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. 2017 Jun 28;7:4355. doi: 10.1038/s41598-017-04351-y

Table 1.

General Characteristics of Included Randomized Clinical Trials

Experimental group Control group Sex(M/F) Age Disease stage Child-Pugh scores KPS score Treatment group Control group
Huang W.K.30 2013 41 41 44/26 48.54 ± 4.16 years old II, III — >60 Cinobufotalin injection + TACE (OXA, EPI) TACE (OXA, EPI,) 3 weeks 1. Clinical effectiveness
2. Life quality
3. Blood routine examination
Cao Y.31 2014 68 68 78/58 E:55.2 ± 7.4 years old — A and B >50 Compound cantharis capsule + FAP (5-FU, EPI, DDP) FAP (5-FU, EPI, DDP) 10 days 1. Clinical effectiveness
2. Life quality
C:57.8 ± 6.9 years old 3. Complication
4. Economic evaluation
Zeng C.S.32 2012 30 30 19-Nov E:51.65 ± 6.92 years old II, III A and B — Jinlong capsule + TACE (THP, DDP, 5-FU) TACE (THP, DDP, 5-FU) 60 days 1. Clinical effectiveness
2. AFP
C:53.20 ± 9.24 years old 3. Liver function
4. Complication
5. Life quality
Deng Z.Y.33 2015 25 24 29/20 E:48.65 ± 16.12 years old — — — Cinobufotalin injection + TACE (THP, DDP) TACE (THP, DDP) 4 weeks 1. AFP
2. Clinical effectiveness
C:48.30 ± 16.24 years old 3. TCM symptoms scores + KPS
4. Complication
Dong M.E.34 2014 60 60 76/44 E:median age 55 years — — — Cinobufotalin injection + TACE (GEM, DDP, 5-FU, CF) TACE (GEM, DDP, 5-FU, CF) 4 weeks 1. Clinical effectiveness
C:median age 53 years 2. Complication
Feng X.M.35 2012 38 32 44/26 E:52.6 ± 11.7 years old II III — >60 Cinobufotalin injection + FOLFOX4 (OXA, 5-FU, CF) FOLFOX4 (OXA, 5-FU, CF) 3 rounds (2 days per round) 1. Clinical effectiveness
C:53.2 ± 11.4 years old 2. Life quality
3. Blood routine examination
Fu Z.L.36 2010 78 78 119/37 E:median age 58 years — — >60 Cinobufotalin injection + TACE (5-FU, DDP, MMC) TACE (5-FU, DDP. MMC) 3 months 1. Clinical effectiveness
C:median age 56 years 2. Life quality
3. Complication
He S.L.37 2012 26 25 37/14 58.8 years old — A and B — Cinobufotalin injection + TACE (OXA, 5-FU, THP) TACE (OXA, 5-FU, THP) 2 weeks 1. Clinical effectiveness
2. MST and TTP
3. VEGF, HIF-1α and AFP
4. KPS
5. Complication
Ji J.F.38 2015 25 22 36/11 62.3 years old — — — Cinobufotalin injection + TACE (DDP, 5-FU, DOX) TACE (DDP, 5-FU, DOX) 4–5 weeks 1. Clinical effectiveness
2. Survival at 6/12/24 months
3. Life quality
4. Comparison of WBC,TBIL and ALT
5. Immunological function
Jia C.H.39 2008 30 30 44/16 E:54.2 ± 6.4 years old I, II, III A, B and C >60 Jinlong capsule + TACE (MMC) TACE (MMC) 3 months 1. Clinical effectiveness
C:51.5 ± 7.0 years old 2. Immunological function. 3. Life quality
Jiang C.Y.40 2013 30 33 36/27 E:median age:57 years II, III —  ≥ 60 Jinlong capsule + TACE (5-FU, THP) TACE (5-FU, THP) 2 rounds (8 days per round) 1. Clinical effectiveness
C:median age:53 years 2. CBR
3. Complication
Ke J.41 2011 38 40 69/9 E:58.32 ± 11.59 years old — A and B >60 Cinobufotalin injection + TACE (5-FU, DDP, DOX) TACE (5-FU, DDP, DOX) 3 rounds (20 days per round) 1. Clinical effectiveness
C:57.09 ± 11.77 years old 2. Life quality
3. Comparison of WBC, TBIL, ALT and AFP
4. Survival at 6/12 months
5. Complication
Kou C.Y.42 2011 31 31 40/22 E:40.5 years old — — >60 Cinobufotalin injection + TACE (HCPT, DDP, DOX) TACE (HCPT, DDP, DOX) 4 weeks 1. Clinical effectiveness
C:41 years old 2. QoL scores
3. Complication
4. Survival at 12/24/36 months
Li B.43 2013 74 73 97/50 Median age:56.4 years — — >60 Jinlong capsule + TACE (5-FU, EPI, DDP, MMC, CF) TACE (5-FU, EPI, DDP, MMC, CF) 2 rounds (28 days per round) 1. Clinical effectiveness
2. Life quality
3. Comparison of Child-pugh, Classification and WBC
Li j.44 2013 43 62 76/29 E:45.2 ± 4.8 years old — A, B and C — Aidi injection + TACE (5-FU, THP, DDP, MMC) TACE (5-FU, THP, DDP, MMC) 10 days 1. Life quality
C:45.7 ± 6.4 years old 2. Survival at 6/12/24/36 months
3. AFP
4. TACE times
Li Q.45 2008 50 46 84/12 50.2 years old I, II, III A and B  ≥ 60 Cinobufotalin injection + TACE (5-FU, HCPT, DOX, MMC) TACE (5-FU, HCPT, DOX, MMC) 4 weeks 1. Clinical effectiveness
2. Life quality
3. Survival at 6/12/24 months
4. Comparison of WBC, TBIL and ALT
5. Immunological function
Li Q.M.46 2003 20 18 28-Oct 29–65 years old II, III —  ≥ 60 Qining injection + TACE (HCPT, 5-FU, MMC) TACE (HCPT, 5-FU, MMC) 7 days 1. Clinical effectiveness
2. Complication
Li W.H.47 2006 19 19 28-Oct 45 years old — — — Cinobufotalin injection + TACE (5-FU, DDP, MMC) TACE (5-FU, DDP, MMC) 2 rounds 1. Life quality
2. Clinical effectiveness
3. Comparison of WBC and AFP
4. Survival at 12/24 months and median survival time
5. Complication
Liang B.L.48 2010 20 20 30-Oct E:59 ± 6 years old — —  ≥ 50 Sodium Cantharidinate and vitamin B6 + TACE (MMC, 5-FU, EPI) TACE (MMC, 5-FU, EPI) 4weeks Comparison of liver function and blood routine examination
C:55 ± 8 years old
Liang C.X.49 2015 30 30 34/26 E:median age 53 years — A and B >80 Sodium Cantharidinate and Vitamin B6 + TACE (5-FU, DDP, OXA, EPI) TACE (5-FU, DDP, OXA, EPI) 3–4 rounds (15 days per round) 1. Clinical effectiveness
C:median age 52 years 2. Comparison of WBC and AFP
3. QoL scores
Liang.T.J.50 2005 116 108 187/37 E:52.1 ± 9.7 years old — A, B and C — Jinlong capsule + TACE (EPI, MMC, CBP) TACE (EPI, MMC, CBP)  ≥ 3 years 1. Survival at 6/12/24/36 months
C:50.4 ± 8.5 years old 2. Clinical effectiveness
3. QoL scores
Liang Y.51 2008 48 48 72/24 Median age:44.5 years — A, B and C  ≥ 70 Cinobufotalin injection + TACE (EPI, DDP, 5-FU) and IFN TACE (EPI, DDP, 5-FU) and IFN 2 rounds (4 weeks) 1. Clinical effectiveness
2. Live quality
3. Comparison of 6/12/18 months
4. Complication
Liu X.H.52 2009 42 42 70/14 48.5 years old — — — Cinobufotalin injection + TACE (5-FU, DDP, EPI) TACE (5-FU, DDP, EPI) 2–3 rounds (4 weeks per round) 1. Clinical effectiveness
2. Survival at 12/24/36 months
3. Comparison of immune function and liver function
4. Complication
Liu Y.Q.53 2010 38 44 72/10 E:54.21 ± 10.32 years old — A and B >60 Cinobufotalin injection + TACE (THP, DDP, MMC) TACE (THP, DDP, MMC) 2–3 rounds (3weeks per round) 1. Lipiodol deposition after TACE
2. Clinical effectiveness
C:55.32 ± 11.62 years old 3. Comparison of TTP
4. Complication
Lu S.J.54 2014 30 30 33/17 E:46.5 years old — — — Cinobufotalin injection + THM and TACE (DDP, DOX, 5-FU) TACE (DDP, DOX, 5-FU) 30 days 1. Clinical effectiveness
C:47.3 years old 2. Life quality
3. Survival at 6/12/24 months
4. Complication
Peng W.D.55 2011 40 40 43/37 E:45.0 ± 13.5 years old II, III —  ≥ 50 Compound cantharis capsule + FAP (5-FU, EPI, DDP) FAP (5-FU, EPI, DDP) 10 days 1. Clinical effectiveness
C:44.0 ± 13.9 years old 2. Life quality
3. Immunological function
Qu J.R.56 2012 40 40 64/16 E:median age 54 years II, III —  ≥ 60 Secretio bufonis injection + TACE (CBP, 5-FU, MMC,DOX) TACE (CBP, 5-FU, MMC, DOX) 28 days 1. Complication
C:median age 56 years 2. Comparison of liver function and blood routine examination
Shen J.J.57 2009 23 24 36/11 52.2 ± 7.4 years old II, III — — Cinobufotalin injection + TACE (5-FU, DDP, MMC) TACE (5-FU, DDP, MMC) 4 weeks 1. Complication 2. Comparison of liver Function and AFP
3. Life quality
4. Solid tumor variation
Shen J.J.58 2015 18 18 23/13 E:57.5 years old — A and B  ≥ 60 Cinobufotalin injection + TACE (Lobaplatin, DDP, MMC) TACE (Lobaplatin, DDP, MMC) 2 weeks 1. Clinical effectiveness
C:54.7 years old 2. Comparison of HIF-1α and VEGF
Shu X.H.59 2004 29 29 48/10 Median age: 51 years II, III —  ≥ 60 Cinobufotalin injection + 5-fluoro-uracil 5-fluorouracil 1–2 rounds (5 days per round) 1. Clinical effectiveness
2. The degree of pain relief
3. Life quality
4. Complication
Su Y.60 2013 33 30 53/10 E:53.2 ± 8.7 years old II, III — >60 Cinobufotalin injection + TACE (5-FU, HCPT, DOX, MMC) TACE (5-FU, HCPT, DOX, MMC) 4 weeks 1. Clinical effectiveness
C:52.7 ± 7.9 years old 2. Life quality
3. Complication
Sun Z.J.61 2002 118 118 197/39 51.4 years old — — — Cinobufotalin injection + TACE (EPI, MMC, CBP) TACE (EPI, MMC, CBP) 2 rounds (4 weeks per round) 1. Clinical effectiveness
2. Survival at 12/24/36 months
3. Immunological function
4. Liver function and complication
Tang J.G.62 1999 46 42 67/21 E:49 years old — — — Cinobufotalin injection + FAM (5-FU, DOX, MMC) FAM (5-FU, DOX, MMC) 1 month 1. Complication
C:48 years old 2. AFP
3. Life quality
Tian X.L.63 2006 36 36 53/19 E:53.4 ± 10.5 years old — —  ≥ 70 Aiyishu injection + TACE (MMC, DOX, 5-FU, DDP) TACE (MMC, DOX, 5-FU, DDP) 2–3 rounds (4–6 weeks per round) 1. Clinical effectiveness
C:52.5 ± 9.6 years old 2. QoL scores
3. Life quality
4. Survival at 6/12/18/24 months
Wang C.J.64 2001 30 30 — 48 years old — A,B and C  ≥ 30 Cinobufotalin injection + TACE (DOX, CBP, MMC) TACE (DOX, CBP, MMC) — 1. Improvement of clinical symptom
2. Complication
3. Child-pugh level
4. Serum levels of hepatic fibrosis
5. AFP
6. Clinical effectiveness
7. Survival at 12/24/36 months
Wang L.J.65 2007 72 70 117/25 E:62.5 years old II, III A and B  ≥ 50 Aidi injection + FAP (5-FU, EPI, DDP) FAP (5-FU, EPI, DDP) 2 rounds (30 days per round) 1. Clinical effectiveness
C:64.1 years old 2. Life quality
3. Child-pugh level
4. AFP
Wang Q.C.66 2013 24 24 41/7 E:median age 55 years — A and B — THM (toad venom, Salvia miltiorrhiza, and matrine) + TACE (MMC, THP, OXA) TACE(MMC, THP, OXA) 3 days Comparison of T-lymphocyte subsets
C:median age 57.2 years
Wei Y.F.67 2015 48 44 61/31 58.6 ± 6.8 years old — A and B  ≥ 70 Sodium cantharidinate and vitamin B6 + TACE (5-FU, EPI, MMC) TACE (5-FU, EPI, MMC) 3 rounds (30 days per round) 1. Clinical effectiveness
2. Complication
3. Survival at 12/24/36 months
Wu H.M.68 200 36 44 69/11 E:52.4 ± 7.2 years old II, III — — Cinobufotalin injection + TACE (5-FU, MMC, DDP) TACE (5-FU, MMC, DDP) 2 rounds (10 days per round) 1. Clinical effectiveness
2. AFP
C:50.5 ± 8.7 years old 3. Comparison of tumor metastasis
4. Survival at 3/6/12 months
5. Complication
Wu J.Y.69 2006 30 30 53/7 E:50 years old III — — Cinobufotalin injection + TACE (HCPT, THP) TACE (HCPT, THP) 25 days 1. Clinical effectiveness
C:50 years old 2. Complication
Wu J.S.70 2015 15 15 26-Apr 44–68 years old — —  ≥ 70 Sodium cantharidinate and vitamin B6 + TACE (5-FU, EPI, MMC) TACE (5-FU, EPI, MMC) 3 rounds 1. Comparison of WBC, ALT and AST
2. Complication
Wu Z.M.71 2010 41 41 50/32 Median age 45 years old — — — Sodium cantharidinate and vitamin B6 + TACE (5-FU, EPI, DDP) TACE (5-FU, EPI, DDP) 2 weeks 1. Clinical effectiveness
2. Comparison of liver function and AFP
3. Comparison of new vessel and portal vein tumor thrombosis
Xiao X.S.72 2011 25 25 35/15 E:65.4 years old — — — Cinobufotalin injection + TACE (MMC, 5-FU, DOX, DDP, HCPT) TACE (MMC, 5-FU, DOX, DDP, HCPT) 2 rounds (15–20 days per round) Clinical effectiveness
C:63.6 years old
Xie J.73 2015 50 50 89/11 E:58.09 ± 11.67 years old — A — Scorpion and earthworm + TACE (5-FU, MMC, EPI) TACE (5-FU, MMC, EPI) 2 months 1. Numbers of TACE
C:58.32 ± 11.55 years old 2. AFP
3. Liver function
4. Lung metastasis
Xie Y.F.74 2003 31 31 49/13 Median age 53.5 years I, II, III — >60 Jinlong capsule + TACE (5-FU, DDP, MMC) TACE (5-FU, DDP, MMC) 21 days 1. Clinical effectiveness
2. Life quality
3. Comparison of WBC
4. Immunologic function
5. AFP
Xu Y.S.75 2011 64 64 84/44 50.25 years old — — >60 Sodium norcantharidate (SNCTD) + TACE (DDP, 5-FU, DOX) TACE (DDP, 5-FU, DOX) 1–3 rounds (15 days per round) 1. Clinical effectiveness
2. Survival at 12/24/36 months
3. KPS
4. Complication
Xue Q.76 2010 32 30 45/17 E:45.75 ± 11.40 years old — — >60 Cinobufotalin injection + TACE (DDP, 5-FU, DOX) TACE (DDP, 5-FU, DOX) 1–3 rounds (28 days per round) 1. Clinical effectiveness
C:45.45 ± 10.70 years old 2. Survival at 6/12/24/36 months
3. Comparison of clinical symptoms
4. KPS
5. Complication
Yang P.Y.77 2013 34 36 48/22 55.1 ± 8.2 years old — A and B  ≥ 60 Jinlong capsule + TACE (EPI, 5-FU, DDP) TACE (EPI, 5-FU, DDP) 42 weeks 1. Clinical effectiveness
2. Comparison of ALT, TBIL and ALB
3. KPS scores
4. TCM clinical symptom
5. TH1 and TH2
6. Safety analysis
You S.Y.78 2006 25 25 32/18 E:49 ± 3 years old — — — Cinobufotalin injection + TACE (5-FU, DDP, EPI) TACE (5-FU, DDP, EPI) 2 rounds 1. Clinical effectiveness
C:48 ± 9 years old 2. Survival at 12/24/36 months
3. Complication
Yu J.G.79 2013 30 30 29-Nov E:49.7 years old — — >60 Cinobufotalin injection + TACE (DDP, DOX, MMC, 5-FU) TACE (DDP, DOX, MMC, 5-FU) 60 days 1. Clinical effectiveness
C:50.8 years old 2. Clinical symptom improvement
3. Comparison of blood routine examination, liver function and AFP
Yuan C.Y.80 2007 20 20 28-Dec E:52.3 ± 3.5 years old II, III — — Cinobufotalin injection + TACE (5-FU, DDP, EPI) TACE (5-FU, DDP, EPI) 2 rounds 1. Clinical effectiveness
C:53.2 ± 3.4 years old 2. AFP
3. Life quality
4. Immunological function
5. Complication
Zhang B.81 2007 51 49 76/24 E:54.3 years old — — >80 Sodium cantharidinate and vitamin B6 + TACE (THP) TACE (THP) 4 weeks 1. Clinical effectiveness
C:50.1 years old 2. Life quality
3. Clinical symptom improvement
4. Complication
Zhang C.Q.82 2005 116 108 187/37 E:52.1 ± 9.7 years old — A, B and C — Jinlong capsule + TACE (EPI, MMC, CBP) TACE (EPI, MMC, CBP) 3 years 1. Survival at 6/12/24/36 months
C:50.4 ± 8.5 years old 2. Clinical effectiveness
3. QoL scores
Zhang M.J.83 2011 38 38 38/38 E:53.99 ± 2.43 years old — —  ≥ 60 Sodium cantharidinate and vitamin B6 + TACE (MMC, DOX) TACE (MMC, DOX) 4–6 weeks 1. Clinical effectiveness
C:55.02 ± 2.16 years old 2. Clinical symptom improvement and weight
3. Life quality
4. Immunological function
5. Complication
Zhang T.S.84 2011 32 32 53/11 E:52 years old — — >60 Cinobufotalin injection + TACE (DOX, CBP, MMC) TACE (DOX, CBP, MMC) 4–6 weeks 1. Clinical effectiveness
C:51 years old 2. AFP
3. Complication
4. Survival at 6/12/24/36 months
Zhou J.S.85 2006 21 22 34/9 60.08 years old II, III A, B and C 50–70 Cinobufotalin injection + TACE (5-FU, DDP, MMC) TACE (5-FU, DDP, MMC) 4 rounds (4 weeks per round) 1. Clinical effectiveness
2. Liver function
3. Clinical symptom improvement
4. Life quality
5. Survival at 18/24 months
6. AFP and KPS
Zhu W.Q.86 2014 48 50 71/27 47.5 years old — — — Sodium cantharidinate and vitamin B6 + TACE (-) TACE (-) 20 days 1. Complication
2. Liver function, Child-Pugh scores
3. Serum hepatic fibrosis markers
4. Clinical effectiveness

Note: E: Experimental group; C: Control group; M: Male; F: Female; KPS: Karnofsky performance score; RCT: Randomized clinical trial; TACE: Transcatheter hepatic arterial chemoembolization; THM: Traditional herb medicine; AFP: Alpha-fetoprotein; Th1: Helper T cell type 1; Th2: Helper T cell type 2; HIF-1α: Hypoxia inducible factor-1α; MST: Median survival time; TTP: Time to progression; QoL: Quality of life; VEGF: Vascular endothelial growth factor; WBC: White blood cell; TBIL: Total bilirubin; ALT: Alanine aminotrnsferase; ALB: Albumin; MTTP: Median time to progression; CBR: Clinical beneficial rate; IFN: Interferon; OXA: Oxaliplatin; EPI: Epirubicin; 5-FU: 5-fluorouracil; THP: Pirarubicin; DDP: Cisplatin; CF: Calcium folinate; GEM: Gemcitabine; DOX: Doxorubicin; MMC: Mitomycin; HCPT: Hydroxycamptothecine; CBP: Carboplatin.