Journal of Hepatology
Volume 43, Issue 3 , Pages 377-380, September 2005

Percutaneous ethanol injection for hepatocellular carcinoma: Alive or dead?

  • Riccardo Lencioni

      Affiliations

    • Division of Diagnostic and Interventional Radiology, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy
    • ,
  • Josep M. Llovet

      Affiliations

    • Mount Sinai Liver Cancer Program, Division of Liver Diseases, Mount Sinai School of Medicine, New York, Madison Ave. 1425, 11F-70, P.O. Box 1104, New York, NY 10029, USA
    • BCLC Group. Liver Unit. Digestive Disease Institute. IDIBAPS. Hospital Clínic. University of Barcelona. Catalonia, Spain
    • Corresponding Author InformationCorresponding author. Address: Mount Sinai Liver Cancer Program, Division of Liver Diseases, Mount Sinai School of Medicine, New York, Madison Ave. 1425, 11F-70, P.O. Box 1104, New York, NY 10029, USA. Tel.: +1 212 2413923; fax: +1 212 2412138/2129969688.

published online 30 June 2005.

See Article, pages 458–464

Article Outline

 

In the early 1980s, two groups of Asian and European investigators independently developed percutaneous ethanol injection (PEI) therapy for hepatocellular carcinoma (HCC) [1], [2]. They showed that absolute ethanol - injected directly into the tumor through a fine needle placed under sonographic guidance—was able to induce chemical ablation of small, nodular-type HCC lesions. The efficacy of PEI was subsequently confirmed by numerous reports. Complete responses were achieved in 80% of tumors smaller than 3cm in diameter, but only in 50% of tumors of 3–5cm in size [3], [4]. Histopathologic studies found that PEI led to complete coagulation necrosis in about 70% of tumors smaller than 3cm in diameter [5]. PEI was considered a safe technique, with low complications and a negligible rate of treatment-related deaths [3]. Analyses of the long-term outcomes of patients with well-compensated cirrhosis and early-stage HCC who were treated with PEI showed that the 5-year survival ranged 47–53% [3], [6], far exceeding the best reported natural history of the tumor (5-year survival of 20%) [7]. Therefore, PEI had a place in the treatment strategy of HCC, generally as a second choice when surgical techniques were precluded in patients with early-stage tumors [8], although in some centers in Italy and Japan it was even used as a first-line treatment option.

The paper by Ebara et al. published in this issue of the Journal can be called the definitive study on PEI for the treatment of small HCC [9]. It comes from the group that first developed PEI and is based on a 20-year observation of 270 patients. The article brings several important messages to light. First, it confirms in a large single-institution series the ability of PEI to achieve local tumor destruction in the absence of mortality or life-threatening complications. Second, it shows that PEI—when administered as first-line treatment to patients with Child-Turcotte-Pugh class A cirrhosis and small HCC lesions—may achieve a 5-year survival as high as 65%. Third, it demonstrates that Child-Turcotte-Pugh class A patients with a solitary tumor smaller than or equal to 2cm in diameter—those defined as bearing a very-early stage HCC (or stage 0 HCC) by the Barcelona Clinic Liver Cancer staging classification [8]—do have different long-term outcomes. Patients with such small tumors not only had the best overall survival, but also showed a rate of tumor recurrences, occurring remotely from the treated nodule, significantly lower than patients bearing a 2–3cm HCC. This confirms a recent study showing that patients with a solitary HCC 2cm or less in diameter treated with percutaneous ablation are more likely to achieve a sustained complete response in the long-term [4].

The paper by Ebara et al. appears in a time in which the role of PEI as the percutaneous treatment of choice for early-stage HCC is challenged by other local ablative techniques. Over the past few years, several methods for thermal tumor destruction through localized heating or freezing—including radiofrequency (RF) ablation, microwave ablation, laser ablation, and cryoablation—have been developed and clinically tested. This has been the result of at least three shortcomings of PEI technique. First, the limited anti-tumoral effect of PEI in HCC larger than 3cm as a result of the incapability to disrupt the intratumoral septa, thus decreasing its capacity to reach and eliminate all neoplastic cells. Second, the increased evidence that PEI, as other loco-regional treatments, is an approach not based on sound oncologic principles. It is known that neoplastic dissemination occurs at very early stages in HCC, first near the boundaries of the tumor, afterwards within the anatomic segments and, finally, beyond them. Tumors of 2cm in diameter already present local metastases (located <10mm of the nodule) in 10% of cases, and microscopic portal invasion in up to 25% of cases [10]. This provides the rationale to produce a 1-cm safety ring surrounding the tumor. RF ablation but not PEI can provide this safety ring, which may reduce late treatment failures (so called local recurrences or local tumor progressions). Finally, PEI is an artesanal technique, very time consuming and requiring an experienced radiologist, an approach that may appear not cost-effective in some modern settings.

RF ablation has emerged as the real competitor of PEI. Unfortunately, a large portion of the published research concerning RF ablation lacks sufficient methodological rigor to be reliable enough to help establish the beneficial and harmful effects of the procedure [11]. The European Association for the Study of the Liver (EASL), recommended to compare all newer methods of tumor destruction with the well-established PEI through randomized controlled trials (RCT) assessing not only initial tumor response, but also survival outcomes [12]. Recently, three randomized studies comparing RF ablation versus PEI for the first-line treatment of early-stage HCC have been published (Table 1) [13], [14], [15]. The first trial, performed in European centers, failed to show a statistically significant difference in overall survival between patients who received RF ablation and those treated with PEI [13]. More recently, survival advantages have been identified in a Japanese study, although they were not confirmed in the subgroup analysis of patients with solitary tumors [15]. Similarly, benefits in survival were also suggested in a subgroup analysis of the third trial coming from Taiwan [14]. All three investigations showed that RF ablation had a greater local anticancer effect than PEI, leading to a better local control of the disease. Therefore, survival data is not robust enough to definitively establish RF ablation as superior to PEI in the treatment of small tumors, although RF ablation appears as the preferred percutaneous therapy for patients with early-stage HCC on the basis of a more consistent local tumor control.

Table 1. Randomized controlled trials comparing percutaneous ethanol injection and radiofrequency ablation as first-line treatment for HCC
Author, Journal, Trial characteristicsComplete response rate2-yr local recurrence rateSurvival
2-yr3-yr
Lencioni, Radiology 2003[13]
End-points: Primary: survival. Secondary: local-recurrence free survival
Selection criteria: single < 5cm, 3 nodules < 3cm, Child-Pugh A/B
Treatment arms
PEI (n=50)82%38%a8873
RF ablation (n=52)95%4%a9681
Lin, Gastroenterology 2004[14]
End-points: Primary: local recurrence
Selection criteria: 3 nodules <4cm, Child-Pugh A/B
Treatment arms
PEI – low dose (n=52)88%45%6150
PEI – high dose (n=53)92%33%6355
RF ablation (n=52)96%18%8274
Shiina, Gastroenterology 2005[15]
End-points: Primary: survival
Selection criteria: 3 nodules <3cm, Child-Pugh A/B
Treatment arms
PEI (n=114)100%11%8263
RF ablation (n=118)100%2%9080

PEI, percutaneous ethanol injection; RF, radiofrequency.

aTwo-year local recurrence-free survival: PEI 62%, RF ablation 96%.

PEI will continue to play a role in the treatment of HCC. It has been shown that RF ablation of lesions with subcapsular location or adjacent to the hepatic hilum increases the risk of complications [16], [17]. In the manuscript of Ebara, the authors state that 25% of lesions could not be treated by RF ablation because of the unfavourable location of the tumor [9]. Although this figure might be overstated, it is estimated that RF ablation cannot be applied in 10–15% of cases, as shown in a recent intention-to-treat analysis [18]. Such rates could further increase on a per-patient basis as new lesions develop during the follow-up. The applicability of RF ablation might be even lower in institutions with limited skills in interventional radiology procedures, as precise insertion and guidance of the large-diameter RF electrode is technically more challenging than that of the fine non-cutting needle commonly used for PEI.

Another important issue is whether any of the available percutaneous techniques can compete with surgical resection as a first-line treatment option for small HCC. Of note, is that no RCT has been published comparing these two approaches, and thus no definitive answer can be provided. Evidence, thus, may only come from thorough analysis of case series and cohort studies. Recently, some reports from Japan and Europe have suggested that the refinement in the selection criteria of patients treated with percutaneous ablation (single tumor < 2cm, Child- Turcotte-Pugh class A patients), may lead to 5-year survival rates of 60–70% (Table 2) [3], [4], [6], [18], [19], [20], [21], [22]. The Ebara manuscript (5-year survival of 78%) has convincingly confirmed these results [9]. In these minute tumors, percutaneous ablation may provide complete necrosis proved by histopathologic examinations performed in explanted livers [23]. These outstanding figures, however, should be compared with the outcomes obtained with resection when applied to very early tumors, where 5-year survival may reach 89–93% [19], [24]. Thus, at this point there is no unequivocal data to back up percutaneous ablation as a replacement for resection as a first-line treatment for patients with early-stage HCC. Unfortunately, for most HCC patients there is no real dilemma, since only around 10% of cases meet current eligibility criteria for surgical resection even when bearing a small solitary tumor [25], [26].

Table 2. Cohort studies and cases series reporting the best long-term outcomes with percutaneous ethanol injection and radiofrequency ablation for HCC treatment
Author, JournalTreatment (n)Selection criteriaSurvival (%)
3 yr5 yr
Livraghi, Radiology 1995 [3]PEI (169)Child A, single <3cm8648
Lencioni, Eur Radiol 1997 [6]PEI (70)Child A, single <3cm8963
Sakamoto, Jpn J Clin Oncol 1998 [19]PEI (88)Single <2cm–71
Arii, Hepatology 2000 [20]PEI (767)Stage I <2cm–54
Sala, Hepatology 2004 [4]PEI/RF (196)Early HCCa6037
PEI /RF (34)Child A, <2cm7263
Livraghi, Liver Transpl 2004 [21]PEI (210)Early HCCa6949
Omata, Gastroenterology 2004 [22]PEI (144)Single <2cm8570
RF (434)Early HCCa7768b
Lencioni, Radiology 2005 [18]RF (116)Child A, single8961
Ebara, J Hepatol 2005 [9]PEI (270)3 nodules <3cm8160
PEI (96)Child A, <2cm8778

PEI, percutaneous ethanol injection; RF, radiofrequency.

aEarly HCC=Single <5cm, 3 nodules <3cm.

bFour-year survival.

Although some investigators have already written its obituary, PEI is not dead in the treatment strategy of HCC. Survival advantages favouring RF ablation are not robust enough in solitary small tumors. Local control of the disease, however, is better with RF ablation particularly in multiple tumors or those exceeding 2cm. Whether percutaneous ablation may be in a position to substitute resection as a first-line option for very early HCC will probably be a matter to be solved by launching a large international RCT.

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Acknowledgements 

Josep M. Llovet is supported by a grant from AGAUR (2003BEAI00138 and 2004BE00226, Generalitat de Catalunya, Spain), Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias 2002-2005, PI02/0596) and Programa ‘Ramon y Cajal’ (IDIBAPS, Ministerio de Ciencia y Tecnología, Spain).

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References 

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PII: S0168-8278(05)00416-2

doi:10.1016/j.jhep.2005.06.001

Journal of Hepatology
Volume 43, Issue 3 , Pages 377-380, September 2005

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