EASL Clinical Practice Guidelines

Local ablation

Local ablation is considered the first line treatment option for patients at early stages not suitable for surgical therapies. Over the past 25 years, several methods for chemical or thermal tumor destruction have been developed and clinically tested [253]. The seminal technique used is percutaneous ethanol injection (PEI), which induces coagulative necrosis of the lesion as a result of cellular dehydration, protein denaturation, and chemical occlusion of small tumor vessels. Subsequently, thermal ablative therapies emerged, and are classified as either hyperthermic treatments (heating of tissue at 60–100 °C) – including radiofrequency ablation (RFA), microwave ablation, and laser ablation – or cryoablation (freezing of tissue at −20 °C and −60 °C). Most procedures are performed using a percutaneous approach, although in some instances ablation with laparoscopy is recommended. PEI is a well-established technique for the treatment of nodular-type HCC that achieves complete necrosis in 90% of tumors <2 cm, 70% in those of 2–3 cm and 50% in those between 3 and 5 cm [[162], [253], [254]]. It has been speculated that ethanol diffusion is blocked either by the intratumoral fibrotic septa and/or the tumor capsule. This undermines the curative capacity of this technique, particularly in tumors larger than 2 cm. The recent introduction of a specific device for single-session PEI, a multi-pronged needle with three retractable prongs, has resulted in a rate of sustained complete response of 80–90% in tumors smaller than 4 cm [255]. In patients with Child–Pugh A cirrhosis and early-stage tumors, treatment with PEI has been shown to result in 5-year survival rates of 47–53% [[256], [257]]. The major limitation of PEI is the high local recurrence rate, which may reach 43% in lesions exceeding 3 cm [258]. Another chemical ablation technique, percutaneous acetic acid injection (PAI), has not offered substantial advantages to PEI [259].

RFA has been the most widely assessed alternative to PEI for local ablation of HCC. The energy generated by RF ablation induces coagulative necrosis of the tumor producing a safety ring in the peritumoral tissue, which might eliminate small-undetected satellites. Consistent with previous studies, RF requires fewer treatment sessions to achieve comparable anti-tumoral effects. Five randomized controlled trials have compared RFA versus PEI for the treatment of early-stage HCC. These investigations consistently showed that RFA has a higher anticancer effect than PEI, leading to a better local control of the disease (2 year local recurrence rate: 2–18% versus 11–45%) [[260], [261], [262], [263], [264]]. The assessment of the impact of RFA on survival has been more controversial. Survival advantages favouring RF versus PEI were identified in the Japanese study including 232 patients [261], but no differences in survival were reported in the two European RCT [[263], [264]]. Two additional RCT from the same group reported survival advantages in the subgroup analysis of tumors larger than 2 cm favouring RF compared with either PEI or PAI [[260], [262]]. In patients with early-stage HCC treated with percutaneous ablation, long-term survival is influenced by multiple different interventions, given that a high percentage of patients will develop recurrent intrahepatic HCC nodules within 5 years of the initial treatment and will receive additional therapies. Nevertheless, three independent meta-analyses including all RCT, have confirmed that treatment with RFA offers a survival benefit as compared with PEI in tumors larger than 2 cm [[265], [266], [267]]. The main drawback of RF is its higher rates of major complications (4%; 95% CI, 1.8–6.4%) compared to PEI (2.7%; 95% CI, 0.4–5.1%) [[267], [268]].

Considering the reported data, the best results obtained in series of HCC patients treated by RFA provide 5-year survival rates of 40–70% [[269], [270]], and even beyond in highly selected candidates [142]. The best outcomes have been reported in Child–Pugh A patients with small single tumors, commonly less than 2 cm in diameter [[159], [162]]. Independent predictors of survival are initial complete response, Child–Pugh score, number or size of nodules, and base-line alpha-fetoprotein levels. Thus, Child–Pugh A patients with non-surgical small tumors – that are expected to achieve complete responses – are the ideal candidates to RFA. Around 10–15% of tumors with difficult-to-treat locations can be approached by PEI [271]. Treatment of patients with larger tumors (3–5 cm), multiple tumors (3 nodules <3 cm) and advanced liver failure (Child–Pugh B) along with combination of both techniques could be reasonable on an individual basis. Although these treatments provide good results, they are unable to achieve response rates and outcomes comparable to surgical treatments, even when applied as the first option [194].

An open question is whether RFA can compete with surgical resection as a first-line treatment for patients with small, solitary HCC. Two RCT have been reported with opposite results [[272], [273]]. While the first one did not identify outcome differences, the second trial suggested a survival advantage for surgical resection. Uncontrolled investigations have reported similar results for resection and RFA in BCLC 0 patients [159]. Further trials should overcome methodological issues which prevent the drawing of robust conclusions from the current studies. In addition, while complete removal of neoplastic tissue (R0) is common after surgical resection, some indications highlight the need to proceed with caution after analyzing the pathological specimens of tumors ablated with RFA. Complete tumor necrosis of less than 50% has been reported in tumors >3 cm because of the heat loss due to perfusion-mediated tissue cooling within the area ablated [274]. In addition, HCC tumors in a subcapsular location or adjacent to the gallbladder have a higher risk of incomplete ablation [275] or major complications [[268], [276], [277]]. Thus, at this point there are no data to support RFA as a replacement of resection as the first-line treatment for patients with early HCC (BCLC A) stage.

Treatments under investigation

Microwave ablation, laser ablation and cryoablation have been proposed for local ablation in HCC. Microwave ablation has an important advantage compared to RFA, which is that treatment efficacy is less affected by vessels located in the proximity of the tumor. Initial studies were limited by inducing a small volume of coagulation [278], and led to suboptimal performances when compared with RFA in the sole reported RCT [279]. Newer devices remain to be tested. Regarding laser ablation, no RCT has been published so far. In a recent multicenter retrospective analysis including 432 nonsurgical patients with early-stage HCC, 5-year overall survival was 34% (41% in Child–Pugh class A patients) [280]. Cryoablation had limited application in HCC, and no RCT have been reported [281]. The complication rate is not negligible, particularly because of the risk for “cryoshock”, a life threatening condition resulting in multiorgan failure, severe coagulopathy and disseminated intravascular coagulation following cryoablation.

Non-Chemical Non-Thermal Ablation Techniques are currently undergoing clinical investigation. Irreversible electroporation is currently in clinical evaluation, after pre-clinical positive approach [282]. HIFU is a novel ablative approach reported in cohorts of patients with small tumors, but no randomized studies are available [283]. Light-activated drug therapy uses light-emitting diodes to activate talaporfin sodium in HCC after intravenously administration. Phase 3 studies with this therapy are ongoing [284].