Challenges of advanced hepatocellular carcinoma

Table 1 Variables included in the most widely used hepatocellular carcinoma staging systems

Staging system	Ascites	Tumor burden	Albumin	Bilirubin	INR	HE	AFP	PVT	EHS	PS	ALP
Okuda	Yes	Yes	Yes	Yes	No	No	No	No	No	No	No
CLIP	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes	No	No	No
BCLC	Yes	Yes	Yes	Yes	Yes	Yes	No	Yes	Yes	Yes	No
GRETCH	No	No	No	Yes	No	No	Yes	Yes	No	Yes	Yes
TNM 7th edition	No	Yes	No	No	No	No	No	Yes	Yes	No	No

AFP: Alpha fetoprotein; ALP: Alkaline phosphatase; EHS: Extrahepatic spread; HE: Hepatic encephalopathy; INR: International normalized ratio; PS: Performance status; PVT: Portal vein thrombosis.

Table 2 Results of studies with molecular targeted therapies as first line in advanced hepatocellular carcinoma

Treatment	Trial	OS	TTP	Ref.
Sorafenib	Phase III vs placebo	10.7 mo vs 7.9 mo, P < 0.001;	5.5 mo vs 2.8 mo, P < 0.001	[10]
	(SHARP)	HR = 0.69; 95%CI: 0.55-0.87
Sorafenib	Phase III vs placebo	6.5 mo vs 4.2 mo, P = 0.014;	2.8 mo vs 1.4 mo, P = 0.0005;	[11]
	(Asia-Pacific)	HR = 0.68; 95%CI: 0.50-0.93	HR = 0.57; 95%CI: 0.42-0.79
Sunitinib	Phase III vs sorafenib	7.9 mo vs 10.2 mo, P = 0.0019; HR = 1.30; 95%CI: 1.13-1.50	4.1 mo vs 3.8 mo, one-sided P = 0.8312;	[31]
	(SUN)		two-sided P = 0.3082; HR = 1.13
Brivanib	Phase III vs sorafenib	9.5 mo vs 9.9 mo, P = 0.3116;	4.2 mo vs 4.1 mo, P = 0.853;	[32]
	(BRISK-FL)	HR = 1.07; 95%CI: 0.94-1.23	HR = 1.01; 95%CI: 0.88-1.16
Linifanib	Phase III vs sorafenib	9.1 mo vs 9.8 mo, P = NS;	5.4 mo vs 4.0 mo, P = 0.001;	[33]
		HR = 1.05; 95%CI: 0.90-1.22	HR = 0.759; 95%CI: 0.64-0.895
Erlotinib	Phase III erlotinib plus sorafenib and eorafenib plus placebo (SEARCH)	9.5 mo vs 8.5 mo, P = 0.408;	3.2 mo vs 4.0 mo, P = NS;	[36]
		HR = 0.929	HR = 1.135; P = 0.18

OS: Overall survival; PFS: Progression-free survival; TTP: Time to progression; CI: Confidence interval; HR: Hazard ratio; NS: Not significant.

Table 3 Results of studies with molecular targeted therapies as second line in advanced hepatocellular carcinoma

Treatment	Trial	OS	TTP/PFS	Ref.
Brivanib	Brivanib vs placebo (BRISK-PS)	9.4 mo vs 8.2 mo, P = 0.3307;	4.2 mo vs 2.7 mo, P < 0.001;	[42]
		HR = 0.89; 95%CI: 0.69-1.15	HR = 0.56; 95%CI: 0.42-0.76
Everolimus	Everolimus vs placebo (EVOLVE-1)	7.6 mo vs 7.3 mo, P = 0.68;	3.0 mo vs 2.6 mo, P = 0.01;	[44]
		HR = 1.05; 95%CI: 0.86-1.27	HR = 0.93; 95%CI: 0.75-1.15
Ramucirumab	Ramucirumab vs placebo (REACH)	9.2 mo vs 7.6 mo, P = 0.14;	2.8 mo vs 2.1 mo, P < 0.0001;	[45]
		HR = 0.87; 95%CI: 0.72-1.05	HR = 0.63; 95%CI: 0.52-0.75

OS: Overall survival; PFS: Progression-free survival; TTP: Time to progression; HR: Hazard ratio.

Table 4 Principal ongoing studies in advanced hepatocellular carcinoma with new molecular targeted therapies

Study	Drug	Status
A multicenter, open-label, phase 3 trial to compare the efficacy and safety of lenvatinib (e7080) vs sorafenib in first-line treatment of subjects with unresectable hepatocellular carcinoma	Lenvatinib vs sorafenib	Active, not recruiting
Study of regorafenib after sorafenib in patients with hepatocellular carcinoma (RESORCE)	Regorafenib vs placebo	Recruiting
A study of dovitinib vs sorafenib in adult patients with hepatocellular carcinoma as a first line treatment	Dovitinib vs sorafenib	Completed (phase 2)
A study of nivolumab vs sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma	Nivolumab vs sorafenib	Recruiting

Table 5 Assessment of target lesion response: Conventional Response Evaluation Criteria in Solid Tumors and modified Response Evaluation Criteria in Solid Tumors assessment for hepatocellular carcinoma following the American Association for the Study of Liver Diseases-Journal of the National Cancer Institute guideline

RECIST	mRECIST
CR: Disappearance of all target lesions.	CR: Disappearance of any intratumoral arterial enhancement in all target lesions.
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of the diameters of target lesions.	PR: At least a 30% decrease in the sum of diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions.
SD: Any cases that do not qualify for either partial response or progressive disease.	SD: Any cases that do not qualify for either partial response or progressive disease.
PD: An increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.	PD: An increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started.

mRECIST: Modified Response Evaluation Criteria in Solid Tumors; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease.