Abstract: We identified no trials comparing RFA versus placebo, no intervention, or liver transplantation. We identified and included 11 randomised clinical trials with 1819 participants that included four comparisons: RFA versus hepatic resection (three trials, 578 participants); RFA versus percutaneous ethanol injection (six trials, 1088 participants) including one three-armed trial that also investigated RFA versus acetic acid injection; RFA versus microwave ablation (one trial, 72 participants); and RFA versus laser ablation (one trial, 81 participants). Ten of the eleven included trials reported on the primary outcome of this review, overall survival. Rates of major complications or procedure-related deaths were reported in 10 trials. The overall risk of bias was considered low in five trials and high in six trials. For a subgroup analysis, we included only low risk of bias trials. Regarding the comparison RFA versus hepatic resection, there was moderate-quality evidence from two low risk of bias trials that hepatic resection seems more effective than RFA regarding overall survival (HR 0.56; 95% CI 0.40 to 0.78) and two-year survival (HR 0.38; 95% CI 0.17 to 0.84). However, if we included a third trial with high risk of bias, the difference became insignificant (overall survival: HR 0.71; 95% CI 0.44 to 1.15). With regards to the outcomes event-free survival and local progression, hepatic resection also yielded better results than RFA. However, the number of complications was higher in surgically treated participants (odds ratio (OR) 8.24; 95% CI 2.12 to 31.95). RFA seemed superior to percutaneous ethanol or acetic acid injection regarding overall survival (HR 1.64; 95% CI 1.31 to 2.07). The RR for mortality was also in favour of RFA, but did not reach statistical significance (150/490 (30.6%) people in the percutaneous ethanol or acetic acid group versus 119/496 (24.0%) people in the RFA group; RR 1.76; 95% CI 0.97 to 3.22). The proportion of adverse events did not differ significantly between RFA and percutaneous ethanol or acetic acid injection (HR 0.70; 95% CI 0.33 to 1.48). Trial sequential analyses revealed that the number of participants in the included trials was insufficient and that more trials are needed to assess the effects of RFA versus other interventions. The effects of RFA versus no intervention, chemotherapeutic treatment, or liver transplantation are unknown. We found moderate-quality evidence that hepatic resection is superior to RFA regarding survival. However, RFA might be associated with fewer complications and a shorter hospital stay than hepatic resection. We found moderate-quality evidence showing that RFA seems superior to percutaneous ethanol injection regarding survival. There were too sparse data to recommend or refute ablation achieved by techniques other than RFA. More randomised clinical trials with low risk of bias and low risks of random errors assessing the effect of RFA are needed.

Plain-language summary: The review authors searched the medical literature in order to clarify the role of RFA for the treatment of hepatocellular carcinoma and to compare its benefits and harms with no treatment, placebo (a pretend treatment), or other treatments (such as hepatic resection, percutaneous ethanol injection (PEI), percutaneous acetic acid injection (PAI), laser or microwave ablation, and liver transplantation). We looked for randomised clinical trials (where people were allocated at random to one of two or more treatments groups) of people with hepatocellular carcinoma who were able to receive RFA. Evidence is current to September 2013. We found no trials comparing RFA versus no intervention, placebo, chemotherapy, or liver transplantation. The review authors found moderate-quality evidence from two trials with low risk of bias (where there was a low risk of a flaw in study design, method of collecting or interpreting results) randomising 578 patients suggesting that hepatic resection yielded better results regarding overall survival (the length of time that the patient remains alive), event-free survival (time that the person remains free of cancer or a certain symptom relating to cancer), and progression (time that the patient lives with cancer without it getting worse) compared with RFA. However, as resection is a more invasive procedure, resection has an eight times higher risk of major complications compared with RFA. Resected patients stayed twice as long in the hospital as the RFA patients. Moderate-quality evidence suggested that RFA prolongs survival and decreases recurrences (where the cancer returns) compared with PEI or PAI. This conclusion was based on data from six randomised clinical trials with 1088 participants. Some patients developed side effects such as fever, rash, and pain. These occurred at the same frequency in both treatment groups. We calculated the number of patients that would be required to judge a relative risk reduction (relative risk is a comparison of the risk of an event happening for one treatment group compared with another treatment group) for survival of 20%. The review authors found that for both comparisons, that is RFA versus PEI or PAI, and RFA versus resection, the number of patients in the included trials was too low to reach valid conclusions. No firm conclusion can be drawn from the comparison of RFA against other interventional techniques or combination approaches. The information provided by the single trials was limited. More randomised clinical trials with low risks of bias (that is low risks of systematic errors, leading to overestimation of benefits and underestimation of harms) and low risk of play of chance (that is random errors, leading to overestimation or underestimation of benefits and harms) are required.