Percutaneous ethanol injection for hepatocellular carcinoma: Alive or dead?

In the early 1980s, two groups of Asian and European investigators independently developed percutaneous ethanol injection (PEI) therapy for hepatocellular carcinoma (HCC) [1Sugiura N. Takara K. Ohto M. Okuda K. Hirooka N. Ultrasound-guided ethanol injection for the treatment of small hepatocellular carcinoma.Acta Hepatol Jpn. 1983; 21: 920Google Scholar, 2Livraghi T. Festi D. Monti F. Salmi A. Vettori C. US-guided percutaneous alcohol injection of small hepatic and abdominal tumors.Radiology. 1986; 161: 309-312PubMed Google Scholar]. 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 3 cm in diameter, but only in 50% of tumors of 3–5 cm in size [3Livraghi T. Giorgio A. Marin G. Salmi A. De Sio I. Bolondi L. et al.Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection.Radiology. 1995; 197: 101-108PubMed Google Scholar, 4Sala M. Llovet J.M. Vilana R. Bianchi L. Sole M. Ayuso C. et al.Barcelona Clinic Liver Cancer Group. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma.Hepatology. 2004; 40: 1352-1360Crossref PubMed Scopus (382) Google Scholar]. Histopathologic studies found that PEI led to complete coagulation necrosis in about 70% of tumors smaller than 3 cm in diameter [[5]Shiina S. Tagawa K. Unuma T. Takanashi R. Yoshiura K. Komatsu Y. et al.Percutaneous ethanol injection therapy for hepatocellular carcinoma: a histopathologic study.Cancer. 1991; 68: 1524-1530Crossref PubMed Scopus (291) Google Scholar]. PEI was considered a safe technique, with low complications and a negligible rate of treatment-related deaths [[3]Livraghi T. Giorgio A. Marin G. Salmi A. De Sio I. Bolondi L. et al.Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection.Radiology. 1995; 197: 101-108PubMed Google Scholar]. 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% [3Livraghi T. Giorgio A. Marin G. Salmi A. De Sio I. Bolondi L. et al.Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection.Radiology. 1995; 197: 101-108PubMed Google Scholar, 6Lencioni R. Pinto F. Armillotta N. Bassi A.M. Moretti M. Di Giulio M. et al.Long-term results of percutaneous ethanol injection therapy for hepatocellular carcinoma in cirrhosis: a European experience.Eur Radiol. 1997; 7: 514-519Crossref PubMed Scopus (162) Google Scholar], far exceeding the best reported natural history of the tumor (5-year survival of 20%) [[7]Llovet J.M. Bustamante J. Castells A. Vilana R. Ayuso M. Sala M. et al.Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials.Hepatology. 1999; 29: 62-67Crossref PubMed Scopus (985) Google Scholar]. 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]Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3751) Google Scholar], 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]Ebara M. Okabe S. Kita K. Sugiura N. Fukuda H. et al.Percutaneous ethanol injection for small hepatocellular carcinoma: Therapeutic efficacy based on 20-year observation.J Hepatol. 2005; 43: 458-464Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar]. 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 2 cm in diameter—those defined as bearing a very-early stage HCC (or stage 0 HCC) by the Barcelona Clinic Liver Cancer staging classification [[8]Llovet J.M. Burroughs A. Bruix J. Hepatocellular carcinoma.Lancet. 2003; 362: 1907-1917Abstract Full Text Full Text PDF PubMed Scopus (3751) Google Scholar]—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 2–3 cm HCC. This confirms a recent study showing that patients with a solitary HCC 2 cm or less in diameter treated with percutaneous ablation are more likely to achieve a sustained complete response in the long-term [[4]Sala M. Llovet J.M. Vilana R. Bianchi L. Sole M. Ayuso C. et al.Barcelona Clinic Liver Cancer Group. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma.Hepatology. 2004; 40: 1352-1360Crossref PubMed Scopus (382) Google Scholar]. 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 3 cm 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 2 cm in diameter already present local metastases (located <10 mm of the nodule) in 10% of cases, and microscopic portal invasion in up to 25% of cases [[10]Kojiro M. Focus on dysplastic nodules and early hepatocellular carcinoma: an eastern point of view.Liver Transpl. 2004; 10: S3-S8Crossref PubMed Scopus (148) Google Scholar]. 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]Lencioni R. Crocetti L. A critical appraisal of the literature on local ablative therapies for hepatocellular carcinoma.Clin Liver Dis. 2005; 9: 301-314Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar]. 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]Bruix J. Sherman M. Llovet J.M. Beaugrand M. Lencioni R. Burroughs A.K. et al.Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver.J Hepatol. 2001; 35: 421-430Abstract Full Text Full Text PDF PubMed Scopus (3749) Google Scholar]. Recently, three randomized studies comparing RF ablation versus PEI for the first-line treatment of early-stage HCC have been published (Table 1) [13Lencioni R. Allgaier H.P. Cioni D. Olschewski M. Deibert P. Crocetti L. et al.Small hepatocellular carcinoma in cirrhosis: randomized comparison of radiofrequency thermal ablation versus percutaneous ethanol injection.Radiology. 2003; 228: 235-240Crossref PubMed Scopus (863) Google Scholar, 14Lin S.M. Lin C.J. Lin C.C. Hsu C.W. Chen Y.C. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or =4 cm.Gastroenterology. 2004; 127: 1714-1723Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar, 15Shiina S, Teratani T, Obi S, Sato S, Tateishi R, Fujishima T. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology; in press.Google Scholar]. 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]Lencioni R. Allgaier H.P. Cioni D. Olschewski M. Deibert P. Crocetti L. et al.Small hepatocellular carcinoma in cirrhosis: randomized comparison of radiofrequency thermal ablation versus percutaneous ethanol injection.Radiology. 2003; 228: 235-240Crossref PubMed Scopus (863) Google Scholar]. 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]Shiina S, Teratani T, Obi S, Sato S, Tateishi R, Fujishima T. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology; in press.Google Scholar]. Similarly, benefits in survival were also suggested in a subgroup analysis of the third trial coming from Taiwan [[14]Lin S.M. Lin C.J. Lin C.C. Hsu C.W. Chen Y.C. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or =4 cm.Gastroenterology. 2004; 127: 1714-1723Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar]. 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 1Randomized controlled trials comparing percutaneous ethanol injection and radiofrequency ablation as first-line treatment for HCCAuthor, Journal, Trial characteristicsComplete response rate2-yr local recurrence rateSurvival2-yr3-yrLencioni, Radiology 2003 [13]Lencioni R. Allgaier H.P. Cioni D. Olschewski M. Deibert P. Crocetti L. et al.Small hepatocellular carcinoma in cirrhosis: randomized comparison of radiofrequency thermal ablation versus percutaneous ethanol injection.Radiology. 2003; 228: 235-240Crossref PubMed Scopus (863) Google Scholar End-points: Primary: survival. Secondary: local-recurrence free survival Selection criteria: single < 5 cm, 3 nodules < 3 cm, Child-Pugh A/B Treatment armsPEI (n=50)82%38%aTwo-year local recurrence-free survival: PEI 62%, RF ablation 96%.8873RF ablation (n=52)95%4%[1]Sugiura N. Takara K. Ohto M. Okuda K. Hirooka N. Ultrasound-guided ethanol injection for the treatment of small hepatocellular carcinoma.Acta Hepatol Jpn. 1983; 21: 920Google Scholar9681Lin, Gastroenterology 2004 [14]Lin S.M. Lin C.J. Lin C.C. Hsu C.W. Chen Y.C. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or =4 cm.Gastroenterology. 2004; 127: 1714-1723Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar End-points: Primary: local recurrence Selection criteria: 3 nodules <4 cm, Child-Pugh A/B Treatment armsPEI – low dose (n=52)88%45%6150PEI – high dose (n=53)92%33%6355RF ablation (n=52)96%18%8274Shiina, Gastroenterology 2005 [15]Shiina S, Teratani T, Obi S, Sato S, Tateishi R, Fujishima T. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology; in press.Google Scholar End-points: Primary: survival Selection criteria: 3 nodules <3 cm, Child-Pugh A/B Treatment armsPEI (n=114)100%11%8263RF ablation (n=118)100%2%9080PEI, percutaneous ethanol injection; RF, radiofrequency.a Two-year local recurrence-free survival: PEI 62%, RF ablation 96%. Open table in a new tab PEI, percutaneous ethanol injection; RF, radiofrequency. 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 [16Llovet J.M. Vilana R. Bru C. Bianchi L. Salmeron J.M. Boix L. et al.Barcelona Clinic Liver Cancer (BCLC) Group. Increased risk of tumor seeding after percutaneous radiofrequency ablation for single hepatocellular carcinoma.Hepatology. 2001; 33: 1124-1129Crossref PubMed Scopus (665) Google Scholar, 17Livraghi T. Solbiati L. Meloni M.F. Gazelle G.S. Halpern E.F. Goldberg S.N. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study.Radiology. 2003; 226: 441-451Crossref PubMed Scopus (1132) Google Scholar]. 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]Ebara M. Okabe S. Kita K. Sugiura N. Fukuda H. et al.Percutaneous ethanol injection for small hepatocellular carcinoma: Therapeutic efficacy based on 20-year observation.J Hepatol. 2005; 43: 458-464Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar]. 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]Lencioni R. Cioni D. Crocetti L. Franchini C. Della Pina C. Lera J. Bartolozzi C. Early-stage hepatocellular carcinoma in cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation.Radiology. 2005; 234: 961-967Crossref PubMed Scopus (700) Google Scholar]. 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 < 2 cm, Child- Turcotte-Pugh class A patients), may lead to 5-year survival rates of 60–70% (Table 2) [3Livraghi T. Giorgio A. Marin G. Salmi A. De Sio I. Bolondi L. et al.Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection.Radiology. 1995; 197: 101-108PubMed Google Scholar, 4Sala M. Llovet J.M. Vilana R. Bianchi L. Sole M. Ayuso C. et al.Barcelona Clinic Liver Cancer Group. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma.Hepatology. 2004; 40: 1352-1360Crossref PubMed Scopus (382) Google Scholar, 6Lencioni R. Pinto F. Armillotta N. Bassi A.M. Moretti M. Di Giulio M. et al.Long-term results of percutaneous ethanol injection therapy for hepatocellular carcinoma in cirrhosis: a European experience.Eur Radiol. 1997; 7: 514-519Crossref PubMed Scopus (162) Google Scholar, 18Lencioni R. Cioni D. Crocetti L. Franchini C. Della Pina C. Lera J. Bartolozzi C. Early-stage hepatocellular carcinoma in cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation.Radiology. 2005; 234: 961-967Crossref PubMed Scopus (700) Google Scholar, 19Sakamoto M. Hirohashi S. Natural history and prognosis of adenomatous hyperplasia and early hepatocellular carcinoma: multi-institutional analysis of 53 nodules followed up for more than 6 months and 141 patients with single early hepatocellular carcinoma treated by surgical resection or percutaneous ethanol injection.Jpn J Clin Oncol. 1998; 28: 604-608Crossref PubMed Scopus (93) Google Scholar, 20Arii S. Yamaoka Y. Futugawa S. Inoue K. Kobayashi K. Kojiro M. et al.Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan.Hepatology. 2000; 32: 1224-1229Crossref PubMed Scopus (697) Google Scholar, 21Livraghi T. Meloni F. Morabito A. Vettori C. Multimodal image-guided tailored therapy of early and intermediate hepatocellular carcinoma: long-term survival in the experience of a single radiologic referral center.Liver Transpl. 2004; 10: S98-S106Crossref PubMed Scopus (80) Google Scholar, 22Omata M. Tateishi R. Yoshida H. Shiina S. Treatment of hepatocellular carcinoma by percutaneous tumor ablation methods: ethanol injection therapy and radiofrequency ablation.Gastroenterology. 2004; 127: S159-S166Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar]. The Ebara manuscript (5-year survival of 78%) has convincingly confirmed these results [[9]Ebara M. Okabe S. Kita K. Sugiura N. Fukuda H. et al.Percutaneous ethanol injection for small hepatocellular carcinoma: Therapeutic efficacy based on 20-year observation.J Hepatol. 2005; 43: 458-464Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar]. In these minute tumors, percutaneous ablation may provide complete necrosis proved by histopathologic examinations performed in explanted livers [[23]Lu D.S. Yu N.C. Raman S.S. Limanond P. Lassman C. Murray K. et al.Radiofrequency ablation of hepatocellular carcinoma: treatment success as defined by histologic examination of the explanted liver.Radiology. 2005; 234: 954-960Crossref PubMed Scopus (318) Google Scholar]. 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% [19Sakamoto M. Hirohashi S. Natural history and prognosis of adenomatous hyperplasia and early hepatocellular carcinoma: multi-institutional analysis of 53 nodules followed up for more than 6 months and 141 patients with single early hepatocellular carcinoma treated by surgical resection or percutaneous ethanol injection.Jpn J Clin Oncol. 1998; 28: 604-608Crossref PubMed Scopus (93) Google Scholar, 24Takayama T. Makuuchi S. Hirohashi S. Sakamoto M. Yamamoto J. Shimada K. et al.Early hepatocellular carcinoma as an entity with a high rate of surgical cure.Hepatology. 1998; 28: 1241-1246Crossref PubMed Scopus (354) Google Scholar]. 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 [25Llovet J.M. Fuster J. Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation.Hepatology. 1999; 30: 1434-1440Crossref PubMed Scopus (1468) Google Scholar, 26Llovet J.M. Schwartz M. Mazzaferro V. Resection and transplantation for HCC.Semin Liver Dis. 2005; 2: 181-200Crossref Scopus (735) Google Scholar].Table 2Cohort studies and cases series reporting the best long-term outcomes with percutaneous ethanol injection and radiofrequency ablation for HCC treatmentAuthor, JournalTreatment (n)Selection criteriaSurvival (%)3 yr5 yrLivraghi, Radiology 1995 [3]Livraghi T. Giorgio A. Marin G. Salmi A. De Sio I. Bolondi L. et al.Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection.Radiology. 1995; 197: 101-108PubMed Google ScholarPEI (169)Child A, single <3 cm8648Lencioni, Eur Radiol 1997 [6]Lencioni R. Pinto F. Armillotta N. Bassi A.M. Moretti M. Di Giulio M. et al.Long-term results of percutaneous ethanol injection therapy for hepatocellular carcinoma in cirrhosis: a European experience.Eur Radiol. 1997; 7: 514-519Crossref PubMed Scopus (162) Google ScholarPEI (70)Child A, single <3 cm8963Sakamoto, Jpn J Clin Oncol 1998 [19]Sakamoto M. Hirohashi S. Natural history and prognosis of adenomatous hyperplasia and early hepatocellular carcinoma: multi-institutional analysis of 53 nodules followed up for more than 6 months and 141 patients with single early hepatocellular carcinoma treated by surgical resection or percutaneous ethanol injection.Jpn J Clin Oncol. 1998; 28: 604-608Crossref PubMed Scopus (93) Google ScholarPEI (88)Single <2 cm–71Arii, Hepatology 2000 [20]Arii S. Yamaoka Y. Futugawa S. Inoue K. Kobayashi K. Kojiro M. et al.Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan.Hepatology. 2000; 32: 1224-1229Crossref PubMed Scopus (697) Google ScholarPEI (767)Stage I <2 cm–54Sala, Hepatology 2004 [4]Sala M. Llovet J.M. Vilana R. Bianchi L. Sole M. Ayuso C. et al.Barcelona Clinic Liver Cancer Group. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma.Hepatology. 2004; 40: 1352-1360Crossref PubMed Scopus (382) Google ScholarPEI/RF (196)Early HCCaEarly HCC=Single <5cm, 3 nodules <3cm.6037PEI /RF (34)Child A, <2 cm7263Livraghi, Liver Transpl 2004 [21]Livraghi T. Meloni F. Morabito A. Vettori C. Multimodal image-guided tailored therapy of early and intermediate hepatocellular carcinoma: long-term survival in the experience of a single radiologic referral center.Liver Transpl. 2004; 10: S98-S106Crossref PubMed Scopus (80) Google ScholarPEI (210)Early HCCaEarly HCC=Single <5cm, 3 nodules <3cm.6949Omata, Gastroenterology 2004 [22]Omata M. Tateishi R. Yoshida H. Shiina S. Treatment of hepatocellular carcinoma by percutaneous tumor ablation methods: ethanol injection therapy and radiofrequency ablation.Gastroenterology. 2004; 127: S159-S166Abstract Full Text Full Text PDF PubMed Scopus (184) Google ScholarPEI (144)Single <2 cm8570RF (434)Early HCCaEarly HCC=Single <5cm, 3 nodules <3cm.7768bFour-year survival.Lencioni, Radiology 2005 [18]Lencioni R. Cioni D. Crocetti L. Franchini C. Della Pina C. Lera J. Bartolozzi C. Early-stage hepatocellular carcinoma in cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation.Radiology. 2005; 234: 961-967Crossref PubMed Scopus (700) Google ScholarRF (116)Child A, single8961Ebara, J Hepatol 2005 [9]Ebara M. Okabe S. Kita K. Sugiura N. Fukuda H. et al.Percutaneous ethanol injection for small hepatocellular carcinoma: Therapeutic efficacy based on 20-year observation.J Hepatol. 2005; 43: 458-464Abstract Full Text Full Text PDF PubMed Scopus (162) Google ScholarPEI (270)3 nodules <3 cm8160PEI (96)Child A, <2 cm8778PEI, percutaneous ethanol injection; RF, radiofrequency.a Early HCC=Single <5 cm, 3 nodules <3 cm.b Four-year survival. Open table in a new tab PEI, percutaneous ethanol injection; RF, radiofrequency. 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 2 cm. 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. 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).