Chemotherapy and target therapy for hepatocellular carcinoma: New advances and challenges

Table 1 Efficacy results of targeted therapies used in advanced hepatocellular carcinoma treatment

	Trial	Dosage	OS (mo)	PFS/TTP (mo)	AEs	Ref.
VEGF/VEGFR
Sorafenib	Phase III (SHARP) vs placebo	400 mg bid	10.7 vs 7.9	5.5 vs 2.8	HFSR, hypophosphatemia, diarrhea	[10]
	Phase III (Asian)	400 mg bid	6.5 vs 4.2	2.8 vs 1.4	HFSR, diarrhea, hypertension	[11]
	+ TACE vs TACE alone	400 mg bid	7.5 vs 5.1	6.3 vs 4.3	HFSR, alopecia, diarrhea	[19]
	+ TACE	400 mg bid	12	8.5	HFSR, diarrhea, rash	[20]
Sunitinib	Phase II	37.5 mg/d	9.8	TTP 4.1	Leukopenia/neutropenia, thrombocytopenia, AST elevation	[24]
	Phase II	50 mg/d	8.0	5.3	HFSR, neutropenia, asthenia, thrombocytopenia,	[25]
	Phase II	50 mg/d	5.8	2.8	Fatigue, nausea, liver failure, encephalopathy	[26]
	Phase III vs sorafenib	37.5 mg/d	7.9 vs 10.2	4.1 vs 3.8	HFSR, thrombocytopenia and neutropenia	[27]
Brivanib	Phase II First-line	800 mg/d	10	2.8	Fatigue, hypertension, and diarrhea	[30]
	Phase II Second-line	800 mg/d	9.79	2.7	Fatigue, hypertension, nausea and diarrhea	[31]
	Phase III (BRISK-PS) vs placebo	800 mg/d	9.4 vs 8.2	4.2 vs 2.7	Fatigue, asthenia, hypertension	[32]
	Phase III (BRISK-FL) vs sorafenib	800 mg/d	9.5 vs 9.9	4.2 vs 4.1	Hyponatremia, AST elevation, fatigue	[33]
Vatalanib (PTK787)	Phase I/II (+ doxorubicin)		7.3	PFS 5.4 mo	Mucositis, alopecia, neutropenia and neutropenic sepsis	[38]
Linifanib	Phase II	0.25 mg/kg	9.7	3.7	Diarrhea, hypertension and fatigue	[35]
TSU-68	Phase I/II	400 mg bid	13.1	2.1	Hypoalbuminemia, diarrhea, anorexia	[40]
EGF/EGFR
Cediranib	Phase II	45 mg /d	5.8	2.8	Fatigue, anorexia and hypertension	[42]
	Phase II	30 mg /d	11.7	PFS 5.3 mo	Hypertension hyponatremia and hyperbilirubinemia	[43]
Erlotinib	Phase II	1500 mg/d	13		Skin rash, diarrhea, fatigue	[51]
	Phase II	1500 mg/d	10.75		Diarrhea, folliculitis, fatigue	[52]
Cetuximab	Phase II	250 mg/m2	9.6	PFS 1.4 mo	Elevated AST, fever, hypomagnesemia	[48]
	Phase II (+ gemcitabine + oxaliplatin)	250 mg/m2 + 1000 mg/m2 + 100 mg/m2	9.5	PFS 4.7 mo	Thrombocytopenia, neutropenia, and anemia	[49]
Lapatinib	Phase II	1500 mg/d	6.2	PFS 2.3 mo	Diarrhea, fatigue, and elevations of AST/ALT	[54]
	Phase II	1500 mg/d	12.6	PFS 1.9 mo	Diarrhea, nausea and rash	[55]
IGF/IGFR
Cixutumumab	Phase II	6 mg/kg weekly	8.0	4-mo-PFS 30%	Diabetes, elevated of AST/ALT, hyponatremia	[59]
PI3K/Akt/mTOR
Everolimus	Phase I/II	5 mg/d or 10 mg/d	8.4	PFS 3.8 mo	Lymphopenia, hyponatremia aspartate transaminase,	[70]
	Phase III vs placebo	7.5 mg/d	7.56 vs 7.33	2.96 vs 2.6		[71]
Sirolimus	Phase II	20 mg/wk	26.4 wk	15.3 wk	Fatigue, ascites, acne, mucositis	[72]
Met
Tivantinib	Phase II vs placebo	360 mg bid	6.6 vs 6.2	1.6 vs 1.4	Neutropenia, anemia, asthenia	[87]
		cMet-high	7.2 vs 3.8	2.7 vs 1.4

OS: Overall survival; PFS: Progression-free survival; TTP: Time to progression; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; mTOR: Mammalian target of rapamycin; PI3K: Phosphatidylinositol-3-kinase; Met: Met proto-oncogene; EGFR: Epidermal growth factor receptor; HFSR: Hand-foot skin reaction; EGF: Epidermal growth factor; TACE: Transarterial chemoembolization; AEs: Adverse events; BRISK-PS: Brivanib study in patients at risk-post sorafenib; AST: Aspartate transaminase; ALT: Alanine transaminas; IGF: Insulin-like growth factor; IGFR; Insulin-like growth factor receptor.