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Zhong et al. Hepatoma Res 2019;5:18 I http://dx.doi.org/10.20517/2394-5079.2019.01 Page 3 of 6

[25]
therapies . Patients in the hepatectomy group had significantly longer median OS than those received
other treatments (2.87 years vs. 1.10 years. However, hepatectomy provided no OS benefit for those with
PVTT affected the main trunk or contralateral branch (Vp3 or 4). Our systematic review involving 4,389
HCC patients with macrovascular invasion showed that hepatectomy provided median OS of 50% at
[20]
1 year and 18% at 5 years . However, median OS after sorafenib therapy was less than 1 year in presence of
[27]
PVTT . Moreover, radioembolization is associated with similar median OS with sorafenib in HCC patients
[27]
with PVTT . These median survival time is not much higher than that of about 5 months after the best
supportive care [13,28] . The OS benefit of palliative treatment is not obvious. Moreover, we should also consider
[29]
that these treatments are always associated with risk of adverse events and high costs .

These findings argue for expanding the Western officical liver guidelines [13,14] to recognize hepatectomy
as a therapeutic option for selected HCC patients with intermediate or advanced disease with good liver
function (mainly Child-Pugh A). It may be true that some situations could decrease the efficacy and/or
safety of hepatectomy. For instance, hepatectomy may be less effective and associated with more morbidity
in HCC patients with multinodular tumors due to the possibility of microvascular invasion and liver/lung
metastasis. In addition, liver cirrhosis and hepatitis activity may increase the risk of mortality, perioperative
morbidity, and long-term tumor recurrence. However, continuous improvements in perioperative care and
surgical technique support expanding the indications of hepatectomy. Surgeons and oncologists should not
shy away from hepatectomy selection when it is feasible. At the same time, doctors should be fully conscious
[30]
of the fact that the procedure is technically demanding . This highlights the need to expand indications for
hepatectomy.

But in fact, expanding indications of hepatectomy will translate into higher rate of tumor recurrence.
Therefore, effective adjuvant therapy to prevent the recurrence of HCC is important to improve patients’
long-term OS after hepatectomy. In recent decades, lots of studies have explored such therapies to prevent
the recurrence of HCC, but until now, none has been officially recommended [13,14] .

Nowadays, many types of postoperative therapies to prevent HCC recurrence were reported, such as
transarterial chemoembolization, nucleos(t)ide analogues (NAs), interferon-α, adoptive immunotherapy,
vitamin K2 analog, autologous tumor vaccination, sorafenib, capecitabine, and so on. Meta-analysis found a
significant improvement in recurrence-free survival and OS when adjuvant transarterial chemoembolization
is used for patients with high risk of early-phase recurrence, such as large tumor, vascular invasion, and
[31]
multinodular tumors . The other postoperative therapies with positive efficacy is NAs for patients with
[34]
HBV-related HCC [32,33] , interferon-α for patients with HCV-infected HCC . All these three therapies are
with acceptable safety. However, the safety and efficacy of the following adjuvant therapies have not been
definitively established, and need further clinical investigation: interferon-β for patients with HCV-related
HCC; interferon-α for patients with HBV-related HCC; vitamin K2 analog, autologous tumor vaccination,
adoptive immunotherapy, heparanase inhibitor PI-88, iodine-131-labeled lipiodol, or capecitabine for
patients with HCC [35,36] . In contrast, the following adjuvant therapies are not recommended for clinical use:
tamoxifen, sorafenib, intravenous chemotherapy and systemic chemotherapy, octreotide, and branched-
chain amino acid supplementation [37-39] . Though most of these reports can create a base for clinical use and
further studies, their findings should be interpreted with caution due to their clinical heterogeneity among
the trials (patients, liver disease, drugs, dosages, treatment duration, etc.) and their small sample size.

Early- and late-phase recurrence of HCC are associated with different risk factors, and patients will have
different prognoses. Macrovascular invasion, tumor rupture, multinodular tumors, large tumor size, absence
of a tumor capsule, poorly differentiated tumor, and narrow resection margin are associated with early-
phase recurrence. Liver cirrhosis, which is the risk factor of liver carcinogenesis, is associated with late-phase
tumor recurrence. Moreover, HBV infection may contribute to both early- and late-phase recurrence. In