Single agent doxorubicin has been the most studied chemotherapy agent for advanced HCC. Although an early trial in 1975 reported dramatic clinical activity and a 79 % response rate [9], subsequent work suggests that the true objective response rate with doxorubicin monotherapy is 20 % or less with doses of 75 mg/m² [10–15]. Lower doses ( ≤ 60 mg/m² per cycle) are associated with even lower objective response rates [16,17]. Despite the modest objective response rate, one controlled trial involving 106 patients suggests that doxorubicin is associated with a small survival advantage compared to best supportive care alone (median survival 10.6 versus 7.5 weeks) [13]. The reason for the disparate survival outcomes in this trial is unclear, but patient selection may have played a role. 5-Fluorouracil (5-FU) has acceptably low toxicity and broad antitumor efficacy. Response rates with 5-FU monotherapy have been low. However, when given in combination with leucovorin, response rates as high as 28 % have been reported [18], although lower rates have been noted by others [19].

Sorafenib is a multi-targeted, orally active, small molecule tyrosine kinase inhibitor (TKI) that inhibits Raf kinase and the VEGFR intracellular kinase pathway [20].

The multi-center European Sorafenib HCC Assessment Randomized Protocol (SHARP) trial randomly assigned 602 patients with inoperable HCC and Child-Pugh A cirrhosis to sorafenib (400 mg twice daily) or placebo [21]. Overall survival, the primary endpoint, was significantly longer in the sorafenib-treated patients (10.7 versus 7.9 months), as was time to radiologic progression (5.5 versus 2.8 months). On the other hand, objective response rates were low (7 partial responses [2 %]). Treatment was well tolerated with manageable side effects. The only grade 3 or 4 adverse effects that occurred significantly more often in the treated group was diarrhea (8 versus 2 %) and hand-foot skin reaction (8 versus < 1 %). There were no differences in liver dysfunction or bleeding. The overall incidence of sorafenib-related side effects was low compared to that reported by others [22]. These results established sorafenib monotherapy as the new reference standard systemic treatment for advanced HCC and formed the basis for approval of sorafenib for unresectable HCC in the United States. The efficacy of sorafenib in Asian patients was the subject of a second placebo-controlled phase III trial, in which 226 patients with Child-Pugh A or B cirrhosis and no prior systemic therapy for HCC received sorafenib 400 mg twice daily or placebo [23]. Patients receiving sorafenib had significantly better median overall survival (6.5 versus 4.2 months) and time to progression (TTP) (2.8 versus 1.4 months). Grade 3 or 4 side effects included hand-foot skin reaction (11 %), diarrhea (6 %), and fatigue (3 %). The magnitude of benefit was markedly less in this trial than seen in the SHARP trial. In fact, the treated group in the Asian trial had shorter survival duration than the control group in the SHARP trial (6.5 versus 7.9 months), despite the fact that both trials used the same entry criteria. Nevertheless, patients accrued to the Asian study were more ill at the start of therapy than those in the SHARP trial, with a generally worse performance status and more advanced stage of disease [24].