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Giovanis et al. Hepatoma Res 2018;4:10 I http://dx.doi.org/10.20517/2394-5079.2018.21 Page 5 of 13

PDGFR-ß are receptor tyrosine kinases. Sorafenib demonstrated a statistically significant improvement of
OS in Child Pugh class A patients with intermediate or advanced HCC (BCLC stages B and C) in two large
phase 3, randomized, placebo-controlled trials performed in Western countries (SHARP) and in Asia-Pacific
(ASIA-PACIFIC) [5,26] .

In the SHARP trial the OS and TTP were respectively 10.7 and 5.5 months (7.9 and 2.8 months respectively
[5]
for the placebo group) , while in the ASIA-PACIFIC trial OS and TTP were 6.5 and 2.8 months respectively
[26]
(4.2 and 1.4 months for the placebo group) . The hazard ratios for OS and TTP were nevertheless
comparable between the two trials, indicating similar magnitude of clinical benefit. The observed differences
in median OS and TTP in these 2 trials were probably due to poorer disease characteristics of advanced
[27]
disease in the ASIA-PACIFIC trial compared to the SHARP trial . Subgroup analyses have shown that
sorafenib consistently provides an OS benefit compared with placebo irrespective of baseline conditions such
as disease etiology, baseline tumor burden, performance status, tumor stage, and prior therapy [5,26,28] .

A pooled global population enrolled in the two pivotal studies was analysed to identify potential predictive
factors of sorafenib treatment benefit. This analysis turned out that sorafenib treatment provided a survival
benefit across all categories of patients, showing a significant magnitude of benefit in patients with disease
confined to the liver (without extrahepatic disease - EHS) or HCV cirrhosis or a low neutrophil-to-
[28]
lymphocyte ratio status .
The efficacy and the safety profile of sorafenib already observed in clinical trials were confirmed in real-
world experiences assessing sorafenib in patients who are not selected by strict clinical trial criteria,
including patients with comorbidities and those receiving concomitant medication [29,30] .

Both in clinical and field-practice studies, the most frequent sorafenib-associated adverse events resulted
in dermatological lesions as hand-foot skin reaction, fatigue and diarrhoea, whereas treatment-related liver
[31]
adverse events are overall less frequently reported . Single experiences reported that the occurrence of
hypertension, diarrhoea and skin lesions are generally correlated to higher survival benefits, therefore the
occurrence of some toxicities should be managed and not immediately address to discontinuation [32-36] . At
this regard, treatment strategies based on temporary suspensions followed by restart of therapy at lower
doses may help in management of sorafenib tolerance in patients presenting relevant adverse events.

The results collected showed poorer outcomes in patients with Child-Pugh B cirrhosis treated with sorafenib,
when compared with patients with Child-Pugh A cirrhosis. This finding could be likely attributed to a more
severe liver dysfunction and more compromised conditions of Child-Pugh B patients and not to an effect of
the drug itself.

With the aim to extend the benefit observed with sorafenib to patients with earlier stages of disease (BCLC-A
and B), many phase 2 and 3 trials were conducted to evaluate safety and efficacy of sorafenib in surgical
adjuvant setting and in combination with loco-regional therapies [37-44] . All these studies did not achieved the
primary endpoint, authors reported possible explanations due to the design of the studies. However new
study of combination or in adjuvant setting are currently ongoing with different treatment schedules.

Failing results were observed also combining sorafenib with systemic therapies. Indeed, the two trials
sorafenib plus erlotinib and doxorubicin plus sorafenib failed to show the superiority of the combination
arms versus sorafenib alone as comparison arm [45,46] .

Currently sorafenib is the standard of care for advanced HCC as reported by many guidelines and the
[47]
improvement of survival associated with this drug is supported by the highest level of evidence .