Meta-analysis of radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma

Background There is no clear consensus on the better therapy [radiofrequency ablation (RFA) versus hepatic resection (HR)] for small hepatocellular carcinoma (HCC) eligible for surgical treatments. This study is a meta-analysis of the available evidence. Methods Systematic review and meta-analysis of trials comparing RFA with HR for small HCC published from 1997 to 2009 in PubMed and Medline. Pooled odds ratios (OR) with 95% confidence intervals (95% CI) were calculated using either the fixed effects model or random effects model. Results One randomized controlled trial, and 9 nonrandomized controlled trials studies were included in this analysis. These studies included a total of 1411 patients: 744 treated with RFA and 667 treated with HR. The overall survival was significantly higher in patients treated with HR than in those treated with RFA at 3 years (OR: 0.56, 95% CI: 0.44-0.71), and at 5 year (OR: 0.60, 95% CI: 0.36-1.01). RFA has a higher rates of local intrahepatic recurrence compared to HR (OR: 4.50, 95% CI: 2.45-8.27). In the HR group the 1, 3, and 5 years disease -free survival rates were significantly better than in the HR-treated patients (respectively: OR: 0.54, 95% CI: 0.35-0.84; OR: 0.44, 95% CI: 0.28-0.68; OR: 0.64, 95% CI: 0.42-0.99). The postoperative morbidity was higher with HR (OR: 0.29, 95% CI: 0.13-0.65), but no significant differences were found concerning mortality. For tumors ≤ 3 cm HR did not differ significantly from RFA for survival, as reported in three NRCTs . Conclusions HR was superior to RFA in the treatment of patients with small HCC eligible for surgical treatments, particularly for tumors > 3 cm. However, the findings have to be carefully interpreted due to the lower level of evidence.


Background
Hepatocellular carcinoma (HCC) is the fifth most common cancers in the world, with an estimated 500,000 deaths per year [1]. Advances in diagnostic imaging and widespread application of screening programs in highrisk populations have allowed detection of small HCC, which can be curable by partial hepatic resection (HR), liver transplantation, or local ablation therapies. Out of these, liver transplantation, which offers the potential to both resect the entire potentially tumor-bearing liver and eliminate the cirrhosis, achieves the best results but can be offered only to a minority of patients because of the shortage of donors and high cost [2]. Therefore, HR has generally been accepted as the first treatment of choice for HCC in many centers. Nevertheless, the associated cirrhosis limits the extent of surgery and thus increases the risk of postoperative liver failure. So, many nonsurgical ablative methods have been developed, such as cryoablation [3], percutaneous ethanol injection (PEI) [4], acetic acid injection [5], radiofrequency ablation (RFA) [6], microwave coagulation [7], and transcatheter arterial chemoembolization (TACE) [8].
Among these therapies, RFA is a promising and recently developed ablation technique. It induces deep thermal injury in hepatic tissue while sparing the normal parenchyma. Its basic principle includes generation of high-frequency alternating current which causes ionic agitation and conversion to heat, with subsequent evapo-ration of intracellular water which leads to irreversible cellular changes, including intracellular protein denaturation, melting of membrane lipid bilayers, and coagulative necrosis of individual tumor cells. RFA was recommended as the best treatment option for patients with early stage HCC who are not suitable for resection or transplantation in addition to PEI in the 2005 practice guidelines issued by the American Association for the Study of Liver Diseases [9]. Recently, a meta-analysis of randomized controlled trial (RCT) showed that RFA ablation is superior to PEI in the treatment of patients with relatively preserved liver function and early-stage non-surgical HCC with respect to survival and local control of the disease [10]. In contrast, whether RFA or HR is the better treatment for HCC eligible for surgical treatments has long been debated. Several RCT and non-randomized controlled trial (NRCT) have been published in an attempt to answer the above question. What follows is a meta-analysis of these studies.

Study selection
Electronic searches were performed of the PubMed and Medline from January 1997 to November 2009. The following Mesh search headings were used: "radiofrequency ablation," "hepatocellular carcinoma". Reference lists of all retrieved articles were manual searched for additional studies. No language restrictions were made.

Data extraction
Two reviewers (BL and DX, respectively) independently extracted the following parameters from each study: 1) first author and year of publication; 2) number of patients, patients characteristics, study design; and lastly, 3) treatment outcome. All relevant text, tables and figures were reviewed for data extraction. Discrepancies between the two reviewers were resolved by discussion and consensus.

Criteria for inclusion and exclusion
For inclusion in the meta-analysis, a study had to fulfil the following criteria: 1) compare the initial therapy effects of RFA and HR for the treatment of small HCC, regardless of the etiology of liver disease, cirrhotics status, or differences in viral hepatitis; 2) report on at least one of the outcome measures mentioned below; 3) clearly document indications for RFA and HR; 4) In dual (or multiple) studies were reported by the same institution and/or authors, either the one of higher quality or the most recent publication was included in the analysis. The primary endpoints were overall survival at 1, 3, and 5 years, and local recurrence. The secondary endpoints were disease-free survival at 1, 3, and 5 years, morbidity, and mortality.
Small HCC are defined according to the criteria developed by Yao et al. [11] from the University of California, San Francisco, 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.
Abstracts, letters, editorials and expert opinions, reviews without original data, case reports and studies lacking control groups were excluded. The following studies were also excluded: 1) those dealing with unresectable HCC or HCC recurrence after hepatectomy; 2) those with no clearly reported outcomes of interest; 3) those evaluating patients with cholangiocellular carcinomas or liver metastases.

Statistical methods
The meta-analysis was performed using the Review Manager (RevMan) software, version 4.2.7. All analyses were performed on dichotomous outcomes. Pooled odds ratios (OR) with 95% confidence intervals (95% CI) were calculated using either the fixed effects model or random effects model. Heterogeneity was evaluated by χ2 and I 2 . I 2 < 25% and I 2 > 50% reflect small and large inconsistency, respectively. P < 0.05 was considered significant.

Intrahepatic recurrence
The pooled analysis of the 5 studies furnishing data showed that RFA has a higher rates of local intrahepatic recurrence compared to HR (OR: 4.50, 95% CI: 2.45-8.27) ( Figure 2). No differences were found between the two groups with respect to the distant intrahepatic recurrence ( Table 2).

Disease-free survival
As Table 2 shows, our results indicate that 1, 3 and 5 year disease-free survival rates were significantly higher in the HR group.

Safety
The rate of postoperative morbidity was significantly higher in patients treated with HR than in those treated with RFA (six trials reported this data, OR: 0.29, 95% CI: 0.13-0.65), but no differences were found between the two groups with respect to postoperative mortality (all trials reported this data, OR: 0.36, 95% CI: 0.10-1.27). There were 1 death reported in the RFA group, and 6 in the HR group, giving a mean mortality rate of 0.1 per cent and 0.8 per cent, respectively ( Table 2).

Comparison between the two groups in HCCs ≤ 3 cm
Three NRCTs compared RFA versus HR for patients with tumors ≤ 3 cm. Of these, two studies included only patients with single tumor [27,28]. There was no significant difference in overall and disease -free survival between the groups at 1, 3, and 5 years in each included study (Table 3). In the further analysis, survival of patients with single or multiple tumors was similar in the two treatment groups, as reported by Vivarelli et al. [21]. Thus, we did not perform a meta-analysis of these studies.

Discussion
Meta-analysis, a quantitative technique for therapeutic evaluation, may be used when controversy persists after several trials. Although meta-analysis has traditionally been applied and is best confined to RCT, meta-analytical techniques using NRCT might be a valid method in some clinical settings in which either the number or the sample size of RCT is insufficient [31]. This meta-analysis shows that in patients with small HCC the treatment with HR is superior to treatment with RFA. HR had a significant better survival in terms of overall survival at 3, and 5 years, and disease-free survival at 1, 3, and 5 years. The difference at 5 years overall survival was marginally significant due to the number of studies furnishing combinable data on this outcome is limited. Although the only RCT shows nearly equivalent survival with the two treatments, however, in this study 19 of 90 patients (21%) who were randomized for RFA converted to HR [25].
High rate of intrhepatic recurrence after ablation therapies and/or surgical resection is the main cause of late death of patients with HCC. In current study, local recurrence was found to be more frequent after RFA than after HR. Local recurrences after RFA may be attributable to insufficient ablation of the primary tumor and/or the presence of tumor venous invasion in the adjacent liver. Surgical resection could remove the primary tumor and venous tumor thrombi [12]. This may explain the better outcomes following HR.  As regards the distant recurrence, no differences were found between the two groups. This fnding is reasonable because the occurrence of distant recurrence is correlated with the host factors and initial tumor factors [32], and the treatment does not affect this outcome.
Although the overall rate of postoperative morbidity was 32.5% in patients treated with HR, which is significantly higher than in those treated with RFA. However, these rates do not translate into an increase in mortality.
The results of this meta-analysis should be interpreted with caution for several reasons. First, the majority of data in the present study comes from NRCTs, and the overall level of clinical evidence is low. Second, there are important heterogeneity between two groups. This could be due to a bias in patient selection in several series in terms of patient demographics and tumor characteristics. Patients undergoing RFA had a few less favourable characteristics such as old age, multiple nodules, severe chronic liver disease, high serum level of alpha-fetoprotein and aspartate aminotransferase level [22,25,27,28]. However, Guglielmi et al. [27] found that these biases did not influence the statistical analysis in the subgroups and in the multivariate analyses. We applied a random effect model to take between study variation into consideration. This does not necessarily rule out the effect of heterogeneity between studies, but one may expect a very limited influence.
Third, RFA can be performed by percutaneous, laparoscopic or open approaches. Laparoscopic and open approaches increase the chance of detection of unknown intrahepatic and extrahepatic tumors because they allow complete abdominal exploration and intraoperative ultrasound assessment. The additional advantages of open and laparoscopic approaches are the accurate placement of electrodes and the possible treatment of tumors in percutaneously inaccessible areas of the liver and tumors in close proximity to or invading the adjacent organs [6]. On the other hand, several different RFA systems were used in the treatment centers, such as RITA Medical System (Mountain View, CA), Radionics (Burlington, MA) and Valleylab (Boulder, CO). Different approaches and RFA systems would also impact on the pooling of data and interpretation of results. Unfortunately, we failed to find any study that compared the outcomes of different approaches and RFA systems on therapy efficacy of HCC. Thus, we were not able to assess the influence of these factors.
Vascular invasion is a well-established prognostic indicator of HCC. Considering that vascular invasion was less frequent in tumors ≤ 3 cm [33], this may explain equivalent survival outcome between two groups, as reported in 3 trials. RFA appears to be an effective alternative treatments modality for HCC ≤ 3 cm. However, the only three studies containing 270 patients make the interpretation of these results insufficient. Recently, in a large, prospective study from the Liver Cancer Study Group of Japan, 7185 patients with no more than 3 tumors (≤ 3 cm) were classified into either a resection (n = 2857), RFA (n = 3022), or PEI group (n = 1306). The comparison of all three groups showed that surgical resection may be superior to ablation with respect to the prevention of recurrence [20]. Thus, the efficacy compared to HR or ablation in the treatment for HCC ≤ 3 cm still is a matter of discussion and further studies are required to provide more adequate data answer this question.

Conclusions
HR was superior to RFA in the treatment of patients with small HCC eligible for surgical treatments, particularly for tumors > 3 cm. However, the findings have to be carefully interpreted due to the lower level of evidence. Further RCT are needed to define the exact value of HR and RFA for small HCC, even for tumors ≤ 3 cm.