Elsevier

Journal of Hepatology

Volume 52, Issue 3, March 2010, Pages 380-388
Journal of Hepatology

Research Article
Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid injection for hepatocelullar carcinoma: A meta-analysis

https://doi.org/10.1016/j.jhep.2009.12.004Get rights and content

Background & Aims

Radiofrequency ablation (RFA) is often the preferred local ablation therapy for hepatocellular carcinoma (HCC). Percutaneous ethanol injection (PEI) is less frequently used, and percutaneous acetic acid injection (PAI) has been mostly abandoned. Robust evidence showing benefit of one therapy versus another is lacking. Our aim was to evaluate the evidence comparing RFA, PEI and PAI using meta-analytical techniques.

Methods

Literature search was undertaken until December 2008 to identify comparative studies evaluating survival, recurrence, complete necrosis of tumour and complications. Only randomized clinical trials and quasi-randomized studies were included. Adjusted indirect comparisons were made when direct comparative studies were insufficient.

Results

Eight studies were identified: RFA vs. PEI (n = 5), PAI vs. PEI (n = 2) and RFA vs. PAI vs. PEI (n = 1) including 1035 patients with nine comparisons. RFA was superior to PEI for survival (OR 0.52; 95% CI 0.35–0.78; p = 0.001), complete necrosis of tumour and local recurrence. For tumours ⩽2 cm RFA was not significantly better than PEI. PAI did not differ significantly from PEI for survival (OR 0.55; 95% CI 0.23–1.33; p = 0.18), and local recurrence but required less sessions. PAI had similar outcomes, except local recurrence, to RFA in the direct and indirect comparison.

Conclusions

RFA seems to be a superior ablative therapy than PEI for HCC, particularly for tumours >2 cm. PAI did not differ significantly from PEI for all the outcomes evaluated. RFA and PAI have similar survival rates. For tumours ⩽2 cm outcome benefits comparing RFA and PEI are similar. PAI needs re-evaluation versus both PEI and RFA for tumours ⩽2 cm.

Introduction

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy worldwide and is the leading cause of death in patients with cirrhosis in Europe [1]. Early detection strategies have increased the number of small HCC amenable to curative treatment [1].

The Barcelona Clinic Liver Cancer classification [2] is the most frequently utilized classification for management of HCC [3]. With early-stage tumours, potentially curative therapies are used: ablation therapy with (1) percutaneous ethanol injection (PEI) (2) acetic acid injection (PAI) or (3) radiofrequency ablation (RFA), and surgical resection or liver transplantation. These treatments provide better survival rates at 5-years of 40–70% vs. <20% for untreated patients; however, they are applicable in only 30–40% of patients with HCC [4], [5].

Percutaneous ablation under ultrasound guidance is currently the best therapy for early-stage HCC when resection or liver transplantation is not possible. PEI with 95% alcohol and RFA result in complete necrosis of 95% of tumours ⩽2 cm [6], [7], [8], but 50% when of 3–5 cm diameter [6], [7], [8], with survival of >50% at 5 years [9]. The best candidates are in Child-Pugh A stage with small HCC [10].

PEI is cheap, well tolerated, simple to perform, and does not require a general anaesthetic. Severe complications are infrequent at 0–2%, including seeding [11]. Tumour necrosis is heterogeneous because ethanol does not diffuse uniformly within the nodule due to internal septa in 33% of nodules [12] and encapsulation of the tumour. Secondly, ethanol is diluted by vascular washout, and thirdly the needle is not centrally positioned [9].

Acetic acid used as a 50% solution is as cheap as alcohol and in contrast penetrates and destroys intra-nodule septa because of its low pH [13] and breaks down lipid and collagen fibres within intra-tumoural septa and capsules which often contain cancer cells. PAI is performed as easily and safely as PEI but requires fewer treatment sessions [14].

In rats, increasing concentrations of acetic acid were more effective with a plateau at 50% [14], [15], but optimal concentration has not been studied in man.

RFA induces temperature changes by using a high-frequency alternating electric current via electrodes placed within the tissue, generating areas of coagulative necrosis and desiccation [16]. As thermal power decreases in proportion to distance squared from the electrode, this limits the therapeutic effect in large tumours. In addition, some lesions are technically difficult to access particularly if close to large vessels or bile ducts, which act as heat sinks reducing thermal power.

RFA often requires intravenous sedation or general anaesthesia to limit pain. Mortality rate is 0.3–0.5% [17], [18] and major complications occur in 2–9% of patients with a median seeding rate of 0.61% (without biopsy) to 0.95% (with biopsy) [11].

Comparative studies suggest RFA may be superior to PEI/PAI due to larger and more predictable ablation volumes and fewer treatment sessions. In randomized trials, complete necrosis of target nodules is 90–98% with RFA, 80–95% with PEI, 90–95% with PAI [19]. Only one study from Japan University [20] has shown RFA to have a survival benefit compared to PEI. However, there is no systematic review showing that RFA results in improved time to progression compared to PEI/PAI, nor whether efficacy is related to size of the nodule.

Two recent meta-analyses only compared RFA with PEI [21], [22] and did not evaluate PAI. Secondly, they did not evaluate the comparison of RFA with PEI with respect to size, which is an important consideration given that surveillance picks up smaller and single tumours [23].

Therefore, we evaluated the available evidence comparing the efficacy of RFA, PEI and PAI for treatment of HCC using meta-analytical techniques.

Section snippets

Identification of trials

MEDLINE, Cochrane Controlled Trial Register (CENTRAL) and EMBASE databases were searched until December 2008. Comparative studies were identified using any of the following key words: hepatocellular carcinoma, HCC, hepatic tumour, liver tumour, hepatic cancer, liver cancer, RFA, radiofrequency ablation, PEI, percutaneous ethanol injection, PAI, or percutaneous acetic acid injection. There were no language restrictions. Only randomized clinical trials (RCTs) and quasi-randomized studies were

Description of studies

A total of 570 references were identified. The reference flow is shown in Fig. 1. A total of eight trials were identified. Five trials compared RFA vs. PEI [20], [33], [43], [44], [45], two compared PAI vs. PEI [13], [46] and one compared all three modalities [38], detailing three separate comparisons, evaluated separately in the meta-analysis. Important details about the included trials are shown in Table 1. The risks of bias in the trials included in the meta-analysis are detailed in Fig. 2.

Discussion

The meta-analysis shows conclusively that RFA is superior to PEI in terms of proportion dead, complete necrosis of targeted nodule, incidence of local recurrence, and number of treatment sessions. Moreover time to death and time to recurrence were significantly better in patients treated with RFA.

The subgroup analysis evaluating tumour size showed no difference in the survival estimates between PEI (n = 54) and RFA (n = 50) for HCC ⩽2 cm. For HCC >2 cm, RFA (n = 64) had better survival and less local

Acknowledgements

The authors who have taken part in this study declared that they do not have anything to declare regarding funding from industry or conflict of interest with respect to this manuscript.

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