Management of hepatocellular carcinoma: an overview of major findings from meta-analyses

Abstract

This paper aims to systematically review the major findings from meta-analyses comparing different treatment options for hepatocellular carcinoma (HCC). A total of 153 relevant papers were searched via the PubMed, EMBASE, and Cochrane library databases. They were classified according to the mainstay treatment modalities (i.e., liver transplantation, surgical resection, radiofrequency ablation, transarterial embolization or chemoembolization, sorafenib, and others). The primary outcome data, such as overall survival, diseases-free survival or recurrence-free survival, progression-free survival, and safety, were summarized. The recommendations and uncertainties regarding the treatment of HCC were also proposed.

INTRODUCTION

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death [1–3]. Currently, the most widely accepted therapeutic algorithm is derived from BCLC staging system [4–5], in which the mainstay treatment options for HCC include liver transplantation (LT), surgical resection, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), transarterial embolization (TAE) or chemoembolization (TACE), and sorafenib. Several novel therapeutic modalities have been also explored, such as percutaneous acetic acid injection (PAI), three-dimensional conformal radiation therapy (3D-CRT), argon-helium cryotherapy system (AHCS), traditional Chinese medicine (TCMs), cytokine-induced killer (CIK) cell therapy, and portal vein embolization (PVE), etc. It remains unclear about whether or such novel therapeutic modalities could be applied to the clinical practice. Meta-analysis can provide the highest level of evidence for our clinical decisions by combining all scattered data [6–7]. Herein, we systematically reviewed the major findings from all meta-analyses regarding the treatment of HCC and attempted to propose the evidence-based recommendations and uncertainties.

RESULTS

Overall, 2039 papers were identified. Among them, 153 meta-analysis papers were finally included [8–160] (Figure 1). The number of relevant papers was gradually increased over years (Supplementary Figure S1). The characteristics of these included papers were shown in Table 1. Their major findings were summarized according to the treatment modalities (Tables 2–5 and Supplementary Tables S1–S8).

Figure 1: Flowchart of study inclusion.

Table 1: Study characteristics: An overview of included studies

First author	Journal (Year)	Country	Type of participants	No. included studies/pts.	Comparisons	Type of studies
						RCT	Non-RCT
Al Hasan	Liver Transpl (2014)	Saudi Arabia	Unselected HCC	7/1388	Living donor LT vs deceased donor LT	0	7
Bouza	BMC Gastroenterol (2009)	Spain	Early, small HCC	6/787	RFA vs PEI	6	0
Breitenstein	Br J Surg (2009)	Switzerland	Unselected HCC	7/620	Interferon after resection or ablation	7	0
Cai	HPB (2013)	China	HCC ≤ 5 cm	5/NA	RFA vs surgical resection	NA	NA
Camma	Radiology (2002)	Italy	Unresectable HCC	18/2466	TACE vs non-active treatment; different transarterial modalities of therapy (TACE, TCE, TAE)	5; 13	0
Cao	Ultrasound Med Biol (2011)	China	Unselected HCC	9/736	TACE plus HIFU vs TACE alone	0	9
Chen	Dig Dis Sci (2011)	China	Unselected HCC	9/1503	Anatomic vs nonanatomic resection	0	9
Chen	Zhonghua Wai Ke Za Zhi (2008)	China	HCC ≤ 5 cm, number of lesions ≤ 3	6/697	RFA vs surgical resection	1	5
Chen	Chinese-German Journal of Clinical Oncology (2013)	China	Unresectable HCC	9/870	CIK cell + TACE	9	0
Cheng	J Cancer Res Clin Oncol (2014)	China	Resectable HCC	10/909	Preoperative TACE vs control; postoperative TACE vs control	4; 6	0; 0
Cheung	Evid Based Complement Alternat Med (2013)	China	Unresectable HCC	67/5211	TACE + Chinese medicines vs TACE alone	67	0
Cho	Hepatology (2009)	Korea	Unselected HCC	4/652	RFA vs PEI	4	0
Cho	Expert Opin Investig Drugs (2009)	China	HCC patients receiving TACE	30/2428	TACE + Chinese herbal therapy vs TACE alone	30	0
Chu	Asian J Surg (2010)	China	Post-operative HCC	5/206	Vitamin analogues (vitamin A and K2) after hepatic resection or local ablative therapy	5	0
Cinco	Hepatology International (2011)	Philippines	Advanced HCC	2/828	Sorafenib vs placebo	9	0
Cucchetti	Ann Surg Oncol (2012)	Italy	Unselected HCC	18/9036	Anatomic vs nonanatomic resection	0	18
Cucchetti	J Hepatol (2013)	Italy	Early HCC ≤ 5 cm	17/8420	RFA vs surgical resection	NA	NA
Dhir	HPB (2012)	USA	Early HCC within Milan Criteria	10/1763	LT vs resection	0	10
Dong	World J Gastroenterol (2014)	China	Unselected HCC	22/NA	Surgical resection vs nonsurgical-resection ablation therapies; RFA vs PEI; RFA vs RFA+TACE	2; 5; 0	10; 0; 5
Duan	World J Surg Oncol (2013)	China	Unselected HCC	12/8612	RFA vs surgical resection	2	12
Duffy	Hepatology (2013)	USA	Unselected HCC	6/2464	Antiangiogenic agents vs placebo	6	21
Estanislao	J Gastroenterol Hepatol (2009)	Philippine	Advanced HCC	NA/NA	Octreotide vs no octreotide	NA	NA
Fancellu	J Surg Res (2011)	Italy	Resectable HCC	9/590	Minimally-invasive vs open hepatectomy	0	9
Feng	J Cancer Res Clin Oncol (2014)	China	Small HCC (1 lesion < 6.5 cm; no more than 3 lesions < 4.5 cm)	23/15482	RFA vs surgical resection	3	20
Flores	J Gastroenterol Hepatol (2009)	Philippines	Post-operative HCC	2/236	Adjuvant immunotherapy in combination with surgical resection	2	0
Fu	Hepato-gastroenterology (2014)	China	Small HCC (single < 6.5 cm, or ≤ 3 lesions, ≤ 4.5 cm)	5/776	RFA vs surgical resection	5	0
Fu	J Cancer Res Clin Oncol (2014)	China	Unselected HCC	9/900	TACE + sorafenib vs TACE alone	5	4
Fu	J Cancer Res Ther (2014)	China	Unresectable HCC	9/608	Kanglaite injection plus hepatic arterial intervention vs hepatic arterial intervention alone	0	9
Furtado	Ann Surg Oncol (2014)	Australia	Unselected HCC	5/334	Surgery + Adjuvant I(131) lipiodol vs surgery alone	2	3
Gao	Hepato-gastroenterology (2013)	China	Unresectable HCC	7/693	DEB-TACE vs conventional TACE	0	7
Germani	J Hepatol (2010)	UK	Unselected HCC	8/1035	RFA vs PEI; Percutaneous acetic acid injection vs PEI	5; 2	0; 0
Geschwind	Am J Clin Oncol (2003)	USA	Unselected HCC	4/268	Therapeutic embolization vs supportive care alone	4	0
Gong	Nucl Med Commun (2014)	China	Unselected HCC	6/466	Adjuvant therapy with intra-arterial iodine-131-labeled lipiodol ((131)I-lipiodol) to hepatic resection	2	8
Grant	Clin Transplant (2013)	Canada	Unselected HCC	16/2202	Living donor LT vs deceased donor LT	0	16
Gu	J Cancer Res Clin Oncol (2014)	China	Unselected HCC	18/2120	TACE + local ablative therapy vs monotherapy	7	11
Guo	J Cancer Res Clin Oncol (2009)	China	Advanced HCC	6/352	Octreotide vs placebo or best supportive care	6	0
Han	Journal of Interventional Radiology (China) (2013)	China	Unselected HCC	8/698	RFA + TACE vs TACE	0	8
Han	PLoS One (2014)	China	Unresectable HCC	5/454	DEB-TACE vs conventional TACE	3	2
Hoshida	Hepatology (2000)	Japan	Non-advanced HCC	17/NA	Surgical resection vs PEI; Surgical resection vs LT	0; 0	5; 12
Hu	HPB (2013)	China	Unselected HCC	18/NA	RFA vs surgical resection	4	14
Huang	Hepato-gastroenterology (2013)	China	Unselected HCC	4/433	RFA vs cryosurgery ablation	0	4
Huang	J Gastroenterol Hepatol (2014)	China	Unresectable HCC	7/700	DEB-TACE vs conventional TACE	2	5
Huang	J Viral Hepat (2013)	China Taiwan	Unselected HCC	22/3156	Adjuvant interferon therapy after curative treatment	10	13
Huang	Zhonghua Nei Ke Za Zhi (2008)	China	Early HCC within Milan Criteria	6/862	RFA vs other therapeutic methods	6	0
Ji	Med Sci Monit (2011)	China	Advanced HCC	9/759	Octreotide vs placebo or no treatment	9	0
Jiang	Tumour Biol (2014)	China	Unselected HCC	19/1728	RFA + TACE vs RFA alone	8	11
Jiang	World J Surg Oncol (2013)	China	Unselected HCC	10/1029	Adjuvant interferon therapy after treatment with surgical resection or TACE	8	2
Kong	Tumour Biol (2014)	China	Unselected HCC	19/1728	RFA + TACE vs RFA alone	8	11
Lan	Journal of Gastroenterology and Hepatology Research (Hong Kong) (2013)	China	Unselected HCC	10/701	Lamivudine treatment vs no antiviral therapy after liver resection or RFA	0	10
Leng	ANZ J Surg (2014)	China	HCC patients with PVTT	5/600	TACE vs control treatment	2	3
Li	World J Gastroenterol (2012)	China	Unselected HCC	11/1013	Primary LT vs salvage LT	0	11
Li	Hepatol Res (2012)	China	Unselected HCC	10/627	Laparoscopic vs open liver resection	0	10
Li	Hepato-gastroenterology (2011)	China	Unselected HCC	4/776	Anatomic vs nonanatomic resection	0	4
Li	J Gastroenterol Hepatol (2012)	China	Unselected HCC	6/877	RFA vs surgical resection	2	4
Li	Chinese Journal of Evidence-Based Medicine (2012)	China	Intermediate-advanced stage	17/907	TACE + thermotherapy vs TACE alone	17	0
Li	Chinese Journal of Evidence-Based Medicine (2013)	China	Intermediate-advanced stage	16/1467	TACE + argon-helium cryotherapy system (AHCS) vs TACE alone; TACE + argon-helium cryotherapy system vs AHCS	15; 7	0
Li	Chinese Journal of Cancer Prevention and Treatment (2013)	China	Unselected HCC	8/818	Adjuvant IFN vs without IFN after curative treatment	8	0
Li	Clin Res Hepatol Gastroenterol (2014)	China	Unresectable HCC	11/936	CIK+TACE+RFA vs TACE+RFA; CIK+TACE vs TACE	6	5
Liang	Liver Transpl (2012)	China	Unselected HCC	7/1310	Living donor LT vs deceased donor LT	0	7
Liang	Liver Transpl (2012)	China	Unselected HCC	5/2950	Sirolimus-based immunosuppression (SRL) after LT vs SRL-free	0	5
Liao	PLoS One (2013)	China	Unselected HCC	28/2497	TACE+PEI vs TACE; TACE+RT vs TACE; TACE+ three-dimensional conformal radiation therapy (3D-CRT) vs TACE; TACE+RFA vs TACE; TACE+HIFU vs TACE	4; 3; 1; 1; 1	5; 4; 5; 0; 4
Liu	World J Gastroenterol (2010)	China	Unselected HCC	10/1522	RFA vs surgical resection	0	10
Liu	Surg Laparosc Endosc Percutan Tech (2010)	China	Unselected HCC	8/1188	RFA vs surgical resection	8	0
Liu	Tumour Biol (2014)	China	Unselected HCC	7/571	RFA + TACE vs RFA alone	7	0
Liu	PLoS One (2014)	China	Unresectable HCC	17/676	TACE + sorafenib vs monotherapy	3	14
Llovet	Hepatology (2003)	Spain	Unresectable HCC	14/1443	TACE vs control treatment; Tamoxifen vs control treatment	7; 7	0; 0
Lu	Eur J Gastroenterol Hepatol (2013)	China	Unselected HCC	7/574	RFA + TACE vs RFA alone	7	0
Ma	Experimental Hematology and Oncology (2012)	China	Unresectable HCC	13/1212	CIK cell therapy vs non-CIK therapy	13	0
Ma	Chinese Journal of Cancer Prevention and Treatment (2011)	China	Post-operative HCC	4/423	Hepatic resection or RFA alone vs surgery + adoptive immunotherapy	4	0
Marelli	Cardiovasc Intervent Radiol (2007)	UK	Unselected HCC	12/NA	TACE vs control treatment; TACE vs TAE alone	9; 3	0
Mathurin	Aliment Pharmacol Ther (2003)	France	Post-operative HCC	21/NA	Adjuvant therapy after curative liver resection	10	11
Meng	Radiother Oncol (2009)	China	Unselected HCC	17/1476	TACE + radiotherapy vs TACE alone	5	12
Meng	Hepatology International (2011)	China	Post-operative HCC	4/209	Vitamin K2 vs placebo after curative treatment	4	0
Meng	J Altern Complement Med (2008)	China	Unresectable HCC	37/2653	TACE + Traditional Chinese Medicine vs TACE alone	NA	NA
Meng	Explore (NY) (2011)	China	Unresectable HCC	12/1008	TACE + Traditional Chinese Medicine vs TACE alone	11	0
Menon	Aliment Pharmacol Ther (2013)	UK	Unselected HCC	5/474	Sirolimus-based immunosuppression (SRL) after LT vs SRL-free	0	5
Miao	World J Gastroenterol (2010)	China	Unselected HCC	16/1224	Adjuvant antiviral therapy after curative therapy	5	8
Miyake	J Viral Hepat (2010)	Japan	Unselected HCC	5/355	Interferon-alpha after curative therapy	3	2
Moriguchi	Hepatology (2006)	Japan	Unselected HCC	4/604	Tumor ablation plus interferon therapy	4	0
Ni	J Cancer Res Clin Oncol (2013)	China	Unselected HCC	10/21494	RFA/PEI (PAT) vs surgical resection	6	4
Ni	World J Gastroenterol (2013)	China	Unselected HCC	8/598	RFA + TACE vs RFA alone	8	0
Ni	J Cancer Res Clin Oncol (2013)	China	Unselected HCC	6/376	RFA + TACE vs RFA or TACE alone	6	0
Nowak	Cochrane Database Syst Rev (2004); Cancer (2005)	Australia	Unresectable HCC	10/1709	Tamoxifen vs placebo/no intervention	10	0
Oliveri	Cochrane Database Syst Rev (2011)	Denmark	Unresectable HCC	9/645	TACE or TAE vs placebo, sham, or no intervention	9	0
Ono	Cancer (2001)	Japan	Post-operative HCC	3/108	Adjuvant chemotherapy after resection	3	0
Orlando	Am J Gastroenterol (2009)	Italy	Small HCC	5/701	RFA vs PEI	5	0
Pang	Chinese Journal of Evidence-Based Medicine (2010)	China	Unselected HCC	7/309	Laparoscopic vs conventional open hepatectomy	0	7
Parks	HPB (Oxford) (2014)	USA	Unselected HCC	15/1002	Laparoscopic vs open liver resection	0	15
Proneth	Ann Surg Oncol (2014)	Germany	Unselected HCC	9/1572	LT vs resection	0	7
Qi	J Clin Gastroenterol (2014)	China	Early-stage HCC	3/559	RFA vs surgical resection	3	0
Rahman	J Gastrointest Surg (2012)	USA	Unselected HCC	9/2279	LT vs resection	0	9
Riaz	BMC Gastroenterol (2012)	Pakistan	Post-operative HCC	5/754	Vitamin K2 or its analogues vs placebo or No vitamin K	5	0
Schoppmeyer	Cochrane Database Syst Rev (2009)	Germany	Early HCC	3/261	PEI vs percutaneous acetic acid injection; PEI vs surgery	2; 1	0; 0
Shen	J Gastroenterol Hepatol (2013)	China	Small HCC < 3 cm	4/766	RFA vs PEI	4	0
Shen	J Clin Gastroenterol (2013)	China	Unresectable HCC	5/1462	Sorafenib vs placebo	5	0
Shen	J Hepatol (2010)	China Taiwan	Unselected HCC	13/1180	Adjuvant interferon therapy after curative therapy	9	4
Shu	Integr Cancer Ther (2005)	USA	Unresectable HCC	26/2079	Chinese herbal medicine + chemotherapy vs chemotherapy alone	24	2
Singal	Aliment Pharmacol Ther (2010)	USA	Unselected HCC	10/645	Interferon after resection or ablation	5	5
Sun	World Chinese Journal of Digestology (2011)	China	Small HCC	11/2965	RFA vs surgical resection	2	9
Sun	PLoS One (2014)	China	Unselected HCC	13/6350	Nucleot(s)ide analogues vs placebo or no treatment after curative treatment	1	12
Sun	Afr J Tradit Complement Altern Med (2012)	China	Unresectable HCC	10/726	TACE + Compound Kushen Injection vs TACE alone	0	10
Tang	Hepato-gastroenterology (2012)	China	Unselected HCC	5/799	Hepatectomy with a margin aiming at 2 cm vs a margin aiming at 1 cm	1	4
Tang	Hepato-gastroenterology (2013)	China	Resectable HCC	12/1829	Anatomic vs nonanatomic resection	0	12
Twaij	World J Gastroenterol (2014)	United Kingdom	Unselected HCC	4/420	Laparoscopic vs open liver resection	0	4
Wang	Hepato-gastroenterology (2011)	China	Unselected HCC	3/257	Preoperative TACE vs control	3	0
Wang	PLoS One (2014)	China	Early HCC	28/11873	RFA vs surgical resection	3	25
Wang N	Med Oncol (2011)	China	Unselected HCC	7/623	TACE + PEI vs TACE alone	7	0
Wang W	Liver Int (2010)	China	Unselected HCC	10/595	TACE + percutaneous ablation therapy (RFA or PEI) vs TACE or percutaneous ablation therapy alone	10	0
Wang	Asian Pac J Cancer Prev (2013)	China	Unselected HCC	4/1382	Sorafenib with or without chemotherapy vs placebo with or without chemotherapy	4	0
Wang	Can J Gastroenterol (2012)	China	Unresectable HCC	4/210	Prophylactic antibiotic treatment vs no prophylactic antibiotic treatment after transarterial therapy	3	1
Wang	Can J Gastroenterol (2013)	China	Post-operative HCC	27/2614	Different adjuvant therapy after potentially curative treatment	27	0
Weis	Cochrane Database Syst Rev (2013)	Germany	Unselected HCC	11/NA	RFA vs surgical resection; RFA vs PEI or RFA vs acetic acid injection; RFA vs microwave ablation; RFA vs laser ablation	3; 6; 1; 1	0; 0; 0; 0
Wong	Aliment Pharmacol Ther (2011)	China	Unselected HCC	9/551	Antiviral treatment vs no anti-viral treatment	0	9
Wu	J Exp Clin Cancer Res (2009)	China	Unresectable HCC	45/3236	Traditional Chinese Medicines vs other treatment	45	0
Wu	J Cancer Res Ther (2014)	China	Unresectable HCC	9/659	TACE + Cinobufacini vs TACE only	0	9
Xie	Tumour Biol (2014)	China	Advanced HCC	5/582	TACE vs TAE	5	0
Xie	J Cancer Res Clin Oncol (2012)	China	Unresectable HCC	13/1840	TACE vs microsphere embolization	7	6
Xie	PLoS One (2012)	China	Post-operative HCC	6/494	Adoptive immunotherapy vs non-immunotherapy after surgery	6	0
Xiong	World J Gastroenterol (2012)	China	Unselected HCC	9/550	Laparoscopic vs open liver resection	0	15
Xu	Journal of Xi’an Jiaotong University (Medical Sciences) (2012)	China	Unselected HCC	9/2145	LT vs resection	0	9
Xu	Hepatobiliary Pancreat Dis Int (2014)	China	Unselected HCC	17/4238	LT vs resection	0	17
Xu	World J Surg Oncol (2012)	China	Early HCC	13/2535	RFA vs surgical resection	2	11
Xu	Eur J Med Res (2014)	China	Small HCC < 5 cm	6/983	RFA vs PEI	6	0
Xu	Hepatol Res (2014)	China	Unselected HCC	9/1565	Adjuvant interferon therapy after surgical treatment	5	4
Xue	BMC Gastroenterol (2013)	China	Advanced HCC with PVTT	8/1601	TACE vs conservative treatment	0	8
Yan	Dig Dis Sci (2012); Dig Dis Sci (2013)	China	Unselected HCC	19/1728	RFA + TACE vs RFA alone	8	11
Yang	Mol Biol Rep (2014)	China	Unresectable HCC	6/1181	TACE + sorafenib vs TACE alone	3	3
Yao	Chinese Journal of Evidence-Based Medicine (2013)	China	Unselected HCC	13/701	Laparoscopic vs open hepatectomy	0	13
Ye	Asian Pac J Cancer Prev (2012)	China	Unselected HCC	11/1576	Anatomic vs nonanatomic resection	0	11
Yin	Ann Surg Oncol (2013)	China	Unselected HCC	15/1238	Laparoscopic vs open hepatectomy	0	15
Yu	Chinese-German Journal of Clinical Oncology (2013)	China	Unselected HCC	7/1347	Preoperative TACE vs control	0	7
Zhang	PLoS One (2014)	China	Unresectable/advanced HCC	6/1254	TACE + sorafenib vs TACE alone	2	4
Zhang	Anticancer Drugs (2010)	China	Advanced HCC	3/924	Sorafenib-based therapy with other agent-based therapy	3	0
Zhang	Hepatobiliary Pancreat Dis Int (2012)	China	Advanced HCC	6/1164	Sorafenib vs placebo	3	3
Zhang	Molecular and Clinical Oncology (2014)	China	Unselected HCC	14/1385	Adjuvant interferon after curative surgery or ablation therapy	9	5
Zhang	Int J Cancer (2009)	China	Post-surgical or ablative HCC	6/600	IFN-alpha with placebo or no treatment after tumor resection or ablation	6	0
Zhao	Journal of Interventional Radiology (China) (2013)	China	Unselected HCC	21/2339	RFA + TACE vs RFA or TACE alone	21	0
Zhao	Zhonghua Wai Ke Za Zhi (2008)	China	Unselected HCC	9/494	Preoperative portal vein embolization (PVE) vs no PVE for extended hepatectomy	0	9
Zheng	Transplantation (2014)	China	Unselected HCC	62/10170	LT vs resection	0	62
Zheng	Int J Cancer (2014)	China	Unselected HCC	48/4747	Hepatectomy + adjuvant chemotherapy vs hepatectomy alone	13	35
Zhong	Hepatol Res (2010)	China	UICC TNM stage 3A HCC	6/659	Postoperative adjuvant TACE	6	0
Zhong	World Chinese Journal of Digestology (2012); PLoS One (2013)	China	Post-operative HCC	6/930	Curative treatments alone vs curative treatments + oral vitamin K2 analogs	6	0
Zhong	Molecular and Clinical Oncology (2014)	China	Post-operative HCC	3/286	Adjuvant conventional oral systemic chemotherapy after curative hepatic resection	3	0
Zhou	Dig Dis Sci (2011)	China	Unselected HCC	10/494	Laparoscopic vs open resection	0	10
Zhou	Langenbecks Arch Surg (2011)	China	Unselected HCC	16/2917	Anatomic vs nonanatomic resection	0	16
Zhou	BMC Gastroenterol (2013)	China	Unselected HCC	21/3210	Preoperative TACE vs no preoperative TACE	4	17
Zhou	Zhonghua Wai Ke Za Zhi (2011)	China	Small HCC (Milan criteria)	4/539	RFA vs surgical resection	4	0
Zhou	BMC Gastroenterol (2010)	China	Small HCC (Yao’s criteria)	10/1411	RFA vs surgical resection	1	9
Zhou	World J Surg (2014)	China	Unselected HCC	20/8204	Antiviral therapy after curative resection	1	19
Zhu	Transplant Proc (2013)	China	Unselected HCC	14/1508	Primary LT vs salvage LT	0	14
Zhuang	PLoS One (2013)	China	Unselected HCC	13/1344	Interferon after curative therapy	13	0
Zhuang	Zhonghua Gan Zang Bing Za Zhi (2012)	China	Unselected HCC	8/857	Interferon after curative therapy	8	0
Zou	Acta Academiae Medicinae Sinicae (2011)	China	Advanced HCC	2/828	Sorafenib vs placebo	2	0

Table 2: Findings of meta-analyses: An overview of included studies regarding LT

First author	Journal (Year)	Comparisons	OS	DFS, RFS, TTP, PFS	Recurrence, time to recurrence	Other endpoints	Major comments
Living donor LT (LDLT) versus deceased donor LT (DDLT)
Al Hasan	Liver Transpl (2014)	LDLT vs DDLT	OS: 1-, 3-, 5-year: statistically similar.	DFS: 1-, 3-, 5-year: statistically similar.	Recurrence: 1-, 3-year: statistically similar. 5-year: favor DDLT.	NA.	OS and DFS are comparable, but long-term recurrence is higher in LDLT.
Grant	Clin Transplant (2013)	LDLT vs DDLT	OS: statistically similar.	DFS: favor DDLT.	NA.	NA.	LDLT has lower DFS than DDLT.
Liang	Liver Transpl (2012)	LDLT vs DDLT	OS: 1-, 3-, 5-year: statistically similar.	RFS: 1-, 3-, 5-year: statistically similar.	Recurrence: statistically similar.	NA.	LDLT is an acceptable option especially for patients within Milan criteria.
Primary LT versus salvage LT
Li	World J Gastroenterol (2012)	Primary LT vs salvage LT	OS: 1-, 3-, 5-year: statistically similar.	DFS: 1-, 3-, 5-year: statistically similar.	NA.	NA.	OS and DFS were not significantly different.
Zhu	Transplant Proc (2013)	Primary LT vs salvage LT	OS: 1-, 3-, 5-year: statistically similar.	DFS: 1-, 3-year: statistically similar. 5-year: favor primary LT.	NA.	Operative time: longer in salvage LT. Intraoperative blood loss: increased in salvage LT. Number of transfused units of packed red blood cells: larger in salvage LT. Length of hospital stay and ICU stay: statistically similar. Peri-operative mortality: statistically similar.	Salvage LT achieves the same short- and long-term outcomes as primary LT.
Sirolimus-based immunosuppression (SRL) after LT
Liang	Liver Transpl (2012)	SRL after LT vs SRL-free	OS: 1-, 3-, 5-year: favor SRL.	DFS: 1-year: favor SRL.	Recurrence: 1-year: favor SRL.	Major SRL-related post-transplant complications: statistically similar.	SRL is safe and prolongs survival and decrease tumor recurrence.
Menon	Aliment Pharmacol Ther (2013)	SRL after LT vs SRL-free	Overall mortality: favor SRL.	RFS: better in SRL (no statistical comparison). Recurrence-related mortality: low in SRL.	Recurrence: favor SRL.	NA.	SRL has lower recurrence rate, lower overall mortality and longer RFS and OS.
LT versus surgical resection
Dhir	HPB (2012)	LT vs resection	OS: 5-year: early HCC: favor LT. early HCC with well compensated cirrhosis: favor LT. early HCC using ITT strategy: statistically similar. early HCC with well compensated cirrhosis using ITT strategy: favor LT.	NA.	NA.	NA.	LT has favorable survival advantage in some settings.
Hoshida	Hepatology (2000)	Surgical resection vs PEI and LT (including LT vs surgical resection)	OS: Surgical resection vs LT: 3-year: statistically similar.	DFS: Surgical resection vs LT: 3-year: favor LT.	NA.	NA.	LT improved 3-year DFS for HCC patients.
Proneth	Ann Surg Oncol (2014)	LT vs resection	OS: 5-year: statistically similar.	NA.	NA.	NA.	LR is a good alternative to LT in patients with resectable HCC in whom both seem feasible.
Rahman	J Gastrointest Surg (2012)	LT vs resection	OS: 1-year: all studies: favor resection. non-ITT analysis: statistically similar. ITT analysis: favor resection. 5-year: all studies: statistically similar. non-ITT analysis: statistically similar. ITT analysis: favor LT. 10-year: all studies: favor LT. non-ITT analysis: favor LT. ITT analysis: favor LT.	DFS: 1-year: all studies: statistically similar. non-ITT analysis: statistically similar. ITT analysis: statistically similar. 5-year survival: all studies: favor LT. non-ITT analysis: favor LT. ITT analysis: favor LT. 10-year: all studies: favor LT. non-ITT analysis: favor LT. ITT analysis: statistically similar.	NA.	NA.	LT results in increased DFS and OS.
Xu	Journal of Xi’an Jiaotong University (2012)	LT vs resection	OS: 1-year: statistically similar. 3-, 5-year survival: favor LT.	DFS: 5-year: favor LT.	Recurrence: favor LT.	NA.	Both treatments were effective. But LT has a better prognosis than resection.
Xu	Hepatobiliary Pancreat Dis Int (2014)	LT vs resection	OS: 1-, 3-year: statistically similar. 5-year survival: favor LT.	DFS: 1-, 3-, 5-year: favor LT.	NA.	Surgery-related morbidity: higher in LT. Surgery-related mortality: higher in LT.	Long-term survival and tumor-free survival are higher in LT than in resection.
Zheng	Transplantation (2014)	LT vs resection	OS: 1-year: statistically similar. 3-, 5-year: favor LT.	DFS: 1-, 3-, 5-year: favor LT.	Recurrence: favor LT.	NA.	LT provides increased survival and lower recurrence rates than resection.

Table 3: Findings of meta-analyses: An overview of included studies regarding surgical resection

Table 4: Findings of meta-analyses: An overview of included studies regarding ablation therapy

Table 5: Findings of meta-analyses: An overview of included studies regarding TACE

LT

Living donor LT (LDLT) versus deceased donor LT (DDLT)

Three meta-analyses compared the outcomes of LDLT versus DDLT [8, 41, 67]. All of them demonstrated that the OS was statistically similar between the two groups [8, 41, 67]. Two of them showed that the 1-, 3-, and 5-year DFS were statistically similar between the two groups [8, 67], but another one favored DDLT in term of DFS [41]. One of them found that the recurrence was statistically similar between the two groups [67]; by comparison, another one favored LDLT in term of 5-year recurrence, but not 1- or 3-year recurrence [8].

Only non-RCT studies, rather than RCTs, were included in the three meta-analyses.

The meta-analysis by Grant had a larger number of included studies than those by Al Hasan and Liang (16 versus 7 and 7) (Supplementary Table S9). Notably, there was an overlap of included studies between the two meta-analyses by Liang and Grant. All studies which were included in the meta-analysis by Liang were also covered by the meta-analysis by Grant. The meta-analysis by Al Hasan did not show the included studies.

Given its superiority in the quantity of non-RCT studies, the results of the meta-analysis by Grant might be more reliable. In details, LDLT has lower DFS than DDLT.

Primary versus salvage LT

Two meta-analyses compared the outcomes of primary versus salvage LT [59, 157]. Both of them demonstrated that the OS and 1- and 3-year DFS were statistically similar between the two groups [59, 157]. One of them favored primary LT in term of 5-year DFS [157]; by comparison, another one showed that the 5-year DFS was statistically similar between the two groups [59]. In addition, salvage LT had significantly longer operative time, increased intra-operative blood loss, and larger number of transfused units of packed red blood cells than primary LT [157]. But the length of hospital and ICU stay was statistically similar between the two groups [157].

Only non-RCT studies, rather than RCTs, were included in the two meta-analyses.

The meta-analysis by Zhu had a larger number of included studies than that by Li (14 versus 11) (Supplementary Table S10). Notably, there was an overlap of included studies between them. All studies which were included in the meta-analysis by Li were also included in the meta-analysis by Zhu.

Given its superiority in the quantity of non-RCT studies, the results of the meta-analysis by Zhu might be more reliable. In details, salvage LT achieves the same short- and long-term survival as primary LT. However, primary LT was significantly superior to salvage LT in terms of operative time, blood loss, and blood transfusion.

Sirolimus-based immunosuppression after LT

Two meta-analyses compared the outcomes of sirolimus-based immunosuppression versus no sirolimus after LT [66, 83]. Both of them favored the use of sirolimus after LT in terms of OS, DFS/RFS, and recurrence [66, 83].

Only non-RCT studies, rather than RCTs, were included in the two meta-analyses.

Both of them had a similar number of included studies (5 versus 5) (Supplementary Table S11). But not all included studies were the same between them.

The results were completely consistent between the two meta-analyses. In details, the use of sirolimus after LT should be favored.

LT versus surgical resection

Seven meta-analyses compared the outcomes of LT versus surgical resection [25, 46, 96, 98, 129, 131, 146]. There were 4, 4, 6, and 1 meta-analyses to compare the 1-, 3-, 5-, and 10-year survival, respectively. As for the 1-year survival, three of them demonstrated that the survival was statistically similar between the two groups [129, 131, 146], but another one favored surgical resection [98]. As for the 3-year survival, two of them found that the survival was statistically similar between the two groups [46, 131], but another two favored LT [129, 146]. As for the 5-year survival, two of them showed that the survival was statistically similar between the two groups [96, 98], but another four favored LT [25, 129, 131, 146]. As for the 10-year survival, the only one meta-analysis favored LT [98]. There were 3, 3, 4, and 1 meta-analyses to compare the 1-, 3-, 5-, and 10-year DFS, respectively. As for the 1-year DFS, two of them favored LT [131, 146], but another one found that the 1-year DFS was statistically similar between the two groups [98]. As for the 3-year DFS, all of them favored LT [46, 131, 146]. As for the 5-year DFS, all of them favored LT [98, 129, 131, 146]. As for the 10-year DFS, the only one meta-analysis favored LT [98]. Two meta-analyses compared the recurrence. Both of them favored LT in term of recurrence [129, 146].

Only non-RCT studies, rather than RCTs, were included in these meta-analyses.

The meta-analysis by Zhang had the largest number of included studies (n = 62) (Supplementary Table S12). By comparison, the number of included studies was less than 20 in 6 other meta-analyses.

Given its superiority in the quantity of non-RCT studies, the results of the meta-analysis by Zhang might be more reliable. In details, LT provides a significantly better survival and a lower recurrence.

Surgical resection

Surgical resection margin 1 cm versus 2 cm

Only one meta-analysis compared the outcomes of hepatectomy with a margin aiming at 2 cm versus those with a margin aiming at 1 cm [109]. Regardless of study design, the 1-year survival was statistically similar between the two groups [109]. In the subgroup analysis of randomized studies, the 3- and 5-year survival and DFS were better in patients undergoing hepatectomy with a margin aiming at 2 cm than in those with a margin aiming at 1 cm [109]. Contrarily, in the subgroup analysis of non-randomized studies, the 3- and 5-year survival and DFS were statistically similar between the two groups [109].

One RCT and 4 non-RCT studies were included in this meta-analysis.

Laparoscopic versus open resection

Nine meta-analyses compared the outcomes of laparoscopic versus open resection [30, 62, 94–95, 111, 126, 135, 137, 156]. All of them demonstrated that the OS and DFS/RFS at any time points were statistically similar between the two groups [30, 62, 94–95, 111, 126, 135, 137, 156]. Two of them also found that the recurrence was statistically similar between the two groups [62, 126]. Eight of them demonstrated statistically similar operative time between the two groups [30, 62, 95, 111, 126, 135, 137, 156], but one demonstrated significantly longer operative time in laparoscopic resection group [94]. All of them demonstrated that blood loss or intraoperative bleeding was significantly less in laparoscopic resection group [30, 62, 94–95, 111, 126, 135, 137, 156]. Among the 7 meta-analyses evaluating the blood transfusion, 6 demonstrated significantly less blood transfusion in laparoscopic resection group [30, 62, 111, 126, 137, 156], and one demonstrated statistically similar blood transfusion between the two groups [94]. Among the 6 meta-analyses evaluating the overall complications, 5 demonstrated significantly less complications in laparoscopic resection group [30, 62, 94, 111, 135], and one demonstrated statistically similar complications between the two groups [126]. Among the 8 meta-analyses evaluating the hospital length, all demonstrated significantly shorter hospital study in laparoscopic resection group [30, 62, 94, 111, 126, 135, 137, 156].

Only non-RCT studies, rather than RCTs, were included in these meta-analyses.

The meta-analyses by Park, Xiong, and Yin had the largest number of included studies (n = 15) followed by the meta-analyses by Yao (n = 13), Zhou (n = 10), Li (n = 10), Fancellu (n = 9), Pang (n = 7), and Twaij (n = 4) (Supplementary Table S13). The included studies were completely same between the two meta-analyses by Xiong and Yin. However, the studies included in the meta-analysis by Park were different from those included in the meta-analyses by Xiong and Yin.

Given its superiority in the quantity of non-RCT studies, the results of the meta-analyses by Park, Xiong, and Yin might be more reliable. In details, they suggested that the operative time was statistically similar between the two groups and that laparoscopic resection was superior to open resection in terms of blood loss, blood transfusion, complications, and hospital stay.

Anatomic resection versus non-anatomic resection

Six meta-analyses compared the outcomes of anatomic versus non-anatomic resection [15, 23, 60, 110, 136, 152]. Four of them demonstrated that the OS was statistically similar between the two groups [15, 60, 110, 136], but another two favored anatomic resection in term of 5-year survival [23, 152]. One of them found that the DFS was statistically similar between the two groups [60], but another four favored anatomic resection in term of DFS [15, 23, 136, 152]. Two of them showed that the recurrence was statistically similar between the two groups [15, 110], but another two favored anatomic resection in term of local intrahepatic recurrence [136, 152]. Post-operative complications were statistically similar between the two groups [23, 110, 136, 152].

Only non-RCT studies, rather than RCTs, were included in these meta-analyses.

The meta-analysis by Cucchetti had the largest number of included studies (n = 18) followed by the meta-analyses by Zhou (n = 16), Tang (n = 12), Ye (n = 11), Chen (n = 9), and Li (n = 4) (Supplementary Table S14).

Given its superiority in the quantity of non-RCT studies, the results of the meta-analysis by Zhang might be more reliable. In details, anatomic resection was superior to non-anatomic resection in terms of OS and DFS.

Surgical resection + I¹³¹ lipiodol versus surgical resection alone

Two meta-analyses compared the outcomes of surgical resection in combination with I¹³¹ lipiodol versus surgical resection alone [36, 40]. Both of them favored the combination therapy in terms of OS, DFS, and recurrence [36, 40].

Only non-RCT studies, rather than RCTs, were included in these meta-analyses.

The meta-analysis by Gong had a larger number of included studies than that by Furtado (10 versus 5) (Supplementary Table S15). Notably, there was an overlap of included studies between them. All studies which were included in the meta-analysis by Furtado were also included in the meta-analysis by Gong.

The results were completely consistent between the two meta-analyses. In details, surgical resection in combination with I¹³¹ lipiodol should be favored.

Surgical resection + TACE versus surgical resection alone

Pre-operative TACE

Four meta-analyses compared the outcomes of surgical resection in combination with pre-operative TACE versus surgical resection alone [17, 116, 138, 153]. All of them found that the OS, DFS, and recurrence were statistically similar between the two groups [17, 116, 138, 153].

RCT studies were included in the meta-analyses by Cheng (n = 4), Wang (n = 3), and Zhou (n = 4), but not in the meta-analysis by Yu (n = 0).

The meta-analysis by Zhou had the largest number of included studies (n = 21) followed by the meta-analyses by Yu (n = 7), Cheng (n = 4), and Wang (n = 3) (Supplementary Table S16). All studies which were included in the two meta-analyses by Cheng and Wang were also included in the meta-analysis by Zhou.

The results were completely consistent between the two meta-analyses. In details, pre-operative TACE did not improve the OS or DFS.

Post-operative TACE

Two meta-analyses compared the outcomes of surgical resection in combination with post-operative TACE versus surgical resection alone [17, 149]. Both of them favored post-operative TACE in terms of OS, DFS, and recurrence [17, 149].

Only RCT studies were included in the two meta-analyses.

Although the number of included studies was the same between the two meta-analysis by Cheng and Zhong (n = 6) (Supplementary Table S17), not all included studies were the same between them.

The results were completely consistent between the two meta-analyses. In details, post-operative TACE should be favored.

Surgical resection + adjuvant chemotherapy versus surgical resection alone

Five meta-analyses compared the outcomes of surgical resection in combination with adjuvant chemotherapy versus surgical resection alone [78, 92, 112, 147–148].

Oral systemic chemotherapy

Oral systemic chemotherapy was evaluated in two meta-analyses [78, 148]. The OS, RFS, and recurrence were statistically similar between patients with and without chemotherapy [78, 148].

RCT studies were included in the meta-analyses by Zhong (n = 3) and Mathurin (n = 1).

The meta-analysis by Zhong had a larger number of included studies than that by Mathurin (3 versus 2) (Supplementary Table S18). Not all included studies were the same between them.

The results were completely consistent between the two meta-analyses. In details, the adjunctive use of oral systemic chemotherapy should not be favored in patients undergoing surgical resection.

Transarterial chemotherapy

Transarterial chemotherapy was evaluated in one meta-analysis [78]. As for the pre-operative transarterial chemotherapy, the overall analysis of both RCTs and non-RCTs demonstrated that chemotherapy improved the 2-year survival, but not the 1- or 3-year survival. The subgroup analysis of RCTs showed that the 1-, 2-, and 3-year recurrence were statistically similar between the two groups. As for the post-operative transarterial chemotherapy, the overall analysis of both RCTs and non-RCTs demonstrated that chemotherapy improved the 1-, 2-, and 3-year survival. The subgroup analysis of RCTs showed that chemotherapy improved the 2- and 3-year survival, but not the 1-year survival.

Approaches of chemotherapy were mixed in three meta-analyses [92, 112, 147]. The statistical results were largely inconsistent among them. One of them favored the chemotherapy in term of OS [147]; one showed that the OS was statistically similar between the two groups [112]; one demonstrated that the OS was decreased by chemotherapy [92].

RCT studies were included in the meta-analyses by Zheng (n = 13), Wang (n = 8), and Ono (n = 3).

The meta-analysis by Zheng had a larger number of included studies than those by Wang and Ono (48 versus 8 and 3) (Supplementary Table S19).

Given its superiority in the quantity of RCT studies, the results of the meta-analysis by Zheng might be more reliable.

Surgical resection + immunotherapy versus surgical resection alone

Four meta-analyses compared the outcomes of surgical resection in combination with immunotherapy versus surgical resection alone [32, 75, 112, 124]. All of them demonstrated that the OS was statistically similar between the two groups [32, 75, 112, 124]. One of them favored the combination therapy in term of RFS. One of them favored the combination therapy in terms of 1- and 3-year recurrence [124]; one favored the combination therapy in term of 1-year recurrence, but not 3-year recurrence [75]; one showed that the recurrence was statistically similar between the two groups [32].

Only RCT studies were included in the meta-analyses by Xie (n = 6), Ma (n = 4), Wang (n = 3), and Flores (n = 2).

The meta-analysis by Xie had the largest number of included studies followed by those by Ma, Wang, and Flores (6 versus 4, 3, and 2) (Supplementary Table S20). Notably, there was an overlap of included studies among them.

Given its superiority in the quantity of RCT studies, the results of the meta-analysis by Xie might be more reliable. In details, the adjunctive use of immunotherapy might not be favored in patients undergoing surgical resection.

Surgical resection + PVE versus surgical resection alone

One meta-analysis compared the outcomes of surgical resection in combination with PVE versus surgical resection alone [145]. The 1-, 3-, and 5-year survival and intrahepatic and distant recurrence were statistically similar between the two groups [145].

Only non-RCT studies were included in the meta-analysis by Zhao.

Ablation therapy

RFA versus surgical resection

Eighteen meta-analyses compared the outcomes of RFA versus surgical resection [11, 16, 24, 27, 31, 33, 47, 61, 69, 72, 89, 97, 106, 117, 119, 127, 151, 153]. As for the OS, seven of them favored surgical resection [27, 31, 47, 61, 97, 106, 127]; four demonstrated that the OS was statistically similar between the two groups [11, 16, 119, 151]; four showed that the 1-year survival was statistically similar between the two groups, but the 5-year survival was better in surgical resection group [33, 72, 89, 117]; one found that the 1- and 5-year survival were statistically similar between the two groups, but the 3-year survival was better in surgical resection group [155]; one reported that surgical resection had better OS than RFA in the subgroup analyses of a single nodule 3–5 cm and ≤ 3 cm, but the OS was statistically similar between the two groups in the subgroup analyses of a single nodule < 2 cm and 2–3 nodules < 3 cm [24].

As for the DFS, nine of them favored surgical resection in terms of DFS/RFS at any time points [11, 27, 31, 61, 72, 89, 97, 106, 155]; three showed that the 1-year DFS was statistically similar between the two groups, but the 3- and/or 5-year DFS were better in surgical resection group than in RFA group [16, 33, 151]; one reported that surgical resection had better DFS than RFA in the subgroup analyses of a single nodule 3–5 cm and ≤ 3 cm, but the DFS was statistically similar between the two groups in the subgroup analyses of a single nodule < 2 cm and 2–3 nodules < 3 cm [24].

As for the recurrence, three of them favored surgical resection [11, 47, 61]; two favored RFA [127, 151]; one found that the recurrence was statistically similar between the two groups [24]; three showed that the 1-year recurrence was statistically similar between the two groups, but the 3-year recurrence was less in surgical resection group than in RFA group [31, 33, 117]; one reported that the 1- and 3-year recurrence were statistically similar between the two groups, but the recurrence at the end of follow-up was less in RFA group than in surgical resection group [69]; one demonstrated that the distant intrahepatic recurrence was statistically similar between the two groups, but the local intrahepatic recurrence was less in surgical resection group than in RFA group [153]; one favored surgical resection in term of recurrence at previous sites, but favored RFA in term of recurrence at new sites [72].

According to the description of each meta-analysis, RCT studies were included the meta-analyses by Liu (Surg Laparosc Endosc Percutan Tech, 2010) (n = 8), Ni (n = 6), Fu (n = 5), Zhou (Zhonghua Wai Ke Za Zhi, 2011) (n = 4), Hu (n = 4), Feng (n = 3), Qi (n = 3), Wang (n = 3), Weis (n = 3), Duan (n = 2), Li (n = 2), Sun (n = 2), Xu (n = 2), Chen (n = 1), and Zhou (BMC Gastroenterol, 2010) (n = 1). The information regarding the inclusion of RCT studies was not available in the meta-analyses by Cai and Cucchetti. After checking the relevant information, we confirmed the following: 1) in the meta-analysis by Liu (Surg Laparosc Endosc Percutan Tech, 2010), all included studies were non-RCTs; 2) in the meta-analysis by Ni, there were one RCT regarding resection v.s. PEI, one RCT regarding resection v.s. PEI or microwave ablation, and two RCTs with overlapped data; 3) in the meta-analysis by Fu, there were one RCT regarding comparison of resection v.s. PEI or microwave ablation and two RCTs with overlapped data; 4) in the meta-analysis by Zhou (Zhonghua Wai Ke Za Zhi, 2011), one included study was non-RCT; and 5) because no included studies were listed in the meta-analysis by Hu, we could not check the accuracy. Thus, the largest number of RCT studies included in the meta-analyses should be 3.

The meta-analysis by Wang had the largest number of included studies (n = 28) followed by the meta-analyses by Feng (n = 23), Hu (n = 18), Cucchetti (n = 17), Xu (n = 13), Duan (n = 12), Sun (n = 11), Zhou (BMC Gastroenterol, 2010) (n = 10), Ni (n = 10), Liu (World J Gastroenterol, 2010) (n = 10), Liu (Surg Laparosc Endosc Percutan Tech, 2010) (n = 8), Li (n = 6), Chen (n = 6), Fu (n = 5), Cai (n = 5), Zhou (Zhonghua Wai Ke Za Zhi, 2011) (n = 4), Weis (n = 3), and Qi (n = 3) (Supplementary Table S21).

Given the superiority in the quantity of RCT studies, the meta-analyses by Feng, Qi, Wang, and Weis might be more reliable. In details, surgical resection should be superior to RFA for the improvement of OS.

PEI versus surgical resection

Two meta-analyses compared the outcomes of PEI versus surgical resection [46, 100]. Both of them demonstrated that OS and RFS were statistically similar between the two groups [46, 100].

Only one RCT study was included in the meta-analysis by Schoppmeyer.

The meta-analysis by Hoshida had a larger number of included studies than that by Schoppmeyer (5 versus 1) (Supplementary Table S22). However, no included studies were overlapped between them.

The results were completely consistent between the two meta-analyses. In details, PEI was similar to surgical resection in terms of OS and RFS.

Non-surgical-resection ablation versus surgical resection

One meta-analysis compared the outcomes of non-surgical-resection ablation versus surgical resection [26]. The 1- and 3-year survival and DFS were statistically similar between the two groups [26].

RFA versus PEI or PAI

Eight meta-analyses compared the outcomes of RFA versus PEI or PAI [9, 20, 26, 38, 93, 102, 119, 130]. All of them favored RFA over PEI in terms of OS, DFS, and/or recurrence [9, 20, 26, 38, 93, 102, 119, 130]. Additionally, one of them found that the OS, local recurrence, de novo tumor, and adverse event were statistically similar between RFA and PAI groups [38].

RCT studies were included in the meta-analyses by Bouza (n = 6), Weis (n = 6), Xu (n = 6), Dong (n = 5), Germani (n = 5), Orlando (n = 5), Cho (n = 4), and Shen (n = 4).

The meta-analyses by Bouza, Weis, and Xu had the largest number of included studies (n = 6) followed by the meta-analyses by Dong (n = 5), Germani (n = 5), Orlando (n = 5), Shen (n = 5), and Cho (n = 4) (Supplementary Table S23).

The results regarding the comparison between RFA v.s. PEI were completely consistent among meta-analyses. In details, RFA should be superior to PEI for the improvement of OS and DFS.

RFA versus cryosurgery ablation

One meta-analysis compared the outcomes of RFA versus cryosurgery ablation [51]. Although the OS was statistically similar between the two groups, RFA had less recurrence and complications than cryosurgery ablation [51].

RFA versus other therapeutic methods

One meta-analysis compared the outcomes of RFA versus any other therapeutic methods [50]. RFA was superior to other treatment methods for early HCC in terms of local recurrence and 3-year survival [50]. However, no subgroup analysis was performed according to the different treatment modalities.

Additionally, one meta-analysis compared the outcomes of RFA versus microwave or laser ablation [119]. However, only one trial was identified for each comparison.

PEI versus PAI

Two meta-analyses compared the outcomes of PEI versus PAI [38, 100]. Both of them showed that the OS, RFS, and recurrence were statistically similar between the two groups [38, 100].

RCT studies were included in the meta-analyses by Germani (n = 2) and Schoppmeyer (n = 2).

Both of them had a similar number of included studies (n = 2) (Supplementary Table S24). However, not all of the included studies were identical.

The results were completely consistent between the two meta-analyses. In details, PEI was similar to PAI in terms of OS and RFS.

RFA + TACE versus mono-therapy

Eleven meta-analyses compared the outcomes of RFA in combination with TACE versus RFA or TACE alone [26, 45, 53, 55, 68, 71, 74, 87–88, 133, 144]. Seven of them favored the combination therapy in term of OS [45, 53, 55, 71, 88, 133, 144]; two favored the combination therapy in terms of 1- and 3-year survival, but not 5-year survival [74, 87]; one favored the combination therapy in term of 5-year survival, but not 1- or 3-year survival [26]; one found that the 1-year survival was statistically similar between the two groups [68].

Three meta-analyses compared the RFS of RFA in combination with TACE versus RFA or TACE alone [71, 87–88]. As for the 1-year RFS, one meta-analysis favored the combination therapy [71], but another two showed that the 1-year RFS was statistically similar between the two groups [87–88]. By comparison, all of them favored the combination therapy in term of 3-year RFS [71, 87–88].

RCT studies were included in the meta-analyses by Zhao (n = 21), Jiang (n = 8), Kong (n = 8), Ni (World J Gastroenterol, 2013) (n = 8), Yan (n = 8), Liu (n = 7), Lu (n = 7), Ni (J Cancer Res Clin Oncol, 2013) (n = 6), and Liao (n = 1), but not in the meta-analyses by Dong and Han.

The meta-analysis by Zhao had the largest number of included studies (n = 21), followed by those by Jiang (n = 19), Kong (n = 19), Yan (n = 19), Yan (n = 18), Han (n = 8), Ni (World J Gastroenterol, 2013) (n = 8), Liu (n = 7), Lu (n = 7), Ni (J Cancer Res Clin Oncol, 2013) (n = 6), Dong (n = 5), and Liao (n = 1) (Supplementary Table S25). Notably, all of the 19 included studies were completely identical among the three meta-analyses by Jiang, Kong, and Yan.

Given the superiority in the number of RCTs, the meta-analyses by Zhao, Jiang, Kong, Ni, and Yan should be more reliable. In details, RFA in combination with TACE should be favored in term of OS.

PEI + TACE versus mono-therapy

Three meta-analyses compared the outcomes of PEI in combination with TACE versus PEI or TACE alone [68, 114–115]. Two of them favored the combination therapy in term of OS [114–115]. Another one meta-analysis was performed according to the study design. In the subgroup analysis of RCTs, the combination therapy significantly improved the 3-year survival, rather than 1-year survival. By contrast, in the subgroup analysis of observational studies, the combination therapy significantly improved the 1-year survival, rather than 3-year survival [68].

RCT studies were included in all of the 3 meta-analyses by Wang N (Med Oncol, 2011) (n = 7), Wang W (Liver Int, 2010) (n = 6), and Liao (PLoS One, 2013) (n = 4).

The meta-analysis by Wang N (Med Oncol, 2011) had a larger number of included studies than those by Wang W (Liver Int, 2010) and Liao (7 versus 6 and 4) (Supplementary Table S26). However, not all studies included by Wang W and Liao were included by Wang N.

Given the superiority in the number of RCTs, the meta-analysis by Wang N (Med Oncol, 2011) might be more reliable. In details, PEI in combination with TACE should be favored in term of OS.

Any ablation therapy + TACE versus mono-therapy

Two meta-analyses compared the outcomes of unclassified ablation therapies in combination with TACE versus mono-therapy [42, 115]. Both of them favored the combination therapy in terms of OS, recurrence, and tumor response [42, 115].

RCT studies were included in the meta-analyses by Wang (n = 10) and Gu (n = 7).

The meta-analysis by Gu had a larger number of included studies than that by Wang (18 versus 10) (Supplementary Table S27). However, not all studies included by Wang were included by Gu.

The results were completely consistent between the two meta-analyses. In details, TACE in combination with ablation therapy was favored.

TACE

TACE/TAE versus no active treatment

Seven meta-analyses compared the outcomes of TACE/TAE versus no active treatment or supportive care [12, 39, 57, 73, 77, 91, 132]. Two of them showed that the OS was statistically similar between the two groups [39, 91]; another five favored TACE/TAE in term of OS [12, 57, 73, 77, 132].

RCT studies were included in the meta-analyses by Marelli (n = 9), Oliveri (n = 8), Llovet (n = 7), Camma (n = 5), Geschwind (n = 4), and Leng (n = 2), but not in the meta-analysis by Xue.

The meta-analysis by Marelli had the largest number of included studies (n = 9) followed by those by Oliveri (n = 8), Xue (n = 8), Llovet (n = 7), Camma (n = 5), Geschwind (n = 4), and Leng (n = 3) (Supplementary Table S28). However, not all included studies were completely overlapped among them.

Given the superiority in the number of RCTs, the meta-analysis by Marelli might be more reliable. In details, TACE/TAE should be favored.

TACE versus TAE

Three meta-analyses compared the outcomes of TACE versus TAE [12, 77, 125]. All of them showed that the OS was statistically similar between the two groups [12, 77, 125].

Only RCT studies were included in the meta-analyses by Xie (n = 5), Marelli (n = 3), and Camma (n = 2).

The meta-analysis by Xie had a larger number of included studies than those by Marelli and Camma (5 versus 3 and 2) (Supplementary Table S29). However, not all included studies were completely overlapped among them.

The results were completely consistent among them. In details, TACE was similar to TAE in term of OS.

Drug-eluting bead (DEB)-TACE versus conventional TACE (cTACE)

Three meta-analyses compared the outcomes of DEB-TACE versus cTACE [37, 44, 48]. One of them evaluated the OS [48]. DEB-TACE was significantly better than cTACE in terms of 1- and 2-year survival. But the 6-month and 3-year survival were statistically similar between the two groups.

Two of them demonstrated that tumor response or disease control rate was statistically similar between them. Another one meta-analysis demonstrated that tumor response rate was significantly higher in DEB-TACE group than in cTACE group.

Two of them evaluated the complications [37, 44]. The incidence of complications was statistically similar between the two groups.

RCT studies were included in the meta-analyses by Han (n = 3) and Huang (n = 2), but not in the meta-analysis by Gao.

The meta-analysis by Huang had a larger number of included studies than those by Han and Gao (7 versus 5 and 2) (Supplementary Table S30). However, not all included studies were completely overlapped among them.

Given the superiority in the number of RCTs, the meta-analysis by Han might be more reliable. In details, DEB-TACE was similar to cTACE in the term of tumor response.

TACE versus microsphere embolization

One meta-analysis compared the outcomes of TACE versus microsphere embolization [123]. Microsphere embolization was superior to TACE in terms of OS, TTP, and tumor response [123]. In the subgroup analyses, the benefit was statistically significant in patients undergoing ³²P glass microspheres, but not in those undergoing ⁹⁰Y microspheres.

RCT studies were included in the meta-analysis by Xie (n = 7).

TACE + sorafenib versus TACE

Four meta-analyses compared the outcomes of TACE in combination with sorafenib versus TACE alone [35, 70, 134, 140]. Three of them favored the combination therapy in term of OS [35, 134, 140], but another one found that the OS was statistically similar between the two groups [70]. The survival benefit of the combination therapy was statistically significant in the subgroup analysis of retrospective studies, but not in that of RCTs [134].

RCT studies were included in the meta-analyses by Liu (n = 3), Yang (n = 3), and Zhang (n = 2), but not in the meta-analysis by Fu.

The meta-analysis by Fu had the largest number of included studies (n = 9), followed by those by Liu (n = 7), Yang (n = 6), and Zhang (n = 6) (Supplementary Table S31). However, not all included studies were completely overlapped among the 4 meta-analyses.

Given the superiority in the number of RCTs, the meta-analysis by Liu and Yang might be more reliable. In details, TACE plus sorafenib was not favored in term of OS.

TACE + high-intensity focused ultrasound (HIFU) versus TACE

Two meta-analyses compared the outcomes of TACE in combination with HIFU versus TACE alone [13, 68]. One of them demonstrated that both OS and tumor response were improved by the combination therapy [13]. Another one meta-analysis was performed according to the study design [68]. In the subgroup analysis of observational studies, both 1- and 3-year survival were significantly improved by the combination therapy [68]. By comparison, in the subgroup analysis of RCTs, only 1-year survival, rather than 3-year survival, was significantly improved by the combination therapy [68].

RCT study was included in the meta-analysis by Liao (n = 1), but not in the meta-analysis by Cao.

The meta-analysis by Cao had a larger number of included studies than that by Liao (9 versus 5) (Supplementary Table S32). All studies which were included in the meta-analysis by Liao were also included in the meta-analysis by Cao.

Given the superiority in the number of RCTs, the meta-analysis by Liao might be more reliable. In details, TACE plus HIFU should be favored in term of 1-year survival, but not 3-year survival.

TACE + thermotherapy versus TACE

Only one meta-analysis compared the outcomes of TACE in combination with thermotherapy versus TACE alone [64]. Both 1- and 2-year survival were significantly improved by the combination therapy, but the 0.5-, 1.5-, and 3-year survival were statistically similar between the two groups [64]. Additionally, the overall effective rate and quality of life were improved by the combination therapy [64].

TACE + AHCS versus TACE or AHCS

Only one meta-analysis compared the outcomes of TACE in combination with AHCS versus TACE or AHCS alone [65]. Compared with TACE alone, the combination therapy had significantly better 0.5-, 1-, 1.5-, 2-, and 2.5-year survival, but the 3-year survival was statistically similar between the two groups [65]. Compared with AHCS alone, the combination therapy had significantly better 0.5-, 1.5-, 2-, and 2.5-year survival, but similar 1- and 3-year survival [65]. Additionally, the combination therapy was superior to the mono-therapy in terms of total effective rate, complete necrosis rate, recurrence, AFP reduction, and CD4 improvement.

TACE + radiotherapy versus TACE alone

Two meta-analyses compared the outcomes of TACE in combination with radiotherapy versus TACE alone [68, 80]. Both of them demonstrated that the combination therapy had significantly better 1-, 2-, 3-, and 5-year survival than TACE alone [68, 80]. Additionally, one of them showed that the combination therapy significantly increased the tumor response, but did not influence the development of adverse events, such as nausea/vomit, leukocyte count declined, alanine aminotransferase level increased, and total bilirubin level increased [80].

RCT studies were included in the meta-analyses by Meng (n = 5) and Liao (n = 3).

The meta-analysis by Meng had a larger number of included studies than that by Liao (17 versus 7) (Supplementary Table S33). All studies which were included in the meta-analysis by Liao were also included in the meta-analysis by Meng.

The results regarding the OS were completely consistent among them. In details, TACE plus radiotherapy should be favored in term of OS.

TACE + 3D-CRT versus TACE alone

Only one meta-analysis compared the outcomes of TACE in combination with 3D-CRT versus TACE alone [68]. Regardless of study design, the combination therapy was superior to TACE alone in terms of 1- and 3-year survival [68].

Only one RCT study was included in the meta-analysis by Liao.

TACE + TCMs versus TACE alone

Six meta-analyses compared the outcomes of TACE in combination with TCMs versus TACE alone [18–19, 79, 81, 108, 122]. Three of them favored the combination therapy in term of OS [18, 79, 108]; one favored the combination therapy in terms of 1-, 2-, and 3-year survival, but not 6-month survival [19]; one favored the combination therapy in term of 2-year survival, but not 1-year survival [122]; one did not report the survival data [81].

Five of them favored the combination therapy in term of tumor response [18–19, 79, 81, 122]. Another one did not report the relevant data [108].

Four of them favored the combination therapy in term of quality of life [18–19, 79, 108]. Another two did not report the relevant data [81, 122].

RCT studies were included in the meta-analyses by Cheung (n = 67), Cho (n = 30), and Meng (Explore (NY), 2011) (n = 11), but not in the meta-analyses by Sun and Wu. The information regarding the inclusion of RCTs was not reported in the meta-analysis by Meng (J Altern Complement Med, 2008).

The meta-analysis by Cheung had the largest number of included studies (n = 67), followed by those by Meng (n = 37), Cho (n = 30), Meng (n = 12), Sun (n = 10), and Wu (n = 9) (Supplementary Table S34). However, not all included studies were completely overlapped among the 6 meta-analyses.

Given the superiority in the number of RCTs, the meta-analysis by Cheung might be more reliable. In details, TACE plus TCMs should be favored in terms of OS, tumor response, and quality of life.

TACE + CIK cell therapy versus TACE alone

Two meta-analyses compared the outcomes of TACE in combination with CIK cell therapy versus TACE alone [14, 63]. The combination therapy was beneficial in terms of OS, RFS, TTP, quality of life, and liver and immune function [14, 63]. Additionally, one of them evaluated whether or not adjunctive CIK cell therapy could improve the outcomes of TACE in combination with RFA [63]. Adjunctive CIK cell therapy was beneficial in terms of OS and RFS [63].

RCT studies were included in the meta-analyses by Chen (n = 9) and Li (n = 6).

The meta-analysis by Li had a larger number of included studies than that by Chen (11 versus 9) (Supplementary Table S35). However, not all included studies were completely overlapped between them.

The results regarding the OS were completely consistent among them. In details, TACE in combination with CIK cell therapy should be favored.

Sorafenib

Seven meta-analyses compared the outcomes of sorafenib versus placebo (Supplementary Table S1) [22, 28, 101, 118, 141, 143, 160]. The use of sorafenib was beneficial in terms of OS, TTP, and disease control rate [22, 101, 118, 141, 143, 160]. However, the time to symptomatic progression was statistically similar between the two groups [22, 118, 160]. The incidence of adverse events was significantly increased by the use of sorafenib [28, 101, 118, 141, 143, 160].

RCT studies were included in the meta-analyses by Shen (n = 5), Duffy (n = 4), Wang (n = 4), Zhang T (Anticancer Drugs, 2010) (n = 3), Zhang X (Hepatobiliary Pancreat Dis Int, 2012) (n = 3), Cinco (n = 2), and Zou (n = 2).

The meta-analysis by Shen had a larger number of included studies than those by Wang, Duffy, Zhang T (Anticancer Drugs, 2010), Zhang X (Hepatobiliary Pancreat Dis Int, 2012), Zou, and Cinco (5 versus 4, 4, 3, 3, 2, and 2) (Supplementary Table S36). All studies which were included in the meta-analysis by Wang, Duffy, Zhang T (Anticancer Drugs, 2010), Zhang X (Hepatobiliary Pancreat Dis Int, 2012), and Zou were also included by Shen. In the meta-analysis by Cinco, the included studies were not reported.

The results were completely consistent among them. In details, sorafenib should be favored.

Antiviral therapy

Nineteen meta-analyses compared the outcomes of antiviral therapy versus no antiviral therapy (Supplementary Table S2) [10, 49, 54, 56, 58, 84–86, 103, 105, 107, 112, 120, 128, 139, 142, 154, 158–159]. Thirteen of them favored the use of antiviral therapy in term of OS [10, 49, 54, 84, 86, 105, 107, 112, 120, 128, 139, 142, 154]; one found that the use of antiviral therapy significantly improved the 5-year survival in HCV patients, but not HBV patients [58]; one demonstrated that the 1-year survival was statistically similar between the two groups [56]; one showed that 1-, 2-, 3-, 4-, and 5-year survival were statistically similar between the two groups [159]; another three did not report the survival data [85, 103, 158].

Five meta-analyses evaluated the DFS/RFS [49, 56, 103, 112, 154]. Four of them favored the use of antiviral therapy in term of DFS/RFS [56, 103, 112, 154]. Another one meta-analysis was performed according to the study design and type of viral hepatitis. In the subgroup analysis of RCTs, the DFS/RFS was statistically similar between the two groups regardless of HCV or HBV [49]. In the subgroup analysis of non-RCTs, antiviral therapy improved the DFS/RFS by in HCV patients, but not HBV patients [49].

Fifteen meta-analyses evaluated the recurrence [10, 54, 56, 58, 84–85, 105, 107, 120, 128, 139, 142, 154, 158–159]. Ten of them favored the use of antiviral therapy in term of recurrence [10, 56, 84–85, 105, 107, 120, 139, 154, 158]; one favored the use of antiviral therapy after TACE, but not surgical resection [54]; two favored the use of antiviral therapy in HCV patients, but not HBV patients [58, 128]; one favored the use of antiviral therapy in terms of 1-, 3-, and 4-year recurrence, but not 2- or 5-year recurrence [159]; one favored the use of antiviral therapy in terms of 1- and 2-year recurrence, but not late recurrence (> 2 year) [142].

RCT studies were included in the meta-analyses by Zhuang (PLoS One, 2013) (n = 13), Huang (n = 10), Shen (n = 9), Wang (n = 9), Zhang (Mol Clin Oncol, 2014) (n = 9), Jiang (n = 8), Li (n = 8), Zhuang (Zhonghua Gan Zang Bing Za Zhi, 2012) (n = 8), Breitenstein (n = 7), Zhang (Int J Cancer, 2009) (n = 6), Miao (n = 5), Singal (n = 5), Xu (n = 5), Moriguchi (n = 4), Miyake (n = 3), Sun (n = 1), and Zhou (n = 1), rather than those by Lan and Wong.

The meta-analysis by Huang had a larger number of included studies than those by Zhang, Zhou, Miao, Shen, Sun, Zhuang (PLoS One, 2013), Jiang, Lan, Miyake, Singal, Wang, Wong, Xu, Li, Zhang, Zhuang (Zhonghua Gan Zang Bing Za Zhi, 2012), Breitenstein, and Moriguchi (23 versus 19, 14, 13, 13, 13, 13, 10, 10, 10, 10, 9, 9, 9, 8, 8, 8, 7, and 4) (Supplementary Table S37). In the meta-analysis by Moriguchi, the included studies were not reported. However, not all included studies were completely overlapped between them.

Given the superiority in the number of RCTs, the meta-analysis by Zhuang (PLoS One, 2013) and Huang might be more reliable. In details, interferon therapy after curative treatment should be favored.

Vitamin

Five meta-analyses compared the outcomes of vitamin versus placebo (Supplementary Table S3) [21, 82, 99, 112, 150]. Two of them favored the use of vitamin in term of OS [112, 150]; two favored the use of vitamin in term of 2-year survival, but not 3-year survival [21, 82]; one showed that the 1- and 2-year survival were statistically similar between the two groups [99].

One meta-analysis favored the use of vitamin in term of RFS [112].

Two meta-analyses favored the use of vitamin in term of 1-year recurrence, but another two did not [21, 82]. Four meta-analyses favored the use of vitamin in terms of 2- and 3-year recurrence [21, 82].

RCT studies were included in the meta-analyses by Wang (n = 6), Zhong (n = 6), Chu (n = 5), Riaz (n = 5), and Meng (n = 4).

The meta-analysis by Zhong had a larger number of included studies than those by Chu, Wang, Riaz, and Meng (7 versus 6, 6, 5, and 4) (Supplementary Table S38). In the meta-analysis by Meng, the included studies were not reported. However, not all included studies were completely overlapped between them.

Given the superiority in the number of RCTs, the meta-analyses by Wang and Zhong should be more reliable. In details, the use of vitamin should be favored in term of OS. However, its benefit was weak.

Octreotide

Three meta-analyses compared the outcomes of octreotide versus placebo (Supplementary Table S4) [29, 43, 52]. As for the 6- and 12-month survival, one of them favored the use of octreotide [52], but another two did not show any significant difference between the two groups [29, 43]. As for the 24-month survival, two of them showed that the survival was statistically similar between the two groups [29, 43], but another one did not report the relevant data [52].

RCT studies were included in the meta-analyses by Ji (n = 9) and Guo (n = 6).

The meta-analysis by Ji had a larger number of included studies than those by Guo and Estanislao (11 versus 6 and 3) (Supplementary Table S39). In the meta-analysis by Estanislao, the included studies were not reported. All studies which were included in the meta-analysis by Guo were also included by Ji.

Given the superiority in the number of RCTs, the meta-analyses by Ji and Guo might be more reliable. In details, the benefit of octreotide remains uncertain.

TCM

One meta-analysis compared the outcomes of kanglaite injection plus hepatic arterial intervention versus hepatic arterial intervention alone (Supplementary Table S5) [34]. The combination therapy was beneficial in terms of tumor response, Karnofsky score improvement, and pain relief [34]. But neither OS nor DFS/RFS was evaluated [34].

One meta-analysis compared the outcomes of Chinese herbal medicine plus chemotherapy versus chemotherapy alone [104]. The combination therapy was beneficial in terms of OS and tumor response [104].

One meta-analysis compared the outcomes of TCM versus other treatment [121]. TCM was superior to other treatments in terms of OS and tumor response [121].

CIK cell therapy

One meta-analysis compared the outcomes of CIK cell therapy versus other treatment (Supplementary Table S6) [76]. CIK cell therapy was superior to other treatments in terms of OS, PFS, disease control rate, tumor response, and quality of life [76].

Tamoxifen

Two meta-analyses compared the outcomes of tamoxifen versus placebo or no treatment (Supplementary Table S7) [73, 90]. Both of them demonstrated that the OS was statistically similar between the two groups [73, 90].

RCT studies were included in the meta-analyses by Nowak (n = 10) and Llovet (n = 7).

Although the meta-analysis by Nowak had a larger number of included studies than that by Llovet (10 versus 7) (Supplementary Table S40), the included studies were not similar between them.

The results were completely consistent among them. In details, tamoxifen should not be favored.

Antibiotics

One meta-analysis compared the outcomes of antibiotics versus no antibiotics after hepatic transarterial therapy [113]. The incidence of fever, bacteremia, septicema, and sepsis were not significantly improved by antibiotics [113].

DISCUSSION

AASLD and EASL guidelines recommend BCLC staging algorithm for the management of HCC. Only 5 treatment modalities have been considered in the current guidelines. In details, the therapeutic modalities of HCC include the LT, surgical resection, and RFA for HCC in the stage 0 and A, TACE for HCC in the stage B, sorafenib for HCC in the stage C, and supportive treatment for HCC in the stage D. However, the BCLC staging algorithm is not flawless and needs to be persistently updated. Nowadays, more and more novel treatment modalities have been widely produced and adopted. Their efficacy and safety have been gradually established. In this circumstance, our study was worthwhile, because it attempted to collect the relevant evidence as many as possible and to provide an overview of outcomes of novel and well-established treatment modalities for HCC based on the results of meta-analyses. More notably, we found that lots of combination therapy might be more effective and safe. For example, the meta-analyses of RCTs demonstrated that RFA plus TACE was superior to mono-therapy, and that surgical resection plus post-operative TACE was superior to surgical resection alone. Given the quality of such meta-analyses, the guidelines should be updated regarding the use of combination therapy.

Limitations

This was a time-consuming work, because a large number of relevant meta-analyses were included. Several limitations should be acknowledged. First, we must clarify that only the results of meta-analyses, but not the accuracy of meta-analyses, were systematically reviewed. Because we cannot repeat every meta-analysis, we cannot guarantee that their findings were accurate. Second, we did not consider the heterogeneity among included studies in every meta-analysis. A significant heterogeneity could affect the stability of a meta-analysis. Third, we arbitrarily evaluated the reliability of meta-analyses according to the number of RCTs and non-RCTs.