Role of anti-angiogenesis therapy in the management of hepatocellular carcinoma: The jury is still out

Table 1 Clinical studies on anti-angiogenesis therapy of hepatocellular carcinoma included in this review

Ref.	Year	Phase	Investigational drug	Outcome
Llovet et al[10]	2008	Phase 3	Sorafenib	Increased survival
Cheng et al[12]	2009	Phase 3	Sorafenib	Increased survival
Lencioni et al[13]	2012	Phase 4	Sorafenib	High safety
Lencioni et al[14]	2014	Phase 4	Sorafenib	High safety
Johnson et al[40]	2013	Phase 3	Brivanib	Less well-tolerated
Cheng et al[41]	2013	Phase 3	Sunitinib	Significantly inferior than sorafenib
Zhu et al[42]	2012	Phase 3	Sorafenib plus erlotinib	No survival benefit
Llovet et al[43]	2013	Phase 3	Brivanib after sorafenib failed	No survival benefit
Zhu et al[44]	2014	Phase 3	Everolimus after sorafenib failed	No survival benefit

Table 2 Studies on the mechanisms of anti-angiogenesis therapy resistance in hepatocellular carcinoma

Ref.	Year	Investigational drug	Pathways/genes involved	Effects
Blivet-Van Eggelpoël et al[21]	2012	Sorafenib	EGFR and HER-3	Restrict cell response
Ezzoukhry et al[22]	2012	Sorafenib	EGFR	Potential determinant of primary resistance
Zhang et al[23]	2009	Sorafenib	pERK	Potential biomarker for sensitivity prediction
Chen et al[24]	2011	Sorafenib	PI3K/Akt	Mediates acquired resistance
Xia et al[25]	2013	Sorafenib	TGF-β-and PI3K/Akt	Mediates acquired resistance
Chen et al[26]	2011	Sorafenib	EMT and hedgehog signaling	Drug resistance
Xin et al[27]	2013	Sorafenib	CSCs	Drug resistance
Chow et al[28]	2013	Sorafenib	EMT	Acquired resistance
Fernando et al[29]	2014	Sorafenib	TGF-β pathway	Prediction of low susceptibility
Huang et al[30]	2013	Sorafenib	EMT	Drug resistance
Shi et al[31]	2011	Sorafenib	Autophagy	Drug resistance
Shimizu et al[32]	2012	Sorafenib	Autophagy	Impair antitumor effects
Zhai et al[33]	2014	Sorafenib	Autophagy	Acquired resistance
Liu et al[34]	2013	Sorafenib	Autophagy	Facilitates resistance
Liang et al[36]	2013	Sorafenib	Hypoxia	Drug resistance
Mao et al[38]	2014	Sorafenib	microRNA-193b	Enhances cell response
Ebos et al[46]	2009	Sunitinib	VEGFR/PDGFR	Accelerate metastasis and decrease overall survival
Pàez-Ribes et al[47]	2009	Sunitinib	VEGFR/PDGFR	Increase local invasion and distant metastasis
Xiong et al[50]	2009	Sorafenib	TECs	Drug resistance
Li et al[53]	2011	Bevacizumab	Dll4-notch signaling	Drug resistance

EGFR: Epidermal growth factor receptor; HER-3: Human epidermal growth factor receptor-3; pERK: Phosphorylated extracellular signal-regulated kinase; PI3K: Phosphatidylinositol 3-kinase; TGF-β: Transforming growth factor beta; EMT: Epithelial-mesenchymal transition; CSCs: Cancer stem cells; TECs: Tumor-derived endothelial cells; VEGFR: Vascular endothelial growth factor receptors; PDGFR: Platelet-derived growth factor receptors; Dll4: Delta-like ligand 4.