Optimal combination of antiangiogenic therapy for hepatocellular carcinoma

Table 1 Circulating biomarker of hepatocellular carcinoma patients receiving antiangiogenic therapy

Treatment	Patient enrolled	Patient n	Predictive value	Prognostic value	Ref.
Sorafenib, bevacizumab or thalidomide/oral 5FU	Elevated AFP	72	AFP responder (AFP decline > 20% in 4 wk) correlate with response	Early AFP responder: associate with PFS, OS	Shao et al[103]
Sorafenib	Advanced	30		High baseline IL-8 correlates with PD; high Ang2, G-CSF, HGF, leptin correlate with shorter PFS	Miyahara et al[104]
Sorafenib	Advanced	491	High baseline sc-KIT, low HGF correlate with sorefinib response	Baseline Ang2, VEGF, AFP correlate with survival	Llovet et al[36]
Sorafenib	Post-operative	29	High phosphor MET correlate with sorafenib resistance		Xiang et al[105]
Sunitinib	Advanced	34		High baseline AFP, IL-8, IL-6, SDF1, TNF correlate with PFS and OS; decreased IL-6, sc-KIT at day 14 correlate with improved PFS and OS	Zhu et al[24]
Sunitinib	Advanced	37	High baseline VEGFC correlates with response	High base VEGFC correlates with TTP; change in VEGFA, sVEGFR2 correlate with OS	Harmon et al[106]
Sunitinib	Advanced	23	Decrease sVEGFR2 or TNF correlate, with decrease in Ktrans Kep; Decrease Ktrans, Kep at week 2 correlate with response		Sahani et al[107]
Bevacizumab	Advanced	43	Increase CEC on day 15 , low IL-8 correlate with disease control	High baseline IL-8, IL-6 correlate with short PFS, OS	Boige et al[108]
Bevacizumab	Advanced	59	High Ang2, EGFR, endothelin 1, no acneiform rash correlate with poor outcome		Kaseb et al[109]
Thalidomide	Advanced	47	No predictive value of VEGF, bFGF, PlGF		Hsu et al[110]
Thalidomide/tegafur/uracil	Advanced	43		High IL-6, IL-8 correlate with short survival	Shao et al[111]
Thalidomide/radiotherapy	Advanced	24	No predictive value of VEGF, bFGF, IL-6, SDF1, TNF	Baseline IL-6, SDF1 at week 2 correlate with PFS. SDF1 at 1 mo post radiotherapy correlates with OS	Ch’ang et al[89]
TSU68	Advanced	35	High sVCAM1 correlates with response		Kanai et al[112]

AFP: α-fetal protein; PFS: Progression free survival; OS: Overall survival; IL: Interleukin; PD: Progressive disease; Ang2: Angiopoetin 2; G-CSF: Granulocyto colony stimulating factor; HGF: Hepatocyte growth factor; VEGF: Vascular endothelial growth factor; SDF: Stem cell derived factor; TNF: Tumor necrosis factor; TTP: Time to progression; sVEGFR: Soluble VEGF receptor; K^trans: Transfer constant; K_ep: Redistribution rate constant; CEC: Circulating endothelial cells; EGFR: Epidermal growth factor receptor; bFGF: Basic fibroblast growth factor; PlGF: Placental growth factor; sVCAM1: Soluble vascular cell adhesion molecule 1.

Table 2 Imaging biomarkers of hepatocellular carcinoma patients receiving antiangiogenic therapy

Treatment	Imaging study	Patient n	Predictive value	Prognostic value	Ref.
Sorefinib or sunitinib	Perfusion CT, DCEUS	19	≤ 40% decrease in AUC at 1 mo correlates with PD		Frampas et al[113]
Sorafenib	CEUS	21	Reduction in enhancement correlates with response		Moschouris et al[114]
Sorafenib	Perfusion CT	10	Increase in MTT correlates with AFP response		Sacco et al[115]
Sunitinib	DCEMRI	24	Decreased Ktrans or Kep correlate PR/SD		Zhu et al[24]
Sunitinib	DWI, MRP	23	Decreased Ktrans or Kep at week 2 correlate with response	High baseline Ktrans and decrease in EVF correlate with longer PFS	Sahani et al[107]
Bevacizumab	Perfusion CT	25	Low baseline MTT correlates with PD; increased MTT correlates with PR/SD		Zhu[2]
Bevacizumab	DCEUS	42	Decrease between day 0-3 of AUC, AUC during wash-in, AUC during wash-out, time to peak intensity correlate with tumor response	Time to peak intensity correlates with PFS; AUC and ACU during wash-out correlate with OS	Lassau et al[116]
Bevacizumab/ gemcitabine and oxaliplatin	Perfusion CT, dual-phase contrast enhanced CT	23	High baseline MTT correlates with PR/SD; high baseline Ktrans correlates with responder	High baseline MTT correlates with better PFS	Jiang et al[117]
Bevacizumab	Perfusion CT	22		Reduction in percentage change of FD and low baseline FD correlate with longer OS	Hayano et al[118]
Thalidomide	Power Doppler US	47	High baseline vascular index in responder		Hsu et al[110]
Thalidomide	Perfusion CT	18	High baseline blood flow and blood volume correlates with progression		Petralia et al[119]
Thalidomide/ radiotherapy	DCEMRI	22	High baseline and week 2 Slope in responder	Perfusion parameters over liver parenchyma correlate with PFS and OS	Liang et al[87]
Pazopanib	DCEMRI	26	Reductions in IAUGC and Ktrans not correlate with pharmacokinetic parameters		Yau et al[120]

CT: Computed tomography; DCEUS: Dynamic contrast enhanced ulatrasonography; AUC: Area under curve; PD: Progressive disease; CEUS: Contrast enhanced ultrasonography; MTT: Mean transit time; AFP: α-fetal protein; DCEMRI: Dynamic contrast enhanced magnetic resonance imaging; K^trans: Transfer constant; K_ep: Redistribution rate constant; PR: Partial response; SD: Stable disease; DWI: Diffusion weighted imaging; MRP: Magnetic resonance imaging derived perfusion parameter; EVF: Extracellular volume fraction; PFS: Progression free survival; FD: Fractal dimension; OS: Overall survival; Slope: Initial first-pass enhancement slope; IAUGC: Initial area under the tissue gadolinium concentration-time curve.