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

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 high-risk 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 evaporation 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.

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.

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.