Transarterial embolization with microspheres in the treatment of monofocal HCC

Available online at www.sciencedirect.com

Digestive and Liver Disease 41 (2009) 143–149

Liver, Pancreas and Biliary Tract

Transarterial embolization with microspheres in the treatment of monofocal HCC A. Nicolini a , P. Fasani a , M.A. Manini b , L. Martinetti a , L.V. Forzenigo a , M. Iavarone b , S. Crespi a , G. Rossi c , P. Biondetti a , M. Colombo b , A. Sangiovanni b,∗ a

Division of Radiology, IRCCS Maggiore Hospital, Fondazione Policlinico, Mangiagalli e Regina Elena, Milan, Italy 1st Division of Gastroenterology, IRCCS Maggiore Hospital, Fondazione Policlinico, Mangiagalli e Regina Elena, Centro A. M. & A. Migliavacca, University of Milan, Milan, Italy c Division of Liver Transplant, IRCCS Maggiore Hospital, Fondazione Policlinico, Mangiagalli e Regina Elena, University of Milan, Milan, Italy

b

Received 21 September 2007; accepted 3 March 2008 Available online 23 April 2008

Abstract Background. Transarterial embolization using one permanent embolic agent alone enhances tumour ischaemia and spares patients with hepatocellular carcinoma form toxic chemotherapeutic drugs. Purpose. We assessed feasibility, tolerability and efficacy of transarterial embolization with microspheres in patients with a single node hepatocellular carcinoma. Materials and methods. Eighteen consecutive patients with compensated cirrhosis, hypervascularized single hepatocellular carcinoma, in whom liver transplantation was indicated (no. = 3), or excluded from radical therapies (no. = 15), received selective transarterial embolization with microspheres. Treatment was repeated every other month until complete devascularitazion was demonstrated by computed tomography, for a maximum of 3 cycles. Results. Fifty transarterial embolization courses (mean: 2.8 courses, range 1–6) were administered, corresponding to a 100% applicability rates. Initial complete response was achieved in 16 (89%) patients and confirmed by histology in 2 transplanted patients. During 21-month follow-up (range 8–36), hepatocellular carcinoma recurred in 10 (62%) patients who achieved initial complete response, and de novo tumour nodes developed in 10 (56%). No patient required analgesics and none had liver function deteriorated following transarterial embolization. Conclusions. Transarterial embolization is a well-tolerated treatment for patients with early or intermediate hepatocellular carcinoma who are not suitable for radical treatment or await liver transplantation, but it allows to achieve a sustained complete response in a minority of patients. © 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Cirrhosis; Hepatocellular carcinoma; Microspheres; TAE

1. Introduction Transarterial embolization (TAE) of hepatocellular carcinoma (HCC) with or without a chemotherapeutic agent has long been in use as a palliative treatment for patients with liver cancer for whom potentially curative treatments are not indicated [1–2]. Recently, a meta-analysis of 18 studies with ∗

Corresponding author. Tel.: +39 02 55035427/32; fax: +39 02 50320410. E-mail address: [email protected] (A. Sangiovanni).

TAE and transarterial chemoembolization (TACE) has clearly indicated that these procedures may increase survival of patients with intermediated stage of HCC, i.e. asymptomatic patients with compensated cirrhosis, and non-invasive large or multinodular tumours [3]. Though therapeutic benefit of TACE is evidence based for patients with the intermediate stage of HCC, the procedure is being currently employed as a bridge therapy for patients awaiting liver transplantation too [4–6], based on the assumption that treatment may prevent dropouts due to tumour progression. TACE performed with a non-permanent embolic agent may require more than

1590-8658/$30 © 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2008.03.004

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one course of treatment along with the infusion of a lipiodol/chemotherapeutic emulsion, thereby causing systemic adverse-effects including deterioration of liver function [7]. Transarterial embolization of the artery feeding the tumour node with permanent embolic agents after superselective artery catheterization without anticancer drugs is promising in terms of effectiveness, safety and tolerability. Circumstantial evidence suggests that TAE performed with a permanent embolic agent alone like microspheres through superselective catheterism of the feeding artery of the tumour, may enhance tumour ischaemia while avoiding the use of potentially toxic chemotherapeutic agents [8]. We prospectively assessed feasibility, tolerability and efficacy of TAE performed with microspheres in cirrhotic patients with HCC, preserved liver function (Child-Pugh A), who were not suitable for percutaneous interstitial therapies or for whom liver transplantation was indicated. To this end, to avoid the confounding factors due to the presence of multiple tumour nodes and previous treatments, we selected consecutive patients with a previously untreated single HCC.

2. Materials and methods 2.1. Study design Between October 2003 and March 2005 we consecutively enrolled patients with a single HCC and compensated cirrhosis (Child-Pugh A) showing hypervascular tumour node during the arterial phase at computed tomography (CT) scan and Barcelona Clinic Liver Cancer (BCLC) stage A or B, who were not suitable for tumour resection, percutaneous ablative treatment, or for whom liver transplantation was indicated. Excluded from this study were patients with more than one tumour node, intra-hepatic portal infiltration and/or portal vein thrombosis, extra-hepatic spread of the tumour, performance status other than 0, BCLC stages C or D, previous HCC treatment, a history of heart or kidney impairment, the latter defined by serum creatinine more than 1.7 mg/dl. Additional criteria for exclusion were plasma prothrombin time (PT) > 1.6 international normalized ratio (INR), partial prothrombin time (PTT) > 1.6 INR and platelets count (PLT) < 50 × 109 /L [9]. A maximum of 3 courses of TAE administered every other month was scheduled until complete devascularization was demonstrated by triphasic CT, performed one month after procedure. Treatment had to be interrupted in patients with tumour progression, technical unfeasibility of the procedure or liver transplantation. Patients with a node that could not be reached by superselective catheterization, were switched to TACE, using an emulsion of ultrafluid lipiodol, epirubicin (30 mg) and gelfoam. Local recurrence was treated with an additional course of TAE for a maximum of 3 additional courses. De novo tumours were treated according to the scheme reported below in Section 2.4. Results were evaluated on intention-to-treat (ITT) basis.

2.2. Investigations All patients were tested for hepatitis B surface antigen (HBsAg) and its antibody (anti-HBs), antibody to hepatitis B core antigen (anti-HBc), and antibody to delta antigen (antiHDV), by commercially available enzyme-immunoassays (Abbott Laboratories, North Chicago, IL, USA). AntiHCV was assessed by a third-generation enzyme-linked immunoassay (ELISA, Ortho Diagnostic Systems, Raritan, NJ, USA). Hereditary hemocromatosis and autoimmune hepatitis were diagnosed according to internationally accepted criteria [10–11]. All patients underwent abdominal US a grey-scale, real time US (Aloka, Tokyo [SSD 430]) and triphasic CT (Light speed CT, GE Medical System, USA), according to a previous published method [12] in the month preceding enrolment. Specific investigations included serum alpha-fetoprotein (AFP) assay (IRMA, Abbott, North Chicago, USA; normal values ≤20 ng/ml). Liver function was assessed by Child-Pugh classification [13]. A detailed medical history was recorded for all the patients. Alcohol abuse was defined by a daily intake of more than 60 g of ethanol in women or more than 80 g in men, for more than l0 years. The patients were classified according to the following nosologic categories for the cause of cirrhosis: (1) HCV: patients positive for the antibody to hepatitis C virus and HCV-RNA; (2) HBV: serologic HBsAg positive; (3) alcohol abuse; (4) multiple causes: more than one of the above reported aetiological factors. 2.3. Diagnosis of HCC Diagnosis of HCC was made according to internationally agreed criteria with either histology or radiology [2]. The diagnosis of HCC was obtained at histology in 11 patients (61%) and by radiology in 7 (39%), i.e. by demonstrating hypervascular nodules lesion during the arterial phase of CT or magnetic resonance (MR) with washout occurring during portal or delayed phase [2]. 2.4. Tumour staging and treatment algorithm Tumour staged was performed 7–21 days before the initiation of treatment by a conventional abdominal CT scan, chest X-ray and bone scintigraphy. Tumour size was defined as the maximum diameter of the tumour node at CT. All patients underwent a baseline CT scan, performed with a 4 detector MDCT (Light speed CT, GE Medical System, USA), 2.5 mm slice thickness, 7.5 table speed rotation. 2.0 mg/kg for a maximum of 150 mg of iodinated contrast medium (Iomeron 400, Bracco, Italy) was injected with a 4.0 ml/s flow. In all patients, the acquisition time from the start of contrast injection and the start of acquisition was 28 s for the arterial phase, after 70 s for the portal venous phase and after 3 min for the delayed phase. Images were read blindly by one experienced radiologist (LVF). Tumour stage was classified according to the BCLC system [14].

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The following treatment algorithm was adopted: (1) hepatic resection for less than 75 years patients with compensated liver disease (Child-Pugh A), single tumour node less than 5 cm in diameter, less than 10 mmHg hepatic vein pressure gradient (HVPG), bilirubin less than 1 mg/dl; (2) liver transplantation for patients younger than 65 yrs with a single tumour less than 5 cm in diameter not suitable for resection, or multifocal tumour ≤3 nodes ≤3 cm in diameter (Milan criteria); (3) percutaneous ethanol injection (PEI) or radiofrequency thermal ablation (RFTA) for patients with compensated liver disease, a tumour within Milan criteria unsuitable for surgery, and no signs of vascular infiltration or extrahepatic spread of the tumour; (4) Transarterial (chemo) embolization was considered for patients with compensated liver disease (Child-Pugh A or B), a larger/multifocal tumour nodes exceeding Milan criteria, with arterial enhancement during the arterial phase, and no vascular infiltration; (5) symptomatic treatment for patients with end-stage disease (BCLC-D). TACE was performed also as bridge therapy to liver transplantation or in patients with strategic localization of the tumour, lack of compliance to other treatments, or >80 years old. The pilot study with TAE with microspheres alone was offered to Child-Pugh A patients with a single tumour. 2.5. TAE In all patients liver vascularization was evaluated through catheterism of the celiac trunk to assess number and origin of the right and left hepatic artery, and eventually the existence of atypical tumour vascularization with feeding arteries originating from the superior mesenteric artery or directly from aorta, as well as the patency of portal vein. Superselective catheterisation of the right anterior or posterior segmental arteries or of the left hepatic artery was then performed with a single catheter using a 4–5 French (Terumo, Tokyo, Japan) to assess vascularization and number of vessels feeding HCC. Subsequently a superselective chateterization of the vessels supplying HCC was performed using a 2.7 French coaxial microcatheter (Progreat, Terumo, Tokyo, Japan), positioned as close as possible to the HCC node. A permanent embolic agent alone consisting of microspheres in Tris–acryl gelatine of 40–120 or 100–300 ␮m size (Biosphere Medical, Roissy en France) was mixed with contrast medium and injected under fluoroscopic supervision in each vessel until cessation of blood flow was achieved. The choice of the particles’ size depended upon the lesion size using the 40–120 microspheres for <2 cm tumour nodes and 100–300 microspheres for >2 cm nodes. 2.6. End points and definition of treatment response The primary endpoint was tumour devascularization. Secondary end point was patient survival. Response to treatment was assessed one month after each TAE course using spiral CT scan [15]; subsequent evaluation

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was carried out every 3 months in patients with a complete response (CR). CR was defined by the disappearance of contrast enhancement during the arteriographic phase of dynamic CT scan. Partial response was the reduction in enhancement equal or greater than 50% as compared to the baseline CT scan, progressive disease was the increase for more than 25% of the enhanced area. Stable disease included the remaining cases [15]. De novo tumours were considered progression of the disease. Results were evaluated by ITT analysis. 2.7. Follow-up The follow-up protocol included medical visits and laboratory investigations the day after and one month after each procedure and every 3 months after termination of treatment. Child-Pugh classification and restaging, including a triphasic CT were performed at the first month after each course and, subsequently, every 3 months after completion of treatment, orthotopic liver transplant (OLT) or death. Patients who had local recurrence of the tumour after a CR underwent additional courses of TAE or TACE for patients unfit for TAE. De novo tumours were treated with TAE or TACE in case of unfeasibility of superselective catheterization of the artery.

3. Results Eighteen patients, 15 (83%) men, mean age 68 years (range: 50–84 years) were found suitable to this study. They represent 13% of a total of 138 patients who had been referred to our Unit with a diagnosis of HCC during the enrolment period. Fifteen patients were not suitable to radical therapies and liver transplantation was indicated for another 3. Reasons for unsuitability for radical treatment were strategic localization in 11 (4 hilar tumour, 3 close to gallbladder, 2 oesophitic, 2 not accessible by ultrasound guide in segment 7), refuse of treatment in 3, advanced age in one. The main characteristics of the patients are reported in Table 1. The mean diameter of the tumour was 2.9 cm (range 1–6) and HCC less than 3 cm in size in 13 (72%). TAE was successfully performed in all patients. A total of 50 courses of TAE were administered, corresponding to a mean of 2.8 courses for patient (range 1–6). Four patients (22%) received one course only, 7 (39%) two courses, whereas 7 (39%) receive three or more courses. Number of courses, response to treatment and outcome, are given in Table 2. CR, with evidence of devascularization of the tumour was achieved in 16 (89%) patients. The remaining two patients had partial response, maintaining residual arterial enhancement of the tumour during the CT scan. One of them refused additional treatment with TAE, while the other one underwent liver transplant after 2 courses of TAE. The latter patient had 50% tumour necrosis at CT scan and 40% necrosis at histological examination of the

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Table 1 Epidemiological and clinical characteristics of 18 patients with Child-Pugh A cirrhosis and a single hepatocellular carcinoma treated by TAE with microspheres Characteristics

Number of patients

Mean age, yrs (range) Males

68 (50–84) 15 (83%)

Risk factors HCV HBsAg Alcohol abuse

14 (78%) 2 (11%) 2 (11%)

Tumour stage BCLC A BCLC B

16 (89%) 2 (11%)

Tumour diameter (cm) ≤3 >3–≤5 >5

13 (72%) 3 (17%) 2 (11%)

Serum AFP (ng/ml) ≤20 >20–≤400 >400

11 (61%) 5 (28%) 2 (11%)

treated tumour node on the explanted liver. The two patients who completed TAE treatment 1 and 2 months before OLT, had complete necrosis of the tumour node upon histological examination of the explanted liver, with incidentally misdiagnosed tumour node of less than 1 cm in size detected in one patient. During a mean follow-up of 21 months (range 8–36), 10 (62%) of the 16 patients with a CR developed a local recurrence while additional tumour nodes developed in 10 (56%) of the 18 patients, including 4 with local recurrence. The time lag between local recurrence of the tumour and assessment of CR was 3.3 months (range 3–6). Local recurrence was treated by additional courses of TAE in 7 patients, and by TACE in 3, CR being achieved in 5 and stable disease in the other 5. Additional de novo tumour nodes were treated by TAE in 7 patients and by TACE in 3, a CR being achieved in 4. Overall, 1 patient died of tumour progression after 15 months, 1 remained alive and tumour-free after 25 months, 3 were transplanted (1 with CR after tumour local recurrence, 1 with stable disease, and 1 with CR of the treated tumour node but one misdiagnosed tumour satellite). The remaining 13 patients are alive with either tumour recurrence (n = 5) or development of new tumours (n = 4) or both (n = 4). No patients required analgesics during the procedure of TAE. Mild abdominal pain occurred a few days following the procedure in 8 (44%) patients and short lasting fever in 9 (50%), requiring treatment with paracetamol or nonsteroidal anti-inflammatory agents. No patient had liver function deteriorated after TAE treatment. During the follow-up, 16 (89%) patients maintained Child-Pugh class A, and 2 patients progressed to Child-Pugh B after 11 and 32 months. Serum AFP value decreased in all the 7 treated patients with values above 20 ng/ml (Fig. 1).

Fig. 1. Behaviour of alpha-fetoprotein in relation to TAE treatment.

4. Discussion TAE with embospheres after superselective chateterization of the artery feeding HCC is a feasible treatment of comparable efficacy to TACE [16]. Interestingly, no patient had liver function deterioration after TAE, which conversely is a common event in patients treated with TACE [16]. Increased safety of TAE compared to TACE may relate to superselctive embolization of the artery feeding the tumour and to the avoidance of chemotherapeutic drugs, thus allowing for treatment of patients with mild liver impairment too. The finding of 89% CR after a mean of 1.6 (range 1–3) courses suggests superiority of TAE over conventional TACE, which resulted in CR rates of 10–60% in historical series of comparable patients [16–17]. Less encouraging were the rate of local recurrence in our patients treated with TAE. Whereas CR was histologically confirmed in the explanted livers in the 2 patients who underwent liver transplantation after completing TAE treatment, CT misdiagnosed a microsatellite in one of them. Moreover, the high rate (62%) of local recurrence in patients with CR suggests that CT scan might overestimate the rates of tumour necrosis. Sala et al. [18] already reported overestimation of response obtained one month after the procedure, suggesting that a correct evaluation of the response to TAE should delayed to 4 months after the complete devascularization of the tumour was achieved. Rapid recurrence of HCC might be partially accounted for by treatment-induced ischaemia that may enhance production of angiogenetic factors, which may accelerate regeneration of residual tumour cells. Although CR could be overestimated, the rate of local recurrence was much higher than the 10–30% reported in patients treated with percutaneous ablative treatment like PEI or RFTA [10], suggesting that TAE cannot be considered a radical treatment of HCC. However, the fact that CR was achieved in 5 (50%) patients with recurrence and disease was stable in the remaining 5 (50%) patients, during a mean follow-up of 21 months, suggests that TAE is a clinically valuable option for treatment of patients with HCC not suitable for radical therapy. The 56% rate of de novo tumour during 21 month of follow-up was surprisingly high too, though 54% of patients

Table 2 Outcome of 18 patients with a single HCC treated with TAE Patient no. HCC diameter (mm)

Percent tumour necrosisa

No. of TAE to obtain CR

Local recurrence of the tumour

Timing of recurrenceb (months)

De novo HCC Total no. Additional of TAE treatmentsc

Follow-up (months)

Notes Explanted liver: 100% tumour necrosis

1

45

100

1

Yes

3

No

3

OLT

9

A

2 3

20 30

100 50

1 n.a.

No –

– –

No Yes

1 2

– OLT

25 19

A A

4 5 6 7 8 9 10 11

25 28 60 15 20 60 20 23

100 – – – 80 100 100 100

1 2 2 1 n.a. 3 1 1

Yes Yes No Yes – No Yes No

3 3 – 3 – – 3 –

Yes No Yes Yes – Yes No Yes

5 2 5 5 1 6 2 2

– TACE – – – – – TACE + OLT

32 15 32 33 11 25 14 19

A A A A A A A A

12 13 14 15 16 17 18

18 10 35 20 50 10 25

100 100 100 100 100 100 100

2 1 2 2 1 1 3

No Yes Yes Yes No Yes Yes

– 3 3 3 – 6 3

Yes No Yes No Yes No Yes

2 2 2 4 2 1 3

– – TACE TACE – – TACE

15 34 10 36 32 8 15

A A A A A L D

Explanted liver: 40% tumour necrosis

Refused other treatment

Explanted liver: 100% tumour necrosis, with 1 microsatellite Tumour progression

A. Nicolini et al. / Digestive and Liver Disease 41 (2009) 143–149

Outcomed

n.a., Not applicable. a Evaluated by CT scan. b Calculated from evidence of CR assessed by CT scan. c TAE, TACE, OLT. d A, alive, D, dead, L, lost.

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successfully treated with tumour resection are expected to have recurrent HCC after 3 years [19]. On the contrary to Varela et al., who report TAE treatment complicated by development of hepatic abscesses in 7% of a series of 27 patients [20], we had no evidence of hepatic abscesses complicating the procedure. This may be due to the limited number of patients included in our series or to the fact that we enrolled only monofocal tumour small in size, with a mean diameter of 2.9 cm. In conclusion, TAE with microspheres is a feasible and well-tolerated modality for patients with early or intermediate HCC who were not suitable for radical treatment or await liver transplantation. However, TAE with microspheres allows to achieve a sustained CR in a minority of patients, despite an high rate of initial CR. Preliminary data suggests that TAE with microspheres may be a bridge therapy for patients awaiting liver transplantation. However, whereas this new treatment seems promising, there is uncertainty about the ultimate impact on survival as compared to conventional TACE, and the treatment needs do be tested in randomized controlled study.

Practice points • TAE with microspheres is a feasible and well-tolerated method to treat HCC, which avoids systemic side effects due to infusion of chemotherapeutic drugs during TACE treatment. • Neither serious side effects, nor deterioration of liver function were reported in our study. • TAE achieves an initial CR in 89% of patients with monofocal HCC, but a sustained CR was a rare event, due to the high rate of both, recurrence and appearance of new nodes.

Research agenda • The possibility to carry chemotherapeutic agents within the microspheres may enhance the therapeutic efficacy of TAE, avoiding systemic chemotherapeutic side effects. • Multimodality treatment of HCC may include a combination of TAE and radiofrequency ablation to enhance the efficacy of the treatment. • The forthcoming availability in the near future of both inhibitor of proliferative factors and antiangiogenetic drugs may be tested in combination with TAE for the treatment and prevention of recurrence of HCC.

Conflict of interest statement None declared.

Acknowledgement The Authors thank Caterina M. Puricelli for her expert secretarial assistance.

References [1] Brown DB, Cardella JF, Sacks D, Goldberg SN, Gervais DA, Rajan D, et al. Quality improvement guidelines for transhepatic arterial chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy. J Vasc Interv Radiol 2006;17:225–32. [2] Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208–36. [3] Camm`a C, Schepis F, Orlando A, Albanese M, Shahied L, Trevisani F, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 2002;224:47–54. [4] Llovet JM, Real MI, Montanya X, Coll S, Aponte AJ, Ayuso C, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002;239:1734–9. [5] Lo CM, Ngan H, Tsso WK, Liu CL, Lam CM, Poon RT, et al. Randomized controlled trial of transarterial lipiodol chemioembolization for unresectable hepatocellular carcinoma. Hepatology 2002;35:1164–71. [6] Graziadei IW, Sandmueller H, Waldenberger P, Koenigsrainer A, Nachbaur K, Jaschke W, et al. Chemoembolization followed by liver transplantation for hepatocellular carcinoma impedes tumour progression while on the waiting list and leads to excellent outcome. Liver Transpl 2003;9:557–63. [7] Chung JW, Park JH, Han JK, Choi BI, Han MC, Lee HS, et al. Hepatic tumours: predisposing factors for complications of transcatheter oily chemoembolization. Radiology 1996;198:33–40. [8] Brown KT, Nevins AB, Getrajdman GI, et al. Particle embolization for hepatocellular carcinoma. J Vasc Interv Radiol 1998;9:822–8. [9] Llovet JM, Bustamante J, Castells A, Vilana R, Ayuso MDC, Sala M, et al. Natural history of untreated non surgical hepatocellular carcinoma: rationale for design and evaluation of therapeutic trials. Hepatology 1999;29:62–7. [10] Powell LW, Summers KM, Board PG, Axelsen E, Webb S, Halliday JW. Expression of hemocromatosis in homozygous subjects. Implications for early diagnosis and prevention. Gastroenterology 1990;98: 1625–32. [11] Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999;31:929–38. [12] Kopp AF, Heuschmid M, Claussen CD. Multidetector helical CT of the liver for tumour detection and characterization. Eur Radiol 2002;12:745–52. [13] Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646–9. [14] Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Sem Liv Dis 1999;19:329–38. [15] Bartolozzi C, Cioni D, Donati F, Granai G, Lencioni R. Imaging evaluation of tumour response. In: Bartolozzi C, Lencioni R, editors. Liver Malignancies. Diagnostic and Interventional Radiology. Berlin: Springer-Verlag; 1999. p. 467–87.

A. Nicolini et al. / Digestive and Liver Disease 41 (2009) 143–149 [16] Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology 2004;127:S179–88. [17] Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003;37:429–42. [18] Sala M, Forner A, Varela M, Bruix J. Prognostic prediction in patients with hepatocellular carcinoma. Semin Liver Dis 2005;25:171–80.

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[19] Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30:1434–40. [20] Varela M, Real MI, Burrel M, Forner A, Sala M, Brunet M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol 2007;46:474–81.