. 2015 Sep 18;7(20):2245–2263. doi: 10.4254/wjh.v7.i20.2245

Table 3.

Treatment-induced changes in biomarkers levels and association with outcome in patients with hepatocellular carcinoma

Ref.	Marker	Patient (n)	Study design	Treatment	Marker treatment-induced changes	Impact value	Comments
Llovet et al[63]	VEGF-A	490	Prospective phase III trial	Sorafenib vs placebo	Increase	No association with OS and ORR	The VEGF-A could serve as pharmacodynamic marker of exposure to sorafenib but did not have prognostic or predictive value
Harmon et al[93]		37	Prospective single arm phase II	Sunitinib	Reversible Increase	Better DCR	Inconsistent results were observed in these trials. The value of VEGF-A to predict response to sunitinib could be confirmed in larger trial
						Better PFS
						Better OS
Zhu et al[91]	VEGF-C	34	Prospective single arm phase II	Sunitinib	Sustained increase	No predictive value
Harmon et al[93]		37	Prospective single arm phase II	Sunitinib	Decrease	Better DC	The predictive value of VEGF-C was not shown for sorafenib probably because of its limited action against the VEGFR-3
Harmon et al[93]		37	Prospective single arm phase II	Sunitinib	Decrease	Better ORR
Harmon et al[93]	sVEGFR-2/ sVEGFR-3	37	Prospective single arm phase II	Sunitinib	Reversible decrease	Better OS (for sVEGFR-2)	The small cohort did not allow a definite conclusion
Zhu et al[91]		34	Prospective single arm phase II	Sunitinib	Decrease	No predictive value	The small cohort did not allow a definite conclusion
Llovet et al[63]	Ang2	490	Prospective phase III trial	Sorafenib vs placebo	No significant change (for sorafenib) Increase (for placebo)	Shorter TTP Shorter OS (for patients who experienced increase)	Ang2 was probably a prognostic biomarker than predictive of response to sorafenib
Llovet et al[63]	c-KIT	245	Prospective single arm phase II	Sorafenib vs placebo	Decrease (sorafenib) no change (placebo)	No predictive value	Tumor expression of KIT was considered as low in HCC, and the role of soluble KIT remains unclear
Zhu et al[91]		34	Prospective single arm phase II	Sunitinib	Decrease	Better TTP
Zhu et al[91]		34	Prospective single arm phase II	Sunitinib	Decrease	Better OS
Harmon et al[93]		37	Prospective single arm phase II	Sunitinib	Decease	Better TTP
Boige et al[98]	CEC	36	Prospective single arm phase II	Bevacizumab	Early increase	Better OR	CEC level was not associated with prognosis in this study. However, it could predict response to bevacizumab. The rarity of CEC level and non-standardized measurement methods limited the use of CEC as a predictive marker of response to treatment in HCC
Boige et al[98]	CEC	36	Prospective single arm phase II	Bevacizumab	Early increase	Better DCR
Zhu et al[91]	CECP	34	Prospective single arm phase II	Sunitinib	Decrease	Progression

Ang2: Angiopoietin 2; CEC: Circulating endothelial cells; CECP: Circulating endothelial cell progenitors; c-KIT: Stem-cell factor receptor; DCR: Disease control; HCC: Hepatocellular carcinoma; ORR: Objective response; OS: Overall survival; PFS: Progression-free survival; sVEGFR: Soluble vascular endothelial growth factors receptor; TTP: Time to progression; VEGF: Vascular endothelial growth factors.