Transarterial Chemoembolization Plus Sorafenib versus Transarterial Chemoembolization Alone for Advanced Hepatocellular Carcinoma: An Umbrella Review of Meta-Analyses and Systematic Reviews

Figures & data

Table 1 Index and Keyword Terms Used in the Databases

Database	Index and Keyword Terms
PubMed	(((((Transcatheter arterial chemoembolization[Title/Abstract]) OR (TACE[Title/Abstract])) OR (transarterial chemoembolization[Title/Abstract])) AND ((Sorafenib[MeSH Terms]) OR (nexavar[Title/Abstract]))) AND ((((((((((((carcinoma, hepatocellular[MeSH Terms])) OR (hepatocellular carcinoma[Title/Abstract])) OR (hepatomas[Title/Abstract])) OR (liver carcinoma[Title/Abstract])) OR (hepatocarcinoma[Title/Abstract])) OR (liver cell carcinoma[Title/Abstract])) OR (liver cancer[Title/Abstract])) OR (HCC[Title/Abstract]))) AND (meta[Title/Abstract])
Cochrane	ID Search #1 MeSH descriptor: [Sorafenib] explode all trees #2 nexavar #3 #1 OR #2 #4 MeSH descriptor: [carcinoma, hepatocellular] explode all trees #5 hepatocellular carcinoma #6 hepatomas #7 liver carcinoma #8 hepatocarcinoma #9 liver cell carcinoma #10 liver cancer #11 HCC #12 #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 #13 Transcatheter arterial chemoembolization #14 TACE #15 transarterial chemoembolization #16 #13 OR #14 OR #15 #17 meta #18 #3 AND # 12 AND #16 AND #17
Web of Science	TS= (Transcatheter arterial chemoembolization OR TACE OR transarterial chemoembolization) AND TS= (carcinoma, hepatocellular OR hepatocellular carcinoma OR hepatomas OR hepatocarcinoma OR liver cell carcinoma OR HCC) AND TS= (Sorafenib OR nexavar) AND TS= (meta)
EMBASE	#1. Transcatheter AND arterial AND chemoembolization #2. transarterial AND chemoembolization #3. #1 OR #2 #4. Carcinoma AND hepatocellular #5. hepatocarcinoma #6. (“liver”/exp OR liver) AND cell AND carcinoma #7. #4 OR #5 OR #6 #8. Sorafenib #9. nexavar #10. #8 OR #9 #11. meta #12. #3 AND #7 AND #10 AND #11

Table 2 Description of the Selected Studies: Objectives, Numbers of Studies and Most Important results

Study	Number of Included Studies	Objectives	Results
Li D^Citation34 2021	23 RCTs	To evaluate the efficacy and safety of sorafenib combined with TACE in the treatment of advanced HCC.	ORR, DCR, TTP, AFP, VEGF, OS and adverse events.
Hu MD^Citation35 2016	3 RCTs, 1 cohort study and 1 prospective non-RCT	To analyze the efficacy of sorafenib in combination with TACE for HCC.	TTP, OS, treatment efficacy and adverse events.
Xie Y^Citation36 2020	6 RCTs	To evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) plus sorafenib compared with TACE plus placebo for hepatocellular carcinoma (HCC) using meta-analytical techniques.	TTP, 0.5-, 1-, 1.5-, and 2-year survival rates, ORR, DCR.
Cheng^Citation37 2020	6 RCTs and 25 retrospective studies	To compare the efficacy of three types of palliative therapy for advanced HCC, TACE monotherapy, sorafenib alone and their combination.	OS, TTP, ORR, DPR, 1-year and 2-year survival rates
Zeng J^Citation38 2016	4 RCTs	To evaluate the efficacy and safety of TACE plus sorafenib versus TACE monotherapy in the early or intermediate stage HCC	TTP, OS, ORR, DCR and adverse events.
Zhang^Citation39 2014	2 RCTs, 2 propensity score-matched cohort studies, and 2 retrospective cohort studies.	To evaluate the efficacy and safety of the combination therapy of TACE plus sorafenib in patients with intermediate or advanced stage of HCC.	OS, TTP, ORR, PFS and adverse events.
Li L^Citation40 2018	14 comparative studies (3 RCTs, 4 non-randomized controlled studies and 7 retrospective studies) and 13 non-comparative studies.	Identifying the efficacy of the combination of TACE with sorafenib, which remains controversial despite years of exploration.	OS, TTP, DCR, ORR, PFS and adverse events.
Zhang^Citation41 2017	Eight retrospective studies	To compare the effectiveness and safety of combination of TACE with sorafenib and TACE alone for HCC with portal vein tumor thrombus.	OS, TTP, tumor objective response and adverse events.
Jin PP^Citation42 2018	5 RCTs, 2 prospective cohort studies, and 6 retrospective studies	To compare efficacy and safety, as well as regional disparities, between TACE plus sorafenib and TACE alone for HCC.	TTP, OS, and adverse events.
Fu QH^Citation43 2014	5 RCTs, and 4 non-RCTs	Evaluation of efficacy and safety between sorafenib plus TACE and TACE alone for HCC.	6-month, 1-year and 2-year mortality, PFR, clinical benefit ratio and adverse events.
Yang^Citation44 2014	3 RCTs and 3 Retrospective studies	To evaluate the effectiveness and safety of TACE plus sorafenib versus TACE alone for unresectable HCC.	OS, TTP, objective response and adverse events
Cai R^Citation45 2017	9 RCTs and 5 non-RCTs	To assess the efficacy and safety of the combination treatment in patients with advanced HCC.	ORR, DCR, OS and adverse events.

Abbreviations: OS, overall survival; ORR, overall response rate; DCR, disease control rate; DPR, disease progression rate; AFP, alpha-fetoprotein; TTP, time of disease progression; PFR, progression free rate; VEGF, vascular endothelial growth factor; TACE, transarterial chemoembolization; HCC, hepatocellular carcinoma; RCT, randomized controlled trials.

Figure 1 PRISMA 2020 flow diagram for new systematic reviews which included searches of databases, registers, and other sources.

Table 3 The Results of the Methodological Quality Assessment of the Meta-Analysis

Study	Year	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Q9	Q10	Q11	Q12	Q13	Q14	Q15	Q16	Quality Assessments
Cheng Z^Citation37	2020	Y	Y	N	PY	Y	Y	N	Y	Y	N	Y	Y	Y	Y	Y	Y	Low
Li D^Citation34	2021	Y	Y	Y	Y	N	Y	N	Y	Y	N	Y	Y	Y	Y	Y	Y	Low
Zeng J^Citation38	2016	Y	PY	Y	Y	Y	Y	N	Y	Y	N	Y	Y	Y	Y	Y	Y	Low
Zhang L^Citation39	2014	N	PY	N	PY	Y	Y	N	Y	N	N	Y	Y	Y	Y	Y	N	Critically low
Li L^Citation40	2018	N	PY	N	Y	Y	Y	N	Y	Y	N	Y	Y	N	Y	N	Y	Critically low
Hu M^Citation35	2016	Y	PY	N	PY	Y	N	N	Y	N	N	Y	N	Y	Y	Y	Y	Critically low
Jin PP^Citation42	2018	Y	Y	Y	PY	Y	N	N	Y	Y	N	Y	Y	Y	Y	Y	Y	Low
Fu Q^Citation43	2014	N	Y	N	Y	Y	N	N	Y	Y	N	N	Y	N	Y	Y	Y	Critically low
Yang M^Citation44	2014	Y	PY	N	PY	Y	Y	N	Y	Y	N	Y	Y	Y	Y	Y	Y	Low
Cai R^Citation45	2017	Y	PY	Y	PY	N	Y	N	N	Y	N	Y	Y	Y	Y	Y	Y	Low
Zhang X^Citation41	2017	Y	PY	Y	Y	Y	Y	N	Y	Y	N	Y	Y	Y	Y	Y	Y	Low
Xie Y^Citation36	2021	Y	Y	Y	PY	Y	N	N	Y	Y	N	Y	Y	Y	Y	Y	Y	Low

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