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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 17  |  Issue : 1  |  Page : 61-67

Role of drug-eluting beads versus conventional transarterial chemoembolization in the treatment of hepatocellular carcinoma


1 Department of Radiodiagnosis, Al-Azhar University, Cairo, Egypt
2 Department of Tropical, Faculty of Medicine, Al-Azhar University, Cairo, Egypt

Date of Submission08-Jan-2019
Date of Acceptance07-Apr-2019
Date of Web Publication12-Sep-2019

Correspondence Address:
Mohammed G Mohamed
Tropica Medicine, El-Hussein University Hospital, Al-Azhar University, Gouhar Al-Kaed Street, Al-Darasah, Cairo 11675
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AZMJ.AZMJ_4_19

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  Abstract 


Background Transarterial chemoembolization has become the current standard therapy for the intermediate-stage hepatocellular carcinoma (HCC) according to the Barcelona Clinic Liver Cancer staging system. Conventional transarterial chemoembolization (cTACE) involves the injection of an embolic agent into the tumor-feeding arteries to block its major nutrient source resulting in tumor ischemic necrosis. Drug-eluting beads transarterial chemoembolization (DEB-TACE) was developed to deliver higher doses of chemotherapeutic agents over longer drug-tumor contact times.
Objective The aim of this study was to highlight on the safety and efficacy of DEB-TACE versus cTACE in patients with intermediate-stage HCC.
Patients and methods This study was carried out on 55 patients presented with irresectable who HCC underwent either cTACE: group 1, 25 patients or DEB-TACE; group 2, 30 patients from July 2016 to June 2017. All patients were subjected to full history taking, thorough clinical examination, investigations, imaging, adequate follow-up at 1, 3, and 6 months and were categorized according to the modified Response Evaluation Criteria in Solid Tumors.
Results According to the modified Response Evaluation Criteria in Solid Tumors responding disease was seen in 28 patients who underwent DEB-TACE and 18 who patients underwent cTACE, while nonresponding disease was found in two patients who underwent DEB-TACE and seven patients underwent cTACE (P=0.033). Complications such as postembolization syndrome and ascites occurs more in patients who underwent cTACE than after DEB-TACE (P=0.04, P=0.61).
Conclusion DEB-TACE is more effective than cTACE in intermediate-stage HCC with less side effects.

Keywords: conventional transarterial chemoembolization, drug-eluting beads transarterial chemoembolization, hepatocellular carcinoma


How to cite this article:
Elfadl MA, Shehata MA, Mohamed MG, Elskaan AS. Role of drug-eluting beads versus conventional transarterial chemoembolization in the treatment of hepatocellular carcinoma. Al-Azhar Assiut Med J 2019;17:61-7

How to cite this URL:
Elfadl MA, Shehata MA, Mohamed MG, Elskaan AS. Role of drug-eluting beads versus conventional transarterial chemoembolization in the treatment of hepatocellular carcinoma. Al-Azhar Assiut Med J [serial online] 2019 [cited 2019 Oct 22];17:61-7. Available from: http://www.azmj.eg.net/text.asp?2019/17/1/61/266736




  Introduction Top


Surgical resection remains the method of choice for the treatment of potentially curable hepatocellular carcinoma (HCC) in most countries, as liver transplantation, which is the best treatment, is limited by lack of suitable donors. Wu et al. [1], the recommended curative procedures for early HCC cases which are not appropriate for surgical resection or liver transplantation are percutaneous ablations, including percutaneous ethanol injection and radiofrequency ablation [2]. Transarterial chemoembolization (TACE) has become the existing standard treatment for intermediate-stage HCC (large or multicentric HCC with a moderately preserved liver functions, no cancer-related symptoms, and absence of vascular invasion or outside metastasis) according to the Barcelona Clinic Liver Cancer (BCLC) staging system [3]. TACE has also been performed as a bridging therapy for HCC downstaging before liver transplantation and to enhance survivall [4]. TACE implicates the blockage of the tumor-feeding arteries by an embolic agent to prevent its main nutrient supply, causing ischemia and necrosis of the targeted tumor [5]. Drug-eluting beads transarterial chemoembolization (DEB-TACE) represents a new drug release embolization system and was developed to release higher doses of chemotherapeutic agents for long time of contact with the targeted tumor [6]. TACE with DEBs achieves higher intra tumoral concentrations of doxorubicin with lower systemic concentrations and low hepatotoxicity than conventional transarterial chemoembolization (cTACE) [7].

Possible complications of transarterial chemoembolization

Postembolization syndrome is the most common complication including abdominal pain, fever, fatigue, nausea, and vomiting. Hepatic failure may occur due to ischemic damage to the nontumoral liver tissue. Other less common complications are hepatic abscess, cholecystitis, and biliary strictures.


  Aim of the work Top


The aim of this study was to evaluate the efficacy and safety of DEB-TACE as compared with cTACE in patients with HCC.


  Patients and methods Top


This study was conducted on 55 patients presented with unresectable HCC who was fulfilling the designed inclusion criteria. This work was approved by the ethical committee of the faculty of medicine Al-Azher University, Cairo, Egypt. The study was carried out in the Interventional Radiology Unit and Tropical Medicine Department at Sayed Galal University Hospital from July 2016 to June 2017. The included patients were randomly recruited into group 1 or 2. Group 1: 25 patients underwent treatment by cTACE and group 2: 30 patients underwent treatment by DEB-TACE. The decision of treatment depends on the stage of the disease according to the BCLC staging system.

General inclusion criteria

HCC without main portal vein thrombosis or extrahepatic spread in Child A and early B patient, and not candidate for surgical management, could be treated with TACE. They should have reasonable performance status [Eastern Cooperative Oncology Group (ECOG) performance status score] of 2 or less, adequate hematologic function, adequate hepatic function, and adequate renal function.

The ECOG (Robert L. Comis, MD, Group Chair) is one of the largest clinical cancer research organizations in the USA. The ECOG performance status is a scale used for the evaluation of a patient’s general condition (e.g. it one of the three components that form the BCLC HCC staging).
  1. Grade 0: fully active, able to carry out all predisease performance without restriction.
  2. Grade 1: restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work.
  3. Grade 2: ambulatory and capable of all self-care but unable to carry out any work activities, up and about more than 50% of waking hours.
  4. Grade 3: capable of only limited self-care, confined to bed or chair for more than 50% of waking hours.
  5. Grade 4: completely disabled, cannot carry out any self-care, totally confined to bed, or chair.
  6. Grade 5: dead.


General exclusion criteria

Patients with thrombosed main portal vein or one of its main branches, patients with extrahepatic invasion and with sever comorbidities or infection, uncontrolled encephalopathy, and any general exclusion criteria of the interventional procedure.

All patients were subjected to the following:

(a) Full history taking: with special stress on symptoms of liver cell failure. (b) Thorough clinical examination: careful repeated general and local abdominal examinations were done for all patients with special stress on signs of liver cell failure. (c) Complete blood count, liver biochemical profile including serum bilirubin, liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST)], total proteins, albumin, prothrombin time, and concentration, hepatitis markers (HBsAg, HBc IgG, and HCV Ab), and serum alpha-fetoprotein. Fasting blood glucose, and kidney function tests and electrolytes (serum sodium and potassium), were evaluated for the patients’ groups. Radiological examination including: ultrasound scan and adequate contrast-enhanced imaging study either computed tomography or MRI to evaluate the size, number, location, and extension of the tumor(s), patency of the portal vein and to get an idea about the arterial supply to the tumor(s) as well as the vascular anatomy and treatment procedures. On the day before chemoembolization procedure either conventional or using DEBs, all patients were evaluated with laboratory blood testing including complete blood count, chemistry panel, and coagulation parameters.

Conventional transarterial chemoembolization procedure

TACE procedures were performed by experienced radiologists by fluoroscopy. After common femoral artery access, selection of the celiac artery and complete hepatic arteriography will be performed at standardized positions with adequate contrast boluses to maximize parenchymal enhancement of malignancies. Contrast-enhanced C-arm images were obtained with the catheter positioned in the common hepatic artery. After determination of anatomy, a coaxial microcatheter was advanced super-selectively into the smallest arterial branches supplying identified tumors. Ten milliliters of Lipiodol was mixed with 100 mg of Doxorubicin hydrochloride emulsified to create a milky solution. Then emulsion was infused into the liver slowly with a dose dependent on the tumor size and the patient’s liver function. Hemostasis at the femoral puncture site was achieved by using simple manual compression.

Transarterial chemoembolization with drug-eluting beads procedure

Loading of the beads with Doxorubicin hydrochloride (100–150 mg) was done in vitro an hour before catheterization. The loaded beads were then aspirated from the vial into a syringe filled with nonionic contrast medium. Under fluoroscopic guidance, selective catheterization of the feeding artery was done and then the loaded beads were injected slowly into the tumor.

Imaging analysis quantifying size reduction and necrosis

Tumor response by cross-sectional imaging either by computed tomography and/or MRI was evaluated on all patients 1–3 months after treatment and approximately every 3 months thereafter and was categorized according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Responding disease was complete response (CR) or partial response (PR) while nonresponding disease was either stable disease (SD) or progressive disease (PD). Objective response rate (OR) was defined as CR plus PR, and disease control as OR plus SD [8].

According to mRECIST: nonappearance of enhanced lesions during the arterial phase, reflecting complete tissue necrosis, CR. At least a 30% decrease in the longest diameter of the enhanced area is PR. At least a 20% increase in the longest diameter of the enhanced area is PD; neither sufficient shrinkage to qualify for PR nor adequate increase to qualify for PD is SD.

Statistical analyses

A commercial software package (SPSS, version 20.0.0; SPSS, Chicago, Illinois, USA) was used for statistical analysis and sample size calculation; a P value of less than 0.05 was considered statistically significant. Comparison between numerical data was performed using unpaired the t test. Comparison between categorical data was performed using the χ2 test. Data were statistically described in terms of mean and SD or n (%).


  Results Top


The study comprised 38 (69.1%) men and 17 (30.9%) women. The age of the patients ranged from 32 to 81 years and the mean age was about 61.4 years. The age of the patients was also divided into less than or equal to 60 and their number is 24 (43.6%) patients, while 31 (56.4%) patients was more than 60 years ([Table 1]).
Table 1 Comparison between both groups as regard age and sex

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As regards the underlying liver disease and risk factors of HCC: HCC was associated with chronic hepatitis C virus (HCV) infection in 51 (92.7%) patients and chronic HBV infection in three (5.5%) patients and cryptogenic (non-B–non-C) in one (1.8%) patient ([Table 2] and [Table 3]).
Table 2 Hepatitis percentage in the study

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Table 3 Comparison between both groups as regard underlying risk factors

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As regard Child–Pugh classification and performance score (ECOG classification) for all studied patients: at the time of treatment, 52 (94.5%) patients were within Child–Pugh class A, three (5.5%) patients were within Child–Pugh class B, and according to performance status (ECOG criteria), 50 (90.9%) patients were graded as grade 0, three 1(5.5%) patients grade, and two (3.6%) patients were of grade 2 ([Table 4] and [Table 5]).
Table 4 Child–Pugh classification in the study

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Table 5 Comparison between both groups as regard Child–Pugh classification and Eastern Cooperative Oncology Group performance status

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Tumor characteristics: the maximum longitudinal tumor dimension in the study was 8 cm, while the minimum was 1 cm with a mean of about 3.92 cm while the median is about 3.70 cm. In 39 (70%) patients the size of the lesion was less than or equal to 5 cm, while in 16 (29.1%) patients were more than 5 cm ([Table 6] and [Table 7]).
Table 6 Size of the lesions in the study

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Table 7 Comparison between both groups as regard tumor size

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As regards the previous intervention in the study, 47 (85.5%) patients had no previous chemoembolization treatment while seven (12.5%) patients underwent previous chemoembolization sessions, and one (1.8%) patient underwent previous percutaneous radiofrequency ablation ([Table 8]).
Table 8 Prior therapy among the study groups

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Regarding overall mRECIST response rate: CR was seen in 34 (61.8%) patients, PR was seen in 12 (21.8%) patients, SD was seen in three (5.5%) patients, and six (10.9%) patients had PD ([Table 9]).
Table 9 Overall modified Response Evaluation Criteria in Solid Tumors in the study

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According to mRECIST criteria responding disease was seen in 28 patients who underwent DEB (Drug Eluting Beads) chemoembolization and 18 patients who underwent conventional chemoembolization, while nonresponding disease was found in two patients who underwent DCB chemoembolization and seven patients underwent conventional chemoembolization. The difference is statistically significant (P=0.033) ([Table 10]).
Table 10 Modified Response Evaluation Criteria in Solid Tumors response rate regarding procedure used

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Compared with baseline laboratory parameters for the patient who underwent adequate follow up at 1, 3, and 6 months. There is decrease in the level of liver enzymes (ALT and AST) in 1 month follow up with mean of about 46 and 56 mg/dl with respect to baseline laboratory parameters mean 81 and 91.3 mg/dl in patients who underwent DEB chemoembolization, while there is increase in their level in patients who underwent conventional chemoembolization with their mean of about 105.4 and 112.2 mg/dl with respect to baseline laboratory parameters, mean 69 and 83 mg/d ([Table 11] and [Table 12]).
Table 11 Mean value of aspartate aminotransferase on follow up period

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Table 12 Mean value of alanine aminotransferase on follow up period

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As regards postprocedural complications, postembolization syndrome including fever, fatigue, anorexia, nausea, and vomiting occurs in 18 patients after cTACE and in 13 patients after DEP-TACE, the difference was statistically significant (P=0.04). Ascites occurs in one patient after DEP-TACE and in three patients after cTACE, the difference was statistically insignificant (P=0.61) ([Table 13]).
Table 13 Complications among the study groups

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  Discussion Top


HCC is the most frequent primary tumor of the liver, the incidence of which is increasing worldwide. Cirrhosis of the liver, regardless of etiology, is the main risk factor for the onset of HCC. HCV and HBV are the main factors related to the presence of cirrhosis of the liver in patients with HCC [9]. TACE is the most broadly used treatment for HCC in nonsurgical patients not appropriate for radiofrequency ablation. Patients who have intermediate-stage HCC according to the BCLC staging system are the optimal candidates for transcatheter arterial chemoembolization as a palliative treatment. Lencioni et al. [3] in cTACE therapy, tumor selectivity is attained when chemotherapeutic agents are mixed with lipidol, to induce ischemia in tumors. In addition, there are side effects of lipidol as it diffuses into the portal venules and hepatic sinusoids and affects hepatic microcirculation; also doxorubicin is lost from lipidol very rapidly.

DEB‐TACE technology using nonabsorbable embolic microspheres, based on polyvinyl alcohol hydrogel has been modified with sulfonate groups loaded with cytotoxic drug, has been developed. The advantage of using it is continued release of chemotherapeutic agents over a long period of time, which differs with the more rapid release of the agents from the lipidol solution in cTACE therapy [2]. With a regulated gradual and local release, contact time of the drugs with the tumor is greater and its plasma levels are lower than those with cTACE therapy. Also increasing the dose using 150 mg instead of 70–100 mg using lipidol, has less side effects. In our study, patients with proved HCC were randomly divided into two groups: group I which included 25 patients, this group was treated by cTACE and group II which included 30 patients. This group was treated by DEP-TACE. Our study comprised 38 (69.1%) men and 17 (30.9%) women. The age of the patients ranged from 32 to 81 years and the mean age is about 61.1 years. This result is similar to that reported by Nawawi et al. [10] who found that 84.2% of the studied patients with HCC were men and 15.8% of patients were women, the age of the patients ranged from 32 to 80 years. This is consistent also with the findings of the PRECISION V trial [11], who found that 86.5% of their studied patients with HCC were men and 13.5% of patients were women. The incidence in men were more than women it is likely due to higher exposure to HCV between men. Regarding the etiology of cirrhosis in both groups, it was found that 26 patients underwent chemoembolization with DEBs had HCV while three patients had HBV and one was cryptogenic (non-B–non-C) while the other group that underwent conventional chemoembolization had HCV. This agrees with Shaker et al. [12] who studied the epidemiological characteristics of HCC in Egypt in 1313 patients and found that HCV Ab was detected in 91.32% of the studied patients. Thus, chronic hepatitis C is considered a major and important risk factor responsible for increased incidence of HCC. All our studied patients were classified either as Child–Pugh class A or Child −Pugh class B. Group 2 study showing 27 patients were within Child A score while three patients were within Child B score; however, the group 1 study was within Child A score. There was no significant difference between both groups (P=0.104). Patients of Child’s classification C were excluded from our studied patients. Regarding ECOG performance state, group 2 study showing 26 patients were with score 0, two patients score 1, and two patients score 2 while group 1 showing 24 patients were with score 0 and one patient score 1, the difference between two groups was statistically insignificant with P value of 0.372. This is consistent with the PRECISION V trial [11], 201 patients with Child–Pugh class A/B cirrhosis and large and/or multinodular unresectable HCCs were enrolled and received either TACE with doxorubicin or TACE with doxorubicin-loaded microspheres, ECOG performance status was 0 or 1 in 19 of the 20 patients. We selected our patients to be good candidates for TACE treatment as regards BCLC classification. In our study, regarding mRECIST criteria, responding disease was seen in 28 (93.3%) who patients underwent DEB chemoembolization and 18 (72%) had patients conventional chemoembolization. While nonresponding disease was found in two (6.6%) patients who underwent DCB chemoembolization and seven (28%) patients underwent conventional chemoembolization. The DEB groups showed significant higher rates of OR compared with the cTACE group (93 vs. 72%, P=0.033). This agrees with the PRECISION V trial [11], which demonstrated that based on the mRECIST criteria, the DEB group showed higher rates of OR compared with the cTACE group (52 vs. 44 %). Also, a retrospective study by Song et al. [13] stated that treatment responses for DEB-TACE were significantly better than those for cTACE (75.6 vs. 34.1%, P<0.001). Huang et al. [7] and Xie et al. [14] showed that significantly better objective tumor response was found for DEB-TACE than for cTACE. However, these significant increase in treatment responses of DEB-TACE relative to those of cTACE were not present in other studies [15], described treatment response of 177 HCC patients including 89 in DEB-TACE and 88 in cTACE. OR showed 74.7 and 74.1% for DEB-TACE and cTACE, respectively (P>0.999). Also Sacco et al. [16], showed insignificant differences in CR and PR rates between DEBs-TACE and cTACE (51.5 and 48.5% vs. 70.6 and 29.4%, respectively, P=0.1). In our study, regarding postprocedural complications, the incidence of postembolization syndrome was significantly lower, in patients receiving DEB-TACE than those receiving cTACE (P=0.04). There is decrease in the level of liver enzymes (ALT and AST) in the 1 month follow up with a mean of about (46 and 56 mg/dl) with respect to baseline laboratory parameters mean (81 and 91.3 mg/dl) in patients who underwent DEB chemoembolization, while there is an increase in their level in patients who underwent conventional chemoembolization with their mean of about (105.4 and 112.2 mg/dl) with respect to baseline laboratory parameters, mean (69 and 83 mg/dl). This agrees with the PRECISION V trial [11], DCB was associated with improved tolerability, with a significantly lower rate of doxorubicin-related side effects (P=0.0001) compared with cTACE. The mean maximum AST and ALT increase in the DC.

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Wu KT, Wang CC, Lu LG, Zhang WD, Zhang FJ, Shi F. Hepatocellular carcinoma, clinical study of long-term survival and choice of treatment modalities. World J Gastroenterol 2013; 19:3649–3657.  Back to cited text no. 1
    
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Yang HJ, Lee JH, Lee DH. Small single-nodule hepatocellular carcinoma: comparison of transarterial chemoembolization, radiofrequency ablation, and hepatic resection by using inverse probability weighting. Radiology 2014; 271:909–918.  Back to cited text no. 2
    
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Lencioni R, Petruzzi P, Crocetti L. Chemoembolization of hepatocellular carcinoma. Semin Intervent Radiol 2013; 30:3–11.  Back to cited text no. 3
    
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Nishikawa H, Kita R, Kimura T. Transcatheter arterial embolic therapies for hepatocellular carcinoma: a literature review. Anticancer Res 2014; 34:6877–6886.  Back to cited text no. 4
    
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European Association for the Study of the Liver, European Organisation For Research, Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56:908–943.  Back to cited text no. 5
    
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Zhou X, Tang Z, Wang J. Doxorubicin-eluting beads versus conventional transarterial chemoembolization for the treatment of hepatocellular carcinoma: a meta-analysis. Int J Clin Exp Med 2014; 7:3892–3903.  Back to cited text no. 6
    
7.
Huang K, Zhou Q, Wang R. Doxorubicin-eluting beads versus conventional transarterial chemoembolization for the treatment of hepatocellular carcinoma. J Gastroenterol Hepatol 2014; 29:920–925.  Back to cited text no. 7
    
8.
Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellu carcinoma. Semin Liver Dis 2010; 30:52–60.  Back to cited text no. 8
    
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El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology 2012; 142:1264–1273.e1  Back to cited text no. 9
    
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Nawawi O, Hazman M, Abdullah B, Vijayananthan A, Manikam J, Mahadeva S, Goh K. Transarterial embolization of hepatocellular carcinoma with doxorubicin-eluting beads: single centre early experience. Biomed Imaging Interv J 2010; 6:e7.  Back to cited text no. 10
    
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Lammer J, Malagari K, Vogl T. Prospective randomized study of doxorubicineluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 2010; 33:41–52.  Back to cited text no. 11
    
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Shaker M, Abdella H, Khalifa M, El Dorry AK. Epidemiological characteristics of hepatocellular carcinoma in Egypt: a retrospective analysis of1313 cases. Liver Int 2013; 33:1601–1606.  Back to cited text no. 12
    
13.
Song MJ, Chun HJ, Song DS, Kim HY, Yoo SH, Park CH et al. Comparative study between doxorubicin-eluting beads and conventional transarterial chemoembolization for treatment of hepatocellular carcinoma. J Hepatol 2012; 57:1244–1250.  Back to cited text no. 13
    
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Xie ZB, Wang XB, Peng YC, Zhu SL, Ma L, Xiang BD et al. Systematic review comparing the safety and efficacy of conventional and drug-eluting bead transarterial chemoembolization for inoperable hepatocellular carcinoma. Hepatol Res 2015; 45:190–200.  Back to cited text no. 14
    
15.
Golfieri R, Giampalma E, Renzulli M, Cioni R, Bargellini I, Bartolozzi C et al. Randomised controlled trial of doxorubicin-eluting beads vs conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer 2014; 111:255–264.  Back to cited text no. 15
    
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Sacco R, Bargellini I, Bertini M, Bozzi E. Conventional versus doxorubicineluting bead transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2011; 22:1545–1552.  Back to cited text no. 16
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13]



 

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