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Corresponding Author: Professor Wan Yee Lau, MD, FRCS, FACS, FRACS(Hon), Professor of Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China (Tel: +852-2632-2626; Fax: +852-2632-5459; Email: josephlau@cuhk.edu.hk)

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

Local ablative therapy is used in treating liver tumors by either injection of cytotoxic agents (chemicals, radioactive isotopes, hyperthermic agents or chemotherapeutic agents) or application of an energy source to achieve thermal ablation, cryoablation or conformal external beam radiation (Table 1).

There are many advantages of local ablative therapy. The treatment is minimally invasive with little damage to surrounding liver parenchyma, little side effects, safe and can be carried out under local anesthesia or intravenous sedation.

Two systematic reviews showed that radiofrequency ablation (RFA) is better than other forms of local ablative therapy in treating patients with liver tumors on overall survival (OS), local tumor recurrence rate, complete tumor necrosis rate and number of treatments required to achieve complete tumor ablation.^{[1, 2]} With the possible exception of microwave ablation, RFA is the best form of local ablative therapy.^[3-5]

Local ablative therapy using RFA mainly involves percutaneous RFA under ultrasound or computed tomographic guidance. For difficult tumor locations, either the laparoscopic or even the open surgical approaches can be used. However, when RFA is done in open surgery, RFA loses the advantages of minimal invasiveness, although the procedure is still less invasive than open liver resection.

RFA uses a closed loop circuit which creates an alternation of electric field agitating ions within target tissues, reaching a temperature of 50 �� to 100 �� and resulting in consequent necrosis.^[6] Large non-randomized studies on Child-Pugh A patients undergoing RFA for early stage hepatocellular carcinoma (HCC) reported that 5-year OS rates were from 50% to 64%, with extremely low post-procedural mortality and morbidity rates.^[7-9]

The excellent results obtained from RFA in treating HCC have led some clinicians to use RFA as the first-line treatment instead of surgery. Furthermore, RFA applications resulted in the change in the recommendation of the Barcelona Clinic Liver Cancer (BCLC) Staging System in treating BCLC stage 0 HCCs.

In the older form of BCLC, for patients with stage 0 HCC [patients with Child-Pugh A, Performance Status Test (PST) 0, a single HCC <2 cm/carcinoma in situ, with no portal hypertension], the recommended first-line treatment is surgical resection.^[10] In the recent BCLC, the recommendation has changed to RFA as the first-line treatment.^[11]

The usual indications for RFA to treat HCC are Child-Pugh A or B, a small HCC (how small is small will be discussed later in this article), usually tumor number ≤3 or otherwise require repeated treatment sessions, and not a candidate for liver transplantation (with portal hypertension or decompensated liver function). RFA is especially suitable for patients who are not candidates for surgical treatment because of poor general condition, poor liver function or recurrence after liver resection.^[12]

What are the evidences in supporting RFA to treat single HCC <2 cm? In other words, why the change in the BCLC recommendation, and at least for some centers to use RFA as the first-line treatment for patients with early stage HCC with cirrhosis?

A multicenter prospective study on patients with single ≤2 cm HCC reported a 97% sustained complete response after RFA.^[13] The main competitor in curative treatment for HCC with a solitary small HCC <5 cm, with good liver function (Child-Pugh A or B) and with good general condition is partial hepatectomy. Liver transplantation cannot be used as a first-line treatment for these patients, especially in regions where the prevalence of HCC is high and the rate of deceased liver donation is low, like in many countries in the East.

Recent advances in liver surgery have significantly decreased the perioperative mortality rate, approaching 0% for non-cirrhotic liver resection and <5% for cirrhotic liver resection.^[14] Unfortunately, only 10%-30% of patients have resectable HCC at the time of diagnosis because of poor general condition, poor liver function or unresectable/metastatic HCC.^[15] In the East, over 70% of HCC are associated with cirrhotic livers. The special risks of cirrhotic liver resection are listed in Table 2. Furthermore, partial hepatectomy, like RFA, is a local treatment but it has higher treatment risks, lower feasibility rate and more postoperative pain.

The most important primary outcome measurement is OS. Other less important secondary outcome measurements include recurrence-free survival, post-treatment morbidity/mortality, collateral damage to adjacent tissues, feasibility (e.g. for multiple tumors, in patients with compromised liver function), chance for re-treatment for recurrent HCC, and the number of re-treatment that can be carried out for tumor re-recurrence.

Only level 1 evidence in evidence based medicine is used to compare the primary outcome measurement of OS, i.e. only randomized comparative studies and meta-analyses are used.

(3) The comparison is limited to patients who are suitable to be treated by both RFA and partial hepatectomy, otherwise the comparison is meaningless. Thus, the comparison is made only for small HCC <5 cm as HCC >5 cm is not suitable for RFA; and the approach used for RFA can be percutaneous (in the majority of patients), laparoscopic or open surgery.

Three randomized comparative studies^[17-19] and a study using the Markov model to simulate a randomized comparative study^[20] showed the OS to be similar between RFA and liver resection. Unfortunately, all these studies have been criticized to have major methodological bias.^[21] On the other hand, a fourth randomized trial demonstrated superiority of liver resection over RFA in achieving OS.^[22]

The main criticism of all the above mentioned level 1 studies is the failure to exclude patients with HCC which are less effective to RFA treatment. These include patients with HCC at difficult sites for RFA (e.g. in the subdiaphragmatic region), HCC near to “heat sinks” and including various sizes of HCC lesions. A large meta-analysis has clearly demonstrated that the effectiveness of RFA rapidly decreases for HCC >3 cm and in lesions near to a large vessel which can produce “heat sink effect”.^[8]

The main limitation of effectiveness of RFA on OS in treating HCC is size of the lesion. Lu et al^[23] conducted a study on the biological behavior of HCC and found that as HCC reached to 3 cm, its biological behavior is more aggressive with increasing incidences of capsular invasion, worsening of histological grades, and exhibiting satellite and tumor nodules. All these aggressive biological behaviors were associated with worse long-term OS after liver resection. The technical solutions to effectively treating large HCC lesions include the use of complex electrode geometry (e.g. Multiple Electrodes, Cool-tip™ Ablation System E Series, Covidien, Boulder, CO, USA, or LeVeen Electrode, Radiotherapeutics, Sunnyvale, CA, USA), or multiple punctures or different treatment sessions.

For HCC 3-5 cm in size, randomized comparative studies have shown that RFA+ethanol injection produced better OS and disease-free survival than RFA alone.^[24] Also, RFA+transarterial chemoembolization (TACE)^[25] and a meta-analysis^[26] has better OS than RFA alone.

Thus, evidence-based medicine suggests that the OS of RFA is equivalent to liver resection for patients with HCC ≤2 cm. For HCC between 2-3 cm, the effect of RFA is possibly equivalent to liver resection. For HCC between 3-5 cm, RFA should be used together with ethanol injection or TACE to achieve OS the same as in liver resection. For HCC >5 cm, liver resection should be the first-line treatment.

Unless treating HCC ≤2 cm, or possibly ≤3 cm, studies showed that the recurrence free survival is worse with RFA than liver resection.^{[21, 22]} However, as these patients can be treated with further sessions of RFA, the OS is not affected as discussed previously if these patients are carefully selected and additional sessions of RFA are given.

A study showed that whether RFA resulted in complete necrosis is an important factor of long-term overall and disease-free survivals.^[27] There are ways to ensure complete tumor necrosis in RFA. During treatment and with the use of SonoVue (Bracco, Mineapolis, MN, USA), a contrast agent used for contrast enhanced ultrasound of the liver, RFA should be given until there is no contrast enhancement in the tumor tissues. Within 4 weeks after RFA treatment, an intravenous contrast CT scan should be carried out and any residual HCC with contrast enhancement should be re-treated with RFA.^[12,^17] The concept of adequate RFA treatment is shown in Fig. This concept is like carrying out histopathological examination of surgically resected specimens to look at the resection margin for R0 liver resection.^{[12, 17]}

The morbidity and mortality rates after RFA range from 2% to 4% and 0.2% to 0.5%, respectively.^[28-31] While the corresponding morbidity and mortality rates after liver resection range from 30% to 50% (15× as high as RFA), and 2% for non-cirrhotic liver resection and 5% for cirrhotic liver resection, respectively.

When compared to liver resection, RFA uses a more minimal invasive approach, there is no need to mobilize the liver, it causes little damage to the liver parenchyma; there is no need for liver blood inflow occlusion which may cause ischemia-reperfusion injury to the liver; there is much less pain after the treatment and the patient recovery is much faster.

For RFA, re-treatment for recurrent HCC can be carried out many times and it is not unusual to have 7 or more re-treatments. For liver re-resection, at the most it can be done 2 to 3 times.

Microwave ablation is an emerging technology which has the potential to achieve larger and more regular necrotic areas in comparison with RFA. It has the following theoretical advantages over RFA: (a) faster delivery; (b) a wider zone of active heating; (c) higher intra-tumoral temperature; (d) less susceptability to ‘heat sink’ when performed near to large vessels.^[32]

In conclusion, RFA is an effective and safe treatment for HCC. In selected patients, it produces similar OS compared to patients treated with liver resection, but with better secondary outcome measurements. The results of RFA in treating HCC 3 to 5 cm can be improved by adding TACE or ethanol injection. Microwave ablation is a new and promising treatment for patients with small HCC.

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