**2.1. Sorafenib**

Sorafenib is a multi-kinase inhibitor of vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptor (PDGFR) and Raf family kinases [2]. Sorafenib has shown to improve overall survival in comparison to placebo in advanced HCC, and it was the first drug to get Food and Drug Administration (FDA) approval as a first-line treatment for Child-Pugh score-A HCC. In the multicenter European SHARP trial, 602 inoperable HCC and Child-Turcotte-Pugh-A cirrhosis patients, were assigned to sorafenib (400 mg twice daily) or placebo [3]. The primary endpoint of the trial was overall survival, which was significantly longer in the sorafenib-treated group (10.7 vs. 7.9 months). Time to radiologic progression was also longer (5.5 vs. 2.8 months). Objective response rates were low at 2%.

Sorafenib was well tolerated in this trial. Diarrhea and hand-foot skin reaction were the only grade 3 or 4 adverse effects that occurred significantly more often in the treated group; (8 vs. 2%) and (8 vs. <1%) respectively. There were no differences in liver dysfunction or bleeding.

An exploratory analysis of SHARP trial showed that hepatitis C related HCC has the highest median overall survival advantage of 6.6 months (14 vs. 7.4 months). This is in comparison to 3.6 months (9.7 vs. 6.1 months) in those with HBV related cirrhosis and 2.3 months (10.3 vs. 8 months) in those with alcohol-related liver disease [4].

Hepatitis B virus is more prevalent in the Asian patients than in the Western population. Sorafenib was tested as a first-line treatment in Asian patients in a placebo-controlled phase III trial in which 226 patients with Child-Turcotte-Pugh A cirrhosis received sorafenib 400 mg twice daily or placebo [5]. Patients receiving sorafenib had significantly higher median overall survival (6.5 vs. 4.2 months). Grade 3 or 4 side effects were similar to SHARP trial.

Based on the results of SHARP trial, the FDA approved sorafenib monotherapy as first-line therapy for unresectable HCC.

It is worth mentioning that the patients enrolled in the above trials had mostly Child-Turcotte-Pugh A cirrhosis. This is not representative of the real practice where a significant number of patients have more advanced cirrhosis. FDA approval of sorafenib for HCC did not particularly specify the underlying cirrhosis state. Data regarding safety and efficacy of sorafenib in patients with Child-Turcotte-Pugh B or C cirrhosis are limited, and suggest that patients have poorer overall survival and overall worse side effect profile in comparison to patients with Child-Turcotte-Pugh A. Advanced progressive cirrhosis rather than sorafenib itself might be an explanation for such differences [6, 7].

Sorafenib is associated with several side effects such as hypertension, cardiotoxicity, arterial thromboembolism, bleeding, renal toxicity, hand-foot skin reaction and others. Sorafenib has been associated with potentially fatal liver toxicity. Liver function tests should regularly be monitored during treatment.

### *2.1.1. Combining sorafenib with doxorubicin*

In a phase II trial, the combination of six cycles of doxorubicin with sorafenib 400 mg twice daily was compared to sorafenib and placebo [8]. Combination therapy was associated significantly longer median time to tumor progression (6.4 vs. 2.8 months) and median overall survival duration (13.7 vs. 6.5 months). The side effect profile was not significantly worse with combined therapy. However those results were not reproduced in the randomized phase III trial, Cancer and Leukemia Group B [CALGB] trial 80,802 [9]. The study was stopped early by the data monitoring safety board after a planned interim analysis suggested futility for the combination. In a preliminary report presented at the 2016 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, median overall survival was not significantly better for the combination (9.3 vs. 10.5 months), nor was median progression-free survival (3.6 vs. 3.2 months), but toxicity was worse.
