Systemic treatment of hepatocellular carcinoma: Past, present and future

Table 1 Doxorubicin as first line treatment in hepatocellular carcinoma

Ref.	n	Line/treatment	Relevant data
Nagahama et al[21]	147	First line doxorubicin	Severe cirrhosis, PS 2-3, tumour occupying > 50% liver do not respond to chemo
Olweny et al[22]	14	First line doxorubicin	RR 79%
Sciarrino et al[23]		First line doxorubicin	RR 10%-20%
Chlebowski et al[24]

RR: Response rate.

Table 2 Clinical trials with chemotherapy agents in hepatocellular carcinoma

Ref.	n	Treatment	Results
Lai et al[25]	60	Doxorubin vs placebo	OS 10.6 wk vs 7.5 wk in favour of chemo
Gish et al[27]		Doxorubicin vs nolatrexed	OS 32.3 wk vs 22.3 wk in favour of doxorubicin
Patt et al[35]	37	Capecitabine	RR 1%, OS 10.1 mo
Qin et al[44]	371	FOLFOX 4 vs doxorubicin	RR 8.15% vs 2.67%	All in favour of FOLFOX 4
			DCR 52.17% vs 31.55%
			PFS 2.93 m vs 1.7 m
			OS 6.4 m vs 4.97 m
Shin et al[45]		Cisplatin, Capecitabine and Doxorubicin	RR 26%
Lee et al[46]		Cisplatin/doxorubicin	RR 19%
Zaanan et al[48]	204	GEMOX	RR 22% DCR 66% PFS 4.5 m
			OS 11 m
Patrikidou et al[49]	40	GEMOX after antiangiogenics failed	Partial responses 20%
			Stable disease 46%
			OS 8.3 m
Yang et al[50]		Cisplatin/gemcitabine	RR 21%
Kim et al[52]		Cisplatin/infusional FU/mitoxantrone	RR 27% but 71% severe neutropenia

RR: Response rate; DCR: Disease control rate; PFS: Progression free survival; OS: Overall survival.

Table 3 Clinical trials with tyrosine kinase inhibitors in hepatocellular carcinoma

Ref.	n	Treatment	Results
Abou-Alfa et al[66]		Sorafenib	OS 9.2 m
			TTP 5.5 m
	602	Sorafenib vs placebo
Cheng et al[67]	226	Sorafenib vs placebo	OS 6.5 m vs 4.2 m
			TTP 2.8 m vs 1.4 m
Abou-Alfa et al[68]		Sorafenib vs doxorubicin	TTP 6.4 m vs 2.8 m
			PFS 6 m vs 2.7 m
			OS 13.7 m vs 6.5 m
Assenat et al[70]	94	Sorafenib vs sorafenib/GEMOX	RR 9% vs 70%	In favour of the combination
			DCR 16% vs 77%
			PFS 54% vs 61%
			OS 13 m vs 13.5 m
Bruix et al[71]	36	Regorafenib second line	DCR in 26/36 patients
			Partial response 1/36
			TTP 4.3 m
			OS 13.8 m
LBA-03[72]		Regorafenib vs placebo	DCR 65.2% vs 36.1%
			PFS 3.1 m vs 1.5 m
			OS 10.6 m vs 7.8 m
Verslype et al[73]	41	Cabozantinib	Partial response 5%
			Stable disease 78%
			PFS 4.4 m
			OS 15.1 m
Exelixis[74,75]	760	Cabozantinib second line (after sorafenib)	Primary end point OS
			Expected data in 2017
Koyama et al[76]	46	Lenvatinib	DCR 78%
			TTP 7.4 m
			OS 18.7 m
Eli Lilly and Company[85]		Ramucirumab vs placebo	OS 9.2 m vs 7.6 m
Qin et al[86]	121	Apatinib vs placebo	TTP 4.2 m vs 3.3 m
			DCR 48.57% vs 37.25%
			OS 9.7 m vs 9.8 m

RR: Response rate; DCR: Disease control rate; PFS: Progression free survival; OS: Overall survival; TTP: Time to progression.

Table 4 Clinical trials with immunotherapy in hepatocellular carcinoma

Authors	n	Phase	Treatment	Primary end-point
Keynote-224	100	II	Pembrolizumab	RR
ongoing		II	Pembrolizumab	DCR
CheckMate-040		I/II	Nivolumab	Safety
CheckMate-459	726	III	Nivolumab vs Sorafenib	OS
				TTP

RR: Response rate; DCR: Disease control rate; OS: Overall survival; TTP: Time to progression.