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Page 2 of 7 Di Costanzo et al. Hepatoma Res 2018;4:53 I http://dx.doi.org/10.20517/2394-5079.2018.56

In nodules up to 2 cm in size, RFA allows the complete ablation in more than 90% of cases and may obtain
results comparable to surgery [9-11] . Randomized studies have shown higher efficacy of RFA as compared to
chemical ablation with ethanol achieving the complete necrosis of HCC nodules ≤ 3 cm with fewer sessions
and reducing the rate of local cancer progression [12-14] . Unfortunately, RFA efficacy in obtaining the complete
ablation of HCC nodules diminishes with increasing tumor size and local tumor progression is more
frequent in larger nodules [15,16] . The lower efficacy of ablation in nodules larger than 3 cm is also due to a
more aggressive biological behaviour of large cancers, as high levels of biomarkers, poor histological grade or
[17]
capsule invasion . Viable tumor cells after partial ablation may develop “resistance” to heat and may exhibit
[18]
a more aggressive growth . Furthermore, the position of nodules and the amount of blood flow inside
and at periphery of nodules may affect the ablative effect of RFA (heat-sink effect) [19,20] . To overcome these
problems, higher-powered generators, different devices and techniques have been attempted. Furthermore,
microwave ablation (MWA) has been introduced with the promise of a large ablative capacity. The treatment
of large HCC lesions represents a great challenge for clinicians because the late diagnosis of such cancer
is not rare despite the use of surveillance. A careful multidisciplinary evaluation of liver function, cancer
characteristics, and patient status is needed to establish the best treatment in the single case.

The aim of this review is to describe the role of thermal ablation ablation for the treatment of large
unresectable HCC.

RADIO FREQUENCY ABLATION
In a seminal study by Livraghi and Coll, 114 patients with 126 nodules larger than 3.0 cm were treated with
single or triple cluster of cool-tip monopolar electrodes. Complete ablation was achieved in 61% of nodules
[21]
in the size range 3.1-5.0 cm, and only in 24% of nodules 5.1-9.5 cm . To improve these results, a protocol
derived from a mathematic model was applied to calculate preoperatively the site and the number of needle
[22]
insertions . The model was based on the analysis of how many overlapping ablation spheres were needed
to cover the HCC nodule. To ablate nodules sized 3.6-7.0 cm, 1-13 electrode placements were performed. The
success rate in 121 nodules was 87%. A limitation of the application of such protocol was the difficulty in de-
termining the accurate placement of needles in larger lesions. Using an open approach and single or cluster
[23]
cool-tip needles a complete ablation rate of 91% may be achieved in nodules of 3.5-8.0 cm . “Surgical RFA”
as compared to percutaneous RFA showed similar efficacy in small nodules, but was associated to better sur-
[24]
vival rates in patients with larger HCC . However, with this approach the rate of complications and post-RFA liver
impairment was higher as compared to patients treated percutaneously. The highest rate of complete ablation using
cool-tip needles has been reported in a large Asian cohort. The authors achieved a complete necrosis in 98.9% of
[25]
360 treatments for HCC 3.1-5.0 cm, and in 97.7% of 44 treatments for tumors > 5.0 cm . These results have never
been reproduced in a Western study. In order to increase the ablation area bipolar and multipolar electrodes
have been attempted. The use of bipolar devices may allow a better distribution of temperature inside the
[26]
tissue . In a small prospective study including 26 patients with 27 tumors 5.0-8.5 cm, three separate bipolar
internally cooled electrodes achieved the complete ablation in 22 among 27 nodules (81%), including three
[27]
tumors that showed segmental portal vein invasion . However, multipolar electrodes resulted more effective
than monopolar devices in obtaining the complete necrosis of nodules up to 4.5 cm, but in larger tumors the
[28]
efficacy was comparable . Another way to increase the ablation area is the use of expandable electrodes and
[29]
interstitial saline infusion that may create lesions significantly larger than not cooled needles . However, in
[30]
small HCC internally cooled electrodes compared to expandable electrodes had similar effectiveness . A
strategy to increase the efficacy of RFA in larger nodules is the insertion of multiple needles inside the tumor
that may be alternatively activated using a swichting algorytm [31,32] . However, with the devices actually avail-
able, RFA ablative capacity in nodules > 5 cm is scarce. To overcome the limited efficacy of RFA in larger
nodules, combination treatments of RFA plus percutaneous ethanol injection or plus transarterial chemo-
embolization (TACE) have been attempted. In Eastern studies, in combining these treatments, a higher rate
of cancer ablation and a better overall and recurrence-free survival than RFA alone have been reported [33-41] .