Evaluation of antiangiogenic efficacy in advanced hepatocellular carcinoma: Biomarkers and functional imaging

Table 2 Prognostic value of baseline circulating factors in patients treated with systemic therapies including antiangiogenic agents for advanced hepatocellular carcinoma

Ref.	Marker	Patient (n)	Study type	Treatment	Levels values	Prognostic value	Conclusion/comments
Kaseb et al[86]	VEGF-A	394	Systemic review including only serum or plasma-based studies	Various (AA alone or combined with CT)	High serum or plasma level	Poorer outcome	Plasma VEGF seemed more relevant than serum VEGF as prognostic factor for HCC
Llovet et al[63]		490	Prospective phase III trial	Sorafenib vs placebo	High plasma level (> 101 pg/mL)	Poor OS	The VEGF level was a prognostic factor for all patient's cohort but surprisingly it did not affect prognosis in patients receiving sorafenib. Moreover, the VEGF level did not predict response
						Better clinical/ demographic parameters
Llovet et al[63]	HGF	251	Prospective phase III trial	Sorafenib vs placebo	High plasma level	Poorer OS	HGF was a prognostic factor for the entire cohort. However, it does not predict response to sorafenib (only a nonsignificant trend)
Miyahara et al[112]	Ang2	30	Prospective?	Sorafenib	High serum level	Shorter PFS Progressive disease	The small cohort and the lack of control arm hamper conclusion on the role of Ang2 as predictive of response to sorafenib
Llovet et al[63]		490	Prospective phase III trial	Sorafenib vs placebo	High plasma level (> 6043.5 pg/mL)	Poorer OS Better clinical/demographic parameters	Ang2 was shown to be a prognostic factor in HCC but did not predict response to sorafenib
Llovet et al[63]	c-KIT	245	Prospective phase III trial	Sorafenib vs placebo	High plasma level (> 11.3 ng/mL)	Trend to a better OS	Soluble c-KIT was shown to be a prognostic factor for HCC. However, it showed only a nonsignificant trend to predict response to sorafenib
						Trend to better TTP
						Better clinical/demographic parameters
Llovet et al[63]	IGF-2	254	Prospective phase III trial	Sorafenib vs placebo	High plasma level (> 797.7 ng/mL)	Better OS	IGF-2 was shown to be prognostic factor in HCC but did not predict response to sorafenib
						Better clinical/demographic parameters
Shao et al[126]	CEC/CECP	40	Prospective	Sorafenib + CT	High CECP level	Poorer PFS Poorer OS	The predictive value of CECP was not confirmed in further investigations

AA: Antiangiogenic; Ang2: Angiopoietin 2; CEC: Circulating endothelial cells; CECP: Circulating endothelial cell progenitors; c-KIT: Stem-cell factor receptor; CT: Chemotherapy; HCC: Hepatocellular carcinoma; HGF: Hepatocyte growth factor; IGF-2: Insulin growth factor 2; OS: Overall survival; PFS: Progression-free survival; TTP: Time to progression; VEGF: Vascular endothelial growth factors.