Thermal ablation combined with different methods in the treatment of hepatocellular carcinoma：a literature review

ZHANG Man-jing，LI Ye-han，ZENG Chen，DU-Yong

(Department of Radiology，Affiliated Hospital of North Sichuan Medical College，Nanchong 637000，Sichuan，China)

【Abstract】Hepatocellular carcinoma(HCC)is one of the most common malignant tumors.Surgery，whether resection or transplant is a radical treatment，yet fewer than 20 percent of patients end up as candidates.Thermal ablation techniques，including radiofrequential ablation(RFA)and microwave ablation(MWA)，have been recognized as a therapeutic approach for patients with surgically unresectable hepatocellular carcinoma.In recent years，a number of combinations have emerged.Thus，the current status of thermal ablation combined with different methods in the treatment of hepatocellular carcinoma was reviewed.

【Key words】Hepatocellular carcinoma；Thermal ablation therapy；Radiofrequency ablation；Microwave ablation

Hepatocellular carcinoma(HCC)is the sixth most common type of cancer worldwide and the third leading cause of cancer-related death[1].There are a variety of treatment options for liver cancer，including minimally invasive local treatment，surgical resection(SR)and orthotopic liver transplantation(OLT)[2-3].For suitable patients，liver transplantation or local resection is considered as a first-line treatment.Unfortunately，about 80 percent of patients suffered from unresectable tumors[4].Liver transplantation is also a treatment option for HCC patients，but the shortage of organ donors limits its application[5].In recent years，locoregional minimally invasive treatment has become one of the hotspots for the treatment of unresectable liver cancer，including transcatheter arterial chemoembolization(TACE)，local ablation therapy，brachytherapy between radioactive particles，and high-intensity focused ultrasoundinvitro[6].Thermal ablation technique is a fundamental technique in the treatment of liver cancer，which can induce irreversible cell damage by extreme temperature.Radiofrequency ablation(RFA)and microwave ablation(MWA)are the most commonly used thermal ablation techniques[7].Many studies have demonstrated that local ablation in combination with other methods is a better solution for nonsurgical patients and for early lesions，which include RFA or MWA combined with TACE，RFA combined with SR，RFA combined with percutaneous ethanol injection(PEI)，and RFA combined with brachytherapy.This paper mainly focused on the recent progress of the application of various integrated techniques based on thermal ablation in the treatment of liver cancer.

1 Thermal ablation technique

1.1 RFA and MWA

The RFA has been demonstrated as a reliable method for creating thermally induced coagulation necrosis using either percutaneous approach with image-guidance or direct surgical placement of thin electrodes into tissues to be treated[8].In the early 1990s，Sandroetal[9]firstly reported the experiment of ultrasonic guidance treatment of liver cancer in animals，and less than 2 cm liver cancer can be treated by radiofrequency.Livraghietal[10]confirmed in a multicentre prospective clinical study in Italy that for resectable small HCC ≤2.0 cm，the 5-years survival rate of RFA alone was 68.5%，which was similar to that of surgical resection，while the postoperative complications were only 1.8%，which was significantly lower than that in the surgical resection group.Therefore，RFA may be an alternative to surgical resection for small HCC ≤2.0 cm in diameter was suggested.Microwave coagulation was developed during hepatectomy in the early 1980s to achieve hemostasis and had dramatically changed the field of thermal ablation in interventional oncology[11].Both RFA and MWA were thermal ablation techniques that use electromagnetic energy to cause rotation of water molecules.However，there was growing interest in the treatment of HCC by MWA because it could produce larger，hotter ablation zones in a shorter time period than RFA[12].MWA was a therapeutic rather than palliative technique when the microwave-generated coagulation tumor area was completely covered within the 5 mm safe margin[13].

1.2 RFA versus MWA

The RFA is one of the potential first-line therapeutic options.RFA could be as effective as surgical resection in terms of disease-free survival(DFS)and overall survival(OS)in patients with HCC[14-15].Generally，RFA could eliminate nodules less than 3 cm in size，but larger than 4 cm was considered ineffective[16].Relatively new MWA，another thermal technique，had been gaining popularity as an alternative to RFA[17].MWA had several advantages over RFA.The ablation time of MWA was less than that of RFA.In addition，MWA could increase the temperature of ablative zone.With the improvement of antennae and therapy strategies，MWA expanded the ablation area to treat tumors 5-8 cm in diameter[18].Despite its advantages，the efficacy and safety of MWA compared to RFA remains controversial.

The clinical data of 460 patients diagnosed with earlystage HCC and treated with percutaneous MWA or RFA were analyzed[19]，and they found that MWA was as safe and effective as RFA in treating earlystage HCC by OS，RFS，complete ablation，LTP，DR，and complication assessment.Similarly，Vogletal[20]retrospectively compared the therapeutic response of RFA and MWA therapy of HCC.Complete therapeutic response was noted in 84.4% of lesions treated with RFA，and 88.9% of lesions treated with MWA(P=0.6).There was no significant difference in rates of residual foci of HCC lesions between RFA and MWA groups(P=0.15).A meta-analysis involving 4 randomized controlled trials and 10 cohort studies showed no significant differences between MWA and RFA in CA，LR，DFS，OS，and major complication rates[21-22].Subgroup analysis showed no difference in CA and LR from percutaneous ablation for tumors ≥3 cm.Retrospective comparison between MWA and RFA in HCC using surgical methods showed that in the tumor larger than 3.5 cm subgroup analysis，5-years OS of MWA and RFA were 75.0% and 28.6%(P=0.022)，and DFS were 25.0% and 4.8%(P=0.207)，respectively.Xuetal[23]concluded that RFA ablated HCC nodules in small sizes had lower local recurrence rates.Meanwhile，MWA performed better in the ablation of small or large nodules，but had higher local recurrence rates than RFA.

2 RFA，MWA combined with TACE，SR，PEI or brachytherapy

2.1 RFA combined with TACE

The TACE is the standard therapy for intermediate-stage HCC.However，TACE is not considered a curative treatment.Therefore，an attempt has been made to add RFA to TACE(TACE+RFA)in clinical practice.Recent studies had reported that TACE+ RFA to treat HCC may have a synergistic effect[24-25].Songetal[26]retrospectively compared HCC recurrence and survival in patients treated with RFA after TACE versus patients treated with TACE or RFA alone.Compared with RFA alone or TACE alone，TACE+RFA was an effective treatment for early HCC，with a lower local tumor recurrence rate and a higher survival rate.In subgroup analysis，long-term survival in patients with tumor size<3 cm was significantly better in the TACE+RFA group than in the TACE or RFA group(P=0.017，P=0.004)respectively.The study reported that the addition of RFA to TACE improved cumulative overall and recurrence-free survival in patients with intermediate-stage HCC，especially in patients with AFP <100 ng/mL[27].Fengetal[28]demonstrated that TACE+RFA can effectively reduce the level of tumor active factor and improve micro-inflammation state of the body.At present，the TACE+RFA was regarded by domestic and foreign scholars as the best combination method for the treatment of middle and advanced HCC[29].

However，a study of 2019 including 34 combining TACE+RFA，87 TACE，and 136 ultrasound-guided RFA，were performed for the treatment of HCC(≤ 3 cm,3 or less).TACE+RFA appeared to result in more frequent patient discomfort requiring medication，longer hospital stay，and more frequent complications than TACE or RFA monotherapy.And 91%(31/34)of TACE+RFA group required medication due to patient discomfort.The frequency in the TACE group was significantly higher than that in TACE(OR=12.02，95% CI=2.52-57.35，P<0.001)or RFA group(OR=34.16，95%CI=7.27-160.52，P<0.001).Hospital stay of TACE+RFA was also significantly longer than that of TACE(r=0.323，P<0.001)or RFA(r=0.333，P<0.001).The frequency of overall complications of TACE+RFA was higher than TACE(P=0.006)or RFA(P=0.009).There was no significant difference in the incidence of major complications among the three groups(P=0.094)[30].

2.2 MWA combined with TACE

The MWA is an emerging therapeutic strategy for HCC.The efficacy of MWA in the treatment of tumors ≤5cm has been repeatedly demonstrated，and has been reported to be superior to RFA[31].In recent decades，the combination of TACE and MWA(TACE+MWA)has been tried in clinic.Early studies confirmed the feasibility of TACE+MWA therapy，but only for small tumors(< 3 cm)[32].Smolocketal[33]showed that TACE+MWA improved local control of 3-5cm HCC and prolonged LTP.Moreover，Chenetal[13]demonstrated that TACE+MWA also showed better TTP in subgroup analysis of tumors ≤3 cm(P<0.001)and 3-5 cm(P=0.004).Recently，a systematic review and meta-analysis showed no significant difference in the incidence of severe AE between the TACE+MWA group and the TACE group(P>0.05).However，subgroup analysis showed that patients with tumor size >5 cm were more likely to be benefited from TACE+MWA，rather than patients with tumor size ≤5 cm[34].Huetal[35]retrospectively evaluated the safety and long-term prognosis of TACE+MWA in a single stage for the treatment of HCC with a maximum diameter of 5.0-10.0 cm.The results showed that TACE+MWA was a safe，feasible and effective method for the treatment of 5.0-10.0 cm HCC patients with cirrhosis.The cumulative incidence of OS at 1-，2-and 3-years was 81%，68% and 49%，respectively.

2.3 TACE combined with RFA versus TACE combined with MWA

Although TACE with either RFA or MWA has shown a survival benefit compared with monotherapy，the debate of whether one of these percutaneous ablation combinations has a survival benefit over the other remains to be answered.Ginsburgetal[36]retrospectively analyzed the local tumor response，tumor and overall PFS，OS，or complications of conventional TACE with RFA versus conventional TACE with MWA in the treatment of HCC.The safety and efficacy of TACE with RFA and TACE with MWA were demonstrated.A randomized-controlled study involving 50 patients with nonresectable single-lesion HCC，demonstrated that MWA+TACE was more effective for tumor response than either RFA+TACE or TACE alone，and had the same complication rate as RFA+TACE，but less than TACE alone[5].In another retrospective study comparing TACE+MWA and TACE+RFA，TACE+MWA showed a higher tendency to provide complete response rates than TACE+RFA(P=0.06).The lesions of 3-5 cm were especially obvious(P=0.01).No difference was found between both lines of treatment for small tumors(less than 3 cm).Better response rates did not efficiently correlated with better survival rates[37].Preliminary data confirmed that TACE combined with either RFA or MWA was effective and promising in treating larger HCC lesions in a review article by Xuetal[23].More clinical data should be analyzed to provide clinicians with better strategies for the treatment of HCC.

2.4 RFA combined with SR

In patients with multiple independent segments of HCC，single-drug surgical resection was often difficult when the residual postoperative liver volume was underestimated.The combination therapy strategy of RFA and SR(SR+RFA)had been applied to some conventional unresectable multifocal liver malignancies，such as colorectal liver metastases，and had been proved to be safe and effective[38].It provided treatment options for multifocal HCC patients who had traditionally been considered unsuitable for SR.In a recent study，Hiraokaetal[39]retrospectively analyzed the efficacy of SR in combination with low invasive RFA in HCC patients with multiple tumors and good liver reserve，who could not be treated by SR alone.The 3-and 5-years OS rates in the SR group were 82.0% and 67.0%，and in the Comb group were 75.2% and 65.6%(P=0.244)，respectively.While the 3-and 5-years DFS rates in the SR group were 45.2% and 28.0%，and those in the Comb group were 37.3% and 23.3%(P=0.257)，respectively.They suggested that the combination of SR and complementary RFA may be an effective strategy for treating HCC patients with numerous multiple tumors，which were otherwise difficult to treat with SR or RFA alone.A recent study showed that SR+RFA provided better long-term survival than TACE in patients with unresectable，multifocal HCC that exceeded the Milan criteria.SR+RFA may serve as an alternative treatment for patients with multifocal HCC[40].

However，Zhouetal[41]conducted a propensity score matching analysis to evaluate the efficacy and safety of SR+RFA compared with SR for multifocal HCC with 2 or 3 nodules.The local recurrence rate of the SR+RFA group was significantly higher than that of the SR group(25.71%vs.14.32%，P=0.011).The incidence of postoperative complications was higher in SR+RFA group(P=0.003).Therefore，the application of SR+RFA should be carefully considered.

2.5 RFA combined with PEI

The PEI is a well-tolerated，low-cost treatment with fewer side effects，fewer complications，and lower tumor seeding rate，and has been shown to have the same OS and RFS as SR[42].In recent years，the combination of RFA and PEI has been used more in the treatment of HCC.Studies have shown that the use of alcohol prior to RFA helps to enhance the therapeutic advantages of RFA because the combined treatment requires less energy than RFA alone[43].While，Kalaretal[44]showed that the RFA combination with alcohol had no significant difference in local tumor recurrence and improved survival in patients with liver cancer compared with RFA alone.Similarly，Kaietal[45]found no significant difference in OS between patients treated with RFA alone and RFA combination with alcohol.

The survival of cirrhotic patients with HCC ≤4 cm who underwent RFA alone or RFA+PEI was studied，which found that the RFA + PEI produced a better OS and RFS rate than RFA alone in Chinese patients with HCC ≤4 cm.The 1-，3-and 5-years cumulative OS rates were 78.0%，44.4% and 30.1% in RFA group，and 88.2%，58.0% and 41.1% in RFA + PEI group，respectively.In addition，the 1-，3-and 5-years cumulative RFS rates were 77.0%，43.8%，and 29.2% in RFA group，and 87.9%，57.6%，and 38.4% in RFA+PEI group，respectively[46].It was reported that the RFA+PEI significantly improved OS and reduced the risk of local recurrence without increasing the rates of major complications according to a meta-analysis of Lietal[47].However，RFA+PEI treatment was associated with a higher incidence of fever.The incidence of fever and pain in the combination group were higher than that in the RFA group，but only the incidence of fever was significantly different(OR=2.27，95% CI=1.20-4.28，P=0.01).

2.6 RFA combined with brachytherapy

In the past three decades，the use of low-energy radionuclides such as iodine-125(125I)and palladium-103 has expanded the indications for brachytherapy[48].In terms of hepatopathy，studies have reported125I implanted seeds combined with RFA for the treatment of liver tumors[49].A prospective randomized controlled trial was conducted to assess whether combined RFA and percutaneous125I seed implantation resulted in better progression-free survival in HCC patients than RFA alone[50].The recurrence rates at 1-，3-，and 5-years in RFA-125I group were 4.5%，22.1% and 39.8%，and 14.8%，35.3%，and 57.4% in the RFA group，respectively.The 1-，3-，and 5-years survival rates of RFA-125I group were 100%，86.7% and 66.1%，and 95.6%，75.0%，and 47.0% in the RFA group，respectively.For patients with small HCC(≤3 cm)，there were significant differences in OS and cumulative recurrence between RFA-125I and RFA.Compared with RFA alone，RFA-125I therapy contributes to better local and intrahepatic tumor control and long-term survival.For multiple nodular hepatocellular carcinoma，it’s proved that RFA combined with125I seed could prolong the progression-free survival，with local control rate advantage，and got better short-term efficacy[51].The overall survival rates in RFA combined with125I seed group at 1-，2-and 3-years(94.4%，78.0%，and 66.8%，respectively)were higher than those in RFA group(88.5%，68.6%，and 57.1%，respectively).

A131I iodide labeled monoclonal antibody(mAb)(131I-ChTNT)targeting DNA exposed to degenerate tumor cells had been shown to be effective against a variety of solid tumors[52].In China，131I-ChTNT was first approved for the treatment of advanced lung cancer in 2006，followed by solid tumors[53].Patients treated with131I-ChTNT combined with RFA had significantly longer survival than those treated with RFA(P=0.052).The median progress-free survival of patients in the two groups was 23-and 7-months，respectively，and the difference was statistically significant(P=0.04).The results suggested that RFA combined with131I-ChTNT was superior to RFA alone in treating the primary HCC with the diameter ≥3 cm[54].

3 Conclusion

Over the past 2 decades，thermal ablation techniques，such as RFA and MWA，have become auspicious treatment options for patients with hepatic malignancies due to their minimal invasiveness，good and still improving efficacy，potential for repeated ablations，and low cost[55].However，the treatment of HCC has evolved from thermal ablation alone to the combination of other therapies，including TACE，SR，PEI and brachytherapy.The application of combined therapy will enrich the treatment strategies of HCC，greatly improve the efficacy of thermal ablation and the quality of life for HCC，and increase the survivals as well.With the development of treatment methods for liver cancer，thermal ablation may be combined with other new technologies to form new treatment schemes.