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Page 10 of 13 Giovanis et al. Hepatoma Res 2018;4:10 I http://dx.doi.org/10.20517/2394-5079.2018.21

immunotherapy must be still understood, evaluating the efficacy and tolerability data deriving from the
ongoing phase 3 studies requested by regulatory agency. These studies have concluded enrollment and final
outcomes will be presented in the next months at congresses.

But a more reliable criterion that could guide the choice of such drugs is the evaluation of tolerability profile
detected in clinical trials. Consequently, the choice of the second line drug should be tailored based on
patients’ characteristics, comorbidities and expected toxicity profile associated with each regimen. At this
regard, pivotal studies indicated that regorafenib had a sorafenib-like liver toxicity profile with hepatic
adverse events resulting like placebo, while cabozantinib increased liver toxicity, as evidenced by the increase
in grade 3/4 transaminases of 12% suggesting attention to patients with very high transaminase values at the
baseline. Similarly, nivolumab does not seem to induce the same toxicity seen for the other two drugs (hand-
foot skin reaction, diarrhea, hypertension), but may have increased liver toxicity, revealed by the increase in
grade 3/4 bilirubin.

An additional therapeutic opportunity for the second-line treatment could be represented also by
ramucirumab. At the day of writing a press release announced that this drug demonstered efficacy in a
[67]
phase 3 study conducted on patients pretreated with sorefenib and with AFP > 400 ng/mL .

CONCLUSION
Improved knowledge of the standard of care and new therapies coming up after 10 years of failure in HCC,
trigger new hopes for patients and hepato-oncological community to extend the survival in a disease that
remains one of the leading causes of cancer-related deaths around the world. Currently the lack of adequate
predictive or potential biomarkers factors makes challenging the identification of patients who will benefit
with durable responses from each therapy.

DECLARATIONS
Authors’ contributions
Conception and manuscript writing, provision of study materials, collection and assembly of data: Giovanis P
Administrative support: D’Ippolito S
Data analysis and interpretation: Giovanis P, Pastorelli D
Final approval of manuscript: all authors

Financial support and sponsorship
This publication has been made possible by the Medical Writing support of dott Roberto Barsanti and
dott Maria Cristina Mazzotta (Medical Department - Bayer SpA). No specific funding or grant have been
provided for this publication.

Conflicts of interest
There are no conflicts of interest.

Patient consent
Not applicable.

Ethics approval
Not applicable.

Copyright
© The Author(s) 2018.