Microwave ablation is superior to radiofrequency ablation in the treatment of hepatocellular carcinoma below 5 cm - A systematic review and meta-analysis

Abstract

The purpose of this study was to systematically evaluate the prognosis of patients with hepatocellular carcinoma (HCC) smaller than 5 cm using microwave ablation (MWA) versus radiofrequency ablation (RFA). PubMed, Cochrane Library and Embase databases were searched for studies reporting comparisons of two interventions (MWA versus RFA) for patients with early-stage HCC published up to 31 December, 2022. The analysis evaluated the recurrence-free survival (RFS), overall survival (OS) and complications. A total of 894 patients were enrolled in six studies (two randomised controlled trials and four propensity score cohort studies). There were 446 patients in the MWA group and 448 patients in the RFA group. Compared with RFA, MWA had a significant advantage in the post-operative 1-, 2-, 3- and 5-year RFS (odds ratios [OR] = 0.58, 95% confidence interval [CI]: 0.40, 0.84; OR = 0.60, 95% CI: 0.45, 0.80; OR = 0.56, 95% CI: 0.33, 0.93; and OR = 0.44, 95% CI: 0.30, 0.65). The OS of MWA was significantly higher than that of RFA in 5 years after ablation (OR = 0.48, 95% CI: 0.34, 0.68). Moreover, MWA had an advantage in the incidence of complications (OR = 2.23, 95% CI: 1.16, 4.29). In the comparison of percutaneous MWA and RFA in the treatment of HCC with a diameter smaller than 5 cm, MWA may have more advantages in improving the prognosis.

INTRODUCTION

Hepatocellular carcinoma (HCC) accounts for 80–85% of primary liver cancer, with the sixth highest incidence and the third highest mortality rate in the world.[1,2] The main characteristics of HCC are a strong ability of invasion and metastasis and poor prognosis. For the treatment of liver cancer, liver transplantation is the first choice only if the liver is cirrhotic and resection cannot be done due to the risk of hepatic decompensation.[3] However, radiofrequency ablation (RFA) is the mainstream treatment for HCC smaller than 5 cm, and microwave ablation (MWA) is a feasible alternative.[4-6]

MWA will eventually lead to coagulative necrosis, large ablation volume and short ablation time, which rely on electromagnetic energy to heat the tissue quickly and evenly. RFA is the heat generated by the transmission of current in the range of radio frequency through the needle electrode, which leads to a slow and steady rise in temperature in the range of 60°C–100°C, resulting in coagulative necrosis of the tissue. A multi-centre retrospective study by Han et al. showed that there was no significant difference in post-ablative recurrence-free survival (RFS) and overall survival (OS) between the two ablation procedures in patients with HCC.[7] However, Ricci et al. believed that MWA has superiority compared to RFA in 1-year OS in patients with HCC.[8] Two studies have compared the differences of the two ablations in the prognosis for early-stage HCC; however, the conclusions are vague.[9,10] One was a meta-analysis of randomised controlled trials (RCTs), which included fewer studies on long-term prognosis. The other one was a meta-analysis of RCTs and cohort studies, which ensured a large sample size; however, it was not known whether the patient’s baseline characteristics are comparable. In the real scene, experts do not agree on the choice of these two ablation methods. Therefore, we included the propensity score cohort studies (PSCs) and RCTs to minimise the bias caused by the unequal baseline characteristics of the two groups on the premise of ensuring the sample size.

MATERIALS AND METHODS

Search strategy

The meta-analysis was performed based on the PRISMA Statement for reporting systematic reviews and meta-analyses of studies that evaluate the health-care interventions: explanation and elaboration.[11] Two researchers conducted independent searches under the guidance of an experienced expert to determine the final search strategy. PubMed, Cochrane Library and Embase databases were searched, using a search strategy that combined keywords and MeSH subject titles based on ‘HCC’, ‘microwave ablation’ and ‘RFA’. The search included papers published between the establishment of the databases to 31 December, 2022.

Inclusion criteria and exclusion criteria

Literature inclusion criteria: (1) study type: RCTs and PSCs were included; (2) subjects: HCC patients over 18 years old, regardless of gender, race and aetiology; (3) intervention measures: microwave ablation; (4) the included patients were diagnosed as HCC according to imaging or clinical diagnoses with Child-Pugh grade A or B, whose tumour diameter was smaller than 5 cm and (5) the study reported outcomes, including RFS, OS and/or complications. Exclusion criteria: (1) reviews, comments, letters and case reports; (2) non-English literature, duplicate publications or conference abstracts; (3) studies on laparoscopic ablation; (4) studies on animals and (5) studies that receive other treatments before ablation, such as transcatheter arterial chemoembolisation (TACE) or hepatectomy.

Data extraction and bias assessment

After importing the retrieved literature into EndNote X9.3 literature management software, duplications were removed. Then, two researchers independently screened the literature according to the pre-defined inclusion and exclusion criteria to finalise the papers included in the study. Any disagreements were resolved through consultation or discussion with experts. The data were extracted from the included literature using a pre-developed data extraction form, which included basic information (author, age, sample size, demographic characteristics, laboratory tests and tumour characteristics) about the included studies, outcomes (RFS, OS and complications) and assessment of the risk of bias. Finally, the two researchers reviewed the data, and any disagreements were resolved through discussion. The quality of the studies was evaluated based on the Newcastle-Ottawa Scale.[12]

Outcome assessment

The main outcome was RFS, and the secondary outcomes were OS and complications. RFS was defined as the proportion of patients with local tumour recurrence at different time points (1-, 2- and 3-year), and OS was defined as the proportion of patients who were surviving at different time points (1-, 2-, 3- and 5-year). Complications were assessed according to the image-guided tumour ablation: standardisation of terminology and reporting criteria – a 10-year update.[13]

Statistical analysis

We assessed the heterogeneity of the included studies using I2. If I2 ≤50%, a meta-analysis with low heterogeneity, and if 50% ≤I2 ≤ 100%, a meta-analysis with high heterogeneity. Due to the lack of included studies, the odds ratios (OR) of the random-effects model based on random effect model were applied to reduce the accuracy of effect estimation. To evaluate the differences in baseline data, continuous variables were expressed as mean differences, and binary variables were expressed as OR and 95% confidence intervals (CIs). In our study, due to the limitation of the number of studies included, we were unable to evaluate publication bias and meta-regression to determine the source of heterogeneity when the heterogeneity is high. StataSE-15.1 (StataCorp., LLC, College Station, TX) was used for the statistical analyses.

RESULTS

Characteristics of the included literature and assessment of bias

As shown in Figure 1, a total of 1278 papers were searched, with 466 duplicate publications and 806 publications that did not meet the pre-defined inclusion criteria being excluded. Finally, six studies meeting the inclusion criteria were included,[14-19] which involved 894 patients (MWA 446 patients vs. RFA 448 patients). The quality and characteristics of the included studies are summarised in Table 1. Of course, six studies were included, four[16-19] in China, one in Egypt[15] and one in France.[14] Five of the included[14-16,18,19] studies reported Milan standard HCC, and only one study[17] was not Milan standard, but the tumour diameter was smaller than 5 cm. There were two RCTs[14,15] and four PSCs.[16-19] The mean ages of the included patients ranged from 42.2 to 69 years in the MWA group and from 38.1 to 67.9 years in the RFA group. All studies included more males than females (84.0% vs. 16.0%).

Figure 1.

The PRISMA flowchart for the selection of the studies. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Table 1.

Basic characteristics of the population included

Study	Country	Research type	MWA (n)	RFA (n)	Quality evaluation (ROB2.0/NOS)
Violi	France	RCT	28	28	Some concerns
Kamal	Egypt	RCT	71	73	High risk
Feng	China	PSC	55	55	7
Liu	China	PSC	123	123	8
An	China	PSC	100	100	8
Zheng	China	PSC	69	69	8

MWA: Microwave ablation, RFA: Radiofrequency ablation, RCT: Randomised controlled trial, PSC: Propensity score cohort study, ROB: Risk of bias, NOS: Newcastle-Ottawa Scale

The baseline characteristics of the population are shown in Table 2. No significant difference in baseline characteristics was observed. The baseline of patients in the two groups was comparable.

Table 2.

Basic characteristics of the population included

	MWA (%)	RFA (%)	MD	OR	CI 95%	P
Demographic characteristics and pre-operative evaluation
Male	373 (91.0)	378 (92.4)		0.99	0.82–1.20	0.996
Age (year)			0.06		−0.22–0.35	0.669
HBV	185 (72.8)	213 (79.2)		0.85	0.53–1.37	0.057
HCV	33 (22.2)	46 (20.6)		0.99	0.60–1.64	0.778
Cirrhosis	255 (46.4)	259 (46.6)		0.99	0.78–1.26	0.998
ALB			0.34		−0.24–0.91	0.253
Child-Pugh A	281 (86.7)	272 (83.7)		1.04	0.83–1.30	0.999
Child-Pugh B	42 (13.0)	53 (16.3)		0.81	0.52–1.26	0.840
Tumour characteristics
Diameter			0.14		−0.11–0.39	0.934
Single	368 (90.4)	367 (90.2)		1.01	0.83–1.22	0.998
AFP			0.16		−0.14–0.47	0.296

MWA: Microwave ablation, RFA: Radiofrequency ablation, MD: Mean difference, OR: Odds radio, CI: Confidence intervals, HBV: Hepatitis B virus, HCV: Hepatitis C virus, ALB: Albumen, AFP: Alpha-fetoprotein

Main outcome

The effects of two ablation techniques on the post-operative RFS were compared in six of the included studies.[14-19] Figure 2 shows that compared with RFA, MWA had a significant advantage in the post-operative 1-, 2-, 3- and 5-year RFS (OR = 0.58, 95% CI: 0.40, 0.84; OR = 0.60, 95% CI: 0.45, 0.80; OR = 0.56, 95% CI: 0.33, 0.93; and OR = 0.44, 95% CI: 0.30, 0.65).

Figure 2.

Forest plots of pooled proportions of (a) one-year RFS between microwave ablation and RFA, (b) two-year RFS between microwave RFA and RFA, (c) three-year RFS between microwave RFA and RFA and (d) five-year RFS between microwave RFA and RFA. OR: Odds ratios, CI: Confidence interval, RFS: Recurrence-free survival, RFA: Radiofrequency ablation

Secondary outcomes

The effects of two ablation techniques on the post-operative OS were compared in three of the included studies.[14-19] There was no significant difference in 1-, 2- and 3-year OS between the two groups in Figure 3a-c. However, As shown in the Figure 3d, the OS of MWA was significantly higher than that of RFA in 5 years after ablation (OR=0.48, 95% CI: 0.34, 0.68). Three studies reported the incidence of complications in patients after treated by two types of ablations.[14-15,19] As Figure 4 shows, MWA had an advantage in the incidence of complications (OR = 2.23, 95% CI: 1.16, 4.29).

Figure 3.

Forest plots of pooled proportions of (a) one-year OS between microwave ablation and RFA, (b) two-year OS between microwave RFA and RFA, (c) three-year OS between microwave RFA and RFA and (d) five-year OS between microwave RFA and RFA. OR: Odds ratios, CI: Confidence interval, OS: Overall survival, RFA: Radiofrequency ablation

Figure 4.

Forest plots of pooled proportions of complications between microwave RFA and RFA. OR: Odds ratios, CI: Confidence interval, RFA: Radiofrequency ablation

DISCUSSION

RFA and microwave ablation are mainstream treatment options for patients with early HCC.[1,2] For the Indian people, the correct choice of ablation can reduce post-operative complications and improve the OS. Previously, some meta-analyses showed that there was no significant difference between MWA and RFA in the prognosis of early-stage HCC. We think that the standards of the literature included in these studies are not strict enough, and there may be some biased factors that affect the outcome of the prognosis. The factors include a combination of percutaneous and laparoscopic studies, tumour characteristics and other treatments (TACE, hepatectomy and chemotherapy) before ablation. The above factors may have a significant impact on the long-term prognosis in the comparison of MWA and RFA treatment. The difference between percutaneous and laparoscopic ablation is due to the location of the tumour and adjacent vital organs and blood vessels. In addition, the combination of other treatments before ablation has a great impact on the long-term prognosis of patients.

We have found several key results. First, compared with RFA, the RFS of MWA is significantly improved in patients with early-stage HCC. This is an interesting result, suggesting that MWA is more effective in reducing the risk of recurrence of HCC. This effect can lead to a higher transmission temperature of the target lesion, resulting in a number of necrosis of tumour cells and surrounding tissues. Secondly, the low tumor progression of hepatocellular carcinoma is related to the smallest ablation range.[20,21] Kim et al. believed that local tumour progression is related to ablation, and failure to establish an ablative margin of at least 3 mm is the only significant risk factor related to local tumour progression.[22] Therefore, there is no doubt that the large ablative margin reduces the rate of local tumour progression. Moreover, MWA overcomes the limitations of RFA on tissue carbonation and evaporation, and the energy consumption on large blood vessels (the so-called heat dissipation effect) is not obvious, eliminating the contraindication of tumour near the adjacent blood vessels, which is also one of his advantages.

Our study included early HCC smaller than 5 cm, and tumour progression became slow after ablation; hence, fewer patients in the two groups died in a short period, resulting in no difference in short-term OS between the two groups. This can be found in the study of Violi[14] and Kamal.[15] There was a significant difference in the 5-year OS rate between the two groups, which is related to the fact that MWA is superior to RFA in RFS. Although there are many treatments after HCC recurrence, the invasion and metastasis of the tumour are more serious than before. As our results show, a 5-year OS of MWA may be better than RFA. In addition, we believe that MWA has an advantage in complications that may be related to lower temperatures within the tumour and more energy around the tumour under the MWA because lower temperatures and a wider ablation range can reduce the post-operative complications and morbidity encountered.

Our study also has some limitations. First, due to the small number of studies included, the accuracy of the results needs to be further verified. Second, two of the six trials did not have a long-term follow-up period (<5 years). Thus, the RFS or OS might provide less evidence than the short-term results.

CONCLUSION

In the comparison of percutaneous MWA and RFA in the treatment of HCC with a diameter smaller than 5 cm, MWA may have more advantages in improving the prognosis.

Financial support and sponsorship

This work was supported by the Natural Science Foundation of Qinghai (grant number: 2019-ZJ-7031).

Conflicts of interest

There are no conflicts of interest.