Current management of hepatocellular carcinoma

Table 1 Existing series on treatment of hepatocellular cancer: evidence based benefit (NCI classification) and outcome

Treatment	Ref.	Year	Number	5 yr survival
Liver resection (evidence 2A)	Llovet et al[4]	1999	77	51%
	1Fong et al[5]	1999	154	57%
	2Roayaie et al[17]	2012	132	70%
Liver transplantation (evidence 2A)	Mazzaferro et al[18]	1996	444	73.3%
	Llovet et al[4]	1999	87	69%
	Yao et al[19]	2001	70	72.4%
	3Roayaie et al[20]	2002	43	44%
	4Mazzaferro et al[21]	2009	48	75%
Radiofrequency ablation (evidence 2A)	2Sala et al[22]	2004	34	63%
	Vivarelli et al[23]	2004	79	33% (3 yr)
	1Chen et al[24]	2006	71	67.9% (4 yr)
Transarterial chemoembolization (evidence 1A)	DETCH[25]	1995	50	38% (2 yr)
	Llovet et al[26]	2002	40	29% (3 yr)
	Lo et al[27]	2002	40	31% (2 yr)
Radiotherapy (evidence 1A)	5Carr[28]	2004	65	Median 21.3 mo
	6Salem et al[29]	2011	123	Median 20.7 mo
Systemic therapy (evidence 1A)	Llovet et al[30]	2008	299	10.7 mo
	Cheng et al[31]	2009	150	6.5 mo

¹< 5 cm HCC;

²< 3 cm HCC;

³> 5 cm HCC;

⁴Within Milan criteria;

⁵Stage I disease;

⁶Child-Pugh A. DETCH: Group d’Etude et de Traitement du Carcinome He´patocellulaire; HCC: Hepatocellular carcinoma.

Table 2 Outcome of patients with hepatocellular carcinoma treated by resection, liver transplantation, and living donor liver transplantation

Treatment	No. of patients	1 yr survival	5 yr survival
Surgical resection
Fong et al[5] 1999	154	81%	37%
Llovet et al[4] 1999	771	85%	51%
Poon et al[46] 2002	1352	90%	70%
Wayne et al[47] 2002	249 ( ≤ 5 cm)	83%	41%
Shrager et al[48] 2012	2061	60%	46%
Roayaie et al[17] 2013	132 ( ≤ 2 cm)	-	70%
Liver transplantation
Mazzaferro et al[18] 1996	48	84%	74%
Bismuth et al[82] 1999	45	82%	74%
Llovet et al[4] 1999	79	86%	75%
Jonas et al[83] 2001	120	90%	71%
Yao et al[19] 2001	64	87%	73%
Living donor transplantation
Gondolesi et al[84] 2004	15	-	86% (3 yr)
Todo et al[85] 2004	137	-	79% (3 yr)

¹Cirrhosis;

²Child A cirrhosis and small lesion HCC. HCC: Hepatocellular carcinoma.

Table 3 Independent predictors of recurrence and survival in patients undergoing resection for hepatocellular carcinoma

Ref.	No. of patients	Variables
Belghiti et al[50] 1991	47	Tumor size ≥ 5 cm
		AFP levels ≥ 100 ng/mL
Llovet et al[4] 1999	77	Differentiation degree
		Multinodularity
		Satellites
Imamura et al[42] 2003	184	Early recurrence (< 2 yr)
		Microvascular invasion
		AFP levels ≥ 32 ng/mL
		Non-anatomical resection
		Late recurrence (> 2 yr)
		Higher grade of hepatitis activity
		Multinodularity
		Gross tumor classification
Roayaie et al[41] 2009	131	Invasion of a vessel with a muscular wall
		Tumor size > 10 cm
Survival
Llovet et al[4] 1999	77	Portal hypertenstion
		Bilirubin level (> 1 mg/dL)
Wayne et al[47] 2002	249	Child-Pugh (B)
		Differentiation degree
		(Edmonson-Steiner 1-2 vs 3-4)
		Fibrosis
		(Ishak score 0-4 vs 5-6)
Vauthey et al[51] 2002	557	Vascular invasion
		Multinodularity
		Tumor size (> 5 cm)
		Fibrosis
Poon et al[52] 2003	518	Vascular invasion
		Tumor size (> 5 cm)
		Multinodularity
		Cirrhosis
		AST > 50 U/L
		Invasion of adjacent organs
Roayaie et al[41] 2009	131	Invasion of a vessel with a muscular wall
		Invasion > 1 cm from tumor

AFP: Alpha-fetoprotein.

Table 4 Result of randomized controlled trials: Adjuvant/neoadjuvant treatment in resected hepatocellular cancer

Ref.	Treatment	Recurrence rate-3 yr
Izumi et al[57] 1994	Adjuvant arterial lipiodolization (23) vs control (27)	No differences
Lai et al[58] 1998	Adjuvant chemoembolization (30) vs control (36)	82% vs 52%, P = NS
Yamasaki et al[59] 1996	Neoadjuvant chemoembolization (50) vs control (47)	54% vs 66%, P = NS
Lau et al[60] 1999	Adjuvant intraarterial lipiodol 131I (21) vs control (22)	75% vs 38%, P = 0.03
Lygidakis et al[61] 1996	Adjuvant chemoembolization + immunotherapy (49) vs control (42)	36 mo vs 18 mo (OS)
Takayama et al[62] 2000	Adjuvant immunotherapy (76) vs control (74)	33% vs 48%, P = 0.008
Yamamoto et al[63] 1996	Adjuvant 5-FU (35) vs control (32)	52% vs 75%, P = NS
Kubo et al[64] 2001	Adjuvant Interferon alpha (15) vs control (15)	30% vs 60%, P= 0.03

NS: Not significant; OS: Overall survival; FU: Fluorouracil.

Table 5 Selection criteria for transplantation in hepatocellular carcinoma

Ref.	No. of patients	Selection criteria	Survival rate at 5 yr
Mazzaferro et al[18] 1996	48	Milan criteria: single HCC < 5 cm or up to 3 nodules < 3 cm	75% (4 yr)
Yao et al[19] 2001	70	UCSF criteria: a maximum tumor size of 6.5 cm or 2 lesions ≤ 4.5 cm in diameter with a total tumor diameter of ≤ 8 m	75%
Kwon et al[86] 2007	114	HCC ≤ 5 cm	87%
		AFP ≤ 400 ng/mL
Lee et al[87] 2008	186	Up to 6 nodules with a maximum diameter of < 5 cm	76%
Mazzaferro et al[21] 2009	283	Up to 7 criteria: 7 as the sum of the largest size (cm) and the number of tumors	71%
Herrero et al[88] 2001	154	HCC ≤ 6 cm or ≤ 3 HCC ≤ 5 cm	73%
Jonas et al[89] 2007	21	Any number, each ≤ 6 cm with cumulated diameter ≤ 15 cm	62% at 3 yr
Toso et al[90] 2008	288	TTV ≤ 115 cm3	72%
Sugawara et al[91] 2007	78	≤ 5 HCC ≤ 5 cm	70% at 3 yr

TTV: Total tumor volume; HCC: Hepatocellular carcinoma; AFP: Alpha-fetoprotein; UCSF: University of California, San Francisco.

Table 6 Independent predictors of recurrence and survival in patients undergoing liver transplantation for hepatocellular carcinoma

Ref.	No. of patients	Variables
Recurrence
Iwatsuki et al[108] 2000	344	Bilobar disease
		Vascular invasion
		Tumor size (2-5 cm, > 5 cm)
Bismuth et al[109] 1993	60	Tumor size
		Number of tumors
		Portal thrombus
Roayaie et al[110] 2000	119	Tumor size
		Vascular invasion
Hemming et al[111] 2002	112	Vascular invasion
Survival
Iwatsuki et al[108] 2000	344	Number of tumors (> 3)
		Vascular invasion
Jonas et al[83] 2001	120	Vascular invasion
		Tumor grade

Table 7 Randomized controlled trial comparing radiofrequency ablation to percutaneous ethanol injection for the treatment of early stage hepatocellular carcinoma

Ref.	No. of patients	Initial response	Failure	3 yr survival	P value
Lencioni et al[128] 2003	RFA (52)	91%	8%	81%	NS
	PEI (50)	82%	34%	73%
Lin et al[129] 2004	RFA (52)	96%	17%	74%	0.014
		88%
	PEI (52)	88%	45%	50%
Shiina et al[122] 2005	RFA (118)	100%	2%	80%	0.020
	PEI (114)	100%	11%	63%
Lin et al[130] 2005	RFA (62)	97%	16%	74%	0.031
	PEI (62)	89%	42%	51%
Brunello et al[131] 2008	RFA (70)	96%	34%	59%	NS
	PEI (69)	66%	64%	57%

RFA: Radiofrequency ablation; PEI: Percutaneous ethanol injection; NS: Not significant.

Table 8 Randomized controlled trias comparing transarterial chemoembolization or transarterial embolization to other treatments

Ref.	No. of patients	1 yr survival	2 yr survival	P value
Lin et al[141] 1988
TAE (gelfoam + ivalon)	21	42%	25	NS
TAE + IV 5-FU	21	20%	20
IV 5-FU	21	13%	13
Pelletier et al[142] 1990
TACE (doxorubicin, gelfoam)	21	24%	-	NS
Conservative treatment	21	33%	-
GETCH[25] 1995
TACE (cisplatin, gelfoam)	50	62%	38	NS
Conservative treatment	46	43%	26
Bruix et al[143] 1998
TAE (gelfoam, coils)	40	70	49	NS
Conservative treatment	40	72	50
Lo et al[27] 2002
TACE (cisplatin, gelfoam)	40	57	31	0.002
Conservative treatment	39	32	11
Llovet et al[26] 2002
TACE (doxorubicin, gelfoam)	40	82	63	0.009
TAE (gelfoam)	37	75	50
Conservative treatment	35	63	27

NS: Not significant; IV: Intravenous; GETCH: Groupe d’Etude et de Traitement du Carcinome He'patocellulaire; TACE: Transarterial chemoembolization; TAE: Transarterial embolization; RCT: Randomized controlled trial; FU: Fluorouracil.

Table 9 Existing series on treatment of hepatocellular cancer: stereotactic body radiation therapy and radioembolization with yttrium-90

Treatment	Ref.	Year	Number	Overall survival
Radiotherapy	Kwon et al[145]	2010	42	58.6% (3 yr)
	Andolino et al[146]	2011	60	67% (2 yr)
	Huang et al[147]	2012	36	64% (2 yr)
	Kang et al[148]	2012	47	68.7% (2 yr)
	Facciuto et al[149]	2012	117	1Median 32 mo
Radioembolization	Carr et al[28]	2004	65	Median 21.3 mo
	Sangro et al[150]	2006	24	Median 7 mo
	Kulik et al[151]	2008	108	2Median 15.6 mo
				3Median 4.4 mo
	Hilgard et al[152]	2010	108	Median 16.4 mo
	Salem et al[153]	2010	291	4Median 7.7 mo
	Salem et al[29]	2011	123	Median 20.7 mo

¹Post liver transplant;

²No portal vein thrombosis;

³With main portal vein thrombosis;

⁴Child B cirrhosis.

Table 10 Ongoing and reported randomized phase II-III trials in the treatment of advanced hepatocellular carcinoma

Treatment	Acronym	Treatment	Primary outcome
First line treatment	1SEARCH	Erlotinib + Sorafenib vs Sorafenib	OS
	1BRISK-FL	Brivanib vs Sorafenib	OS
	-	Linifanib vs Sorafenib	OS
Second line treatment	1EVOLVE-1	Everolimus vs Placebo	OS
	1BRISK	Brivanib vs Placebo	OS
	1BRISK-APS	Brivanib vs Placebo	OS
	Toh et al[158] 2010	Linifanib	OS: 9.7 mo
Phase 2 trial (reported)	Hsu et al[159] 2010	Sorafenib + Tegafur/Uracil	OS: 7.4 mo
	Thomas et al[160] 2007	Erlotinib	OS: 6.25 mo
	Thomas et al[161] 2009	Erlotinib + Bevacizumab	OS: 15.7 mo
	Faivre et al[162] 2009	Sunitinib	OS: 8 mo

¹ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov/. OS: Overall survival.