Treatment strategies for advanced hepatocellular carcinoma: Sorafenib vs hepatic arterial infusion chemotherapy

Table 1 Guidelines for the clinical management of hepatocellular carcinoma

	Publishing year	Guidelines	Drafted by	Treatment algorithm for advanced HCC(BCLC C)	Ref.
Asia	2014	JSH-LCSGJ	Japan Society of Hepatology and Liver Cancer Study Group of Japan	HAIC (Vp1-4), Sorafenib (Vp1-3), TACE (Vp1, 2), Resection (Vp1, 2)	[6]
	2014	KLCSG-NCC	Korean Liver Cancer Study Group and National Cancer Center	TACE, Sorafenib	[7]
	2014	HKLC	Hong Kong Liver Cancer	Systemic therapy, Supportive care	[8]
	2017	APASL	Asian-Pacific Association for the Study of the Liver	Systemic therapy (sorafenib and regorafenib), TACE for patients with no extrahepatic metastasis	[9]
	2017	JSH	Japan Society of Hepatology	TACE, Resection, HAIC, Molecular targeted agents	[10]
Europe	2018	EASL	European Association for the Study of the Liver	Sorafenib (sorafenib, lenvatinib, regorafenib, and cabozantinib)	[11]
	2012	ESMO-ESDO	European Society for Medical Oncology and European Society of Digestive Oncology	Sorafenib	[12]
United States	2011	AASLD	American Association for the Study of Liver Disease	Sorafenib	[13]

HAIC: Hepatic arterial infusion chemotherapy; Vp1-4: Portal vein invasion according to JSH-LCSGJ; TACE: Transcatheter arterial chemoembolization; BCLC: Barcelona clinic liver cancer.

Table 2 Serum and plasma biomarkers of sorafenib response and survival

Biomarkers	Ref.	Publishing year	Case number	Predictive factors for response	Predictive factors for survival	Others
VEGF	Llovet et al[25]	2012	299	No predictive value	Not prognostic value
	Miyahara et al[26]	2013	120	No predictive value	Not prognostic value
	Tsuchya et al[27]	2014	63	No predictive value	VEGF response (a > 5% decrease during 8 wk of treatment): Better OS
Ang-2	Llovet et al[25]	2012	299	No predictive value	Low Ang-2: Better OS
	Miyahara et al[26]	2013	120	High Ang2: PD	Low Ang-2: Better OS
Changes of AFP	Personeni et al[28]	2012	85	AFP response (a > 20% decrease during 8 wk of treatment): Better ORR, DCR	AFP response: Better OS
	Yau et al[29]	2011	94	AFP response (a > 20% decrease during 6 wk of treatment): Better DCR	AFP response: Better PFS
	Kuzuya et al[30]	2015	47	-	High AFP ratio (a > 1.2 at 2 wk relative to baseline): Poor OS	High poor prognostic score (the absence of disapperance of arterial tumor enhancement on CE-CT, AFP ratio of > 1.2, and two or more increments in CP score after 2 wk of Treatment): Poor OS and DCR
	Nakazawa et al[31]	2013	59	AFP increase (more than 20% from baseline during 4 wk of treatment): PD	AFP increase: Better OS and PFS
AFP	Llovet et al[25]	2012	299	-	AFP > 200 ng/mL: Poor OS
	Miyahara et al[26]	2013	120	-	Not prognostic value
	Kuzuya et al[30]	2015	47	-	Not prognostic value
NLR	Zheng et al[32]	2013	65	-	High NLR (> 4): Poor OS and TTP
	Howell et al[33]	2017	175	-	High NLR (> 2.52): Poor OS
TEMs	Shoji et al[34]	2017	25	High ΔTEMs (changes in TEMs before and at 1 mo after therapy): PD	High ΔTEMs (changes in TEMs before and at 1 mo after therapy): Poor OS
MicroRNA	Stiuso et al[35]	2015	39	Upregulation of miR-423-5p after treatment: SD or PR	-
	Yoon et al[36]	2017	24	-	Low miR-10b-3p: Poor OS
	Nishida et al[37]	2017	53	High miR-181a-5p: PR + SD	High miR-181a-5p: Better OS
CTCs	Li et al[38]	2016	59	pERK+/pAkt- CTCs: Better DCR	pERK+/pAkt- CTCs: Better DCR

Ang-2: Angiopoietin-2; CE-CT: Contrast-enhanced computed tomography; NLR: Neutrophil-to lymphocyte ratio; AFP: Alpha-fetoprotein; CTC: Circulating tumor cells; TEMs: TIE-2-expression monocytes; VEGF: Vascular endothelial growth factor; PD: Progressive disease; OS: Overall survival; DCR: Disease control rate; ORR: Overall response rate; PFS: Progression-free survival; CP: Child-Pugh; pERK: Phosphorylated extracellular signal-regulated kinase; PR: Partial response; SD: Stable disease; TTP: Time to progression.

Table 3 Tissue biomarkers of sorafenib response and survival

Biomarkers	Ref.	Publishing year	Case number	Predictive factors for response	Predictive factors for survival
Expression of p-ERK	Abou-Alfa et al[39]	2012	33	-	High pERK: Longer TTP
	Chen et al[40]	2013	54	-	High pERK: Longer TTP
	Negri et al[41]	2015	77	-	High pERK: Shorter OS and PFS
Expression of p-c-Jun	Hagiwara et al[42]	2012	39	High p-c-jun: Poor response	High p-c-jun: Shorter TTP and OS
Expression of VEGFR-2	Negri et al[41]	2015	54	-	High VEGFR-2: Shorter OS and PFS
FGF3/FGF4 amplification	Arao et al[43]	2013	48	FGF3/FGF4 amplification: Responder	-

ERK: Extracellular signal-regulated kinase; FGF: Fibroblast growth factor; TTP: Time to progression; OS: Overall survival; pERK: Phosphorylated extracellular signal-regulated kinase; PFS: Progressive-free survival; VEGFR: Vascular endothelial growth factor receptor.

Table 4 Regimens of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma

Ref.	Publishing year	Case number	Vascular invasion (%)	Regimens	Response rate (%)	Median survival time (mo)
Saeki et al[48]	2015	90	ND	Low-dose FP, including the combination of LV/IV or IV plus IFN	34.4	10.6
Nouso et al[49]	2013	476	44.1	CDDP + 5-FU	40.5	14.0 (341 patients)
Monden et al[50]	2012	34	90	IFNα, 5-FU	26.7	8.4
		35	90.3	Low-dose FP/CDDP	25.8	11.8
Yamashita et al[52]	2011	57	26.7	IFNα, CDDP, 5-FU	45.6	17.6
		57	50	IFNα, 5-FU	24.6	10.5
Nagano et al[57]	2011	102	100	IFNα, 5-FU	39.2	9
Obi et al[53]	2006	116	100	IFNα, 5-FU	52	6.9
Ikeda et al[54]	2013	25	100	CDDP powder (IA call)	28	7.6
Iwasa et al[55]	2011	84	31	CDDP powder (IA call)	3.6	7.1
Kim et al[51]	2011	41	83.3	CDDP	12.2	7.5
		97		CDDP, 5-FU	27.8	12
Yoshikawa et al[56]	2008	80	27.5	CDDP powder (IA call)	33.8	ND

ND: Not described; Low-dose FP: Low-dose 5-FU plus Cisplatin; LV: Leucovorin; IV: Isovorin; IFN: Interferon; CDDP: Cisplatin.

Table 5 Predictive factors for response and survival of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma

Ref.	Publishing year	Case number	Regimens	Poor predictive factors for response	Poor predictive factors for survival
Saeki et al[48]	2015	90	Low-dose FP with/without LV, IV, or IV plus IFN	DCP reduction or increase of < 20% from baseline to 2 wk after HAIC	Child-Pugh B, AFP reduction or increase of < 20% from baseline to 2 wk after HAIC, DCP reduction or increase < 20% from baseline to 2 wk after HAIC
Terashima et al[58]	2015	266	IFNα, 5-FU with/without CDDP	NLR ≥ 2.87 (cut-off, median value), presence of vascular invasion, presence of extrahepatic metastasis	NLR ≥ 2.87 (cut-off, median value), ECOG PS 1/2, Child-Pugh score 8-9, presence of extrahepatic metastasis, CRP ≥ 0.8 mg/dL, AFP ≥ 235.5 ng/mL
Zaitsu et al[59]	2014	44	Low-dose FP with/without IV, or IV plus IFN	ND	Child-Pugh B, serum transferrin < 190 mg/dL
Nouso et al[49]	2013	476	CDDP + 5-FU	ND	HBs antigen positive, Child-Pugh B, tumor number > 3, tumor size > 3 cm, presence of extrahepatic metastasis, Vp3/4, AFP > 400 ng/mL
Niizeki et al[60]	2012	71	Low-dose FP	VEGF ≥ 100 pg/mL	Child-Pugh B, VEGF ≥ 100 pg/mL, therapeutic effect SD + PD
Miyaki et al[61]	2012	249	Low-dose FP (106 patients); IFNα, 5-FU (143 patients)	HCV antibody negative, platelet count ≥ 15 × 104/μL	ECOG PS 1-2, Child-Pugh score 8-9, presence of extrahepatic metastasis, AFP ≥ 1000 ng/mL, abcence of additional therapy, theraputic effect SD + PD + DO
Obi et al[53]	2006	116	IFNα, 5-FU	Not detect	Vp4, Total bilirubin ≥ 1.0 mg/dL, theraputic effect PR + SD + PD

Low-dose FP: Low-dose 5-FU plus Cisplatin; LV: Leucovorin; IV: Isovorin; IFN: Interferon; CDDP: Cisplatin; DCP: Des-gamma-carboxy prothrombin; NLR: Neutrophil-to-lymphocyte ratio; ND: Not described; VEGF: Vascular endothelial growth factor; PS: Performance status; SD: Stable disease; PD: Progressive disease; DO: Drop-out; CR: Complete response.

Table 6 Clinical characteristics of three advanced hepatocellular carcinoma patients with complete response who have survived over 10 years

Age diagnosed as HCC	Sex	Etiology	Child-Pugh	Tumor stage1	Previous treatment	Maximum tumor size (mm)	Vascular invasion1	Regimen	Therapeutic effect	AFP (ng/mL)	DCP (mAU/mL)	HCC recurrence	Prognosis	Cause of death
67	Male	HCV	A (5)	IVA	None	110	Vp4, Vv0	Low-dose FP	CR	120700	260	62 mo	151 mo (dead)	Hepatic failure
66	Male	HCV	A (5)	III	None	50	Vp0, Vv0	Low-dose FP + IV	CR	6.4	2970	None	176 mo (dead)	Larynx cancer
44	Male	HBV	B (7)	III	None	150	Vp3, Vv3	Low-dose FP + IV + Peg IFN	CR	7145	233640	None	148 mo (alive2)	-

¹According to the Liver Cancer Study Group of Japan;

²The follow-up period ended on January 31, 2018. HCC: Hepatocellular carcinoma; AFP: Alpha-fetoprotein; DCP: Des-γ-carboxyprothrombin; HCV: Hepatitis C virus; HBV: Hepatitis B virus; CR: Complete remission; Low-dose FP: Low-dose cisplatin combined with 5-FU; IV: Isovorin; Peg IFN: Pegylated interferon.