A network meta-analysis on the efficacy and prognosis of different interventional therapies for early-stage hepatocellular carcinoma

Figures & data

Figure 1. PRISMA-NMA diagram of the literature search evaluating interventional RCTs for early-stage HCC through a selection process. Studies were identified from PubMed, Embase, Cochrane Library and Clinicaltrial.gov databases. There were 1202 references identified from the databases and a total of 35 RCTs were included in this study.

Figure 2. Network plot of enrolled studies. The number labeled beside each line is the number of studies comparing these two intervention therapies.

Figure 3. Quality assessment of included studies using Cochrane Collaboration’s tool. (A) Overall and (B) study-level risk of bias were assessed in these seven aspects.

Table 1. Baseline characteristics of included studies.

Study	Year	Journal	Group	Stage, tumor size	sample size	Age	Sex (male/total)	Child-Pugh (A/B)	Follow-up	Main outcomes	Complications
Abdelaziz	2014	Endo Surg	RFA versus MWA	BCLC Stage A, <5 cm	45 versus 66	56.8 ± 7.3 versus 53.6 ± 5	31 versus 48%	24/21 versus 25/41	2 years	LTP, OS	5/45 in RFA group versus 2/66 in MWA group
Qian	2012	Eur Radiol	RFA versus MWA	—; <3 cm	20 versus 22	56.0 ± 11.0 versus 52.0 ± 12.0	95 versus 91%	—	1 year	LTP	Pain, fever, etc
Shibata	2002	Radiology	RFA versus MWA	—; <4 cm	36 versus 36	63.6 versus 62.5	26/10 versus 24/12	21/15 versus 19/17	2 years	LTP	No significant difference of major complications
Yu	2017	Gut	RFA versus MWA	—; <5 cm	200 versus 203	—	—	—	5 years	LTP, OS, disease-free survival	No data
Chen	2006	Ann Surg	RFA versus surgery	—; Solitary, <5 cm	71 versus 90	51.9 ± 11.2 versus 49.4 ± 10.9	78.9% versus 83.3%	71/0 versus 90/0	5 years	OS, disease-free survival	Ascites, pain, etc. surgery > RFA
Fang	2014	J Gastroenterol Hepatol	RFA versus surgery	—; <3 cm	60 versus 60	51.4 ± 8.1 versus 53.5 ± 1 1.0	70% versus 76.7%	32/23 versus 43/17	40 months	Total recurrence rate, OS, disease-free survival	Major complication, 14/60 in surgery versus 1/60 in RFA
Feng	2012	J Hepatol	RFA versus surgery	—; <4 cm	84 versus 84	51 versus 47	94 versus 89%	39/45 versus 43/41	3 years	Total recurrence, OS, disease-free survival	8/84 in RFA versus 18/84 in surgery
Huang	2010	Radio Med	RFA versus surgery	Met the Milan criteria; <5 cm	115 versus 115	56.6 ± 14.3 versus 55.9 ± 12.7	68.7 versus 73.9%	110/5 versus 106/9	5 years	LTP, total recurrence, disease-free survival, OS	5/115 in RFA versus 32/115 in surgery
Lee	2018	Ann Surg Treat Res	RFA versus surgery	—; <4 cm	34 versus 29	56.1 ± 7.4 versus 55.6 ± 7.9	70.6 versus 79.3%	31/3 versus 29/0	5 years	LTP, OS, disease-free survival	9/34 versus 11/29, no significant difference
Lv	2006	Natl Med J China	RFA versus surgery	Milan criteria; <5 cm	51 versus 54	55 ± 13 versus 49 ± 14	82.4 versus 68.5%	46/5 versus 50/4	46 months	OS, disease-free survival	4/51 versus 6/54, no significant difference
Ng	2017	Br J Surg	RFA versus surgery	—; <5 cm	109 versus 109	57 versus 55	78.9 versus 81.7%	104/5 versus 107/2	10 years	LTP, tumor recurrence, OS, disease-free survival	No significant difference of postoperative complications between RFA and surgery
Azab	2011	Arab J Gastroenterol	RFA versus PEI	—, <5 cm	33 versus 32	—	—	—	1.5 years	OS	Pain, fever, portal vein thrombosis, etc, without significant difference
Brunello	2008	Scand J Gastroenterol	RFA versus PEI	—; <3 cm	70 versus 69	69.0 ± 7.7 versus 70.3 ± 8.1	61.4 versus 71.0%	39/31 versus 38/30	4 years	OS	10/70 in RFA versus 12/69 in PEI, without significant difference
Giorgio	2011	Anticancer Res	RFA versus PEI	—; <3 cm	142 versus 143	70 ± 2 versus 72 ± 6	73.9 versus 71.3%	70/72 versus 75/68	5 years	LTP, OS, costs	1/142 in RFA versus 3/143 in PEI, without significant difference
Lencioni	2003	Radiology	RFA versus PEI	—; <5 cm	52 versus 50	67 ± 6.0 versus 69 ± 7.4	69 versus 60%	45/7 versus 35/15	3 years	LTP, LTP-free survival, disease-free survival	Pain, fever, no severe complications were observed
Lin	2004	Gastroenterol	RFA versus PEI	—; <4 cm	52 versus 52	62 ± 11 versus 59 ± 10	67 versus 65%	41/11 versus 39/12	42 months	LTP, OS, disease-free survival	No severe complications were observed
Lin	2005	Gut	RFA versus PEI	—; <3 cm	62 versus 62	61 ± 10 versus 60 ± 8	65 versus 63%	46/16 versus 47/15	42 months	LTP, OS, disease-free survival	Major complication was 3/62 in RFA versus 0/125 in PEI and PAI group
Shiina	2005	Gastroenterol	RFA versus PEI	—; <3 cm	118 versus 114	—	67 versus 76%	85/33 versus 85/29	4 years	OS, Tumor recurrence rate	No significant difference between RFA versus PEI
Di Costanzo	2015	J Gastroenterol Hepatol	RFA versus laser ablation	—; <5 cm	70 versus 70	70 versus 70	75.7 versus 67.1%	63/7 versus 67/3	5 years	LTP, LTP-free survival, OS	No significant difference between RFA versus laser ablation
Ferrari	2007	Radio Med	RFA versus laser ablation	—; <4 cm	40 versus 41	70.5 ± 5.3 versus 68.3 ± 6.4	70.0 versus 68.3%	28/12 versus 31/10	5 years	LTP, total recurrence, OS	No data
Orlacchio	2014	Radio Med	RFA versus laser ablation	—; <4 cm	15 versus 15	71.5 ± 4.6 versus 73.5 ± 6.7	73.3 versus 66.7%	9/6 versus 10/5	1 year	Total recurrence, OS	No major complications, laser ablation has less minor complications compared with RFA
Wang	2015	Hepatology	RFA versus cryoablation	—; <4 cm	180 versus 180	53.3 ± 8.9 versus 53.9 ± 9.6	83.3 versus 77.8%	109/71 versus 121/59	5 years	LTP, OS, disease-free survival	Major complication was 7/180 in RFA group versus 6/180 in cryoablation group
Bian	2014	J Natl Cancer Inst	RFA versus RFA + radiotherapy	BCLC 0-B; —	65 versus 62	55 versus 55	86.2 versus 88.7%	51/14 versus 56/6	3 years	Tumor recurrence rate, OS	No serious adverse events or treatment-related deaths were observed
Chen	2014	J Hepatol	RFA versus RFA + radiotherapy	BCLC 0-A; -	68 versus 68	48.9 ± 7.3 versus 50.8 ± 6.8	77.9 versus 82.4%	47/21 versus 42/26	5 years	Tumor recurrence rate, OS	No significant difference was observed
Chen	2005	Chin J Oncol	RFA versus RFA + PEI	—; <5 cm	41 versus 45	50 versus 48	90.2 versus 80%	—	29 months	LTP, OS	No data
Azab	2011	Arab J Gastroenterol	RFA versus RFA + PEI	—; <5 cm	33 versus 33	—	—	—	1.5 years	OS	Pain, fever, portal vein thrombosis, etc, without significant difference
Zhang	2007	Radiology	RFA versus RFA + PEI	—; <7 cm	67 versus 66	52.2 ± 10.3 versus 53.3 ± 11.3	86.6 versus 86.4%	37/24 versus 42/20	5 years	LTP, total recurrence, OS	No procedure-related mortalities or major complications
Kobayashi	2008	Liver International	RFA versus RFA + TACE	—; <3 cm	10 versus 10	63 versus 67	80 versus 70%	3/5 versus 4/5	4 years	Tumor recurrence rate	No severe complication was observed
Morimoto	2010	Cancer	RFA versus RFA + TACE	—; <5 cm	18 versus 19	73 versus 70	67 versus 79%	16/2 versus 18/1	45 months	Tumor recurrence rate, OS	No severe complication was observed, no significant difference as to minor complications
Peng	2013	J Clin Oncol	RFA versus RFA + TACE	—; <7 cm	95 versus 94	55.3 ± 13.3 versus 53.3 ± 11.0	74.7 versus 79.8%	90/5 versus 90/4	5 years	Tumor recurrence rate, OS, recurrence-free survival	No significant difference
Shibata	2010	Radiology	RFA versus RFA + TACE	—; <3 cm	43 versus 46	69.8 ± 8.0 versus 67.2 ± 8.9	76.7 versus 67.4%	33/10 versus 32/14	4 years	LTP; OS; LTP-free survival; Event-free survival	Major complications: 1/43 in RFA group versus 1/46 in combined group
Yan	2016	Oncol Lett	Surgery versus RFA + Sorafineb	—; <3 cm	60 versus 60	62.6 ± 2.5	56.7%	—	5 years	LTP, tumor recurrence rate, OS, disease-free survival	Surgery has more adverse reactions compared with RFA
Huang	2005	Ann Surg	Surgery versus PEI	—; <3 cm	38 versus 38	59 ± 11.4 versus 63 ± 10.9	71.1 versus 50%	28/0 versus 29/3	5 years	Recurrence rate, OS	No significant complications in surgery and PEI groups
Liu	2016	Br J Surg	Surgery versus RFA + TACE	Met the Milan criteria; <5 cm	100 versus 100	49 versus 52	94 versus 86%	98/2 versus 96/4	5 years	LTP, OS	23/100 in surgery versus 11/100 in RFA + TACE group
Koda	2011	Cancer	PEI versus TACE + PEI	—; <3 cm	26 versus 26	66.4 ± 6.6 versus 66.2 ± 8.0	69.2 versus 53.8%	14/8 versus 19/5	7 years	LTP, OS	No significant difference was observed
Mizuki	2010	Oncol Lett	PEI versus TACE + PEI	—; <4 cm	14 versus 13	63.6 ± 6.2 versus 65.8 ± 7.3	50 versus 69.2%	–	5 years	LTP, OS, disease-free survival	No significant difference was observed

BCLC: Barcelona Clinic Liver Cancer; MWA: microwave ablation; PEI: percutaneous ethanol injection; LTP: local tumor progression; OS: overall survival; RFA: radiofrequency ablation; TACE: transcatheter arterial chemoembolization.

Figure 4. Network meta-analysis for analysing the rate of different interventional treatments on LTP at 1, 2, 3 and longer than 3 years. (A) Network plots of the included studies and the connections among them. The four panels indicate the subgroup analysis of LTP at 1, 2, 3 and longer than 3 years. Abbreviations: RFA: radiofrequency ablation; MWA: microwave ablation; PEI: percutaneous ethanol injection; TACE: transcatheter arterial chemoembolization. (B) The relative forest plots of different interventional arms on LTP compared with RFA, using risk ratio (RR) values and 95% credible intervals (CrIs). (C) The results of treatment ranks using R-software. The abbreviations were the same as in (A). The dark bars indicate the high probability of being the best interventional arms, whereas the light bars suggest being the worst arms in this outcome.

Figure 5. Network meta-analysis for analysing the rate of different interventional treatments on total recurrence at 1, 2, 3 and longer than 3 years. (A) Network plots of the included studies and the connections among them. The four panels indicate the subgroup analysis of total recurrence at 1, 2, 3 and longer than 3 years. Abbreviations: MWA: microwave ablation; PEI: percutaneous ethanol injection; RFA: radiofrequency ablation; TACE: transcatheter arterial chemoembolization. (B) The relative forest plots of different interventional arms on total recurrence rates compared with RFA, using risk ratio (RR) values and 95% credible intervals (CrIs). (C) The results of treatment ranks using R-software. The abbreviations were the same in (A).

Figure 6. Network meta-analysis for analysing the rate of different interventional treatments on overall, disease-free and LTP-free survival rates. (A) Network plots of the included studies and the connections among them in the comparison of survival rates. The three panels indicate the analyses of overall survival rates at 1, 2, 3 and longer than 3 years. Abbreviations: MWA: microwave ablation; PEI: percutaneous ethanol injection; RFA: radiofrequency ablation; TACE: transcatheter arterial chemoembolization. (B) The relative forest plots of different interventional arms on overall survival, disease-free survival and LTP-free survival rates compared with RFA, using HR values and 95% credible intervals (CrIs). (C) The results of treatment ranks using R-software. The abbreviations were the same in (A).