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Page 12 of 18 Galicia-Moreno et al. Hepatoma Res 2020;6:20 I http://dx.doi.org/10.20517/2394-5079.2019.36

8 medical centers in 5 South American countries between January 2010 and June 2017, showed that 38% of
cases was due to HCV and the median survival after initiation of treatment was 7.5 months (IQR 2-17) in all
[94]
subjects .
According to current guidelines established by ALEH, Sorafenib is standard systemic therapy for HCC in
patients categorized as Child-Pugh C, or with underlying cirrhosis and advanced tumor (stage C according
to BCLC guidelines), or with tumor progression even after loco-regional therapy. However, there are no
[5]
other therapeutic alternatives in the event of treatment failure with Sorafenib .

Levantinib
This is a tyrosine kinase inhibitor that blocks VEGFR1-3, fibroblast growth factor receptors (FGFRs)
1-4, PEGFR, RET, and KIT. The overall mean survival time after treatment is 13.6 months and the rate of
objective response (according to response evaluation criteria in solid tumors) is 18.8% for patients receiving
levantinib (< 1% complete response and 18% partial response). The most common adverse events for this
[95]
treatment are hypertension, diarrhea, decreased appetite, and weight loss .

Sorafenib and levatinib are approved as first-line therapy while regorafenib and cabozantinib are indicated in
[96]
patients who have progressed or are intolerant to sorafenib .

Regorafenib
This is a multi-target inhibitor of VEGFR1, TIE-2, RETRAF-1, BRAF, PDGFR, FGFR, and CSF1R. It
improves overall survival with a hazard ratio of 0.63, and the median duration of overall survival of patients
who received it is 10.6 months. Adverse events include hypertension, hand and foot skin reactions, and
diarrhea .
[97]

Cabozantinib
This targets the mesenchymal-epithelial transition factor (c-Met) pathway, as well as the VEGF and RET
receptors. Compared to placebo, cabozantinib increased the median overall survival (10.2 months vs.
8.0 months). The hazard ratio for death by treatment is 0.76; (95%CI: 0.63-0.92). However, grade 3 or 4
adverse events occurred in 68% and 36% of patients in the cabozantinib and placebo groups respectively. The
most common high-grade adverse events include palmar-plantar erythrodysesthesia, hypertension, increased
[98]
aspartate aminotransferase level, fatigue and diarrhea .
Ramucirumab
This is a fully humanized IgG1 monoclonal antibody directed against the extracellular domain of VEGFR-2.
It has shown clinical efficacy either alone or in combination with chemotherapy in the treatment of a number
of malignancies. It can be given on a twice or thrice weekly schedule and binds with much higher affinity to
VEGFR-2 than its natural ligands, thus preventing the VEGF-VEGFR-2 interaction. Ramucirumab has also
shown an advantage in delaying the worsening of disease-related symptoms and prolonging overall survival
[99]
compared with placebo .

Nivolumab
This is a fully human immunoglobulin G4, anti-PD-1 monoclonal antibody that has been approved for the
treatment of multiple advanced malignancies. In the phase I/II trial Checkmate-040, nivolumab showed
response across all cohorts in 14%-20% of patients. The most common adverse events were fatigue, pruritus
and rash, but manageable. Grade 3/4 serious adverse events occurred in 4% [100] .

Doxorubicin
This is the most studied and widely used chemotherapeutic agent for HCC treatment and is chosen when the
patient’s disease is critical. It is a DNA intercalating agent and its mechanism of action is related to inhibition