Anti-angiogenesis in hepatocellular carcinoma treatment: Current evidence and future perspectives

Table 1 Efficacy of systemic targeted monotherapy in hepatocellular carcinoma according to current phase I-III studies

Author	Year	Phase	Investigational drug	n	RR	DS	PFS/TTP	PFS-6m	OS
O'Neil et al[59]1	2009	II	AZD 6244	16	0	37.5	NR	NR	NR
Malka et al[60]	2007	II	Bevacizumab	30	12.5	54	3.5/NR	17	NR
Schwartz et al[61]	2006	II	Bevacizumab	30	6.7	57	NR/6.4	NR	NR
Siegel et al[58]	2008	II	Bevacizumab	46	13	NR	6.9/NR	NR	12.4
Raoul et al[62]	2009	II	Brivanib	55	11	10	NR/2.8	NR	10
Gruenwald et al[63]	2007	II	Cetuximab	27	0	44	2.0/1.9	22.2	NR
Zhu et al[64]	2007	II	Cetuximab	30	0	17	1.4/NR	NR	9.6
Philip et al[65]	2005	II	Erlotinib	38	9	50	3.2/NR	32	13
Thomas et al[66]	2007	II	Erlotinib	40	0	43	3.1/NR	NR	6.25 (10.75)2
Blaszkowsky et al[67]	2010	III	Everolimus	25	4	44	3.8/3.9	8%	8.4
O’Dwyer et al[68]	2006	II	Gefitinib	31	3	22.5	2.8/NR	NR	6.5
Lin et al[69]	2008	II	Imatinib	15	0	13.3	NR/NR	NR	NR
Ramanathan et al[70]	2006	II	Lapatinib	37	5	35	2.3/NR	2.3	6.2
Rizell et al[71]	2008	II	Sirolimus	21	4.8	23.8	NR/NR	NR	6.5
Abou-Alfa et al[12]	2006	II	Sorafenib	137	2.2	33.6	NR/4.2	NR	9.2
Cheng et al[72]	2009	III	Sorafenib	226 (150 treated)	3.3	54	NR/2.8	NR	6.5
Furuse et al[13]	2008	I	Sorafenib	27	4	83	NR/4.9	46.2	15.6
Llovet et al[11]	2008	III	Sorafenib	602 (299 treated)	2	71	NR/5.5	NR	10.7
Yau et al[14]	2009	II	Sorafenib	51	8	18	3.0/NR	NR	5
Zhu et al[73]	2009	II	Sunitinib	34	2.9	47	3.9/4.1	NR	9.8
Faivre et al[74]	2009	II	Sunitinib	37	2.7	35	3.7/5.3	NR	8
Hoda et al[75]	2008	II	Sunitinib	23	6	35	NR/NR	NR	NR
Koeberle et al[54]	2010	II	Sunitinib	45	2	40	2.8/2.8	NR	9.3
Kanai et al[57]	2010	I/II	TSU-68	35	8.6	42.8	NR/2.1	NR	13.1

¹Trial stopped;

²Recorded from therapy start (recorded from diagnosis). DS: Disease stabilization (%); NR: Not reported; OS: Overall survival (mo); PFS/TTP: Progression free survival/time to progression (mo); PFS-6m: Progression free survival rate at 6 mo (%); RR: Response rate [complete + partial response (%)].

Table 2 Efficacy of combination therapy with systemic acting agents and targeted therapy in hepatocellular carcinoma according to current phase I-II studies

Author	Year	Phase	Investigational drug	n	RR	DS	PFS/TTP	PFS-6m (%)	OS
Sun et al[76]	2007	II	Bevacizumab/CapOx	30	11	78	4.5/NR	40	NR
Thomas et al[55]	2009	II	Bevacizumab/erlotinib	40	25	42.5	9.0/NR	NR	15.7
Hsu et al[77]	2008	II	Bevacizumab/capecitabine	45	9	42	4.1/NR	NR	10.7
Zhu et al[78]	2006	II	Bevacizumab/GemOX	33	20	27	5.3/NR	NR	9.6
Berlin et al[79]	2008	II	Bortezomib/doxorubicin	39	2.3	25.6	2.4/NR	NR	5.7
Asnacios et al[80]1	2008	II	Cetuximab/GemOx	45	20	40	4.7/NR	NR	9.5
Louafi et al[81]1	2007	II	Cetuximab/GemOx	35	24	4.5	NR/NR	40	9.2
Knox et al[82]2	2008	II	G3139/doxorubicin	17	0	35	NR/1.8	17.2	5.4
Abou-Alfa et al[83]3	2010	II	Sorafenib/doxorubicin	96	4	77	6.9/8.6	2.7	13.7
Richly et al[84]	2009	I	Sorafenib/doxorubicin	18	6.3	69	4.04/NR	NR	NR

¹Overlap of patient cohorts cannot be excluded from information provided in the abstracts; ²Trial stopped due to lack of efficacy; ³Trial stopped due to superiority of sorafenib;

⁴Calculated from a median duration of disease control rate (combined endpoint for complete and partial response as well as stable disease) of 17.4 wk. CapOx: Capecitabine and oxaliplatin; DS: Disease stabilization (%); GemOx: Gemcitabine and oxaliplatin; NR: Not reported; OS: Overall survival (mo); PFS/TTP: Progression free survival/time to progression (mo); PFS-6m: Progression free survival rate at 6 mo (%); RR: Response rate [complete + partial response (%)].

Table 3 Efficacy of sorafenib and transarterial chemoembolization in hepatocellular carcinoma (sequential therapy not included) according to current phase I-II studies

Author	Year	Phase	Investigational drug	n	RR	DS	PFS/TTP	OS
Chow et al[45]	2010	II	Sorafenib + SIRT	35	31.4	77.1	NR/NR	10.8
Chung et al[47]1	2010	II	Sorafenib + TACE	50	NR2	96	NR/NR	NR
Dufour et al[48]	2010	I	Sorafenib + TACE	14	NR3	NR3	NR3	NR3
Erhardt et al[46]1	2009	II	Sorafenib + TACE	44	NR4	63.6	8.0/16.1	11.7
Reyes et al[49]1	2009	II	Sorafenib + DEB-TACE	50	NR5	NR	NR/NR	NR

¹Interim analysis;

²20/50 patients received 2 cycles of transarterial chemoembolization (TACE), only, and 18 of these 20 patients achieved complete response compared to 2 patients with progressive disease. 30/50 patients received more than 2 cycles of TACE and achieved partial response or stable disease;

³Primary objective of this prospective trial was evaluation of safety and tolerability of a continuous regimen of sorafenib combined with TACE;

⁴According to 31 patients who received at least 1 cycle of TACE, 2/31 (6.5%) showed complete response, 15/31 (48.4%) showed partial response, and 11/31 (35.5%) showed stable disease. PFS, TTP, and OS are given for all 44 patients enrolled at time point of interim analysis;

⁵Patients who completed DEB-TACE showed 100% objective tumor response and 100% partial response or stable disease according to EASL or RECIST criteria, respectively. DEB-TACE: (Drug eluting beads)-transarterial chemoembolization; NR: Not reported; DS: Disease stabilization (%); OS: Overall survival (mo); PFS/TTP: Progression free survival/time to progression (mo); PFS-6m: Progression free survival rate at 6 mo (%); RR: Response rate [complete + partial response (%)]; SIRT: Selective internal radio therapy.