Transcatheter Arterial Chemoembolization Using HepaSphere Microspheres: Experience in 251 Patients With Unresectable Hepatocellular Carcinoma

Abstract: Objective: The purpose of this study is to show results in drug-eluting bead transarterial chemoembolization (DEB-TACE) using HepaSphere Microspheres (Merit Medical) loaded with doxorubicin in patients with unresectable hepatocellular carcinoma. Materials and Methods: From December 2005 to December 2015, 251 patients (198 male, 53 female; mean age 69 years, 6-month of median follow-up underwent selective TACE using HepaSphere Microspheres loaded with doxorubicin. Diameter of lesions (4 maximum for each patient) ranged from 25 mm to 176 mm, with a mean of 64.2 mm. Before treatment, Child Pugh score was A in 74.7% of patients and B in 25.3%. According to BCLC staging, 33.3% of patients were stage A, 64.6% stage B, and 2.1% stage C. Etiology of cirrhosis was attributed to hepatitis C in 138 patients and hepatitis B in 24, was alcohol-related in 49, and was attributed to nonalcoholic steatohepatitis (NASH) in 40 patients. Results: The technical success rate of the procedure was 100%, with complete devascularization of target lesions. Overall survival at 6, 12, 24, and 36 months was 84.2%, 66.3%, 54.2% and 44.3% respectively. Dividing our cohort per BCLC staging, stage A has a 91% 6-month survival rate, stage B 86%, and stage C 50%; stage A and B had 12-month survival rates of 75% and 74% respectively; stage A and B had 24-month survival rates of 61% and 64% respectively; and stage A and B had 36-month survival rates of 60% and 50% respectively. Conclusions: Our experience demonstrates that TACE using HepaSphere is feasible, with low complication rate and proved efficacy. Furthermore, it confirms DEB-TACE as first-line treatment in unresectable HCC. Larger series and randomized studies could give further confirmation.

Key words: hepatocellular carcinoma, cirrhosis, chemoembolization


Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death in the world. HCC is often associated with well-known risk factors: 90% of HCC cases arise in patients with cirrhosis, often due to chronic viral hepatitis or alcohol abuse.1 The BCLC staging system has indeed become widely adopted in Italy and Europe to define patients’ stage and prognosis.2,3 Local ablation is the first-line treatment option for patients with early-stage disease. It is associated with high rates of complete necrosis and up to 70% 5-year survival rates.4

Despite the development of surveillance programs, more than 80% of patients are diagnosed at an intermediate or advanced stage of disease, and they are therefore not amenable to curative treatment.5 Transarterial chemoembolization (TACE) is considered a standard of care in patients with intermediate-stage HCC, and it has been shown through level 1 evidence to prolong survival compared with best supportive care.6,7

Conventional TACE (cTACE) involves the selective injection of a chemotherapeutic agent (usually doxorubicin) emulsified in a viscous carrier (ethiodized oil), followed by embolic material into the feeding arteries of the tumor. Recently, TACE with drug-eluting microspheres has been associated with reduced liver toxicity and systemic side effects relative to cTACE.8 As drug-loaded embolics allow administration of higher drug doses to the malignant lesion with lower systemic exposure, they offer possible improvements in tumor response and long-term clinical outcomes. The aim of this paper is to present our experience using HepaSphere Microspheres (Merit Medical) loaded with doxorubicin in patients with unresectable intermediate-stage HCC. 


This study was a single-center retrospective review of patients with HCC treated with selective TACE using doxorubicin-loaded HepaSphere Microspheres between December 2005 and December 2015. Inclusion criteria for the review were the presence of HCC that was not suitable for surgical resection or thermal ablation, and Child-Pugh stage A or B. Patients with thrombus of the main portal vein or extrahepatic metastases were excluded from the study.

We adopted CIRSE guidelines for classifying complications; minor complications were those with nominal therapy and no consequences, and major complications were those requiring therapy and hospitalization as well as those that caused permanent adverse events and death.9

Features and Preparation

HepaSphere Microspheres are expandable, polyvinyl alcohol-sodium acrylate copolymer microspheres, sold in dehydrated form, that are approved and indicated in Europe for hepatic embolization and chemoembolization. The microspheres used for TACE were 50-100 μm or 30-60 μm (available since 2012) in diameter, expanding up to 4 times that size when rehydrated with physiologic saline solution or nonionic (isotonic) contrast medium. The microspheres are negatively charged (anionic polymer), enabling strong interactions with positively charged drugs such as doxorubicin.

The preparation of HepaSphere is relatively simple and consists of placing the chemotherapeutic solution in direct contact with the dehydrated HepaSphere Microspheres. It is necessary to wait 60 minutes to be certain that greater than 90% of the chemotherapeutic solution has been loaded by the microspheres. After loading the drug into the microspheres, the supernatant is removed and contrast medium is added to obtain at least 20 cc of final injectable volume.

The Procedure

The embolization procedure was performed as selectively as possible using a 2.7 Fr or 2.4 Fr microcatheter. The catheter tip was positioned as close as possible to the treatment site to avoid accidental occlusion of normal vessels.10 Slow injection of the microspheres was performed until the complete intended dose was administered or until intratumoral vascularity was obliterated.11 Lesions supplied by extrahepatic arteries (for example, the phrenic or mammary arteries) were also treated, always with the use of a microcatheter with the endpoint of intratumoral vessel blockade. The injection of the microspheres was performed far from the origin of the gastroduodenal, right gastric, and cystic arteries.

Each patient received a maximum of 50 mg of doxorubicin loaded in one vial of HepaSphere Microspheres, and no lipiodol was used.12 During the procedures, all patients received 8 mg dexamethasone, 50 mg ranitidine intravenously and 8 mg to 16 mg ondansetron. Pain relief with nonsteroidal anti-inflammatory drugs or opioids (tramadol 200 mg) was administered as needed. In patients with bilobar lesions, the left and right lobes were typically treated in separate procedures 2 months apart.

Imaging Follow-up

Patients underwent multiphasic computed tomography (CT) 1 month after TACE and contrast-enhanced ultrasound (CEUS) at 3 months of follow-up. In cases of complete response, a follow-up exam was performed every 3 months, once with CEUS and once with CT. Computed tomography was performed with 64 slices using a Philips Brilliance (Figure 1). Tumor response on CT images was evaluated according to mRECIST criteria.

CEUS was performed with a Siemens Sonoline Antares using Sonovue (Bracco) as an enhancing agent with the sudden injection of saline solution (10 cc). If follow-up showed new lesions or recurrence of previously treated lesions, TACE was repeated.


The retrospective chart review yielded 251 patients (198 male, 53 female, mean age 69 years) with HCC treated by selective TACE using doxorubicin-loaded HepaSphere Microspheres. Diameter of the HCC lesions ranged from 25 mm to 176 mm, with a mean diameter of 64.2 mm and a maximum of 4 lesions. 

At baseline, 74.7% of patients were Child-Pugh stage A, and 25.3% were Child-Pugh stage B; according to BCLC staging, 33.3% of patients were stage A, 64.6% were stage B, and 2.1% were stage C. The etiology of liver disease was hepatitis C in 138 patients, hepatitis B in 24, alcohol-related liver disease in 49, and nonalcoholic steatohepatitis in 40. One TACE procedure was performed in 135 patients, and multiple treatments (range, 2 to 12) were performed in 116 patients. In case of local recurrence, repeat TACE procedures were performed as needed (Figure 2). Ten patients underwent a combined procedure consisting of TACE and radiofrequency ablation (RFA) at the same time (Figure 3). Additionally, 51 patients underwent RFA either before or after their TACE procedures. 

Technical success was achieved in 100% of cases, with complete devascularization of the lesions at the conclusion of all procedures. No cases of hepatic failure or major allergic reactions were observed, but major complications occurred in 5 patients: one patient developed cholecystitis due to accidental embolization of the cholecystic artery, positioned near the treated lesion; one patient showed intrahepatic biloma; and 3 patients developed pancreatitis. Postembolization syndrome, characterized by fever (>38° C or 100.4° F), nausea, and pain, occurred in 45 (18%) of cases. 

The cohort had a median follow-up duration of 6 months. Overall survival was 84.2% at 6 months, 66.3% at 12 months, 54.2% at 24 months, and 44.3% at 36 months (Figure 4). By BCLC stage, 6-month survival was 91%, 86%, and 50% for stages A, B, and C, respectively; 12-month survival was 75% and 74% for stages A and B, respectively; 24-month survival was 61% 64% for stages A and B, respectively; and 36-month survival was 60% and 50% for stages A and B, respectively.

According to mRECIST criteria,13 we obtained complete response in 39.4% of patients (99/251), a partial response in 44.2% (111/251), and stable or progressive disease in the remaining 16.4% (41/251).


Currently, DEB-TACE is the standard first-line treatment for patients with inoperable and intermediate HCC. In the literature, there have been few studies comparing DEB-TACE to bland embolization with controversial results. In the study by Brown et al,14 the authors found no differences between the two treatments. However, Malagari et al15 found encouraging statistically significant data on tumor response and minor recurrences in patients treated with DEB-TACE. The PRECISION V study comparing DEB-TACE to cTACE demonstrated no evident superiority of DEB-TACE even if the results were better regarding side effects.16

Our results demonstrate that using HepaSphere Microspheres should play an important role as an alternative to cTACE, with good quality of life for patients, low complication rates, and proven efficacy.17 The variety of sizes in which HepaSphere is available allows the physician to select the embolic diameter that best fits each lesion. We were able to use 30 μm to 60 μm microspheres in HCC recurrences that had previously been treated with at least one TACE procedure and for lesions with diameters larger than 4.5 cm (Figure 5). Owing to the lack of damage to hepatic arteries relative to cTACE, we were able to perform TACE up to 12 times in a single patient.

TACE also offers the possibility of combined therapy with thermal ablation. This combination is feasible in hypovascular lesions in which TACE alone is generally less effective; performing TACE after thermal ablation could be useful to treat the peripheral vital tissue around the necrotized core of the HCC. Our data regarding combined treatment were not conducive to statistical analysis because of the small sample size (only 10 patients underwent this procedure).

Our study was limited by the lack of randomization, and the confounding effect of additional treatments before and after the embolization procedure. Many patients were lost to follow-up over the 10-year study period, and the cause of death was unknown in many cases. Randomized studies, comparing the use of Hepasphere to conventional TACE could give further confirmation to our results.


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Editor’s note: Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Grosso reports receiving speakers’ bureau fees and reimbursement of travel fees.

Manuscript received May 12, 2016; provisional acceptance given June 15, 2016; manuscript accepted September 2, 2016. 

Suggested citation: Grosso M, Pedrazzini S, Bongiovanni I, et al. Transcatheter arterial chemoembolization using HepaSphere microspheres: experience in 251 patients with unresectable hepatocellular carcinoma. Intervent Oncol 360. 2016;4(12):E191-E200.