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Copyright ©2014 Baishideng Publishing Group Inc.
World J Gastroenterol. Aug 14, 2014; 20(30): 10223-10237
Published online Aug 14, 2014. doi: 10.3748/wjg.v20.i30.10223
Table 1 Existing series on treatment of hepatocellular cancer: evidence based benefit (NCI classification) and outcome
TreatmentRef.YearNumber5 yr survival
Liver resection (evidence 2A)Llovet et al[4]19997751%
1Fong et al[5]199915457%
2Roayaie et al[17]201213270%
Liver transplantation (evidence 2A)Mazzaferro et al[18]199644473.3%
Llovet et al[4]19998769%
Yao et al[19]20017072.4%
3Roayaie et al[20]20024344%
4Mazzaferro et al[21]20094875%
Radiofrequency ablation (evidence 2A)2Sala et al[22]20043463%
Vivarelli et al[23]20047933% (3 yr)
1Chen et al[24]20067167.9% (4 yr)
Transarterial chemoembolization (evidence 1A)DETCH[25]19955038% (2 yr)
Llovet et al[26]20024029% (3 yr)
Lo et al[27]20024031% (2 yr)
Radiotherapy (evidence 1A)5Carr[28]200465Median 21.3 mo
6Salem et al[29]2011123Median 20.7 mo
Systemic therapy (evidence 1A)Llovet et al[30]200829910.7 mo
Cheng et al[31]20091506.5 mo
Table 2 Outcome of patients with hepatocellular carcinoma treated by resection, liver transplantation, and living donor liver transplantation
TreatmentNo. of patients1 yr survival5 yr survival
Surgical resection
Fong et al[5] 199915481%37%
Llovet et al[4] 199977185%51%
Poon et al[46] 2002135290%70%
Wayne et al[47] 2002249 ( ≤ 5 cm)83%41%
Shrager et al[48] 2012206160%46%
Roayaie et al[17] 2013132 ( ≤ 2 cm)-70%
Liver transplantation
Mazzaferro et al[18] 19964884%74%
Bismuth et al[82] 19994582%74%
Llovet et al[4] 19997986%75%
Jonas et al[83] 200112090%71%
Yao et al[19] 20016487%73%
Living donor transplantation
Gondolesi et al[84] 200415-86% (3 yr)
Todo et al[85] 2004137-79% (3 yr)
Table 3 Independent predictors of recurrence and survival in patients undergoing resection for hepatocellular carcinoma
Ref.No. of patientsVariables
Belghiti et al[50] 199147Tumor size ≥ 5 cm
AFP levels ≥ 100 ng/mL
Llovet et al[4] 199977Differentiation degree
Multinodularity
Satellites
Imamura et al[42] 2003184Early 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] 2009131Invasion of a vessel with a muscular wall
Tumor size > 10 cm
Survival
Llovet et al[4] 199977Portal hypertenstion
Bilirubin level (> 1 mg/dL)
Wayne et al[47] 2002249Child-Pugh (B)
Differentiation degree
(Edmonson-Steiner 1-2 vs 3-4)
Fibrosis
(Ishak score 0-4 vs 5-6)
Vauthey et al[51] 2002557Vascular invasion
Multinodularity
Tumor size (> 5 cm)
Fibrosis
Poon et al[52] 2003518Vascular invasion
Tumor size (> 5 cm)
Multinodularity
Cirrhosis
AST > 50 U/L
Invasion of adjacent organs
Roayaie et al[41] 2009131Invasion of a vessel with a muscular wall
Invasion > 1 cm from tumor
Table 4 Result of randomized controlled trials: Adjuvant/neoadjuvant treatment in resected hepatocellular cancer
Ref.TreatmentRecurrence rate-3 yr
Izumi et al[57] 1994Adjuvant arterial lipiodolization (23) vs control (27)No differences
Lai et al[58] 1998Adjuvant chemoembolization (30) vs control (36)82% vs 52%, P = NS
Yamasaki et al[59] 1996Neoadjuvant chemoembolization (50) vs control (47)54% vs 66%, P = NS
Lau et al[60] 1999Adjuvant intraarterial lipiodol 131I (21) vs control (22)75% vs 38%, P = 0.03
Lygidakis et al[61] 1996Adjuvant chemoembolization + immunotherapy (49) vs control (42)36 mo vs 18 mo (OS)
Takayama et al[62] 2000Adjuvant immunotherapy (76) vs control (74)33% vs 48%, P = 0.008
Yamamoto et al[63] 1996Adjuvant 5-FU (35) vs control (32)52% vs 75%, P = NS
Kubo et al[64] 2001Adjuvant Interferon alpha (15) vs control (15)30% vs 60%, P= 0.03
Table 5 Selection criteria for transplantation in hepatocellular carcinoma
Ref.No. of patientsSelection criteriaSurvival rate at 5 yr
Mazzaferro et al[18] 199648Milan criteria: single HCC < 5 cm or up to 3 nodules < 3 cm75% (4 yr)
Yao et al[19] 200170UCSF criteria: a maximum tumor size of 6.5 cm or 2 lesions ≤ 4.5 cm in diameter with a total tumor diameter of ≤ 8 m75%
Kwon et al[86] 2007114HCC ≤ 5 cm87%
AFP ≤ 400 ng/mL
Lee et al[87] 2008186Up to 6 nodules with a maximum diameter of < 5 cm76%
Mazzaferro et al[21] 2009283Up to 7 criteria: 7 as the sum of the largest size (cm) and the number of tumors71%
Herrero et al[88] 2001154HCC ≤ 6 cm or ≤ 3 HCC ≤ 5 cm73%
Jonas et al[89] 200721Any number, each ≤ 6 cm with cumulated diameter ≤ 15 cm62% at 3 yr
Toso et al[90] 2008288TTV ≤ 115 cm372%
Sugawara et al[91] 200778 ≤ 5 HCC ≤ 5 cm70% at 3 yr
Table 6 Independent predictors of recurrence and survival in patients undergoing liver transplantation for hepatocellular carcinoma
Ref.No. of patientsVariables
Recurrence
Iwatsuki et al[108] 2000344Bilobar disease
Vascular invasion
Tumor size (2-5 cm, > 5 cm)
Bismuth et al[109] 199360Tumor size
Number of tumors
Portal thrombus
Roayaie et al[110] 2000119Tumor size
Vascular invasion
Hemming et al[111] 2002112Vascular invasion
Survival
Iwatsuki et al[108] 2000344Number of tumors (> 3)
Vascular invasion
Jonas et al[83] 2001120Vascular 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 patientsInitial responseFailure3 yr survivalP value
Lencioni et al[128] 2003RFA (52)91%8%81%NS
PEI (50)82%34%73%
Lin et al[129] 2004RFA (52)96%17%74%0.014
88%
PEI (52)88%45%50%
Shiina et al[122] 2005RFA (118)100%2%80%0.020
PEI (114)100%11%63%
Lin et al[130] 2005RFA (62)97%16%74%0.031
PEI (62)89%42%51%
Brunello et al[131] 2008RFA (70)96%34%59%NS
PEI (69)66%64%57%
Table 8 Randomized controlled trias comparing transarterial chemoembolization or transarterial embolization to other treatments
Ref.No. of patients1 yr survival2 yr survivalP value
Lin et al[141] 1988
TAE (gelfoam + ivalon)2142%25NS
TAE + IV 5-FU2120%20
IV 5-FU2113%13
Pelletier et al[142] 1990
TACE (doxorubicin, gelfoam)2124%-NS
Conservative treatment2133%-
GETCH[25] 1995
TACE (cisplatin, gelfoam)5062%38NS
Conservative treatment4643%26
Bruix et al[143] 1998
TAE (gelfoam, coils)407049NS
Conservative treatment407250
Lo et al[27] 2002
TACE (cisplatin, gelfoam)4057310.002
Conservative treatment393211
Llovet et al[26] 2002
TACE (doxorubicin, gelfoam)4082630.009
TAE (gelfoam)377550
Conservative treatment356327
Table 9 Existing series on treatment of hepatocellular cancer: stereotactic body radiation therapy and radioembolization with yttrium-90
TreatmentRef.YearNumberOverall survival
RadiotherapyKwon et al[145]20104258.6% (3 yr)
Andolino et al[146]20116067% (2 yr)
Huang et al[147]20123664% (2 yr)
Kang et al[148]20124768.7% (2 yr)
Facciuto et al[149]20121171Median 32 mo
RadioembolizationCarr et al[28]200465Median 21.3 mo
Sangro et al[150]200624Median 7 mo
Kulik et al[151]20081082Median 15.6 mo
3Median 4.4 mo
Hilgard et al[152]2010108Median 16.4 mo
Salem et al[153]20102914Median 7.7 mo
Salem et al[29]2011123Median 20.7 mo
Table 10 Ongoing and reported randomized phase II-III trials in the treatment of advanced hepatocellular carcinoma
TreatmentAcronymTreatmentPrimary outcome
First line treatment1SEARCHErlotinib + Sorafenib vs SorafenibOS
1BRISK-FLBrivanib vs SorafenibOS
-Linifanib vs SorafenibOS
Second line treatment1EVOLVE-1Everolimus vs PlaceboOS
1BRISKBrivanib vs PlaceboOS
1BRISK-APSBrivanib vs PlaceboOS
Toh et al[158] 2010LinifanibOS: 9.7 mo
Phase 2 trial (reported)Hsu et al[159] 2010Sorafenib + Tegafur/UracilOS: 7.4 mo
Thomas et al[160] 2007ErlotinibOS: 6.25 mo
Thomas et al[161] 2009Erlotinib + BevacizumabOS: 15.7 mo
Faivre et al[162] 2009SunitinibOS: 8 mo