Radiofrequency ablation combined with percutaneous ethanol injection for hepatocellular carcinoma: a systematic review and meta-analysis

Figures & data

Figure 1. Selection flow chart of studies to evaluate RFA and PEI for HCC.

Table 1. Baseline characteristics of the studies included in the systematic review.

Study and year	Region	Design	P/T	Treatment arms (n)	Aetiology: HBV/HCV (n)	No. of tumours (1/≥2) (%)	Main HCC mean size (cm)	Mean treatment sessions per tumour	Mean follow-up (months)
Livraghi et al. (1999) [20]	Italy	RCT	86 (112)	RFA (42)	5/33	79/21	2.3	1.2	10
				PEI (44)	6/34	77/23	2.5	4.8	10
Lencioni et al. (2003) [21]	Italy	RCT	102 (142)	RFA (52)	6/22	77/23	2.8	1.1	22.9
				PEI (50)	9/20	62/38	2.8	5.4	22.4
Lin et al. (2004) [22]	Taiwan, China	RCT	157 (186)	RFA (52)	35/16	73/27	2.9	1.6	24.5
				PEI (105)	74/30	77/23	2.8	4.6	24
Lin et al. (2005) [23]	Taiwan, China	RCT	124 (154)	RFA (62)	41/20	79/21	2.5	1.3	28
				PEI (62)	42/19	79/21	2.3	4.9	26
Shiina et al. (2005) [24]	Japan	RCT	232 (379)	RFA (118)	18/90	61/39	NR	2.1	37
				PEI (114)	11/98	53/47	NR	6.4	35
Brunello et al. (2008) [25]	Italy	RCT	139 (177)	RFA (70)	6/44	77/23	2.4	NR	26.1
				PEI (69)	0/47	79/21	2.3	NR	25.3
Giorgio et al. (2011) [26]	Italy	RCT	271 (271)	RFA (128)	61/81^§	100/0	2.3	5	22
				PEI (143)	56/87	100/0	2.3	8	22
Azab et al. (2011) [27]	Egypt	RCT	90 (98)	RFA (30)	NR	NR	NR	1.5	18
				PEI (30)	NR	NR	NR	7.7	18
				RFA-PEI (30)	NR	NR	NR	1.1	18
Shankar et al. (2004) [28]	America	CCT	50 (58)	RFA (20)	NR	NR	8.8	NR	NR
				RFA-PEI (30)	NR	NR	8.4	NR	NR
Kurokohchi et al. (2005) [29]	Japan	CCT	75 (NR)	RFA (15)	NR	NR	2.5	NR	NR
				RFA-PEI (60)	NR	NR	3.0	NR	NR
Zhang et al. (2007) [30]	China	RCT	133 (210)	RFA (67)	65/2	61/39	NR	NR	32.2
				RFA-PEI (66)	61/5	64/36	NR	NR	33.5
Wong et al. (2008) [31]	Taiwan, China	CCT	142 (208)	RFA (158^#)	NR	NR	NR	NR	9.8
				RFA-PEI (50^#)	NR	NR	2.8	NR	9.8
Cha et al. (2013) [32]	Korea	CCS	20 (20)	PEI (12)	NR	NR	NR	NR	NR
				RFA-PEI (8)	NR	NR	NR	NR	NR

RCT: randomised controlled trial; CCT: controlled clinical trial; CCS: case control study; RFA: radiofrequency ablation; PEI: percutaneous ethanol injection; HCC: hepatocellular carcinoma; P: patient; T: tumour; HBV: hepatitis B virus; HCV: hepatitis C virus; NR: not reported in the text.

§ Aetiologies of 14 patients ineligible for RFA and shifted to PEI were not provided. Accordingly, we extracted the data from randomisation.

# Here is the number of tumours instead of the number of patients because this trial divided groups by the tumour characteristics.

Table 2. Quality assessment of the studies included in the systematic review.

Study and year	Random sequence generation	Allocation concealment	Blinding	Incomplete outcome data	Selective outcome reporting	Other biases
Livraghi et al. (1999) [20]	distance of case	Yes	Low risk of bias	Yes (n = 7)	No	Unclear
Lencioni et al. (2003) [21]	computer-generated	Yes	Low risk of bias	No	No	Unclear
Lin et al. (2004) [22]	computer-generated	Yes	Low risk of bias	No	No	Unclear
Lin et al. (2005) [23]	computer-generated	Yes	Low risk of bias	Yes (n = 4)	No	Unclear
Shiina et al. (2005) [24]	computer-generated	Unclear	Low risk of bias	No	No	Unclear
Brunello et al. (2008) [25]	computer-generated	sealed envelopes	Low risk of bias	Yes (n = 9)	No	Unclear
Giorgio et al. (2011) [26]	random number generator	Yes	Low risk of bias	No	No	Unclear
Azab et al. (2011) [27]	Yes	Unclear	Low risk of bias	No	No	Unclear
Shankar et al. (2004) [28]	Unclear	Unclear	Low risk of bias	No	No	Unclear
Kurokohchi et al. (2005) [29]	Unclear	Unclear	Low risk of bias	No	No	Unclear
Zhang et al. (2007) [30]	computer-generated	Yes	Yes	No	No	Unclear
Wong et al. (2008) [31]	Non-randomised	Unclear	Low risk of bias	No	No	Unclear
Cha et al. (2013) [32]	retrospective study	Unclear	Low risk of bias	No	No	Unclear

Figure 2. Meta-analysis of the overall survival rate between RFA and PEI.

Table 3. Meta-analysis of the efficacy and safety between RFA and PEI.

		RFA		PEI		Heterogeneity			Result of meta-analysis
Outcome	Included studies	n	n	n	n	I^2%	p	Statistical method	OR (95% CI)	p
1-year cancer-free survival	3 [21–23]	132	166	147	217	0	.57	M–H, Fixed	1.75 [1.08, 2.83]	=.02
2-year cancer-free survival	3 [21–23]	101	166	93	217	0	.94	M–H, Fixed	2.08 [1.37, 3.15]	=.0006
3-year cancer-free survival	2 [22,23]	46	114	33	167	0	.76	M–H, Fixed	2.66 [1.55, 4.58]	=.0004
1-year local recurrence rate	5 [21–24,26]	20	412	59	474	16	.31	M–H, Fixed	0.40 [0.23, 0.67]	=.0006
2-year local recurrence rate	5 [21–24,26]	31	412	103	474	45	.12	M–H, Fixed	0.31 [0.20, 0.48]	<.00001
3-year local recurrence rate	4 [22–24,26]	32	360	87	424	17	.30	M–H, Fixed	0.41 [0.27, 0.65]	<.0001
New HCC recurrence	5 [21–25]	153	354	174	400	0	.98	M–H, Fixed	0.92 [0.68, 1.25]	=.59
Complete tumour necrosis	7 [20–25,27]	421	439	428	492	9	.36	M–H, Fixed	3.76 [2.17, 6.54]	<.00001
Total complication	8 [20–27]	213	554	185	617	45	.09	M–H, Fixed	2.02 [1.27, 3.20]	=.003
Major complication	6 [20,23–27]	18	450	8	462	1	.41	M–H, Fixed	2.12 [0.97, 4.65]	=.06

RFA: radiofrequency ablation; PEI: percutaneous ethanol injection; HCC: hepatocellular carcinoma; M–H: Mantel–Haenszel; CI: confidence interval.

Table 4. Comparison of complications between RFA and PEI.

Major complication	RFA (n)	PEI (n)	Other complication	RFA (n)	PEI (n)
Procedure-related death	0	1	Pain	104	104
Seeding of malignant cells	3	2	Fever	68	57
Haemothorax	4	0	Pleural effusions	6	0
Haemoperitoneum	1	1	Ascites	1	4
Gastric bleeding§	1	0	Portal thrombosis	5	9
Liver abscess§	0	1	Arteriovenous shunts	3	0
Hepatic infarction§	1	0	Others	8	3
Jaundice§	1	0	–	–	–
Skin burn§	6	0	–	–	–
Others§	1	3	–	–	–
SUM (n)	18	8	SUM (n)	195	177

RFA: radiofrequency ablation; PEI: percutaneous ethanol injection.

§ The major complication was regarded as other complication due to different standards in some trials included in this article.

Figure 3. Meta-analysis of the overall survival rate between RFA-PEI and RFA alone.

Table 5. Meta-analysis of the efficacy and safety between RFA-PEI and RFA alone.

		RFA-PEI		RFA		Heterogeneity			Result of meta-analysis
Outcome	Included studies	n	n	n	n	I^2 %	p	Statistical method	OR (95% CI)	p
Local recurrence rate	2 [27,30]	6	96	18	97	0	.55	M–H, Fixed	0.29 [0.11, 0.77]	=.01
Complete tumour necrosis	2 [27,30]	78	96	64	97	68	.08	M–H, Random	2.63 [0.71, 9.78]	=.15
Fever incidence rate	2 [27,30]	37	96	21	97	0	.71	M–H, Fixed	2.27 [1.20, 4.28]	=.01
Pain incidence rate	2 [27,30]	39	96	33	97	0	.94	M–H, Fixed	1.36 [0.73, 2.53]	=.33

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