Chemotherapy for advanced hepatocellular carcinoma in the sorafenib age

Table 1 Overall survivals in sorafenib treatment

Clinical trial	Sorafenib			Placebo			P value
	n	Median OS (mo)	95%CI	n	Median OS (mo)	95%CI
SHARP[5]	299	10.7	9.4–13.3	303	7.9	6.8–9.1	< 0.001
AP[6]	150	6.5	5.56–7.56	76	4.2	3.75–5.46	0.014

OS: Overall survival; AP: Asia-Pacific.

Table 2 Biomarkers for predicting outcomes with sorafenib

Ref.	Year	Obtained from	Biomarker
Llovet et al[16]	2012	Plasma	HGF, c-KIT
Miyahara et al[17]	2011	Serum	Angiogenesis-related cytokines1
Arao et al[18]	2013	Tissue	FGF3/FGF4
Huang et al[19]	2013	Tissue	αB-Crystallin
Hagiwara et al[20]	2012	Tissue	JNK
Abou-Alfa et al[21]	2006	Tissue	pERK
Shan et al[25]	2012	Cell line	Nanog
Blivet-Van Eggelpoël et al[26]	2012	Cell line	EGFR, HER-3
Chen et al[27]	2012	Cell line	SIRT1
Tai et al[28]	2011	Cell line	STAT3
Liu et al[4]	2006	Cell line	Mcl-1, eIF4E

¹These include angiopoietin-2, follistatin, granulocyte colony-stimulating factor, hepatocyte growth factor, leptin, platelet-derived growth factor-BB, platelet endothelial cell adhesion molecule-1, and vascular endothelial growth factor. HGF: Hepatocyte growth factor; c-KIT: Also known as SCFR (mast/stem cell growth factor receptor); FGF: Fibroblast growth factors; JNK: c-Jun N-terminal kinase; pERK: Phosphorylated extracellular signal regulated kinase; EGFR: Epidermal growth factor receptor; HER-3: Also known as ErbB3; STAT3: Signal transducer and activator of transcription 3; Mcl-1: Myeloid cell leukemia-1; eIF4E: Eukaryotic translation initiation factor 4E.

Table 3 Incidence of drug-related adverse events of sorafenib treatment

Adverse event, %	SHARP[5]	AP[6]	GIDEON (second interim analysis)[89]
	(n = 297)	(n = 149)	(n = 1571)
Any adverse event	80	82	64
Diarrhea	39	26	25
Hand-foot skin reaction	21	45	24
Fatigue	22	20	14
Rash⁄desquamation	16	20	12
Anorexia	14	13	9
Hypertension	5	19	7
Alopecia	14	25	7
Nausea	11	11	6
Weight loss	9	NA1	5

¹NA: Not available; this adverse event was observed in < 10% of patients in AP trial. Incidence of all grades of adverse events was shown. Adverse events in ≥ 5% of the total population in GIDEON study were listed.

Table 4 Clinical trials for evaluating the effect of transcatheter arterial chemoembolization with sorafenib in intermediate stage of hepatocellular carcinoma

Ref.	Acronym (NCT number)	Reported year	Trial phase	Study design	n	TACE	Outcomes
Pawlik et al[56]	-	2011	II	Single-arm (TACE plus sorafenib)	33	DEB/scheduled	Disease control rate = 100%, per lesion. Objective response = 58%, per lesion
Park et al[57]	-	2012	II	Single-arm (TACE plus sorafenib)	50	Conventional1/on demand	Median TTP = 7.1 mo
							6-mo PFS rate = 52%
Kudo et al[59]	Post TACE study	2011	III	TACE plus sorafenib vs TACE plus placebo	458	Conventional1/1 or 2 sessions	Median TTP = 5.4 (sorafenib)/3.7 (placebo) mo. HR [sorafenib] = 0.87; 95%CI: 0.70-1.09; P = 0.252
Lencioni et al[58]	SPACE	2012	II	TACE plus sorafenib vs TACE plus placebo	307	DEB/scheduled	Median TTP = 169 (sorafenib)/166 (placebo) d. HR [sorafenib] = 0.79; 95%CI: 0.588-1.080; P = 0.072
Kudo et al2	TACTICS (NCT01217034)	Currently recruiting participants	II	TACE plus sorafenib vs TACE alone	2283	Conventional1/on demand	Time to untreatable progression4
Meyer et al2	CRUK-TACE-2 (NCT01324076)	Currently recruiting participants	III	TACE plus sorafenib vs TACE plus placebo	4123	DEB/1 session	PFS4
Kauh et al2	(NCT01004978)	Currently recruiting participants	III	TACE plus sorafenib vs TACE plus placebo	4003	Conventional1 or DEB/scheduled	PFS4

¹Conventional TACE indicated transcatheter arterial chemoembolization with gelatin foam and lipiodol;

²The information of the trial can be accessed at ClinicalTrials.gov;

³Estimated Enrollment;

⁴Primary Outcome Measures. DBE: Drug-eluting beads; NCT: National clinical trial; PFS: Progression-free survival; TACE: Transcatheter arterial chemoembolization; TTP: Time to progression.