Medical treatment of unresectable hepatocellular carcinoma: Going beyond sorafenib

Table 1 Molecularly targeted agents currently tested in HCC

Agent		Targets	Development stage
Sorafenib (BAY 43-9006)	Small molecule	VEGFR-2 e -3, PDGFR-β, Raf	Registered
Sunitinib (SUO11248)	Small molecule	VEGFR-1, e 2 (-3), PDGFR-α e-β, Flt-3, C-Kit, RET	Phase II
Vatalanib (PTK787/ZK222584)	Small molecule	VEGFR-1, -2 e-3, PDGFR, C-Kit, c-Fms	Phase II
Cediranib (AZD2171)	Small molecule	VEGFR-1, -2 e-3, C-Kit	Phase II
Brivanib (BMS-582664)	Small molecule	VEGFR-2, FGFR-1	Phase II
Bevacizumab	Monoclonal antibody	VEGF-A	Phase II
Gefinitib (ZD1839)	Small molecule	EGFR/ErbB1/Her1	Phase II
Erlotinib (OSI774)	Small molecule	EGFR/ErbB1/Her1	Phase II
Lapatinib (GW572016)	Small molecule	EGFR/ErbB1/Her1, ErbB2/Her2neu	Phase II
Cetuximab	Monoclonal antibody	EGFR/ErbB1/Her1	Phase II
Everolimus (RAD001)	Small molecule	mTOR	Phase I/II
Bortezomib	Small molecule	Proteasome	Phase I/II
Belinostat (PXD101)	Small molecule	Histone-deacetylase (HDAC)	Phase II
AZD6244	Small molecule	MEK	Phase II
PI-88	Small molecule	Eparanase	Phase III
TAC-101	Small molecule	RAR-α	Phase II

VEGFR: Vascular endothelial growth factor receptors; PDGFR: Platelet-derived growth factor receptors; VEGF: Vascular endothelial growth factor; EGFR: Epidermal growth factor receptor; HDAC: Histone-deacetylase; mTOR: Mammalian target of rapamycin; HCC: Hepatocellular carcinoma.

Table 2 Summary of the results obtained so far with anti-EGFR drugs in HCC

Class	Agent	Development	Comments
Small molecules
	Erlotinib	As single-agent	Cytostatic more than cytotoxic
		In combination with bevacizumab	Active (high ORR), but toxic
	Gefitinib	As single-agent	Not active
	Lapatinib	As single-agent	Too early to draw conclusions
Monoclonal antibodies
	Cetuximab	As single-agent	Low ORR (but prolonged survival)
		In combination with chemotherapy	High DCR, but toxic

DCR: Disease control rate; ORR: Overall response rate.

Table 3 Summary of the results obtained so far with Bevacizumab and Bevacizumab-based combinations in HCC

	Development	Comments
Bevacizumab	As single agent, i.v. route	Active (high DCR), but increased risk of bleeding from esophageal varices
	As single agent, i.a. route	Promising early results
	In combination with other molecularly targeted agents, e.g. erlotininib	Active (high ORR), but toxic
	In combination with chemotherapy	Not particularly active and toxic