J Cancer Res Clin Oncol DOI 10.1007/s00432-014-1708-1
Review – Cancer Research
Efficacy and safety of percutaneous radiofrequency ablation versus surgical resection for small hepatocellular carcinoma: a meta-analysis of 23 studies Qian Feng · Yugang Chi · Yanqian Liu · Ling Zhang · Qi Liu
Received: 2 March 2014 / Accepted: 9 May 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose The aim of our meta-analysis was to compare the efficacy and safety of radiofrequency ablation (RFA) versus surgical resection for patients with small hepatocellular carcinoma (SHCC). Methods Randomized controlled trials (RCTs) or retrospective studies comparing the RFA with surgical resection for patients with SHCC published from 2004 to 2014 were selected from database of PubMed, EMBASE and Cochrane library. The outcomes including overall survival rate, recurrence-free survival rate, recurrence rate and complications (mortality rate and morbidity rate) were abstracted. Individual and pooled odds ratio with 95 % confidence interval of each outcome was analyzed. Results Three RCTs and twenty retrospective studies were included with a total of 15,482 patients. The 1-, 3and 5-year overall survival rate and recurrence-free survival rate of surgical resection were significantly higher than RFA. The 2- and 3-year but not 1-year recurrence rate of RFA was significantly higher than surgical resection. The morbidity rate of complication in surgical resection group was higher than it in RFA group, but the mortality was not different between the two groups. Conclusion Surgical resection led to a higher overall survival and recurrence-free survival rate in treating SHCC. However, RFA led to a lower morbidity rate of complication than surgical resection.
Q. Feng · Y. Chi · Y. Liu · L. Zhang · Q. Liu (*) The Key Laboratory of Molecular Biology for Infectious Disease, Chinese Ministry of Education, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 74 Lin Jiang Road, Chongqing 400010, China e-mail: [email protected]
Keywords Radiofrequency ablation · Surgical resection · Small hepatocellular carcinoma · Meta-analysis
Introduction Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide, which leads to a 500,000 deaths per year. At the same time, 660,000 new cases were identified in the world every year with an increasing incidence (Llovet et al. 2003; Marrero 2013; Venook et al. 2010). Liver transplantation might be the best cure for patients with HCC, yet it is limited by the high cost and donor shortage. Surgical resection has been widely accepted for patients who are unwilling or unable to receive liver transplantations (Duffy et al. 2008). Recently, radiofrequency ablation (RFA) has attracted great attention to become a first-line treatment because of its safety, cost-effectiveness and minimal invasiveness (Rhim et al. 2010). A few of meta-analyses have been conducted to compare the efficacy and safety of the surgical resection with RFA in the treatment of patients with small hepatocellular carcinoma (SHCC) (Chen et al. 2006; Cho et al. 2011; Feng et al. 2012; Huang et al. 2010; Li et al. 2012; Xu et al. 2012; Zhou et al. 2010). But the results are still controversial. Interestingly, these studies have not mentioned the effect of characteristic of tumor on the treatment outcomes. Several RCTs and retrospective cohort studies were newly conducted regarding the curative effect of RFA and surgical resection in recent years. Herein, we performed this meta-analysis to compare RFA with surgical resection in the treatment of SHCC using these recently reported studies. Moreover, we also conducted two subgroup analysis based on characteristics of tumors to evaluate the effect
13
of single tumor size (≤3 or >3 cm) and number of tumor nodules (single or multiple) on the treatment outcomes.
Methods Study selection Two reviewers independently carried out a comprehensive search of PubMed, EMBASE and Cochrane library for relevant articles published January 1, 2004 to February 1, 2014. The key words in this strategy with MeSH heading: “radiofrequency ablation,” “surgical resection,” “hepatocellular carcinoma.” Only articles written in English were included in. The searches were limited to human subjects, and the research design type was RCTs or retrospective studies.
J Cancer Res Clin Oncol
identified when P 3 cm. All calculation was conducted using Revman 5.1 software if there is no special mention.
Results
Criteria for inclusion and exclusion
Selection of studies
For inclusion in the meta-analysis, a study had to fulfill the following criteria: (1) Patients involved in these studies had not treated with RFA or surgical resection before; (2) First RFA treatment was conducted by percutaneous; (3) All patients were suitable candidates for surgical resection and/ or RFA; (4) For similar studies reported by the same institution and/or authors, only the most recent study with high quality was included in this analysis; and (5) Included studies must report on at least one of the following outcomes: the overall and recurrence-free survival rate of 1-, 3- and 5-year, the recurrence rate of 1-, 2- and 3-year and complications (including mortality and morbidity). Briefly, according to Yao et al. (2001), SHCC was defined as a single HCC nodule of up to 6.5 cm, or with up to 3 lesions, the largest of which is no larger than 4.5 cm.
In accordance with the search, 38 potentially relevant publications were identified after the first round of selection. Among these publications, six were reported for one identical group of patients, eleven were comments or reviews. Two additional NRCT were identified by hand-searched. Finally, a total of 23 studies (3 RCTS and 20 retrospective studies) (Abu-Hilal et al. 2008; Chen et al. 2006; Desiderio et al. 2013; Feng et al. 2012; Guglielmi et al. 2008; Guo et al. 2013; Hasegawa et al. 2013; Hiraoka et al. 2008; Huang et al. 2010; Hung et al. 2011; Ikeda et al. 2011; Imai et al. 2012; Kong et al. 2011; Lupo et al. 2007; Nishikawa et al. 2011; Peng et al. 2012; Pompili et al. 2013; Sung et al. 2005; Tohme et al. 2013; Ueno et al. 2009; Wang et al. 2012; Wong et al. 2012; Yun et al. 2011) were selected, which involving 7,958 patients treated with RFA and 7,524 patients treated with surgical resection (Fig. 1). The details of these studies were listed in Table 1.
Data abstraction Two reviewers independently abstracted data in duplicate. The extracted data included first author, publication year, type of study, period of patient enrolment, cases of patients, gender, age, number of nodules, size of tumors; and result data include overall and recurrence-free survival rate of 1-, 3- and 5-year, recurrence rate of 1-, 2- and 3-year, mortality and morbidity rate. Any disagreements were resolved by discussion. Data analysis Binary end points (for example, survival and recurrence rate) were analyzed by calculating odds ratios (ORs) with 95 % confidence intervals (CIs). The heterogeneity of included studies was assessed using Chi square (χ2) and I2 statistics. Significant statistical heterogeneity between studies was
13
Overall survival Most studies reported the overall survival rate, twenty-one, twenty-two and eighteen articles reported 1-, 3- and 5-year survival rate, respectively. The patients of surgical resection group had higher overall survival rates than RFA group in 1-year (OR 0.71, 95 % CI 0.52–0.96) (Fig. 2), 3-year (OR 0.62, 95 % CI 0.49–0.78) and 5-year (OR 0.55, 95 % CI 0.47–0.66). Significant heterogeneity was found in the analysis of the 3- and 5-year overall survival rate but not 1-year overall survival rate (Table 2). Recurrence‑free survival Nineteen, eighteen and fifteen articles, respectively, reported the 1-, 3- and 5-year recurrence-free survival rate.
J Cancer Res Clin Oncol
significantly lower than in surgical resection group (OR 0.37, 95 % CI 0.24–0.58) (Fig. 5). Significant heterogeneity was found in the meta-analysis of mortality rate but not morbidity rate (Table 2). Subgroup analysis
Fig. 1 Flow diagram for identification of relevant clinical designs examining effect of RFA or surgical resection on the treatment of SHCC
A total of seven studies were included in the subgroup analysis of Child–Pugh class. The results suggested that RFA or surgical resection has the equally effect on the overall survival rate (1-, 3-, 5-year) and recurrence-free survival rate (1-, 5-year) when the patients have a liver function Child– Pugh class A (Table 3). Eight studies were included in the subgroup analysis of single nodule. Generally, the results suggested that surgical resection led to a better survival rate than RFA (Table 3). In brief, for single nodule ≤3 cm, significant difference was observed in the 5-year but not 1-year, 3-year overall survival rate between RFA and surgical resection groups. However, significant difference was also observed in 1- and 3-year but not 5-year recurrencefree survival rate; for single nodule >3 cm, significant difference was found in 1- and 3-year but not 5-year overall survival rate, nor in recurrence-free rate. In addition, for single tumor nodule, significant difference was observed in 3- and 5-year but not in 1-year overall survival rate as well as in 1-, 3- and 5-year recurrence-free rate; however, for multiple nodules, significant difference was only found in 5-year overall survival rate (Table 3). Sensitivity analysis and publication bias
The surgical resection group had a relatively higher recurrence-free survival rate than RFA group (OR 0.58, 95 % CI 0.45–0.76 for 1-year; OR 0.52, 95 % CI 0.40–0.68 for 3-year; OR 0.50, 95 % CI 0.34–0.76 for 5-year) (Fig. 3). Significant heterogeneity was found in the analysis of recurrence-free survival rate (Table 2). Recurrence Four studies reported the 1- and 3-year recurrence rate while only three studies reported the 2-year recurrence rate. No significant difference was observed between the two groups (OR 1.12, 95 % CI 0.78–1.59 for 1-year; OR 1.75, 95 % CI 1.28–2.39 for 2-year; OR 1.68, 95 % CI 1.30–2.17 for 3-year) (Fig. 4). No significant heterogeneity was found in the analysis of recurrence rate (Table 2). Complication Seven studies reported the mortality rate, and thirteen articles reported the morbidity rate. The mortality rate was of no difference between the two groups (OR 0.80, 95 % CI 0.30–2.15). However, the morbidity rate in RFA group was
We investigated the influence of single study on the overall pooled estimate by eliminating one study in each turn. No significant influence was observed for the results of meta-analysis except the 1-year overall survival rate. Publication bias was assessed using the Begg and Egger test. No significant publication bias was found for the overall survival rate, the recurrence-free survival rate and the morbidity rate. The funnel plot of 1-year overall survival rate was almost visually symmetrical (Fig. 6). The publication bias was not assessed for the recurrence rate and mortality rate, because only a small number of studies reported those outcomes.
Discussion Although meta-analysis has been commonly applied for evaluations of controversy trials especially of randomized controlled trials (RCTs), it is also available for non-randomized controlled trials (NRCTs), in which either the number or the sample size is insufficient for RCT (Mathurin et al. 2003). Our study suggested that surgical resection was
13
J Cancer Res Clin Oncol
Table 1 Baseline patient and tumor characteristics presented in the studies for SHCC, treated with radiofrequency ablation or surgical resection Author
Year
Sung N. H.
2005 NRCT
Chen M. S. Lupo L. Abu-Hilal M. Hiraoka A.
Design Study period Treatment
2006 RCT 2007 NRCT 2008 NRCT 2008 NRCT
1999–2001 1999–2004 1999–2006 1991–2003 2000–2007
Guglielmi A.
2008 NRCT
1996–2006
Ueno S.
2009 NRCT
2000–2005
Yun W. K. Hung H. H. Nishikawa H.
2010 RCT 2011 NRCT 2011 NRCT 2011 NRCT
2003–2005 2000–2007 2002–2007 2004–2010
2011 NRCT
1999–2006
Kong W.
2011 NRCT
2002–2009
Feng K. Wong K. M. Wang J. H.
Peng Z. W. Imai K.
2012 RCT 2012 NRCT 2012 NRCT
2012 NRCT 2012 NRCT
2005–2008 2004–2009 2002–2009
2003–2008 2000–2011
Pompili M. Guo W. X.
2013 NRCT 2013 NRCT 2013 NRCT
2001–2011 1999–2010 2002–2007
55 41/14
59.1 ± 9.6
NA
2.4 ± 0.6
49.2 ± 9.9
NA
2.5 ± 0.8
RFA
71 56/15
51.9 ± 11.2
NA
Surgical resection
90 75/15
49.4 ± 10.9
NA
RFA
60 47/13
68 (42–85)
NA
Surgical resection
42 33/9
67 (28–80)
NA
2013 NRCT
2004–2012
Hasegawa K.
2013 NRCT
2000–2005
≤3/>3; 37/34
≤3/>3; 42/48
3.65 (3.0–5.0)
4.0 (3.0–5.0)
RFA
34 27/7
65
NA
3.0 (2.0–5.0)
Surgical resection
34 26/8
67
NA
3.8 (1.3–5.0)
105 76/29
69.4 ± 9.1
NA
1.98 ± 0.52
Surgical resection
RFA
59 44/15
62.4 ± 10.6
NA
2.27 ± 0.55
RFA
32 NA
NA
NA
NA
31 NA
NA
NA
NA
RFA
155 100/55
66 (40–79)
101/54 (65/35 %)
2.0 ± 0.1
Surgical resection
123 82/41
67 (28–85)
110/13 (89/11 %)
2.7 ± 0.1
RFA
115 79/36
56.57 ± 14.30
84/31 (73/27 %)
NA
Surgical resection
115 85/30
55.91 ± 12.68
89/26 (77 %/23 %)
NA
RFA
255 197/58
57.0 ± 9.9
NA
2.1 ± 0.5
Surgical resection
215 171/44
51.7 ± 9.7
NA
2.1 ± 0.5
RFA
190 121/69
67.42 ± 11.45
152/38 (80/20 %)
2.37 ± 0.92
Surgical resection
229 184/45
60.07 ± 12.56
181/48 (79/21 %)
2.88 ± 1.06
RFA
162 95/67
68.4 ± 8.7
NA
1.99 ± 0.62
69 50/19
67.4 ± 9.7
NA
2.68 ± 0.49
RFA
236 145/91
67 (38–87)
NA
1.8 (0.8–3.0)
Surgical resection
138 101/37
2.0 (0.5–3.0)
62.5 (29–80)
NA
RFA
47 37/10
57 ± 14
40/7 (85/15 %)
Surgical resection
40 35/5
53 ± 13
38/2 (95/5 %)
RFA
84 79/5
51 (24–83)
48/36 (57/43 %)
Surgical resection
84 75/9
47(18–76)
52/32 (62/38 %)
≤2/2–5; 27/73 %
≤2/2–5; 21/79 % 2.4 ± 0.6
2.6 ± 0.8
RFA
36 18/18
63.5 ± 13
NA
1.9 ± 0.6
Surgical resection
46 30/16
55.1 ± 12
NA
2.1 ± 0.6
RFA
52 35/17
Surgical resection
52 38/14
RFA
254 161/93
Surgical resection
208 168/40
RFA
71 63/8
Surgical resection
74 65/9
RFA
≤60/>60; 29/23
≤60/>60; 35/17
NA
NA
NA
NA
≤60/>60; 85/169 173/81 (68 %/32 %)
NA
≤60/>60; 113/95 189/19 (91 %/9 %)
NA
53.1 ± 12.1
NA
NA
51.5 ± 12.1
NA
NA
82 46/36
67.6 ± 8.5
NA
1.87 ± 0.50
101 75/26
63.3 ± 9.7
NA
2.14 ± 0.55
RFA
60 38/22
65.6 ± 12
47/13 (78.3/21.7 %)
2.36 ± 0.94
Surgical resection
50 31/19
66.3 ± 1
39/11 (78/22 %)
3.07 ± 1.17
RFA
116 92/24
69 (38–85)
NA
2.3 (1.3–3.0)
Surgical resection
116 87/29
67 (41–83)
NA
2.3 (0.8–3.0)
RFA Surgical resection
Desiderio J.
Mean tumor size (cm)
93 69/24
Surgical resection Tohme S.
Tumor number (single/multiple)
RFA
Surgical resection Ikeda K.
Age (years)
Surgical resection
Surgical resection
Huang J.
Cases Sex (M/F)
RFA Surgical resection
56 (19–75)
63/31 (67/33 %)
102 94/8
94 78/16
52 (18–75)
75/27 (74/26 %)
44 35/9
64.4 ± 6.5
19/25 (43/57 %)
52 37/15
65.6 ± 4.8
22/30 (42/58 %)
≤3/>3; 62/32
≤3/>3; 75/27 NA
NA
RFA
5,548 3,569/1,979 69 (52–80)
4,068/1,480 (73/27 %) 2.0 (1.0–3.0)
Surgical resection
5,361 3,967/1,394 66 (48–77)
4,458/903 (83/17 %)
2.3 (1.2–3.0)
RFA Radiofrequency ablation, M/F male/female, NA not available, RCT randomized controlled trial, NRCT non-randomized controlled trial
13
J Cancer Res Clin Oncol
Fig. 2 The results of meta-analysis about 1-year overall survival rate. M–H Mantel–Haenszel test, RFA radiofrequency ablation
Table 2 Relevant results indicators of RFA versus surgical resection on the treatment of SHCC
T/P No. of trials/no. of patients, OR odds ratio, P–He* P value of heterogeneity
T/P
Results (%)
OR (95 % CI)
P value
P–He*
Model
RFA
Surgical resection
95.0 80.4 61.7
96.4 85.4 72.2
0.71 (0.52, 0.96) 0.62 (0.49, 0.78) 0.55 (0.47, 0.66)
0.03
Review – Cancer Research
Efficacy and safety of percutaneous radiofrequency ablation versus surgical resection for small hepatocellular carcinoma: a meta-analysis of 23 studies Qian Feng · Yugang Chi · Yanqian Liu · Ling Zhang · Qi Liu
Received: 2 March 2014 / Accepted: 9 May 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose The aim of our meta-analysis was to compare the efficacy and safety of radiofrequency ablation (RFA) versus surgical resection for patients with small hepatocellular carcinoma (SHCC). Methods Randomized controlled trials (RCTs) or retrospective studies comparing the RFA with surgical resection for patients with SHCC published from 2004 to 2014 were selected from database of PubMed, EMBASE and Cochrane library. The outcomes including overall survival rate, recurrence-free survival rate, recurrence rate and complications (mortality rate and morbidity rate) were abstracted. Individual and pooled odds ratio with 95 % confidence interval of each outcome was analyzed. Results Three RCTs and twenty retrospective studies were included with a total of 15,482 patients. The 1-, 3and 5-year overall survival rate and recurrence-free survival rate of surgical resection were significantly higher than RFA. The 2- and 3-year but not 1-year recurrence rate of RFA was significantly higher than surgical resection. The morbidity rate of complication in surgical resection group was higher than it in RFA group, but the mortality was not different between the two groups. Conclusion Surgical resection led to a higher overall survival and recurrence-free survival rate in treating SHCC. However, RFA led to a lower morbidity rate of complication than surgical resection.
Q. Feng · Y. Chi · Y. Liu · L. Zhang · Q. Liu (*) The Key Laboratory of Molecular Biology for Infectious Disease, Chinese Ministry of Education, Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, 74 Lin Jiang Road, Chongqing 400010, China e-mail: [email protected]
Keywords Radiofrequency ablation · Surgical resection · Small hepatocellular carcinoma · Meta-analysis
Introduction Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide, which leads to a 500,000 deaths per year. At the same time, 660,000 new cases were identified in the world every year with an increasing incidence (Llovet et al. 2003; Marrero 2013; Venook et al. 2010). Liver transplantation might be the best cure for patients with HCC, yet it is limited by the high cost and donor shortage. Surgical resection has been widely accepted for patients who are unwilling or unable to receive liver transplantations (Duffy et al. 2008). Recently, radiofrequency ablation (RFA) has attracted great attention to become a first-line treatment because of its safety, cost-effectiveness and minimal invasiveness (Rhim et al. 2010). A few of meta-analyses have been conducted to compare the efficacy and safety of the surgical resection with RFA in the treatment of patients with small hepatocellular carcinoma (SHCC) (Chen et al. 2006; Cho et al. 2011; Feng et al. 2012; Huang et al. 2010; Li et al. 2012; Xu et al. 2012; Zhou et al. 2010). But the results are still controversial. Interestingly, these studies have not mentioned the effect of characteristic of tumor on the treatment outcomes. Several RCTs and retrospective cohort studies were newly conducted regarding the curative effect of RFA and surgical resection in recent years. Herein, we performed this meta-analysis to compare RFA with surgical resection in the treatment of SHCC using these recently reported studies. Moreover, we also conducted two subgroup analysis based on characteristics of tumors to evaluate the effect
13
of single tumor size (≤3 or >3 cm) and number of tumor nodules (single or multiple) on the treatment outcomes.
Methods Study selection Two reviewers independently carried out a comprehensive search of PubMed, EMBASE and Cochrane library for relevant articles published January 1, 2004 to February 1, 2014. The key words in this strategy with MeSH heading: “radiofrequency ablation,” “surgical resection,” “hepatocellular carcinoma.” Only articles written in English were included in. The searches were limited to human subjects, and the research design type was RCTs or retrospective studies.
J Cancer Res Clin Oncol
identified when P 3 cm. All calculation was conducted using Revman 5.1 software if there is no special mention.
Results
Criteria for inclusion and exclusion
Selection of studies
For inclusion in the meta-analysis, a study had to fulfill the following criteria: (1) Patients involved in these studies had not treated with RFA or surgical resection before; (2) First RFA treatment was conducted by percutaneous; (3) All patients were suitable candidates for surgical resection and/ or RFA; (4) For similar studies reported by the same institution and/or authors, only the most recent study with high quality was included in this analysis; and (5) Included studies must report on at least one of the following outcomes: the overall and recurrence-free survival rate of 1-, 3- and 5-year, the recurrence rate of 1-, 2- and 3-year and complications (including mortality and morbidity). Briefly, according to Yao et al. (2001), SHCC was defined as a single HCC nodule of up to 6.5 cm, or with up to 3 lesions, the largest of which is no larger than 4.5 cm.
In accordance with the search, 38 potentially relevant publications were identified after the first round of selection. Among these publications, six were reported for one identical group of patients, eleven were comments or reviews. Two additional NRCT were identified by hand-searched. Finally, a total of 23 studies (3 RCTS and 20 retrospective studies) (Abu-Hilal et al. 2008; Chen et al. 2006; Desiderio et al. 2013; Feng et al. 2012; Guglielmi et al. 2008; Guo et al. 2013; Hasegawa et al. 2013; Hiraoka et al. 2008; Huang et al. 2010; Hung et al. 2011; Ikeda et al. 2011; Imai et al. 2012; Kong et al. 2011; Lupo et al. 2007; Nishikawa et al. 2011; Peng et al. 2012; Pompili et al. 2013; Sung et al. 2005; Tohme et al. 2013; Ueno et al. 2009; Wang et al. 2012; Wong et al. 2012; Yun et al. 2011) were selected, which involving 7,958 patients treated with RFA and 7,524 patients treated with surgical resection (Fig. 1). The details of these studies were listed in Table 1.
Data abstraction Two reviewers independently abstracted data in duplicate. The extracted data included first author, publication year, type of study, period of patient enrolment, cases of patients, gender, age, number of nodules, size of tumors; and result data include overall and recurrence-free survival rate of 1-, 3- and 5-year, recurrence rate of 1-, 2- and 3-year, mortality and morbidity rate. Any disagreements were resolved by discussion. Data analysis Binary end points (for example, survival and recurrence rate) were analyzed by calculating odds ratios (ORs) with 95 % confidence intervals (CIs). The heterogeneity of included studies was assessed using Chi square (χ2) and I2 statistics. Significant statistical heterogeneity between studies was
13
Overall survival Most studies reported the overall survival rate, twenty-one, twenty-two and eighteen articles reported 1-, 3- and 5-year survival rate, respectively. The patients of surgical resection group had higher overall survival rates than RFA group in 1-year (OR 0.71, 95 % CI 0.52–0.96) (Fig. 2), 3-year (OR 0.62, 95 % CI 0.49–0.78) and 5-year (OR 0.55, 95 % CI 0.47–0.66). Significant heterogeneity was found in the analysis of the 3- and 5-year overall survival rate but not 1-year overall survival rate (Table 2). Recurrence‑free survival Nineteen, eighteen and fifteen articles, respectively, reported the 1-, 3- and 5-year recurrence-free survival rate.
J Cancer Res Clin Oncol
significantly lower than in surgical resection group (OR 0.37, 95 % CI 0.24–0.58) (Fig. 5). Significant heterogeneity was found in the meta-analysis of mortality rate but not morbidity rate (Table 2). Subgroup analysis
Fig. 1 Flow diagram for identification of relevant clinical designs examining effect of RFA or surgical resection on the treatment of SHCC
A total of seven studies were included in the subgroup analysis of Child–Pugh class. The results suggested that RFA or surgical resection has the equally effect on the overall survival rate (1-, 3-, 5-year) and recurrence-free survival rate (1-, 5-year) when the patients have a liver function Child– Pugh class A (Table 3). Eight studies were included in the subgroup analysis of single nodule. Generally, the results suggested that surgical resection led to a better survival rate than RFA (Table 3). In brief, for single nodule ≤3 cm, significant difference was observed in the 5-year but not 1-year, 3-year overall survival rate between RFA and surgical resection groups. However, significant difference was also observed in 1- and 3-year but not 5-year recurrencefree survival rate; for single nodule >3 cm, significant difference was found in 1- and 3-year but not 5-year overall survival rate, nor in recurrence-free rate. In addition, for single tumor nodule, significant difference was observed in 3- and 5-year but not in 1-year overall survival rate as well as in 1-, 3- and 5-year recurrence-free rate; however, for multiple nodules, significant difference was only found in 5-year overall survival rate (Table 3). Sensitivity analysis and publication bias
The surgical resection group had a relatively higher recurrence-free survival rate than RFA group (OR 0.58, 95 % CI 0.45–0.76 for 1-year; OR 0.52, 95 % CI 0.40–0.68 for 3-year; OR 0.50, 95 % CI 0.34–0.76 for 5-year) (Fig. 3). Significant heterogeneity was found in the analysis of recurrence-free survival rate (Table 2). Recurrence Four studies reported the 1- and 3-year recurrence rate while only three studies reported the 2-year recurrence rate. No significant difference was observed between the two groups (OR 1.12, 95 % CI 0.78–1.59 for 1-year; OR 1.75, 95 % CI 1.28–2.39 for 2-year; OR 1.68, 95 % CI 1.30–2.17 for 3-year) (Fig. 4). No significant heterogeneity was found in the analysis of recurrence rate (Table 2). Complication Seven studies reported the mortality rate, and thirteen articles reported the morbidity rate. The mortality rate was of no difference between the two groups (OR 0.80, 95 % CI 0.30–2.15). However, the morbidity rate in RFA group was
We investigated the influence of single study on the overall pooled estimate by eliminating one study in each turn. No significant influence was observed for the results of meta-analysis except the 1-year overall survival rate. Publication bias was assessed using the Begg and Egger test. No significant publication bias was found for the overall survival rate, the recurrence-free survival rate and the morbidity rate. The funnel plot of 1-year overall survival rate was almost visually symmetrical (Fig. 6). The publication bias was not assessed for the recurrence rate and mortality rate, because only a small number of studies reported those outcomes.
Discussion Although meta-analysis has been commonly applied for evaluations of controversy trials especially of randomized controlled trials (RCTs), it is also available for non-randomized controlled trials (NRCTs), in which either the number or the sample size is insufficient for RCT (Mathurin et al. 2003). Our study suggested that surgical resection was
13
J Cancer Res Clin Oncol
Table 1 Baseline patient and tumor characteristics presented in the studies for SHCC, treated with radiofrequency ablation or surgical resection Author
Year
Sung N. H.
2005 NRCT
Chen M. S. Lupo L. Abu-Hilal M. Hiraoka A.
Design Study period Treatment
2006 RCT 2007 NRCT 2008 NRCT 2008 NRCT
1999–2001 1999–2004 1999–2006 1991–2003 2000–2007
Guglielmi A.
2008 NRCT
1996–2006
Ueno S.
2009 NRCT
2000–2005
Yun W. K. Hung H. H. Nishikawa H.
2010 RCT 2011 NRCT 2011 NRCT 2011 NRCT
2003–2005 2000–2007 2002–2007 2004–2010
2011 NRCT
1999–2006
Kong W.
2011 NRCT
2002–2009
Feng K. Wong K. M. Wang J. H.
Peng Z. W. Imai K.
2012 RCT 2012 NRCT 2012 NRCT
2012 NRCT 2012 NRCT
2005–2008 2004–2009 2002–2009
2003–2008 2000–2011
Pompili M. Guo W. X.
2013 NRCT 2013 NRCT 2013 NRCT
2001–2011 1999–2010 2002–2007
55 41/14
59.1 ± 9.6
NA
2.4 ± 0.6
49.2 ± 9.9
NA
2.5 ± 0.8
RFA
71 56/15
51.9 ± 11.2
NA
Surgical resection
90 75/15
49.4 ± 10.9
NA
RFA
60 47/13
68 (42–85)
NA
Surgical resection
42 33/9
67 (28–80)
NA
2013 NRCT
2004–2012
Hasegawa K.
2013 NRCT
2000–2005
≤3/>3; 37/34
≤3/>3; 42/48
3.65 (3.0–5.0)
4.0 (3.0–5.0)
RFA
34 27/7
65
NA
3.0 (2.0–5.0)
Surgical resection
34 26/8
67
NA
3.8 (1.3–5.0)
105 76/29
69.4 ± 9.1
NA
1.98 ± 0.52
Surgical resection
RFA
59 44/15
62.4 ± 10.6
NA
2.27 ± 0.55
RFA
32 NA
NA
NA
NA
31 NA
NA
NA
NA
RFA
155 100/55
66 (40–79)
101/54 (65/35 %)
2.0 ± 0.1
Surgical resection
123 82/41
67 (28–85)
110/13 (89/11 %)
2.7 ± 0.1
RFA
115 79/36
56.57 ± 14.30
84/31 (73/27 %)
NA
Surgical resection
115 85/30
55.91 ± 12.68
89/26 (77 %/23 %)
NA
RFA
255 197/58
57.0 ± 9.9
NA
2.1 ± 0.5
Surgical resection
215 171/44
51.7 ± 9.7
NA
2.1 ± 0.5
RFA
190 121/69
67.42 ± 11.45
152/38 (80/20 %)
2.37 ± 0.92
Surgical resection
229 184/45
60.07 ± 12.56
181/48 (79/21 %)
2.88 ± 1.06
RFA
162 95/67
68.4 ± 8.7
NA
1.99 ± 0.62
69 50/19
67.4 ± 9.7
NA
2.68 ± 0.49
RFA
236 145/91
67 (38–87)
NA
1.8 (0.8–3.0)
Surgical resection
138 101/37
2.0 (0.5–3.0)
62.5 (29–80)
NA
RFA
47 37/10
57 ± 14
40/7 (85/15 %)
Surgical resection
40 35/5
53 ± 13
38/2 (95/5 %)
RFA
84 79/5
51 (24–83)
48/36 (57/43 %)
Surgical resection
84 75/9
47(18–76)
52/32 (62/38 %)
≤2/2–5; 27/73 %
≤2/2–5; 21/79 % 2.4 ± 0.6
2.6 ± 0.8
RFA
36 18/18
63.5 ± 13
NA
1.9 ± 0.6
Surgical resection
46 30/16
55.1 ± 12
NA
2.1 ± 0.6
RFA
52 35/17
Surgical resection
52 38/14
RFA
254 161/93
Surgical resection
208 168/40
RFA
71 63/8
Surgical resection
74 65/9
RFA
≤60/>60; 29/23
≤60/>60; 35/17
NA
NA
NA
NA
≤60/>60; 85/169 173/81 (68 %/32 %)
NA
≤60/>60; 113/95 189/19 (91 %/9 %)
NA
53.1 ± 12.1
NA
NA
51.5 ± 12.1
NA
NA
82 46/36
67.6 ± 8.5
NA
1.87 ± 0.50
101 75/26
63.3 ± 9.7
NA
2.14 ± 0.55
RFA
60 38/22
65.6 ± 12
47/13 (78.3/21.7 %)
2.36 ± 0.94
Surgical resection
50 31/19
66.3 ± 1
39/11 (78/22 %)
3.07 ± 1.17
RFA
116 92/24
69 (38–85)
NA
2.3 (1.3–3.0)
Surgical resection
116 87/29
67 (41–83)
NA
2.3 (0.8–3.0)
RFA Surgical resection
Desiderio J.
Mean tumor size (cm)
93 69/24
Surgical resection Tohme S.
Tumor number (single/multiple)
RFA
Surgical resection Ikeda K.
Age (years)
Surgical resection
Surgical resection
Huang J.
Cases Sex (M/F)
RFA Surgical resection
56 (19–75)
63/31 (67/33 %)
102 94/8
94 78/16
52 (18–75)
75/27 (74/26 %)
44 35/9
64.4 ± 6.5
19/25 (43/57 %)
52 37/15
65.6 ± 4.8
22/30 (42/58 %)
≤3/>3; 62/32
≤3/>3; 75/27 NA
NA
RFA
5,548 3,569/1,979 69 (52–80)
4,068/1,480 (73/27 %) 2.0 (1.0–3.0)
Surgical resection
5,361 3,967/1,394 66 (48–77)
4,458/903 (83/17 %)
2.3 (1.2–3.0)
RFA Radiofrequency ablation, M/F male/female, NA not available, RCT randomized controlled trial, NRCT non-randomized controlled trial
13
J Cancer Res Clin Oncol
Fig. 2 The results of meta-analysis about 1-year overall survival rate. M–H Mantel–Haenszel test, RFA radiofrequency ablation
Table 2 Relevant results indicators of RFA versus surgical resection on the treatment of SHCC
T/P No. of trials/no. of patients, OR odds ratio, P–He* P value of heterogeneity
T/P
Results (%)
OR (95 % CI)
P value
P–He*
Model
RFA
Surgical resection
95.0 80.4 61.7
96.4 85.4 72.2
0.71 (0.52, 0.96) 0.62 (0.49, 0.78) 0.55 (0.47, 0.66)
0.03
