Review article: percutaneous treatment of hepatocellular carcinoma

Aliment Pharmacol Ther 2003; 17 (Suppl. 2): 103 110. Review article: percutaneous treatment of hepatocellular carcinoma S. GAIANI, N. CELLI, L. CECILIONI, F. PISCAGLIA & L. BOLONDI Dipartimento di Medicina Interna e Gastroenterologia, Università di Bologna, Italy SUMMARY In early stage hepatocellular carcinoma (HCC), liver transplantation, surgical resection and percutaneous techniques are classified as radical treatments, and may be offered to about 25% of all patients with HCC evaluated in referral centres. The restricted inclusion criteria for surgical resection and the shortage of liver donors for transplantation have stimulated an increasing demand for minimally invasive treatments able to achieve effective and reproducible percutaneous tumour ablation, with less associated morbidity and lower cost than other interventions. Among percutaneous techniques, ethanol injection has proven to be highly effective in single HCC up to 3 cm, with a rate of complete response of 80%, being well tolerated and with a limited risk of minor complication. In larger and or multinodular HCC the efficacy is reduced to 50% of complete response in nodules between 3 and 5 cm, and to lower rate in larger tumours. Alternative options to ethanol injection have been recently proposed, including radiofrequency, microwave and laser thermal ablation, aimed to extend the necrotic area thus improving the rate of complete response. To date, radiofrequency is the most used technique, with a reported rate of complete response of 90 98% in nodules smaller than 3 cm, and with the advantage of fewer sessions, otherwise counteracted by a higher rate of side-effects. Microwave and laser are promising technologies, but only few clinical data are available. Randomized controlled trials are needed in order to assess treatment response, long-term survival, rate of complication and cost-efficacy of newer technologies in comparison to ethanol injection. INTRODUCTION The incidence of hepatocellular carcinoma (HCC) is increasing world-wide, being the fifth most common cancer in the world (over 500 000 cases year) and the third cause of cancer-related death. 1, 2 Striking geographical differences are observed for both risk factors and occurrence. Cirrhosis, mainly caused by hepatitis B and C viruses, constitutes the main risk factor for HCC, with the 5-year cumulative incidence ranging between 15% and 20%. 3 In Italy and in other areas with intermediate incidence of HCC (5 20 cases per 100 000 inhabitants) HCC is associated with liver cirrhosis in more than 90% of cases. Cirrhotic men with increased a-fetoprotein (AFP) concentration bear the highest risk. Correspondence to: Dr S. Gaiani, Dipartimento di Medicina Interna e Gastroenterologia, Università di Bologna via Albertoni 15, 40138 Bologna, Italy. E-mail: sgaiani@med.unibo.it Surveillance is the sole strategy to potentially decrease tumour related mortality because it may detect HCC at an early stage, when curative therapies can be applied. 4 The available data on tumour volume doubling time provide the rationale for the current recommended surveillance policy: ultrasound (US) and AFP determination every 6 months. 3 By applying this policy, 40 80% of HCCs detected are solitary, but only half of them are radically treated. 5, 6 The main factors affecting prognosis include: the stage, aggressiveness and growth rate of the tumour, the general health of the patient, the liver function and the specific therapeutic intervention. BACKGROUND The treatment decision should be based on the tumour stage at diagnosis and the degree of impairment of liver function as a result of the underlying cirrhosis. As Ó 2003 Copyright Blackwell Publishing Ltd 103

104 S. GAIANI et al. recently stated in the Barcelona EASL Conference, surgical resection, liver transplantation and percutaneous ablation techniques should be considered radical treatments for early stage HCC, because they achieve a high rate of complete response in properly selected candidates thus improving the natural history of the disease and prolonging the survival of patients with single HCC smaller than 5 cm or three nodules smaller than 3 cm. 3 Surgical resection and liver transplantation are considered the first line options, although the best treatment strategy has not been established. Liver transplantation is claimed to simultaneously cure the tumour and the underlying cirrhosis in well-selected patients and is therefore presented as the optimal treatment. 7 Properly selected candidates for liver transplantation achieve a 70% 5-year survival rate with a recurrence rate below 25%. 8 10 This theoretical superiority, however, is dampened by the severe shortage of liver donors, and the progressively increasing waiting time deteriorates the results of liver transplantation when analysed according to intention-to-treat. Surgical resection provides excellent results for solitary HCC in patients with preserved liver function (Child class A). Five-year survival in well-selected patients with resectable HCC is approximately 50%, 11, 12 reaching a 70% rate in those with normal bilirubin concentration and without portal hypertension. 13 Surgical resection for HCC is affected by a high recurrence rate, as compared with liver transplantation, that may exceed 50% at 3 years and 70% at 5 years, 12, 14, 15 due to the multifocal nature of the disease. In clinical practice, only 20 30% of all the HCC patients currently evaluated in referral centres may receive radical treatment for early stage tumours. 7 PERCUTANEOUS TREATMENT Percutaneous treatment of HCC, initially proposed in patients where surgery was contraindicated, has now become an alternative choice to surgery. The rationale for the use of percutaneous ablation techniques of HCC is based on some relevant advantages: to destroy the tumour avoiding the loss or the damage of nontumoral liver parenchyma, as occurs with resection and arterial chemoembolization; the low risk of complication associated with the procedure, with 16, 17 a mortality rate of 0 0.09% for ethanol injection; the possibility to easily repeat the treatment in case of recurrent lesions, which develop in the majority of patients within 5 years; and finally, to be easy available and relatively inexpensive, considering that the cost of an alcohol injection cicle is about 1000 US dollars, compared with a cost of over 25 000 US dollars for liver 18, 19 resection. ETHANOL INJECTION In the last decade, the most extensive clinical experience has been based on percutaneous ethanol injection (PEI), which has become very popular as a result of the combination of low cost and a high antitumoral efficacy in small solitary tumours. The mechanism of action of ethanol depends on its ability to penetrate the tumoral cells, producing coagulative necrosis as a consequence of deydratation of cytoplasmic proteins. In addition, ethanol causes the thrombosis of tumoral microcirculation, as a result of necrosis of endothelial cells and platelet aggregation, with consequent ischaemia of the neoplastic tissue. The toxic action of ethanol is facilitated by the pathological features of HCC such as hypervascularity, which favours its uniform distribution within the nodule, and the softer consistency of the tumour in comparison to the surrounding cirrhotic parenchyma, which allows an easy and selective diffusion of the injected ethanol. PEI has proven to be highly effective in single HCC up to 3 cm, obtaining a complete response in 80% of cases, 20 being well tolerated and with a limited risk of minor complication. In larger and or multinodular HCC the efficacy is reduced to 50% of complete response in nodules between 3 and 5 cm, and to a lower rate in larger tumours. The size of the tumour also influences the rate of local recurrence. 16 The decreased efficacy in the treatment of large tumours and continuous multinodular HCC is due to intratumoral septa that limits ethanol diffusion and prevents homogeneous distribution throughout the tumour. Also, multiple treatment sessions, which lead to a prolonged treatment period, may increase the chance of tumour cell seeding. 16 Long-term efficacy of PEI has been reported in several studies (Table 1). In the study by Ebara et al. on 95 patients with 120 HCC smaller than 3 cm, 1-, 3- and 5- year survival was, respectively, 96, 72 and 51% for patients with Child A; 90, 62 and 48% for Child B; and 94, 25 and 0% for patients with Child C cirrhosis. 21 Shiina et al. studied a series of 50 patients including

REVIEW: PERCUTANEOUS TREATMENT OF HEPATOCELLULAR CARCINOMA 105 Table 1. Reported outcomes in patients with HCC treated by percutaneous ethanol injection (PEI) HCC up to 6 cm in size, reporting a 1-, 3- and 5-year survival of 87, 62 and 43%. 22 In a group of 70 selected patients with compensated cirrhosis and single HCC smaller than 3 cm, Lencioni et al. reported a 3- and 5-year survival of 89 and 67%, respectively. 23 In a multicentric Italian study, 1-, 3- and 5-year survival in patients with single HCC smaller than 5 cm was, respectively, 98, 79 and 47% (293 patients in Child A), 93, 63 and 29% (149 patients in Child B), and 64, 12 and 0% (20 patients in Child C). 16 Similar results were reported in the nationwide survey in Japan, 24 with 1- and 5-year survival of 96% and 54% in HCC smaller than 2 cm, and 95% and 38% in HCC 2 5 cm in size in stage I patients; 92% and 33% in HCC smaller than 2 cm, and 87% and 28% in HCC 2 5 cm in stage II patients. The long-term outcome after PEI is characterized by a high recurrence rate, ranging from 64% to 98% at 5 years 16, 21 23 being higher in multifocal HCC, while local recurrence rates ranged from 4% in lesions smaller than 3 cm 21 to 17% in lesions of 3 5 cm. 16 Other than the size of the tumour and multifocality, increased rate n Survival (%) 3 years 5 years Ebara et al. 21 95 Child A 72 51 Child B 62 48 Child C 25 0 Shiina et al. 22 98 62 52 Lencioni et al. 23 Child A 79 53 HCC 3cm 78 54 Child A, HCC 3cm 70 89 67 Livraghi et al. 16 Child A 293 79 47 Child B 149 63 29 Child C 20 12 0 Arii et al. 12 Stage I, HCC < 2 cm 767 54 Stage I, HCC 2 5 cm 587 38 Stage II, HCC < 2 cm 426 33 Stage II, HCC 2 5 cm 483 28 Livraghi et al. 26 Large encapsulated HCC (> 5 cm) 57 Large infiltrating HCC (> 5 cm) 42 of recurrence is dependant on the tightly related pathological features, such as poor differentiation degree, vascular invasion and satellites. In the case of intermediate HCC, conventional PEI may require an exceedingly high number of sessions, thus prolonging the period of treatment and increasing the risk of complications related to repeated needle insertions. Livraghi et al. proposed the injection of a large volume of ethanol (up to 50 70 ml) in a single session, performed under general anaesthesia. 25 Using this technique, a 3-year survival of 57% and 42% was obtained, respectively, in encapsulated and infiltrating HCC larger than 5 cm. 26 A combination of transarterial embolization with PEI has been proposed on the assumption that ischaemia induced by arterial obstruction could destroy the intratumoral septa and facilitate the diffusion of ethanol. Some encouraging reports have described a relatively high complete response rate and 3- and 5-year survival 27, 28 of 75 100% and 59 75% in Child class A patients. The long-term benefits of this approach have been recently assessed within a randomized controlled study. 29 The combination therapy with transarterial embolization-pei was superior to PEI alone in terms of local residual disease and recurrence rates in a series of 52 patients with small HCC (<3 cm). The survival rate was higher for the combination therapy in the subgroup of patients with nodules smaller than 2 cm, while the cumulative survival rates did not significantly differ between the two groups. An alternative approach to ethanol injection is to use other agents with a higher diffusion capacity, such as acetic acid. A randomized trial reported that the injection of acetic acid provided better results in terms of local efficacy, recurrence rate and survival in comparison with PEI. These promising results, however, have been achieved by only one group in Japan, and their results using PEI were less than optimal. 30 THERMAL ABLATION In recent years, many efforts have been made to investigate alternative percutaneous treatment modalities of HCC, able to increase the rate of complete response while maintaining the same safety of PEI. These include the use of energies able to produce a thermal ablation of tumoral cells, such as radiofrequency, microwave and laser. To date, other techniques

106 S. GAIANI et al. such as cryotherapy and high-intensity focused ultrasound are confined to experimental studies. The main aim of thermal ablation therapy is to destroy the entire tumour by using heat to kill malignant cells in a minimally invasive fashion, without damaging adjacent vital structures. Independently from the source of energy used to produce the thermal ablation, the heat cells interaction is strictly dependant on the temperature reached and the exposure time. Cellular homeostasis can be maintained with mild elevation of temperature to 40 C, while at temperatures between 42 C and 45 C, cells experience an increased susceptibility to damage produced by other agents such as chemotherapy and radiation. Higher temperatures, between 46 C and 60 C, are associated with irreversible cellular damage that is proportional to the exposure time; between 60 C and 100 C, a nearly instantaneous induction of protein coagulation occurs, with irreversible damage of key cytosolic and mitochondrial enzymes and nucleic acidhistone complexes. Temperatures greater than 105 C result in tissue boiling, vaporization and carbonization. These processes increase the impedance of the tumoral tissue surrounding the needle tip electrode, thus decreasing the energy transmission deepening into the tissue and the consequent ablation volume. Thus, the key aim for thermal ablative therapies is achieving and maintaining a 60 100 C temperature range throughout the entire target volume. Multiple energy sources have been used to provide the thermal induced coagulation necrosis, and electromagnetic energy has been used in the form of both radiofrequency and microwaves. RADIOFREQUENCY THERMAL ABLATION To date, the interest and enthusiasm for radiofrequency thermal ablation has far exceeded that for either microwave or laser ablation, and the largest clinical experience has been based in the last years on this ablation technique. The radiofrequency ablation system uses wave frequencies of 480 500 KHz, and the energy is delivered to the tumour by an needle electrode (16 18 gauge) that is electrically insulated along all but the distal 1 3 cm of the shaft. Radiofrequency emanates from the exposed noninsulated portion of the electrode. This energy, as it attempts to reach a grounding pad (placed on the patient s back or thigh), is converted into heat, inducing cellular death through coagulation necrosis. Until recently, an important limitation of percutaneous thermal ablation techniques was the extent of the volume of coagulation produced in a single session treatment, and a major focus of research has been the improvement of radiofrequency technology to enable an increase in the size of coagulation necrosis. Expandable electrode needles increase the radiating surface by an array of multiple wires that expand from the needle tip after insertion within the tumour. Cooled-tip electrodes consist of dual-lumen needles, with an internal lumen through which 0 C saline is circulated. 31 This prevents tissue boiling and cavitation immediately adjacent to the needle tip, thus increasing generator output during radiofrequency application. Electrodes can be inserted either singly or as a cluster array of three electrodes 32, 33 spaced 0.5 cm apart. These techniques offer the potential of large volume coagulation necrosis produced with a single needle insertion. The uniformity and reproducibility of thermal lesions with two different ablation devices were compared in explanted calf liver and in vivo pig liver. 34 The triple cluster cooled-tip needle induced significantly larger lesions than the expandable needle, but the lesions produced by the expandable needle were more reproducible and uniform in shape. Despite the lack of comparative studies in humans, both devices are currently used in clinical practice with similar results in terms of extent of necrosis (Table 2). The results from preliminary clinical series suggest that radiofrequency ablation is promising for the Table 2. Clinical studies on percutaneous radiofrequency thermal ablation in patients with HCC n Size Needle Sessions Complete response Rossi et al. 36 26 1.3 3.5 Exp 1.4 26 26 (100%) Livraghi et al. 37 52 1.2 3 Cool 1.2 47 52 (90%) Lencioni et al. 38 54 1 3 Exp cool 1.3 49 54 (95%) Curley et al. 39 48 1 3 Exp 47 48 (98%) Curley et al. 40 110 2.8 4.6 Exp 106 110 (97%) Livraghi et al. 43 80 3.1 5 Cool 1.1 49 80 (61%) 46 5.1 9.5 Cool 1.1 11 46 (24%) exp ¼ expandable needle; cool ¼ cooled-tip needle.

REVIEW: PERCUTANEOUS TREATMENT OF HEPATOCELLULAR CARCINOMA 107 treatment of hepatic tumours, although the long-term clinical benefits remain relatively unproved, because of the relatively short follow-up period (Table 2). Rossi et al. 35 treated 39 patients with 41 HCC, all but one being smaller than 3 cm, with a monopolar and bipolar needle. With a mean of 3.3 treatment session, a recurrence rate of 41% was observed at a mean followup of 22 months. Subsequently, Rossi et al. 36 reported the results obtained in 23 patients with 26 HCC of 1.3 3.5 cm in size using an expandable needle that reduced the number of sessions to 1.4 per tumour. They obtained a complete response of 100%, with a recurrence rate of 29% at 10 months. Other studies report a rate of complete response ranging from 90% to 98% in small HCC (< 3 cm), using both the cooled-tip and the expandable needle. 37 40 Ethanol injection remains the standard percutaneous technique for small HCC, therefore the results of new ablation techniques should be compared with that of PEI. Livraghi et al. 37 compared radiofrequency with PEI in 86 patients with 112 HCC ( 3 cm) reporting a rate of complete necrosis of 90.3% after radiofrequency and of 80% after PEI, without reaching statistical significance. Treatment with radiofrequency required significantly fewer sessions than did treatment with PEI (1.2 vs. 4.8), while more complications were observed with radiofrequency than with PEI. Similar results were reported in a randomized trial by Lencioni et al. in 80 patients with 115 HCC ( 3 cm), with a rate of complete response of 91% for radiofrequency and 85% for PEI, and with a longterm control in 87% of lesions treated with radiofrequency in comparison with 70% of lesions treated with PEI. 38 In a third study complete tumour ablation was obtained in 100% of 23 HCC treated with radiofrequency and in 94% of 96 HCC treated with Table 3. Comparison of percutaneous ethanol injection (PEI) and radiofrequency (RF) thermal ablation in patients with small HCC ( 3 cm) n Sessions Complete response (%) PEI RF PEI RF Livraghi et al. 37 112 4.8 1.2 80 90.3 Lencioni et al. 38 * 115 3.3 1.3 85 91 Ikeda et al. 41 119 94 100 *Randomized trial. PEI, with a local recurrence rate at 1 year of 15% and 14%, respectively, 41 (Table 3). Worse results are expected in the treatment of recurrent HCC, accordingly to the more aggressive biological behaviour of the tumour over time. Preliminary data report that recurrence after radiofrequency ablation is higher in patients treated for recurrent HCC than in patients treated for HCC at the first diagnosis. 42 Treatment of large tumours is still problematic. Livraghi et al. 43 treated 114 patients with 126 nodules of HCC greater than 3 cm (mean 5.4 cm), achieving a complete response in 61% of HCC < 5 cm and of 24% of nodules 5 cm. Noninfiltrating tumours were treated successfully significantly more often than infiltrating tumours. As a consequence, there is currently a focus on a multimodal strategy to ensure a more effective treatment of large tumour nodules. Rossi et al. 44 treated 62 patients with HCC nodules of 3.5 8.5 cm in diameter with radiofrequency sessions after occlusion of either the hepatic artery with a balloon catheter or the feeding arteries with gelatin sponge particles. The 1-year local recurrence rate was 18%, while the overall intrahepatic recurrence was 48%. A relatively high rate of complications have been reported with radiofrequency thermal ablation, including tumoral dissemination in the case of subcapsular HCC. 45 This risk may be greatly reduced by proper selection criteria with the exclusion of those nodules that cannot be reached through a path of liver tissue. 46 Proximity with the gall-bladder or with large intrahepatic vessels are other factors that may contraindicate radiofrequency thermal ablation. On the other hand, a recent multicentre study including 1620 patients with HCC treated by radiofrequency ablation reports a low risk of major complications (2.1%), with 0.25% of death and 0.49% of tumoral seeding. 47 MICROWAVE THERMAL ABLATION Microwave thermal tissue coagulator emits 2450 MHz electromagnetic radiation. Its mechanism of heating is similar to that of radiofrequency. The electrode inside the tissue acts as an antenna, concentrating a high intensity electromagnetic field with polarization of the molecules and consequent tissue heating. The technique has been used in few clinical studies. Seki et al. 48 treated 18 HCC < 2 cm with one to four sessions, with complete response and recurrence in three out of 18

108 S. GAIANI et al. cases at 11 33 months. Recently, a larger series has been published, including 50 patients with 107 HCC (mean size 2.7 cm) treated with single or multiple microwave sessions. Complete necrosis was attained in 98% of nodules < 2 cm and in 92% of nodules > 2 cm, with a recurrence rate at 1 year of 45%. 49 Microwave ablation has been retrospectively compared with PEI in 90 HCC 2 cm, with similar results in terms of local response and overall 5-year survival (78% for PEI and 70% for microwave), while the survival was better for microwave than for PEI (78% vs. 35%) in the sub-group of poorly to moderately differentiated HCC. 50 Finally, microwave has been compared with radiofrequency ablation in a randomized controlled trial including 94 HCC of 1 3.7 cm in size, reporting equiv alent therapeutic effects and complication rates, but fewer treatment sessions for radiofrequency. 51 With the available technology, microwave ablation seems to be effective in tumours 2 cm, but requires the insertion of multiple large needles (1.6 mm) and repeated treatment sessions in case of tumours > 2.5 cm in diameter. LASER THERMAL ABLATION Laser is a monochromatic, collimated and coherent radiation with a wavelength of 1024 nm produced by a Nd:YAG generator, which concentrates extremely high energy in small focalized areas. It may be transmitted inside the tumour by single or multiple quartz optical fibres inserted through fine needles (21 gauge), thus converting the intense light energy to tissue heating. Tumours 1.5 2 cm can be treated with a single fibre, while larger nodules require the splitting of the laser beam with the insertion of multiple fibres (up to four) by 20 21 gauge fine needles, whose precise positioning may be technically difficult. Laser ablation has been mainly used in the treatment of liver metastases, while very few data are available on the treatment of HCC. Giorgio et al. 52 treated 85 HCC of 1 6.6 cm with one to four laser fibres inserted and single or multiple sessions, obtaining a complete necrosis in 82%. In the study of Pacella et al. 53 92 HCC 4 cm were treated with multiple fibre insertion, with an average of 1.3 sessions per tumour. Complete necrosis was obtained in 97%, while a mean follow-up of 25 months showed a local and elsewhere in the liver recurrence of 6% and 49%, respectively. The same investigators treated 30 large HCC (3.5 9.6 cm) by laser thermal ablation followed by segmental transarterial embolization at 30 90 days, obtaining complete tumour necrosis in 90%, with cancer-free survival rate at 1- and 2-years of 74% and 34%, respectively. 54 CONCLUSIONS Screening programmes based on ultrasound and AFP determination have substantially increased the proportion of solitary or paucifocal HCC that can be radically treated. The restricted inclusion criteria for surgical resection and the shortage of liver donors for transplantation have stimulated an increasing demand for percutaneous tumour ablation procedures, which have been demonstrated to be effective and safe, with less associated morbidity and lower cost than other interventions. Analysis of the published data demonstrates that the size of the tumour to be treated is the crucial factor in determining whether complete necrosis can be achieved. In general, lesions smaller than 2.5 cm in diameter have been reported to have a greater than 90% chance of being destroyed. For lesions measuring 2.5 3.5 cm, approximately 70 90% may be completely treated with current ablation techniques, while the rate of complete response decreases for larger nodules. In such cases percutaneous techniques should be limited to those excluded by surgery, possibly in association with segmental transarterial embolization. To date, PEI should be considered the standard percutaneous technique, however radiofrequency ablation seems to produce at least similar results in terms of efficacy, with fewer sessions, otherwise counteracted by a relatively higher risk of complication. Future research should be focused on both technical and clinical issues. The former include: (a) the development of optimal ablation techniques that can increase the volume of tissue destroyed, (b) the identification of mechanisms that can integrate and enhance the ablation technique by haemodynamic and pharmacological agents, and (c) the development of new and less invasive thermal ablation modalities (i.e. extracorporeal high intensity focused ultrasound). Clinical issues for the future include: (a) the assessment of efficacy of multimodal and combined treatments, (b) the optimization of a properly selection of patients, and (c) the design of randomized controlled trials aimed to assess treatment response, long-term survival, rates of complication and cost-efficacy of newer technologies in comparison to ethanol injection.

REVIEW: PERCUTANEOUS TREATMENT OF HEPATOCELLULAR CARCINOMA 109 REFERENCES 1 El Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the united states. N Engl J Med 1999; 340: 745 50. 2 Parkin DM, Bray F, Ferlay J, et al. Estimating the world cancer burden: GLOBOCAN 2000. Int J Cancer 2001; 94: 153 6. 3 Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of Barcelona-2000 EASL Conference. J Hepatol 2001; 35: 421 30. 4 Camma C, Giunta M, Andreone P, et al. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach. J Hepatol 2001; 34: 606 9. 5 Colombo M, de Franchis R, Del Ninno E, et al. Hepatocellular carcinoma in Italian patients with cirrhosis. N Engl Med 1991; 325: 675 80. 6 Bolondi L, Sofia S, Siringo S, et al. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis. Gut 2001; 48: 251 9. 7 Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 2002; 35: 519 24. 8 Llovet JM, Fuster J, Bruix J, et al. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999; 30: 1434 40. 9 Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: 693 9. 10 Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of tumor size limits does not adversely impact survival. Hepatology 2001; 33: 1394 403. 11 LCSG. Predictive factors for long term prognosis after partial hepatectomy for patients with hepatocellular carcinoma: clues for the best strategy. Hepatology 2000; 31: 1019 21. 12 Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. Hepatology 2000; 32: 1224 9. 13 Bruix J, Castells A, Bosch J, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996; 111: 1018 22. 14 Poon RT, Fan ST, Ng IO, et al. Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer 2000; 89: 500 7. 15 Llovet JM, Bruix J, Gores GJ. Surgical resection versus transplantation for early hepatocellular carcinoma: clues for the best strategy. Hepatology 2000; 31: 1019 21. 16 Livraghi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 1995; 197: 101 8. 17 Di Stasi M, Buscarini L, Livraghi T, et al. Percutaneous ethanol injection in the treatment of hepatocellular carcinoma: a multicenter survey of evaluation practices and complications rates. Scand J Gastroenterol 1997; 32: 1168 73. 18 Livraghi T. Guidelines for treatment of liver cancer. Eur J Ultrasound 2001; 13: 167 76. 19 Kotoh K, Sakai H, Sakamoto S, et al. The effect of percutaneous ethanol injection therapy on small solitary hepatocellular carcinoma is comparable to that of hepatectomy. Am J Gastroenterol 1994; 89: 194 8. 20 Vilana R, Bruix J, Bru C, Ayuso C, Sole M, Rodes J. Tumor size determines the efficacy of percutaneous ethanol injection for the treatment of small hepatocellular carcinoma. Hepatology 1992; 16: 353 7. 21 Ebara M, Ohto M, Sugiura N, et al. Percutaneous ethanol injection for the treatment of small hepatocellular carcinoma. Study of 95 patients. J Gastroenterol Hepatol 1990; 5: 616 26. 22 Shiina S, Tagawa K, Niwa Y, et al. Percutaneous ethanol injection therapy for hepatocellular carcinoma: results in 146 patients. Am J Roentgenol 1993; 160: 1023 8. 23 Lencioni R, Pinto F, Armillotta N, et al. Long-term results of percutaneous ethanol injection therapy for hepatocellular carcinoma in cirrhosis: a European experience. Eur Radiol 1997; 7: 514 9. 24 Arii S, Yamaoka Y, Futagawa S, et al. Results of surgical and nonsurgical treatment for small-sized hepatocellular carcinomas: a retrospective and nationwide survey in Japan. The Liver Cancer Study Group Japan Hepatol 2000; 32: 1224 9. 25 Livraghi T, Lazzaroni S, Pellicano S, et al. Percutaneous ethanol injection of hepatic tumors: single-session therapy with general anesthesia. Am J Roentgenol 1993; 161: 1065 9. 26 Livraghi T, Benedini V, Lazzaroni S, Meloni F, Torzilli G, Vettori C. Long term results of single session percutaneous ethanol injection in patients with large hepatocellular carcinoma. Cancer 1998; 83: 48 57. 27 Tanaka K, Nakamura S, Numata K, et al. The long term efficacy of combined transcatheter arterial embolization and percutaneous ethanol injection in the treatment of patients with large hepatocellular carcinoma and cirrhosis. Cancer 1998; 82: 78 85. 28 Lencioni R, Paolicchi A, Moretti M, et al. Combined transcatheter arterial chemoembolization and percutaneous ethanol injection for the treatment of large hepatocellular carcinoma: local therapeutic effect and long-term survival rate. Eur Radiol 1998; 8: 439 44. 29 Koda M, Murawaki Y, Mitsuda A, et al. Combination therapy with transcatheter arterial chemoembolization and percutaneous ethanol injection compared with percutaneous ethanol injection alone for patients with small hepatocellular carcinoma: a randomized control study. Cancer 2001; 92: 1516 24. 30 Ohnishi K, Yoshioka H, Ito S, Fujiwara K. Prospective randomized controlled trial comparing percutaneous acetic acid injection and percutaneous ethanol injection for small hepatocellular carcinoma. Hepatology 1998; 27: 67 72. 31 Goldberg SN, Gazelle GS, Halpern EF, et al. Radiofrequency tissue ablation: importance of local temperature along the electrode tip exposure in determining lesion size and shape. Acad Radiol 1996; 3: 212 8. 32 Lorentzen T, Christensen NE, Nolsoe CP, et al. Radiofrequency tissue ablation with cooled needle in vitro: ultrasonography,

110 S. GAIANI et al. dose response, and lesion temperature. Acad Radiol 1997; 4: 292 7. 33 Goldberg SN, Sobiati L, Hahn PF, et al. Radiofrequency tumor ablation using a clustered electrode technique: results in animals and patients with liver metastases. Radiology 1998; 209: 371 9. 34 de Baere T, Denys A, Wood BJ, et al. Radiofrequency liver ablation: experimental comparative study of water-cooled versus expandable systems. Am J Roentgenol 2001; 176: 187 92. 35 Rossi S, Di Stasi M, Buscarini E, et al. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. Am J Roentgenol 1996; 167: 759 68. 36 Rossi S, Buscarini E, Garbagnati F, et al. Percutaneous treatment of small hepatic tumours by an expandable RF needle electrode. Am J Roentgenol 1998; 170: 1015 22. 37 Livraghi T, Goldberg SN, Lazzaroni S, et al. Small hepatocellular carcinoma: treatment with radiofrequency ablation versus ethanol injection. Radiology 1999; 210: 655 61. 38 Lencioni R, Cioni D, Donati F, et al. Percutaneous treatment of small hepatocellular carcinoma in cirrhosis: Rf thermal ablation vs. PEI. A prospecctive randomized trial. Radiology 1999; 213: 123. 39 Curley SA, Izzo F, Delria P, et al. Radiofrequency ablation of unresectable primary ad metastatic hepatic malignancies: results in 123 patients. Ann Surg 1999; 230: 1 8. 40 Curley SA, Izzo F, Ellis LM, Nicolas Vauthey J, Vallone P. Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg 2000; 232: 381 91. 41 Ikeda M, Okada S, Ueno H, Okusaka T, Kuriyama H. Radiofrequency ablation and percutaneous ethanol injection in patients with small hepatocellular carcinoma: a comparative study. Jpn J Clin Oncol 2001; 31: 322 6. 42 Gaiani S, Piscaglia F, Celli N, et al. Percutaneous radio-frequency thermal ablation of hepatocellular carcinoma. Results and follow-up in primary and recurrent nodules. Hepatology 2001; 34: 323. 43 Livraghi T, Meloni F, Goldberg SN, et al. Hepatocellular carcinoma: radiofrequency ablation of medium and large lesions. Radiology 2000; 214: 761 8. 44 Rossi S, Garbagnati F, Lencioni R, et al. Unresectable hepatocellular carcinoma: percutaneous radiofrequency thermal ablation after occlusion of tumor blood supply. Radiology 2000; 217: 119 26. 45 Llovet JM, Vilana R, Bru C, et al. Increased risk of tumor seeding after percutaneous radiofrequency ablation for single hepatocellular carcinoma. Hepatology 2001; 33: 1124 9. 46 Bolondi L, Gaiani S, Celli N, et al. Tumor dissemination after radiofrequency ablation of hepatocellular carcinoma. Hepatology 2001; 34: 608. 47 Livraghi T, Solbiati L, Meloni F, et al. Percutaneous radiofrequency ablation: complication encountered in a multicenter study of the treatment of focal liver tumors. Radiology 2003; 226: 441 51. 48 Seki T, Wakabayashi M, Nakagawa T, et al. Ultrasonically guided percutaneous microwave coagulation therapy for small hepatocellular carcinoma. Cancer 1994; 74: 817 25. 49 Lu MD, Chen JW, Xie XY, et al. Hepatocellular carcinoma: US-guided percutaneous microwave coagulation therapy. Radiology 2001; 221: 167 72. 50 Seki T, Wakabayashi M, Nakagawa T, et al. Percutaneous microwave coagulation therapy for patients with small hepatocellular carcinoma: comparison with percutaneous ethanol injection therapy. Cancer 1999; 85: 1694 702. 51 Shibata T, Iimuro Y, Yamamoto Y, et al. Small hepatocellular carcinoma: comparison of radio-frequency ablation and percutaneous microwave coagulation therapy. Radiology 2002; 223: 331 7. 52 Giorgio A, Tarantino L, de Stefano G, et al. Interstitial laser photocoagulation under ultrasound guidance of liver tumors: results in 104 treated patients. Eur J Ultrasound 2000; 11: 181 8. 53 Pacella CM, Bizzarri G, Magnolfi F, et al. Laser thermal ablation in the treatment of small hepatocellular carcinoma: results in 74 patients. Radiology 2001; 221: 712 20. 54 Pacella CM, Bizzarri G, Cecconi P, et al. Hepatocellular carcinoma: long-term results of combined treatment with laser thermal ablation and transcatheter arterial chemoembolization. Radiology 2001; 219: 669 78.