNOTE 937 trial) are being studied as
adjuvant treatments in placebo-controlled trials.

Preliminary results of the NIVOLVE trial were presented in 2021. In this phase II single arm trial, 55
patients after surgery (n = 33) or ablation (n = 22) received nivolumab for 12 months. The median
recurrence-free survival was 26 months. Grade 3-4 treatment-related adverse events were described in 18.9%
and adverse events leading to treatment withdraw occurred in 32.1% . Table 1 shows the main ongoing
[30]
phase III studies with immune checkpoint inhibitors in the adjuvant setting.

Traditional Chinese medicine
Developments in hepatocarcinogenesis knowledge provided opportunity to identify mechanisms whereby
traditional Chinese medicine could improve tumor control and improve clinical outcomes. For example,
Huaier is a wood mushroom that has been used for 1500 years in China and is suggested to induce cell cycle
arrest at G0/G1 phase and inhibit angiogenesis . A randomized trial with 1044 HCC patients showed that
[31]
Huaier resulted in longer recurrence-free survival over placebo after surgical resection . Another trial
[32]
showed that traditional herbal medicine provided superior overall survival compared to TACE after HCC
resection . Due to the lack of multinational data and experience, this approach is not part of Western
[33]
guidelines.