Intermediate stage hepatocellular carcinoma: a summary review

Figures & data

Table 1 Bolondi’s subclassification for Barcelona Clinic Liver Cancer (BCLC) B

Barcelona Clinic Liver Cancer (BCLC) class B subclassification	B1	B2	B3	B4
Child-Pugh score	5–7	5–6	7	8–9
Beyond Milan within up-to-7 criteria	In	Out	Out	Out
Eastern Cooperative Oncology Group (ECOG) tumor related performance status	0	0	0	0–1
Portal vein thrombosis	No	No	No	No
First treatment option	Transarterial chemo-embolization (TACE)	TACE or Selective internal radiotherapy (SIRT)		Best supportive care
Alternative treatment	Liver transplantation (LTx)or TACE + ablation	Sorafenib	Trials TACE + Sorafenib	LTx

Table 2 Kinki criteria

Barcelona Clinic Liver Cancer (BCLC) class B subclassification	B1	B2	B3
Child-Pugh score	5–7	5–7	8, 9
Beyond Milan within up to-7 criteria	In	Out	any
Treatment allocation
Concept of treatment	Curative	Palliative	3a: if within up-to-7 criteria leading to curative intent	3b: out of up-to-7 criteria leading to palliative or best supportive care

Table 3 Illustrating response evaluation according to modified Response Evaluation Criteria in Solid Tumors (mRECIST)

Terminology	Response	Description
Target lesions	Complete response (CR)	Disappearance of any intra-tumoral arterial enhancement in all target lesions
	Partial response (PR)	At least a 30% decrease in the sum of the diameters of viable (enhancement in the arterial phase) target lesions, taking as reference the baseline sum of the diameters of target lesions
	Stable disease^Citation76	Any cases that do not qualify for either PR or PD
	Progressive disease (PD)	An increase of at least 20% in the sum of the diameters of viable (enhancement in the arterial phase) target lesions recorded since treatment started
Non-target lesions	Complete response (CR)	Disappearance of any intra-tumoral arterial enhancement in all non-target lesions
	Stable disease^Citation76 or incomplete response (IR)	Persistence of intra-tumoral arterial enhancement in one or more non-target lesions
	Progressive disease (PD)	Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions
Additional recommendations	New lesion	A new lesion can be classified as hepatocellular carcinoma (HCC) if its longest diameter is at least 1 cm and the enhancement pattern is typical for HCC. A lesion with atypical radiological pattern can be diagnosed as HCC by evidence of at least 1 cm interval growth
	Pleural effusion or ascites	Cytopathological confirmation of the neoplastic nature of any effusion that appears or worsens during treatment is required to declare PD
	Lymph nodes in the porta hepatis	Lymph nodes detected at the porta hepatis can be considered malignant if the lymph node short axis is at least 2 cm
	Portal vein thrombosis	Malignant portal vein thrombosis should be considered as a non-measurable lesion and thus included in the non-target lesion group

Table 4 Hepatoma arterial-embolization prognostic (HAP) score

Parameter	Scoring	Stages	Points
Albumin <36 g/dL	1 point	HAP A	0 point
Alpha-fetoprotein (AFP) >400 ng/mL	1 point	HAP B	1 point
Bilirubin >17 μmol/L	1 point	HAP C	2 points
Max TU diameter >7 cm	1 point	HAP D	>2 points

Table 5 Modified hepatoma arterial-embolization prognostic (mHAP) II score

Risk factors	Scoring
Tumor size (>7 cm)	1
Tumor number (≥2)	1
Alpha-fetoprotein (AFP>400 ng/mL)	1
Total bilirubin (>0.9 mg/dL)	1
Serum albumin (<3.6 g/dL)	1
mHAP-II classification
mHAP-II A	0
mHAP-II B	1
mHAP-II C	2
mHAP-II D	3–5

Table 6 Chiba HCC in intermediate-stage prognostic (CHIP) score

Prognostic factor	Points
Child-Pugh score
5	0
6	1
7	2
8–9	3
Number of liver tumors
1	0
2–7	2
8	3
HCV-RNA positive
Absent	0
Present	1

Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus.

Table 7 Munich-transarterial chemo-embolization (TACE) score

Parameters	Points
	0	2	3	4	6
Alpha-fetoprotein (AFP) (ng/mL)	<35	–	35–999	–	≥1,000
Bilirubin (mg/dL)	<1.1	–	1.1–3.0	–	≥3.1
C-reactive protein (CRP) (mg/dL)	<0.5	–	0.5–1.9	–	≥2
Tumor extension*	Category A	–	–	Category B	–
Creatinine (mg/dL)	<1.3	≥1.3	–	–	–
Quick^Citation77	≥75	<75	–	–	–

Notes: * Tumor extension category B: positive if one of the following criteria is met: large (one nodule >5 cm) or multilocular (exceeding the limits of three nodules ≤3 cm) or vascular involvement or M1. Otherwise category A. Stages: Stage I (low mortality risk): 0–9 points. Stage II (intermediate mortality risk): 10–13 points. Stage III (high mortality risk): 14–26 points.

Table 8 Assessment for Retreatment with TACE (ART) score

Parameter	Scoring	Stages	Points
Absence of radiologic response	1 point	Risk group 1	0–1.5
Aspartate aminotransferase (AST) increase >25%	4 points	Risk group 2	≥2.5
Child-Pugh increase: 1 point ≥2 points	1.5 points 3 points

Table 9 ABCR score

Prognostic factor	Points
Baseline
Barcelona Clinic Liver Cancer stage
A	0
B	2
C	3
Alpha-fetoprotein (AFP)	1
After first transarterial chemo-embolization
Child-Pugh score ≥2 points	2
Radiologic tumor response^Citation78	−3
Stages
Stage 1: 0 points Stage 2: 1–3 points Stage 3: ≥4 points

Table 10 Summary of different studies comparing different treatment options for patients with intermediate stage hepatocellular carcinoma

Study	Type of treatments in comparison	Objective response rate (OR and 95% CI)	Patient’s survival (HR and 95% CI)
Mabed et al 2009^Citation79	Conventional transarterial chemo-embolization (TACE) vs control treatment	4.24 (1.41–12.70)	0.66 (0.41, 1.05)
Llovet et al 2002^Citation80	Bland transarterial embolization (TAE) vs control treatment	54.49 (3.11, 955.28)	0.57 (0.31, 1.04)
Meyer et al 2013^Citation81	Bland TAE vs conventional TACE	0.43 (0.18, 1.07)	0.91 (0.51, 1.62)
Yu et al 2014^Citation82	Bland TAE vs conventional TACE	1.89 (0.88, 4.06)	0.83 (0.47, 1.46)
Kolligs et al 2015^Citation83	Transarterial radioembolization (TARE) vs conventional TACE	2.89 (0.43, 19.28)	2.13 (0.59, 7.73)
Salem et al 2016^Citation58	TARE vs conventional TACE	2.38 (0.49, 11.63)	0.99 (0.40, 2.45)
Golfieri et al 2014^Citation84	Drug-eluting bead (DEB)-TACE vs conventional TACE	0.82 (0.45, 1.47)	0.99 (0.62, 1.56)
Brown et al 2015^Citation85	DEB-TACE vs conventional TAE	0.92 (0.36, 3.27)	0.90 (0.58, 1.41)
Kudo et al 2014^Citation86	Conventional TACE plus adjuvant systemic therapy vs conventional TACE alone	1.29 (0.91, 1.83)	0.90 (0.66, 1.23)
Wang et al 2015^Citation87	Conventional TACE plus adjuvant systemic therapy vs conventional TACE alone	3.11 (1.37, 7.07)	0.37 (0.20, 0.69)
Pinter et al 2015^Citation88	Conventional TACE plus adjuvant systemic therapy vs conventional TACE alone	0.92 (0.11, 7.67)	1.70 (0.80, 3.61)
Lencioni et al 2016^Citation89	DEB-TACE plus adjuvant systemic therapy vs DEB- TACE alone	1.42 (0.88, 2.30)	0.90 (0.61, 1.33)
Zhang et al 2012^Citation78	Conventional TACE plus external radiation therapy vs conventional TACE alone	4.97 (2.79, 8.85)	0.59 (0.44, 0.80)
Liu et al 2009^Citation90	Conventional TACE plus local tumor ablative therapy vs conventional TACE alone	3.81 (1.21, 11.96)	0.52 (0.25, 1.090
Zhao et al 2011^Citation91	Conventional TACE plus local tumor ablative therapy vs conventional TACE alone	5.64 (1.32, 24.17)	0.53 (0.32, 0.87)
Huang et al 2017^Citation92	Conventional TACE plus local tumor ablative therapy vs conventional TACE alone	19.60 (6.29, 61.09)	0.53 (0.46, 0.64)

Hasdemir DB, Davila LA, Schweitzer N, et al. Evaluation of CT vascularization patterns for survival prognosis in patients with hepatocellular carcinoma treated by conventional TACE. Diagn Interv Radiol. 2017;23:217–222. doi:10.5152/dir.2016.1600628256449

 PubMed Web of Science ®Google Scholar

Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91–96. doi:10.1053/gast.2003.50016

 Google Scholar

Hayes CN, Zhang P, Zhang Y, Chayama K. Molecular mechanisms of hepatocarcinogenesis following sustained virological response in patients with chronic hepatitis C virus infection. Viruses. 2018;10:531. doi:10.3390/v10100531

 Web of Science ®Google Scholar

Mabed M, Esmaeel M, El-Khodary T, Awad M, Amer T. A randomized controlled trial of transcatheter arterial chemoembolization with lipiodol, doxorubicin and cisplatin versus intravenous doxorubicin for patients with unresectable hepatocellular carcinoma. Eur J Cancer Care (Engl). 2009;18:492–499. doi:10.1111/j.1365-2354.2008.00984.x19453695

 PubMed Web of Science ®Google Scholar

Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359:1734–1739. doi:10.1016/S0140-6736(02)08649-X12049862

 PubMed Web of Science ®Google Scholar

Meyer T, Kirkwood A, Roughton M, et al. A randomised phase II/III trial of 3-weekly cisplatin-based sequential transarterial chemoembolisation vs embolisation alone for hepatocellular carcinoma. Br J Cancer. 2013;108:1252–1259. doi:10.1038/bjc.2013.8523449352

 PubMed Web of Science ®Google Scholar

Yu SC, Hui JW, Hui EP, et al. Unresectable hepatocellular carcinoma: randomized controlled trial of transarterial ethanol ablation versus transcatheter arterial chemoembolization. Radiology. 2014;270:607–620. doi:10.1148/radiol.1313049824126369

 PubMed Web of Science ®Google Scholar

Kolligs FT, Bilbao JI, Jakobs T, et al. Pilot randomized trial of selective internal radiation therapy vs. chemoembolization in unresectable hepatocellular carcinoma. Liver Int. 2015;35:1715–1721. doi:10.1111/liv.1275025443863

 PubMed Web of Science ®Google Scholar

Salem R, Gordon AC, Mouli S, et al. Y90 radioembolization significantly prolongs time to progression compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology. 2016;151:1155–1163.e2. doi:10.1053/j.gastro.2016.08.02927575820

 PubMed Web of Science ®Google Scholar

Golfieri R, Giampalma E, Renzulli M, et al. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer. 2014;111:255–264. doi:10.1038/bjc.2014.19924937669

 PubMed Web of Science ®Google Scholar

Brown KT, Do RK, Gonen M, et al. Randomized Trial of hepatic artery embolization for hepatocellular carcinoma using doxorubicin-eluting microspheres compared with embolization with microspheres alone. J Clin Oncol. 2016;34:2046–2053. doi:10.1200/JCO.2015.64.082126834067

 PubMed Web of Science ®Google Scholar

Kudo M, Han G, Finn RS, et al. Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial. Hepatology. 2014;60:1697–1707. doi:10.1002/hep.2729024996197

 PubMed Web of Science ®Google Scholar

Wang H, Liu Y, Wang X, et al. Randomized clinical control study of locoregional therapy combined with arsenic trioxide for the treatment of hepatocellular carcinoma. Cancer. 2015;121:2917–2925. doi:10.1002/cncr.2945626033499

 PubMed Web of Science ®Google Scholar

Pinter M, Ulbrich G, Sieghart W, et al. Hepatocellular carcinoma: a phase II randomized controlled double-blind trial of transarterial chemoembolization in combination with biweekly intravenous administration of bevacizumab or a placebo. Radiology. 2015;277:903–912. doi:10.1148/radiol.201514214026131911

 PubMed Web of Science ®Google Scholar

Lencioni R, Cioni D. RFA plus lyso-thermosensitive liposomal doxorubicin: in search of the optimal approach to cure intermediate-size hepatocellular carcinoma. Hepat Oncol. 2016;3:193–200. doi:10.2217/hep-2016-000530191041

 PubMed Web of Science ®Google Scholar

Liu D, Li H, Li P, et al. Evaluation of TACE combined with RFA and PEI in treating advanced hepatic carcinoma. J Interventional Radiol. 2009;18:389–391.

 Google Scholar

Zhao M, Wang JP, Li W, et al. [Comparison of safety and efficacy for transcatheter arterial chemoembolization alone and plus radiofrequency ablation in the treatment of single branch portal vein tumor thrombus of hepatocellular carcinoma and their prognosis factors]. Zhonghua Yi Xue Za Zhi. 2011;91:1167–1172.21756768

 PubMedGoogle Scholar

Huang D, Chen Y, Chen S, et al. TACE plus percutaneous chemotherapy-lipiodol treatment of unresectable pedunculated hepatocellular carcinoma. Medicine (Baltimore). 2017;96:e7650. doi:10.1097/MD.000000000000765028746230

 PubMed Web of Science ®Google Scholar