Radiología. 2011;53(3):246-253 ISSN: 0033-8338
RADIOLOGÍA
RADIOLOGÍA
Publicación Oficial de la Sociedad Española de Radiología Médica Incluida en Index Medicus/MEDLINE
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ORIGINAL
Comparison of doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) with conventional transarterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma M.D. Ferrer Puchol*, C. la Parra, E. Esteban, M. Vaño, M. Forment, A. Vera, O. Cosín Radiología Intervencionista, Hospital de la Ribera, Alzira, Valencia, Spain Received 3 May 2010; accepted 18 July 2010
KEYWORDS Hepatocellular carcinoma; Intra-arterial chemoembolization; Treatment; Liver; Doxorubicin-eluting beads; Carcinoma
Abstract Objective: To compare conventional transarterial chemoembolization (TACE) with doxorubicineluting bead transarterial chemoembolization (DEB-TACE) for the treatment of hepatocellular carcinoma, evaluating the tumor response, complications after treatment, and survival. Material and methods: We present 72 patients diagnosed with hepatocellular carcinoma treated consecutively between January 2000 and December 2009. We studied 25 patients treated with TACE (Group A) and 47 patients treated with DEB-TACE (Group B); adriamycin (doxorubicin) was the chemotherapy agent used in both groups. All patients had compensated cirrhosis of the liver classified on the Child-Pugh score. The results were analyzed according to the RECIST criteria. Statistical analyses consisted of ANOVA, chi-square tests, Student’s t-tests, and Kaplan-Meier log-rank tests. Results: Patient’s age, tumor size, number of tumors, and hepatic reserve were similar in the two groups. The mean number of sessions per patient was 1.32 ± 0.67 in Group A versus 2.13 ± 0.95 in Group B. The mean dose of adriamycin per patient was 50.60 ± 29.95 mg in Group A and 231.91 ± 110.2 mg in Group B. A complete response of the tumor to treatment was observed in 5.6 % of the patients in Group A and in 13.9 % of those in Group B. According to the RECIST criteria, no significant differences were found. DEB-TACE was better tolerated and had fewer immediate complications (p = 0.001). No significant differences were found in the survival of patients in the two groups (Group A: mean 686.24 days, median 709 days; Group B: mean 765.32 days, median 672 days. Conclusion: In patients with unresectable hepatocellular carcinoma, DEB-TACE is safe and better tolerated than conventional TACE; moreover, it seems to lead to greater necrosis of the tumors. © 2010 SERAM. Published by Elsevier España, S.L. All rights reserved.
*Corresponding author. E-mail:
[email protected] (M.D. Ferrer Puchol). 0033-8338/$ - see front matter © 2010 SERAM. Published by Elsevier España, S.L. All rights reserved.
Comparison of DEB-TACE with TACE for the treatment of hepatocellular carcinoma
PALABRAS CLAVE Hepatocarcinoma; Quimioembolización intraarterial; Terapéutica; Hígado; Microesferas de adriamicina; Carcinoma
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Quimioembolización del hepatocarcinoma: partículas cargadas frente a quimioembolización convencional Resumen Objetivo: Comparar la quimioembolización transarterial (TACE) convencional con la quimioembolización con partículas cargadas (DEB-TACE) para el tratamiento del hepatocarcinoma, valorando la respuesta tumoral, las complicaciones tras el tratamiento y la supervivencia. Material y métodos: Presentamos 72 pacientes diagnosticados de hepatocarcinoma. El estudio incluye 25 pacientes tratados con TACE (Grupo A) y 47 pacientes tratados con DED-TACE (Grupo B), empleando en ambos grupos adriamicina. Todos los pacientes se tratan consecutivamente desde enero de 2000 hasta diciembre de 2009. Todos presentaban una cirrosis en estadio Child-Pugh compensada. Los resultados se estudiaron conforme al criterio RECIST. El estudio estadístico consistió en ANOVA, Chi 2, T-Test y estudio de Kaplan-Meier (test de Log-Rank). Resultados: La edad, el tamaño, el número de tumores y la reserva hepática en los dos grupos de pacientes fueron estadísticamente similares. El número de sesiones por paciente fue: Grupo A media 1,32 ± 0,67 veces, Grupo B media 2,13 ± 0,95 veces. La media de dosis de adriamicina por paciente fue: 50,60 ± 29,95 mg en grupo A y 231,91 ± 110,2 mg en grupo B. Se observó una respuesta completa del tumor en 5,6 % en el grupo A y 13,9 % en el grupo B. Conforme al sistema RECIST no se encontraron diferencias estadísticamente significativas. La DEB-TACE fue mejor tolerada con menos complicaciones inmediatas (p = 0,001). No se encontraron diferencias significativas en la supervivencia entre los dos grupos. grupo A: media 686,24, mediana 709 días, y grupo B: media 765,32, mediana 672 días. Conclusión: En los pacientes con hepatocarcinoma irresecable, la quimioembolización con partículas cargadas de adriamicina es segura y mejor tolerada que la quimioembolización convencional y parece producir una mayor necrosis tumoral. © 2010 SERAM. Publicado por Elsevier España, S.L. Todos los derechos reservados.
Introduction Hepatocellular carcinoma (HCC) accounts for 80-90 % of all primary liver neoplasms and for nearly 5 % of all malignant cancers. Cirrhosis is in more than 90 % of cases the cause of HCC1. Curative therapies for early-stage HCC include tumor resection, liver transplant and radiofrequency ablation 2. Transarterial chemoembolization (TACE) is the only palliative treatment that has proved effective in terms of survival and it takes advantage of the predominantly arterial blood supply of HCC 3,4. The ideal TACE scheme should allow a maximum concentration of chemotherapy agent within the tumor combined with maximum vessel obstruction. The use of beads loaded with adriamycin is a novel concept of TACE that combines the induction of ischemia and cell lysis. Preclinical trials with these particles have demonstrated a sustained release of adriamycin, resulting in a reduction in toxicity for the patient 5,6. Recent studies have reported that the treatment of HCC with adriamycin-eluting beads has higher rates of tumor necrosis and tumor response in a shorter follow-up than conventional therapy 6-9.
The aim of this work is to compare the tumor response using imaging techniques, to evaluate immediate and long-term complications and the survival of each group (patients treated with conventional chemotherapy and patients treated with drug-eluting bead chemoembolization) in order to assess whether there are statistically significant differences.
Material and methods Patients The comparative study between both treatments was authorized by the Hospital de la Ribera and its Ethics Committee and was in accordance with the Declaration of Helsinki. This prospective study compares the results obtained after CHH treatment with conventional transarterial chemoembolization (TACE) and loaded bead transarterial chemoembolization (DEB-TACE), in two groups of patients during consecutive years. In total, seventy-two patients with unresectable HCC and well-preserved liver function (stage B) were
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Table 1 Inclusion and exclusion criteria for HCC treatment. Inclusion criteria for hepatocellular carcinoma treatment Patients with confirmed HCC according to the EASL criteria Patients with HCC non elegible for surgical resection or liver transplant Patients with recurrent tumor after RF ablation Patients with preserved hepatic function, stage I according to the BCLC Exclusion criteria for hepatocellular carcinoma treatment Altered hepatic functional reserve Gastrointestinal bleeding, encephalopathy or ascitis Bilirrubin > 3 mg/dl Involvement of > 50 % of liver parenchyma Contraindication for adriamycin administration Contraindication for intraarterial embolization Portal systemic shunts Hepatofugal flow Serum creatinine > 2 mg/dl
consecutively treated between January 1999 and December 31, 2009, according to the consensus criteria of the Barcelona Clinic Liver Cancer (BCLC) classification 10. The patients included in both groups fulfilled the inclusion and exclusion criteria summarized in Table 1. The diagnosis of HCC was based on MRI and/or CT findings of a lesion > 2 cm in diameter, hypervascular in arterial phase, early washout in venous phase (typical vascular pattern), demonstrated by at least two imaging techniques with dynamic enhancement, or a lesion with typical vascular pattern on one imaging technique and levels of alpha-phetoprotein > 400 U/L, or based on histologic findings in those cases not fulfilling the preceding criteria11. The longest tumor diameter was measured in millimetres and, in case of multiple lesions, the two largest lesions were measured and analyzed. None of the patients were candidates for curative therapies such as surgical resection, liver transplant or percutaneous ablation (radiofrequency or alcohol injection). The patients were provided information about the procedure and gave their informed consent. None of the patients had undergone previous treatments. From January 1, 2000, to December 31, 2006, the patients were treated with conventional TACE with adriamycin, and from January 1, 2007, to December 31, 2009, the chemoembolization was performed with beads previously loaded with adriamycin. Experienced interventional radiologists with a Philips Allura XPER FD20 angiographic system and using the same technique performed all the procedures.
M.D. Ferrer Puchol et al
Conventional transarterial chemoembolization (TACE) technique. Group A Using the Seldinger technique, a 18 G needle was used to puncture the right common femoral artery, the left common femoral artery or the left brachial artery, depending on the possibilities of access. A hydrophilic guidewire (Terumo, Europe, Leuven, Belgium) and a 5 F pigtail catheter were introduced through a 5 F vascular sheath to undertake an abdominal aorta angiogram for the identifi cation of the hepatic arterial anatomy and i t s p o t e n t i a l v a r i a n t s . S u b s e q u e n t l y, a s e l e c t i v e catheterization of the celiac trunk with a vascular Cobra 2 or Simmons 2 catheter (Terumo, Europe, Leuven, Belgium) was performed to access to the hepatic artery. In four patients with anatomic variants, the access to the right hepatic artery was done through the superior mesenteric artery. Once the hepatic arterial mapping was obtained, a 2.7/2.9 F Progreat microcatheter (Terumo Europe, Leuven, Belgium), with a hydrophilic guidewire of 0.021” to improve precision, was used to navigate through the segmental artery that supplies the tumor. The tumor was treated with 50 mg adriamycin in a 1:1 dilution of lipiodol, followed by the infusion of p o l y v i n y l a l c o h o l o f 3 0 0 t o 5 0 0 mm ( B e a d B l o c k , Biocompatibles, UK) until total occlusion of the feeding artery was achieved. None of the patients received antibiotic prophylaxis. Patients with bilobar tumors underwent two sessions spaced four weeks apart. Adriamycin-eluting bead transarterial chemoembolization technique. Group B The hepatic artery catheterization was performed with the procedure described previously. Sixty minutes were required to load with adriamycin the 100-500 mm particles (DCBead Precision V, Terumo, UK) prior to chemoembolization. This procedure was performed in the Pharmacy Department of our institution. Once loaded, the particles were mixed with non-ionic contrast agent (1:1). The bead diameter depended on the tumor size and blood supply. Two different sizes were used: 100-300 mm, which were introduced first, and 300-500 mm, introduced next. In case of multinodular lesions, the infusion was homogeneously distributed. The patients received a maximum of 150 mg of adriamycin in two DC Bead vials (in total, 4ml) per procedure with no antibiotic prophylaxis.
Immediate follow-up The patients were hospitalized for at least 48 hours and an individual follow-up was performed for the detection of post-embolization syndrome, with administration of antiemetics and painkillers when necessary. For Group B patients, the second chemoembolization was spaced two months apart. Patient follow-up Patients underwent clinical, analytical and imaging evaluation 4 to 6 weeks after the conclusion of the
Comparison of DEB-TACE with TACE for the treatment of hepatocellular carcinoma
treatment, including a complete blood count and biochemical test. The imaging evaluation of tumor response (criteria adopted from the European Association for the Study of the Liver, EASL) was performed using triple-phase computed tomography with intravenous contrast and/or triple-phase gadolinium-enhanced MRI, measuring the longest diameter of the viable tumor related to the longest total diameter. Non-enhanced tumor areas on both CT and MRI sequences reflected tissue necrosis 11. For the statistical analysis, the tumor response criteria were divided into two groups: objective response (complete necrosis and 30 % reduction of viable tumor) and poor response (no response, > 25 % increase of viable tumor and presence of new lesions). When one part of the tumor was viable (presence of contrast enhancement and washout), a second treatment was prescribed. If the enhancing area was < 3 cm a radiofrenquency (RF) ablation procedure was scheduled; for areas > 3 cm a second intraarterial chemoembolization was scheduled. After re-evaluation, if the patient required treatment, this was performed always within a month. In total, 23.6 % of patients required RF ablation. The time, in days, was measured from the date of the first diagnostic CT or MRI until the end of the follow-up: death, progression of an otherwise untreatable disease, the date the patient was lost to follow-up, or the date of the last follow-up in living patients. Statistical analysis The SPSS program, version 14.0., was used for statistical analysis. The analysis was done using descriptive statistics of frequencies. For continuous variables, the mean, standard deviation and range were estimated. In order to evaluate if the quantitative data of Group A were signifi cantly different from those of Group B an ANOVA test was used. For quantitative variables, the t-test was used to compare the similarity of the means. The chi-square test was used for the analysis of tumor response2. Kaplan-Meier curves were used for estimating the survival function, using the Log Rank test (Mantel-Cox test) to compare the survival distributions of both groups.
Results In total, 72 patients with HCC associated with an underlying condition were enrolled in this study, 63 patients (87.5 %) in Child-Pugh A, and 9 patients (12.5 %) in Child-Pugh B. All the patients had well-preserved liver function, with no vascular invasion or extrahepatic metastases. The cause of liver disease was hepatitis B virus infection in 9/72 cases (12.5 %), hepatitis C virus infection in 52/72 cases (72.2 %), alcoholism 9/72 cases (12.5 %) and other causes two cases (2.8 %). Uninodular HCC was present in 40/72 patients (55.6 %), 4/72 patients (19.4 %)
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has two HCCs and 18/72 patients (25 %) had three or more tumors. Patients were divided into two groups: 1) Group A comprised 25 patients treated from January 2000 to December 31, 2006, with intraarterial chemoembolization with conventional adriamycina (TACE). Mean age was 68.40 ± 8.54 years. In this group, 13/25 patients (52 %) had more than one tumor. The initial size of the main tumor was 48.44 ± 26.40mm and the initial size of the second tumor was 22.62 ± 14.47 mm. Each patient received 1.32 ± 0.67 sessions of treatment, with a total dose of adriamycin of 50.60 ± 29.95 mg per patient. 2) Group B comprised 47 patients treated from January 2007 to December 31, 2009, with doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE). Mean age was 69.26 ± 11.80 years. In this group, 19/47 patients (42.5 %) had more than one tumors. The initial size of the main tumor was 45.96 ± 23.20 mm and the initial size of the second tumor was 26.42 ± 14.37 mm. Each patient received 2.13 ± 0.95 sessions of treatment, with a total dose of adriamycin of 231.91 ± 110.2 mg per patient. In order to evaluate if the quantitative data of Group A were significantly different from those of Group B an ANOVA test was used. In this respect, only the number of sessions and the dose of adriamycin were statistically significant in favour of Group B, with no statistically significant differences for the rest of the variables. The imaging evaluation of the tumor response is summarized in Table 2 and Table 3. For the statistical analysis, the patients were divided into two groups: good response and poor response. Both groups were compared using the Pearson’s Chi square test and the Fisher’s exact text and no statistically differences were found, but there was a trend toward good response in a higher percentage of patients treated with DEB-TACE (Figure 1, Figure 2). Four patients of Group A (5.6 %) and 10 patients of Group B (13.9 %) developed new lesions. In total, 17/72 (23.6 %) patients had postoperative complications. For both groups, the most common complication was severe pain post-embolization (18.1 %) that appeared in nine patients of Group A and i n f o u r p a t i e n t s o f G r o u p B . Ta b l e 4 s h o w s t h e description of the complications that appeared in both groups. The t-test, used to compare the similarity of the means, was used to analyze if the presence of more complications correlated with higher doses of adriamyzin, but not statistically significant differences were found. At the time of data collection, all the patients of Group A had died, and 26 of Group B (later in time), which means a death rate of 44.7 % for this group over a three-year period. The survival analysis showed no
250
Table 2
M.D. Ferrer Puchol et al
Imaging assessment of tumor response.
TACE DEB-TACE total
Table 3
Tumor disapp.
Reduction > 30 %
No response
Increase > 25 %
New lesions
Total
4 10 14
7 16 23
6 4 10
4 7 11
4 10 14
25 47 72
Imaging assessment of tumor response.
Treatment
TACE DEB-TACE TOTAL
Objective response 1
Poor response 2
Total
N
% of the total
N
% of the total
N
% of the total
11 26 37
15.3 36.1
14 21 35
19.4 29.2
25 47 72
34.7 65.3
Treatment response is divided into good response and poor response and a Pearson’s chi-square test, with Fisher’s exact test were used. There were no statistically significant differences. 1: objetive response: tumor disappearance or reduction > 30 %. 2: poor response: no response, increase > 25 %, new lesions. IB
Men superior sin y con contraste 136278
D
I
RM-Higado sin y con contraste 436276
D
I
P
P
Figure 1 Hepatocellular carcinoma before treatment. Arterial-phase 3D GRE FS T1-weighted MR image shows contrast enhancement of the tumor.
Figure 2 Tumor response after treatment. Arterial-phase 3D GRE FS T1-weighted RM image shows no contrast enhancement of the tumor.
Table 4
Post-chemoembolization complications.
Complications
Number of cases
TACE
DEB-TACE
Nausea Pain Fever Alopecia Myelotoxicity Liver insufficiency Cholecystitis Abscesses UDB
5 13 5 1 1 1 0 0 3
4 9 4
1 4 1 1 1
(6.9 %) (18.1 %) (6.9 %) (1.4 %) (1.4 %) (1.4 %)
1
(4.2 %)
3
UDB: upper digestive bleeding.
statistically significant differences as shown by Table 5 and Figure 3.
Discussion The incidence of HCC is increasing worldwide, which is closely linked to an increase in hepatitis C virus infection. In fact, 80 % of HCCs in our environment are associated with hepatitis C virus, whereas, only 9 % with hepatitis B virus. This high incidence justifies the ultrasound screening tests, repeated every six months, and the determination of alpha-phetoprotein levels in patients with hepatitis C virus infection and in all the patients with viral cirrhosis12.
Comparison of DEB-TACE with TACE for the treatment of hepatocellular carcinoma
Table 5
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Means and medians of the survival analysis for a confidence interval of 95%.
Treatment
Mean days
Conventional chemoembolization Loaded beads
Median days
Estimated
Standard error
Estimated
Standard error
686.240 765.320
67.892 76.28
709.00 672
170.69 46.95
Log Rank test (Mantel-Cox) shows no statistically significant differences.
In recent years, the use of polyvinyl alcohol spheres loaded with adriamycin is undergoing evaluation. Theses spheres provide a gradual release of the chemotherapy agent into the tumor and reduce the number of complications 7. The study by Lencioni et al. reported significant differences in the imaging evaluation of the tumor response between the patients treated with drug-eluting beads, who showed higher rates of tumor necrosis, and those treated with conventional TACE 7 . Our study reported no statistically differences regarding imaging evaluation of tumor response, although there was a trend to show a larger area of necrosis. In this respect, 36.1 % of patients of Group B (treated with loaded beads) showed good response, with either complete tumor disappearance or tumor necrosis > 30 %, compared with 15.3 % of Group A. A recent study analyzes the concentration of adriamycin in liver tumors in a pig model using loaded beads. Adriamycin concentration was determined by microspectrofluorimetry and the study demonstrated the presence of the drug for a minimum of three months
I n t r a a r t e r i a l c h e m o e m b o l i z a t i o n ( TA C E ) i s n o w generally accepted as an effective palliative treatment for patients with unresectable HCC and well-preserved liver function (intermediate stage). With the help of selective catheters and microcatheters a superselective embolization of the arteries that supply the tumor may be achieved, sparing the unaffected areas of the liver parenchyma (Figure 2). This technique has proved to reduce systemic toxicity and to increase the local effects of chemotherapy. The optimal embolic agent should allow a maximum concentration of chemotherapy agent within the tumor and minimum systemic concentration, combined with obstruction of the vessels supplying the tumor. The chemotherapy agent (adriamicyn in this study) is emulsified in poppyseed oil (lipiodol) and together they form a medium that retain and concentrate the agents within the tumor 13. Despite selecting the patients and performing a superselective embolization, TACE is not without risks. Complication may range from postembolization syndrome (of variable intensity) to liver abscesses, hepatic insufficiency, ischemic cholecystitis or cases of death have even been described14.
Survival functions Treatment
++ +
1.0
+ ++
0.8
++ Cum survival
Loaded particles Conventional Chemoembolization + Censored Loaded particles
0.6
++
+ + + +
0.4
+
++ +
0.2
+ +
0.0 0
Figure 3
300
600
900
1200
1500
Survival graph created using the Kaplan-Meier method for both groups of patients.
252
after treatment 15 , representing another important advantage of this therapy. The drug not only stays longer within the tumor, but there is a more controlled drug release, as proven by Varela et al. who analyzed adriamycin pharmacokinetics reporting no drug peaks in plasma concentration after treatment, resulting in a reduction of complications 6. In this study, we found a statistically signifi cant lower number of complications, particularly immediate complications. A reduction in the cases of post-embolization syndrome in patients treated with DEB-TACE was reported, although one patient had alopecia two months after completing two sessions of DEB-TACE. It is worth mentioning that no correlation between the presence of complications and high doses of adriamycin was found, so even if the dose of drug used in patients treated with DEB-TACE was much higher, this did not result in more complications. The fi rst multicenter randomized trial that compares the safety and effectiveness of TACE with those of DEB-TACE in 212 patients has been recently published. The authors have reported that the treatment with adriamicyn-loaded beads reduces complications, despite the fact that a much higher dose of adriamycin is administered 16. These data are consistent with the results of our study, despite the fact that this included a lower number of patients. So far the only palliative treatment that has proved beneficial for patients with intermediate-stage HCC in terms of survival is TACE, since two randomized controlled trials found that TACE yielded better results than placebo 17,18, with a median survival of about 20 months (600 days). In this study, the median survival found was similar for the two groups (Figure 3) with no statistically significant differences between them. The limitations of the present study include the low number of patients and the follow-up of Group B patients that are still alive and receiving treatment. We also believe that the great variation in the number of sessions received by each patient is a source of bias in this study. In conclusion, according to our data, the treatment of HCC with adriamycin-eluting beads is a safe and effective treatment that allows the administration of higher doses of drug with a reduction in complications when compared with conventional chemoembolization. We have found no significant differences in survival between the two groups of patients.
Authorship M.ª Dolores Ferrer Puchol has contributed to the conception and design of the study and she is responsible for its integrity. She has carried out the analysis and interpretation of data as well as the statistical analysis and drafting of the manuscript. Cristina la Parra has contributed to the acquisition of data, drafting of the paper and critical review with relevant intellectual contributions. Enrique Esteban has contributed to the acquisition of data, bibliographic search and drafting of the paper.
M.D. Ferrer Puchol et al
María Vaño has contributed to the design of the study and to the analysis, interpretation and acquisition of data. Miquel Forment has contributed to the acquisition of data, bibliographic search and drafting of the manuscript. Almudena Vera has contributed to the acquisition of data, bibliographic search and critical review. Octavio Cosín has contributed to the acquisition and interpretation of data and bibliographic search. All the authors have read and approved the final version of the manuscript.
Conflict of interest The authors declare no conflicts of interest.
References 1. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the World cancer burden: Globocan 2000. Int J Cancer. 2001;94:153-6. 2. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology. 2002;35: 519-24. 3. Llovet JM, Bruix J. Systematic review of randomized trial for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology. 2003;37:429-42. 4. Forner A, Ayuso C, Real MI, Sastre J, Robles R, Sangro B, et al. Diagnóstico y tratamiento del carcinoma hepatocelular. Med Clin (Barc). 2009;132:272-87. 5. Lewis AL, Taylor RR, Hall B. Pharmacokinetic and safety study of doxorubicin-eluting beads in a porcine model of hepatic arterial embolization. J Vasc Interv Radiol. 2006;17: 1335-43. 6. Varela M, Real MI, Burrel M. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics. J Hepatol. 2007;46: 474-81. 7. Lencioni R, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, et al. A randomized phase II trial of a drug eluting bead in the treatment of hepatocellular carcinoma by transcatherer arterial chemoembolization. J Clin Oncol. 2009;27:4523. 8. Dhanasekaran R, Kooby DA, Staley CA, Kauh JS, Kim HS. Drug eluting beads versus conventional TACE for unresecable hepatocellular carcinoma: Survival benefits and safety. J Clin Oncol. 2009;27:4524. 9. Malagari K, Alexopoulou E, Chatzimichail K, Hall B, Koskinas J, Ryan S, et al. Transcatheter chemoembolization in the treatment of HCC in patients not eligible for curative treatments: midterm results of doxorubicin-loaded DC bead. Abdominal Imaging. 2008;33:512-9. 10. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19:329-38. 11. Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, 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;35:421-30. 12. Collier J, Sherman M. Screening for hepatocellular Carcinoma. Hepatology. 1998;27:273-9.
Comparison of DEB-TACE with TACE for the treatment of hepatocellular carcinoma 13. Bruix J, Sheman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-36. 14. Buijs M, Vossen JA, Frangakis C, Hong K, Georgiades CS, Chen Y, et al. Nonresectable hepatocellular carcinoma: long-term toxicity in patients treated with transarterial chemoembolization. Single-Center Experience. Radiology. 2008;249:346-54. 15. Namur J, Wassef M, Millot JM, Lewis AL, Manfait M, Laurent A. Durug-eluting beads for liver embolization: concentration of doxorubicin in tissue and in beads in a pig model. J Vasc Interv Radiol. 2010;21:259-67. 16. Lammer J, Malagari K, Vogl T, Pilleul F, Denys A, Watkinson A, et al. Prospective randomized study of doxorubicin-
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eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33:41-2. 17. Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35:1164-71. 18. Llovet JM, Real I, Montaña X, Planas R, Coll S, Aponre J, et al. Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma. A randomized controlled trial. Lancet. 2002;359:1734-9.
