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Podlasek, A.; Abdulla, M.; Broering, D.; Bzeizi, K. Radiofrequency Ablation in Hepatocellular Carcinoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/46846 (accessed on 13 July 2024).
Podlasek A, Abdulla M, Broering D, Bzeizi K. Radiofrequency Ablation in Hepatocellular Carcinoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/46846. Accessed July 13, 2024.
Podlasek, Anna, Maheeba Abdulla, Dieter Broering, Khalid Bzeizi. "Radiofrequency Ablation in Hepatocellular Carcinoma" Encyclopedia, https://encyclopedia.pub/entry/46846 (accessed July 13, 2024).
Podlasek, A., Abdulla, M., Broering, D., & Bzeizi, K. (2023, July 16). Radiofrequency Ablation in Hepatocellular Carcinoma. In Encyclopedia. https://encyclopedia.pub/entry/46846
Podlasek, Anna, et al. "Radiofrequency Ablation in Hepatocellular Carcinoma." Encyclopedia. Web. 16 July, 2023.
Radiofrequency Ablation in Hepatocellular Carcinoma
Edit

Hepatocellular carcinoma (HCC) is responsible for 90% of primary hepatic cancer cases, and its incidence with associated morbidity and mortality is growing worldwide. There are three main types of locoregional therapy: radiofrequency ablation, transarterial chemoembolisation, and transarterial radioembolisation.

hepatocellular carcinoma liver neoplasms radiofrequency ablation

1. Introduction

Hepatocellular carcinoma (HCC) is responsible for 90% of primary hepatic cancer cases. Its incidence is growing; currently, it is the fifth most common cancer worldwide, accounting for over 800,000 new cases in 2018 [1]. According to Cancer Today by WHO, it is the second most common oncological reason for death, with 50% of cases occurring in East Asia [1]. Its incidence tripled between 1980 and 2020 in the United States [2]. In Asia and Africa, HCC is usually associated with hepatitis B, whereas, in Europe, Japan, and the US, it is more often associated with hepatitis C, non-alcoholic fatty liver disease (NAFLD) and chronic alcohol abuse [1][3][4]. Other factors associated with HCC are genetic haemochromatosis, tyrosinosis, alpha-one antitrypsin deficiency, and primary biliary cirrhosis [3][5].
The diagnosis of HCC Is based on a combination of clinical, laboratory, radiographic, and histopathologic features [5]. The imaging diagnosis is based on the detection of the lesion’s vascularity [6]. Advanced imaging techniques, such as contrast-enhanced ultrasound (CEUS) and magnetic resonance imaging (MRI), have shown promising results in detecting and characterising HCC [6]. CEUS utilises microbubble-based contrast agents to provide real-time imaging of the tumour vasculature, allowing for improved lesion detection and differentiation from non-malignant liver lesions. On the other hand, MRI offers multiparametric imaging capabilities, including dynamic contrast-enhanced and diffusion-weighted imaging, enabling better tumour characterisation and assessment of treatment response [6][7]. Moreover, molecular imaging techniques, such as positron emission tomography (PET) using tracers like fluorodeoxyglucose (FDG), have shown potential in assessing HCC metabolic activity and predicting prognosis [6]. Recent advancements in imaging technology have also facilitated the integration of artificial intelligence (AI) algorithms to aid in diagnosing and staging HCC. These AI-based approaches leverage machine learning techniques and large datasets to improve the accuracy and efficiency of HCC diagnosis, allowing for earlier detection and intervention [8].
The tumour typically starts as a small nodule and grows during the asymptomatic phase [3]. It doubles in a median of 6 months [3]. The 1 year survival is 50–90% among untreated patients with Child–Pugh A and only 20% with Child–Pugh C [3]. The 5 year survival is low, at less than 20% worldwide [1]. Treatment is challenging as it depends on the tumour burden and the level of associated liver cirrhosis [1]. Unfortunately, despite the availability of targeted screening for HCC among high-risk groups and improvements in the prevention and treatment of risk factors, such as hepatitis B/C or NAFLD, mortality rates continue to rise [3][5][9][10]. Only 10–30% of HCC patients are candidates for surgical treatment—a curative option—because most cancers are recognised at an intermediate or advanced stage [11][12][13]. However, adding biochemical markers—such as alpha fetoprotein—significantly increases the early detection of HCC in clinical practice [14].
Globally, multiple staging systems are used to select the best treatment option for patients. The first one is the Okuda staging system, which is based on three factors: liver functional status (albumin, ascites, and bilirubin) and tumor stage (more or less than 50% of liver area involved). It is used in Japan and other countries. The second is the Barcelona Clinic Liver Cancer (BCLC) system, comprising tumour stage, liver function, and physical status. This system has been widely adopted in Europe for HCC staging and treatment [5]. Thirdly, the mUICC staging system, adopted by Korea, is based on the number of tumours, the diameter of the largest tumour, and vascular or bile duct invasion [5].
The stages of HCC vary worldwide in their presentation. In the UK, patients usually present with advanced disease, which is most often detected among people with already abnormal liver function. In contrast, 80% of HCC cases in Japan are detected when asymptomatic due to widespread screening of all people with liver cirrhosis [3]. At the time of diagnosis, 75% of HCC nodules are inoperable [15][16]. When tumours have not expanded outside the liver, locoregional treatments are applied to downstage and increase the number of liver transplant candidates or improve outcomes of patients undergoing liver resection [17][18][19][20]. The potential increase in early-stage detection based on imaging and biochemical markers may lead to increased utilisation of locoregional therapies, which currently play a leading role in 50–60% of HCC treatments [4]. The choice of liver transplantation, resection, percutaneous ablation, transarterial chemoembolisation (TACE), and/or radioembolisation treatment largely depends on tumour burden and location, as well as comorbidities [5][21]. Systemic therapy is used in moderate and advanced diseases. Classical oncological treatments, such as cytotoxic chemotherapy and hormonal therapy, have not proven successful in hepatic cancer [2]. In recent years, multiple immunotherapy options and drugs have become available [2]. The first systemic treatment for HCC was sorafenib—a multi-kinase inhibitor [2][4][21]. Around 50–60% of HCCs are managed primarily by locoregional therapies, defined as imaging-guided liver tumour-directed procedures [4]. They can be based on local ablation or intraarterial technique. The primary aim is to prolong survival by decreasing or, if feasible, eliminating the burden of hepatic tumours [4]. Patients with advanced diseases and those in the terminal stage should receive the best supportive, palliative care [5].
The treatment algorithm for HCC is constantly changing, mainly driven by the expansion of criteria for hepatic resection, advancement of locoregional and radiation therapies, and novel systemic therapies [5].
Optimal management of liver cancers depends on a multidisciplinary approach, with input and collaboration from diagnostic radiology, pathology, hepatology, transplant surgery, surgical oncology, medical oncology, radiation oncology, and interventional radiology to achieve individualised and evidence-driven patient care. Patient preferences should also be taken into consideration [7][9].
Current guidelines recommend 6 monthly surveillance of high-risk patients with ultrasound [22][23]. Further research is ongoing to optimise follow-up pathways, especially regarding MRI-based imaging [6][7]. mRECIST has become a standard tool for measuring radiological endpoints that are added to the standard cancer overall survival rates [24].

2. Radiofrequency Ablation (RFA)

Radiofrequency ablation was introduced in the 1990s as a treatment for osteoid osteomas [25]. It is now considered the standard treatment option among local ablative techniques for very-early-stage hepatic tumours (<2 cm) and for early-stage tumours that were disqualified from the surgical approach [4]. RFA has often been deemed a curative treatment modality, with a 5 year overall survival rate of around 40–70% [2][11][26]. It is also considered the most promising locoregional treatment [27][28][29][30][31]. The electrodes are inserted into pathological tissue, and, by delivering high-frequency alternating currents, they induce coagulative necrosis and tissue desiccation [27][28][29][30][31]. The major advantages of RFA are the potential for repeatability and safety for people with significant medical comorbidities due to the lack of a need for general anaesthesia [27][32]. There is also moderate evidence for using microwaves for ablation, and low evidence for using cryoablation and irreversible electroporation [4].
Local tumour progression post RFA is the Achilles heel of this well-established treatment modality [11][33]. The 5 year tumour recurrence has been reported to be as high as 80%. RFA also suffers from the following limitations: ablation volume up to 5 cm, limitations related to tumour localisation (i.e., hilar or subphrenic), heat-sink effect, spreading by intratumoral pressure during RFA, and tumour seeding [27][34][35][36][37].
Every medical procedure has inherent complication risks. RFA can be complicated by severe haemorrhage, RFA needle-track seeding, abscess formation, perforation of the gastrointestinal tract, liver failure, biloma, biliary stricture, portal vein thrombosis, and haemothorax or pneumothorax requiring drainage. It has been reported that complications affect 0.6–8.9% of procedures [27][38][39]. It is worth noting that the departments treating larger numbers of patients per month had a smaller number of complications and deaths [27][40].
There are conflicting reports in the literature comparing RFA to local surgical resection. Nevertheless, local surgical resection provides better long-term oncological outcomes [41][42].
Usually, RFA is performed under ultrasonographic guidance. Recently, six reported studies compared RFA using intraprocedural CT/MRI fusion imaging versus the standard of treatment. They suggested using fusion imaging to treat large tumours in difficult anatomical positions [43].
Advanced imaging with CT or MRI is typically used to assess treatment efficacy [27]. It is separated into the following categories:
  • Grade A—absolutely curative with 5 mm ablative margin around the entire tumour.
  • Grade B—relatively curative, mostly as grade A with some places with the lower margin.
  • Grade C—an incomplete ablative margin around the tumour, although no residual tumour is apparent.
  • Grade D—absolutely noncurative; the tumour was not completely ablated [27][44].
It was reported that liver ultrasound elastography with liver stiffness could be a reliable tool for predicting recurrence after RFA [45].
RFA is often compared with microwave frequency ablation, as they are primary types of percutaneous thermal ablation. Recent summaries of studies comparing those two techniques found little to no difference in their efficacy and safety [46][47][48][49][50][51][52].
Unanswered questions remain about combination techniques. A meta-analysis of 854 patients suggested that adding percutaneous ethanol injections improves overall survival; however, the evidence is heterogeneous [53]. A network meta-analysis of 3675 patients with advanced HCC revealed that the RAF with hepatic arterial infusion chemotherapy (HAIC) achieved the highest probability of 1 year overall survival and overall response rate [54]. TACE combined with RFA or MWA can provide significantly better overall survival (HR, 0.50, 95% confidence interval [CI]: 0.40–0.62), progression-free survival (HR, 0.47, 95% CI: 0.37–0.61), and local tumour control (OR, 0.36, 95% CI: 0.24–0.53) than TACE monotherapy for patients with intermediate-stage HCC, without increasing the risk of major complications (OR, 1.26, 95% CI: 0.74–2.16) [55]. Moreover, TACE + RFA offer comparable oncologic outcomes in patients with HCC compared to surgical resection and with the added benefit of lower morbidity [56].
There is continued effort to identify the best treatment technique for HCC. A study by Kwak et al. compared percutaneous and laparoscopic RAF for HCC in the subphrenic region. The laparoscopic approach resulted in fewer local tumour progressions and increased overall survival; therefore, it is proposed as a method of choice [57].
Within the last 3 years, researchers identified nine randomised controlled trials involving RFA for HCC. They are summarised in Table 1.
Table 1. Summary of the recent randomised controlled trials on radiofrequency ablation (RAF).
Author, Year, Trial Name Population Sample Size Intervention Comparison Outcome
Hendriks, 2022, HORA EST HCC Trial [58] HCC patients with a solitary lesion 2–5 cm, or a maximum of 3 lesions of ≤3 cm each NA Day 1 post RFA: selective infusion 99mTc-MAA), days 5–10 post RFA:
166Ho-MS administration
60 Gy, 90 Gy, and
120 Gy of 166Ho-MS
Perfused liver volume; final outcome not yet available
Radosevic, 2022 [59] HCC and patients with metastatic disease with 1.5–4 cm tumours, suitable for ablation 82 Ablation: MWA and RFA Between MWA and RFA in S.L.R., T.S., LTP After a median 2-year follow-up, MWA vs. RFA:
SLR: 0.5 vs. 0.5
p = 0.229
TS: 98% vs. 90%
p = 0.108
LTP: 21% vs. 12%
p = 0.238
Suh, 2021 [60] Eligible patients for RFA with H.C.C. 73 RFA: conventional or no NT-RFA using twin internally cooled wet electrodes in the bipolar mode Between NT-RFA and RFA groups in LTP rates The 1 and 3 year cumulative LTP rates were 5.6% in the NT-RFA group, and they were 11.8% and 21.3%, respectively, in the conventional RFA group (p = 0.073, log-rank)
Bockonry, 2022 [61] For HCC tumours sized 3.5–7 cm 20 Priming with 400 mg sorafenib BD for 10 days prior to RFA or placebo Priming versus placebo in volume and diameter of the RFA coagulation zone No increase in ablation volume/diameter; decreased blood perfusion to the tumour by 27.9% (p = 0.01)
Kim, 2021 [62] ≤2 recurrent H.C.C. of <3 cm 144 PBT or RFA PBT vs. RFA in LPFS PBT showed LPFS values that were noninferior to those for RFA
Choi, 2020 [63] Recurrent HCC after locoregional treatment 77 RFA: TICW, bipolar, using twin internally cooled wet electrodes or SC: switching monopolar RFA, using separable clustered electrodes TICW-RFA vs. SC-RFA
in minimum diameter
of the ablation zone
per unit ablation
time
No significant
Difference
Choi, 2021 [62] HCC 80 RFA; DSM: dual-switching monopolar; SSM conventional single-switching monopolar DSM-RFA vs. SSM-RFA in minimum diameter
of the ablation
zone per unit
ablation time
No significant
Difference
Chong, 2020, McRFA trial [64] HCC suitable for local ablation 93 Ablation: MWA and RFA MWA vs. RFA in treatment-related morbidity, as well as overall and disease-free survival No significant difference in the treatment-related morbidity or overall and disease-free survival; MWA had a significantly shorter overall ablation time when compared with RFA (12 min vs. 24 min, p < 0.001)
Paul, 2020 [65] HCC < 5 cm 55 PAAI, RFA PAAI vs. RFA in tumour response and survival rate Similar efficacy
99mTc-MAA, technetium-99-labeled microalbumin aggregates; 166Ho-MS, holmium-166; MWA, microwave ablation; SLR, short-to-long diameter ratio of ablation zone; TS, Primary technical success; LTP, cumulative local tumour progression; NT-RFA, no-touch RFA; PBT, proton beam therapy; LPFS, 2 year local progression-free survival; PAAI, percutaneous acetic acid.

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