Molecular targeting agents associated with transarterial chemoembolization or radiofrequency ablation in hepatocarcinoma treatment

Table 1 Clinical studies that analyzed targeted therapy in combination with transarterial chemoembolization

Author, Ref. or No. of clinical trials	Phase	Drug	Patients (n)	Type of TACE	Timing	Primary endpoint
Dufour et al[26]	I	Sorafenib	14	Classical (doxorubicin, mytomicin-C)	7 d before TACE and continuously	Safety
		(from 400 to 800 mg/d)
NCT01042041	I	Sorafenib	18 TR	Classical (cisplatin, doxorubicin, and mitomycin-C)	2 wk before TACE and continuously	Dose adjustment
		(800 mg/d)
Pawlik et al[27]	II	Sorafenib	35	DEB-TACE (doxorubicin)	1 wk before TACE and continuously	Safety, toxicity
		(800 mg/d)
Sieghart et al[28]	Pilot trial	Sorafenib	15	Classical (bilirubin-adjusted doxorubicin doses)	2 wk before TACE and continuously	Safety
		(800 mg/d)
Chung et al[29]START study	II	Sorafenib	165	Classical (doxorubicin)	After TACE (interrupted schedule)	Safety, efficacy
		(800 mg/d)
Park eet al[30]	II	Sorafenib	50	Classical (doxorubicin)	3 d after TACE for up to 24 wk	Safety,
		(800 mg/d)				TTP
Sansonno et al[31]	RCT	Sorafenib	62 (with HCV infection)	Classical (doxorubicin and mytomicin C)	30 d after TACE (sequential schedule)	TTP
		(800 mg/d)
NCT01556815	II	Sorafenib	40 TR (with HBV infection)	Classical (doxorubicin)	1 wk after TACE (sequential schedule)	TTP
		(800 mg/d)
Kudo et al[32]	III	Sorafenib	458	Classical (epirubicin, cisplatin, doxorubicin, mitomycin-C)	After TACE (sequential schedule)	TTP
		(800 mg/d)
Lencioni et al[33]SPACE trial	II	Sorafenib	307	DEB-TACE (doxorubicin)	3-7 d before TACE and continuously	TTP
		(800 mg/d)
TATICS trial NCT01217034	II	Sorafenib	TR not specified	Classical (drugs not specified)	Before TACE (interrupted schedule)	TTUP
		(from 400 to 800 mg/d)
ECOG 1208 trial NCT01004978	III	Sorafenib	TR not specified	Classic (doxorubicin, mitomycin-C, cisplatin) or DEB-TACE (doxorubicin)	2 wk before TACE (interrupted schedule)	PFS
		(800 mg/d)
Meyer et al[34]	III	Sorafenib	412 TR	DEB-TACE with doxorubicin	Together with TACE and continuously	PFS
TACE 2 trial		(800 mg/d)
Hoffmann et al[75]	III	Sorafenib	208 (waiting LT)	Classical (carboplatin)	Together with TACE and continuously	TTP
		(800 mg/d)
Britten et al[37]	Pilot trial	Bevacizumab	23	DEB-TACE (doxorubicin, cisplatin, mitomycin-C)	1 wk before TACE beyond week 16	Neovessel by angiography
		10 mg/kg every 14 d
AVATACE-1 NCT00280007	II	Bevacizumab	32	Classical (drugs not specified)	After TACE for 52 wk	Effectiveness
		5 mg/kg iv every 14 d for 52 wk
NCT00049322	II	Bevacizumab	31	Classical (doxorubicin, cisplatin, mitomycin-C)	Before TACE continuously	Neovessel formation by angiography
		(10 mg/kg) every 14 d
NCT00335829	II	Bevacizumab (dose not specified)	26	Classical (drugs not specified)	Before TACE in weeks 1, 3, 5 (up to a maximum of 5 courses)	Median PFS
NCT00518557	II	Recombinant human endostatin	60 TR	Classical (epirubicin)	During TACE (via hepatic artery)	Safety, tolerability, mortality
Hao et al[45]	RCT	Thalidomide	108	Classical (gemcitabine, oxaliplatin, floxuridine)	Before TACE and continuously for 3–6 mo	Median OS
		(200 mg/d)
NCT00006016	II	Thalidomide	75 TR	Classical (doxorubicin)	Before TACE (interrupted schedule)	Feasibility, potential activity of thalidomide
		(dose not specified)
NCT00921531	III	Thalidomide	200 TR	Classical (5-fluorouracil, oxaliplatin, mitomycin-C)	After TACE continuously	OS
		(from 200 mg/d to 400 mg/d)
NCT01009801	I-II	Everolimus	98 TR	DEB-TACE (doxorubicin)	Before TACE for up to 12 mo	Dose-limiting toxicity,
		(10 mg/d)				PFS
TRACER study NCT01379521	II	Everolimus	80	Classical (drugs not specified)	Together with TACE continuously	TTP
		(dose not specified)
SATURNE trial NCT01164202	II-III	Sunitinib	190 TR	Classical (drugs not specified)	7-10 d before TACE and after TACE (every 6 wk for 1 year)	Unacceptable bleeding or hepatic failure, OS
		(50 mg/d on days 1-28 before TACE)
NCT00524316	II	Sunitinib	16 TR	Classical (doxorubicin)	7 d before TACE (interrupted schedule)	RR,
		(50 mg/d on days 1-1 and-15-35 in course 1 before TACE and on days 1-28 after TACE)				PFS

TR: Target recruitment; RCT: Randomized clinical trial; TTUP: Time to untreatable progression (defined as time from randomization to untreatable progression and will be evaluated every 8 wk); LT: Liver transplantation; PFS: Progression free survival; OS: Overall survival; TACE: Transarterial chemoembolization; RR: Risk ratio; TTP: Time to progression.

Table 2 Ongoing clinical studies that analyzed targeted therapy in combination with radiofrequency ablation

Number of clinical trials	Phase	Drug	Patients (n)	Timing	Primary endpoint
NCT01470495	Randomized study	Sorafenib (dose non specified)	200 TR	Together with RFA continuously	TTP
NCT00813293	II	Sorafenib (800 mg/d)	20	9 d before RFA	Effectiveness
SORAMIC trial	II	Sorafenib (dose non specified)	1500	After RFA or SIRT	Time to recurrence, OS
NCT01126645
STORM trial NCT00692770	III	Sorafenib(800 mg/d)	1114	After RFA continuously	RFS
NCT00728078	II-III	Thalidomide (150 mg/d)	200	After RFA for 6 mo	PFS, morbidity

TR: Target recruitment; RFS: Recurrence free survival; RFA: Radiofrequency ablation; TTP: Time to progression; OS: Overall survival; PFS: Progression free survival.