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Page 8 of 19 Marasco et al. Hepatoma Res 2020;6:33 I http://dx.doi.org/10.20517/2394-5079.2020.01

acetic acid with the use of a multiple-tine infusion device resulted in larger diameters of contiguous tumor
coagulation and enabled greater volumes of infusion than the standard technique [126] . However, as this is
associated with higher recurrence rates and inferior OS compared to hyper-thermic ablation [127,128] , it only
plays a secondary role in HCC treatment today, having widely been replaced by more modern techniques
such as RFA [129] , mainly because it has to be performed repetitively compared to RFA. Furthermore, it is
difficult to obtain complete necrosis for tumors larger than 3 cm [114] .

RADIOFREQUENCY ABLATION
RFA is a non-surgical, curative treatment for HCC [165] which is designed to destroy the tumor by heating [166] .
The heat (above 60 °C) generated by alternating current passing down from the tip of an electrode into the
surrounding tissues induces changes in ionic agitation and drives extracellular and intracellular water out of
tissues, resulting in their destruction by coagulative necrosis [166,167] . Heat is administered by probes that are
inserted through the skin (percutaneously), laparoscopically or with open surgery [168] . In cirrhotic patients
treated with RFA for HCC, the 5-year OS reached 74% [169] . Thus, RFA is considered a viable and curative
alternative treatment to LR in these patients [170] . Based on current guidelines, RFA is performed on single
[2]
lesions < 5 cm in diameter or ≤ 3 lesions < 3 cm in largest diameter, Child-Pugh class A or B, and ECOG 0 .
The high rates of post-procedural recurrence, which might be up to 70% at 5 years, remain a major challenge
for long-term survival [130] . Recurrence after RFA for HCC occurs as a result of local tumor progression (LTP)
or intrahepatic distant recurrence. LTP occurs along the peripheral margin of the ablative zone when the
primary tumor had not been controlled completely after RFA [131] . Several risk factors have been associated
with local recurrence including tumor size more than 2 cm, poorly differentiated carcinoma, advanced
[13]
tumor stage, high AFP levels, and an insufficient safety margin . An ablative margin of at least 5 mm is
required to avoid the risk of LTP because microsatellite lesions are frequently present and surround the HCC
nodule [134] . The risk of local recurrence is also closely related to the location of the tumor: HCCs next to the
portal vein or major hepatic veins were associated with a higher risk for local recurrence (HR = 1.70-2.81)
because the patient’s blood flow reduces elevation of the tumor’s temperature during RFA [171] . Several studies
have reported the ability of AFP levels to predict response to ablation: serum AFP increase have been shown
to predict a higher risk of HCC recurrence after ablation treatment [130] . The heterogeneity of the studies
precludes the formulation of a definite magnitude level, but it is suggested that AFP cut off levels of > 200
[2]
and/or > 400 ng/mL are associated with poor outcomes . In contrast to local recurrence, distant intrahepatic
recurrence is observed far from the ablation zone and corresponds usually to de novo hepatocarcinogenesis
on cirrhosis or metastatic dissemination [172] . Similar to LR, HCC recurrence following RFA occurring early -
within 2 years of follow-up - is considered the result of an intrahepatic metastatic process from the primary
tumor (related to tumor biology), whereas late recurrence after 2 years would result only from de novo
carcinogenesis in cirrhosis [170] . The Child-Pugh score is associated with distant HCC recurrence; this would
suggest that the severity of liver disease is a risk factor not only for HCC occurrence but also for distant HCC
recurrence [173] . The link between HBV replication (high pre-procedural serum viral load ≥ 2000 UI/mL) and
the recurrence of HCC after RFA suggests that secondary chemoprevention with nucleos(t)ide analogues
could improve the prognosis following percutaneous ablation [147,148,174] . Similarly, several studies found
that patients with HCV related cirrhosis who have achieved sustained response to antiviral therapy have a
substantially lower rate of HCC recurrence after percutaneous ablation in cirrhotic patients with HCC [175] .
The development of non-invasive methods to assess the degree of liver fibrosis including blood marker
tests and transient elastography has revolutionized the assessment of liver fibrosis over the last decade [176] .
Recent data reported the role of transient elastography in predicting intrahepatic distant recurrence of HCC
following RFA [177] . In conclusion, RFA is a potential curative modality for cirrhotic patients with early HCC.
Predictors of HCC recurrence after RFA are summarized in Table 2. Additional studies are needed to identify
patients with a higher risk of early and late recurrence to improve disease control.