Transarterial embolisation of hepatocellular carcinoma with doxorubicin-eluting beads: single centre early experience
1 Department of Biomedical Imaging, University of Malaya, Kuala Lumpur, Malaysia
2 Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Purpose: This is a retrospective study to evaluate the
results of our early experience of using doxorubicin eluting beads (DEB) to
treat patients with early and intermediate hepatocellular carcinoma (HCC).
Material and methods: A cohort of 19 patients (84.2% male;
15.8% female; mean age 59.2 years � 11.0; range, 32‑80 years) with
documented HCC of size 1.8-10cm (mean, 4.0cm � 1.8 ) undergoing DEB
transarterial chembolisation (TACE) was reviewed. All patients had at least one
image examination (multiphase computed tomography or magnetic resonance
imaging) after embolisation.
Results: A total of 32 procedures were performed. The
objective response according to the European Association for the Study of the
Liver criteria was 57.9% at 1-month, 42.8% at 6-month and 50.0% at 1-year
follow up. There were 4 (21.1%) treatment-related complications (1 liver
abscess, 2 pancreatitis and 1 tumour rupture) which resulted in 2 deaths. One
death occurred 3 weeks after second embolisation, due to ruptured pancreatic
pseudocyst, giving a 5.3% 30-day mortality rate. Another patient died 2 months
after embolisation caused by tumour rupture. Eight patients received
radiofrequency ablation after embolisation for residual or recurrent tumours.
The 1-year survival rate in the DEB TACE only group was 80% while the 1- and
2-year survival rate in the group that received radiofrequency after DEB TACE
was 85.7% and 100% respectively.
Conclusion: DEB TACE is safe and effective in select group
of patients. Survival may be improved when combined with other treatment modality.
� 2010 Biomedical Imaging and Intervention Journal. All rights reserved.
Keywords: Drug-eluting beads, doxorubicin, embolisation,
Transarterial chemoembolisation (TACE) involves selective
delivery of a chemotherapeutic agent such as cis-platin, doxorubicin, and
mitomycin in an emulsion with viscous material such as lipiodol, followed by
injection of an embolising agent into the vessel supplying the liver tumour.
This procedure is recommended by the Society of Interventional Radiology (SIR)
as the first line treatment of inoperable hepatocellular carcinoma (HCC) with
preserved liver function . The advantages of TACE are the ability to deliver
high concentration of drugs to the tumour and reduction of serious systemic
side effects such as cardiac toxicity, myelosuppression and alopecia compared
with systemic chemotherapy. TACE functions by de-arterialisation of tumour by
the embolic agents and selective delivery of chemotherapeutic agents to the
tumour. Recent randomised trials and studies have shown statistical survival
benefits and improved therapeutic efficacy of TACE in unresectable HCC over
supportive care or systemic chemotherapy [2, 3, 4]
Recently, embolic microspheres that have the ability to
sequester doxorubicin hydrochloride from the solution and release it in a
controlled and sustainable fashion were introduced for intra-arterial
injection. The embolisation particles are made from a unique drug-eluting
technology i.e., doxorubicin-eluting beads (DEB), based on a hydrogel that has
been modified with sulphonate group . They are available in diameters
ranging from 40 to 1200 �m designed to allow gradual release of chemotherapy
over time, to prolong the contact time between cancer cells and to avoid damage
of the hepatic microcirculation . Selective delivery of the loaded beads
into the feeding arteries leads to vessel lumen occlusion and ischaemia, while
doxorubicin is gradually released locally, leading to tumour necrosis [5, 7,
8]. Several studies have shown that following DEB TACE, systemic levels of
doxorubicin are reduced significantly when compared with conventional TACE [8,
9, 10]. DEB has been shown to elute doxorubicin over a sustained period of time
resulting in greater tumour response .
In this paper, the authors present the results of their
early experience treating 19 confirmed HCC patients using DEB. The study
population includes patients with early and intermediate HCC (stage A and B).
They also calculated the survival rate of patients who received radiofrequency
ablation after DEB TACE.
Material and Methods
This study is a retrospective cohort study based on the
analysis of 19 patients (16 male and 3 female, mean age 59.2 years � 11.0) with
HCC, treated with transarterial embolisation of doxorubicin-eluting DC beads
(Biocompatibles UK, Surrey, UK) from February 2007 to October 2008 in a single
centre. Following embolisation, all patients had at least one follow-up imaging
with either multiphase CT or MRI. Diagnosis of HCC was either confirmed by
biopsy or based on radiological findings and alpha-feto protein level according
to the Barcelona criteria . The inclusion criteria for treatment with
doxorubicin loaded beads were as follows: patients with HCC who were not
suitable for resection, liver transplantation or percutaneous ablation;
patients who developed recurrence following resection, percutaneous ablation or
conventional TACE and patients who have declined surgery or radiofrequency
ablation. Liver function criteria for enrolment included bilirubin <51
�mol/L and liver enzymes (aspartate aminotransferase and alanine
aminotransferase) < 270 IU/L.
The exclusion criteria for treatment with doxorubicin (DC)
loaded beads were patients with: extrahepatic metastasis, portal vein invasion,
portosystemic shunts, encephalopathy, gastrointestinal bleeding,
contraindication for hepatic embolisation (impaired clotting tests, renal
insufficiency/failure, sepsis and bleeding coagulopathy) and tumour burden
>50% of the liver volume.
Embolisation technique and surveillance imaging
All procedures were performed in the interventional
radiology suite by interventional radiologists after informed consent for the
procedure was obtained from the patients; approval of an ethics committee was
not required. Prior to embolisation, angiography of the coeliac and hepatic
artery was performed to determine the feeding arteries of the tumour, identify
variation in the liver arterial supply and exclude portal venous shunting.
Loading of the beads was done in vitro an hour before the beginning of catheterization.
The loaded beads were then aspirated from the vial into a syringe filled with
nonionic contrast medium. Three different sizes of DC beads were used, 100-300 μm,
300-500 μm and 500‑700 μm. The diameter of the beads chosen
depended on the calibre of the feeder, size of tumour and vascularity of the
tumour. For small tumours measuring less than 3 cm, DC beads of 100-300 μm
were used while DC beads of 300-500 μm and 500-700 μm were used for
larger tumours. Once the feeding artery was identified and catheter was in
placement, the loaded beads were infused slowly under fluoroscopic guidance.
The injection of the loaded beads was performed as selective as possible using
either a 4F diagnostic catheter (hepatic catheter or Yashiro) or 2.7F
microcatheter (Progreat; Terumo). For diffuse or multifocal tumours, lobar or
segmental embolisation was performed. The beads were injected distal to the
origin of the gastroduodenal, right gastric and cystic artery. Pre-treatment
coil embolisation of non target arteries was not performed in any of the
patients. The embolisation endpoint was sluggish flow of the tumour feeder
vessels. Intravenous analgesia and antiemetic were administered before and
during the procedure.
Follow up imaging was performed 4 weeks after embolisation
and every 3 months after that. Repeat embolisation was scheduled �on demand�
basis, 2 to 4 weeks after follow up imaging if there was residual viable
tumour deemed unsuitable for radiofrequency ablation or surgery.
All CT scan studies were performed with a 16-slice
multidetector CT (Light speed, General Electric Medical Systems, USA and Siemen Somatom Sensation 16, Munich, Germany). CT examination was performed using a 5-phase
protocol including a non-enhanced acquisition. Early arterial phase (delay 20
s), late arterial phase (delay 30 s), portal venous phase (delay 60 s) and
delayed venous phase (delay 80 s) were obtained using 120 mL of contrast
(Iopromide 300 mg I/L, Schering, Germany) at a rate of 4 mL/s. The images were
acquired with slice thickness 1.25 mm, collimation 2.5 mm and table speed 7.5
mm per gantry rotation. In a few select patients, gadoxetic acid enhanced MRI
using General Electric 1.5 Tesla Signa (GE Medical System, Milwaukee, Wisconsin)
Tumour response to procedure was evaluated according to
the amount of tumour necrosis detected on CT or MRI follow-up imaging as
recommended by European Association for the Study of the Liver Disease (EASL)
. The EASL acknowledges �viable areas� as those that �present enhancement�
and �necrotic� as those that �do not present enhancement�. In the EASL
criteria, complete response (CR) is defined as complete disappearance of all
known disease and no new lesions are seen; partial response (PR) when a 50%
reduction in all tumoural area of all measurable lesions is present; stable
disease (SD) in all other cases and progressive disease (PD) when there is 25%
increase in size of one or more measurable lesions or if new lesions appear.
Objective response (OR) included both a complete and partial response. Patients
who underwent other treatment modalities (radiofrequency ablation, conventional
TACE, surgical resection) following DC beads embolisation were analysed
separately. The authors considered a complication that occurred within 4 weeks
of the embolisation as procedure-related complication.
Statistical analysis was performed using SPSS version 17.
Values for all continuous variables are quoted as mean, standard deviation,
minimum and maximum throughout. The paired t-test was used to demonstrate
changes in biochemistry over time.
Table 1 tabulates baseline characteristics, response and
survival of patients analysed in this series. Of the 19 patients that
underwent the procedure, 12 (63.2%) patients presented with Child-Pugh score A
and 7 (36.8%) with Child-Pugh score B. Fifteen (78.9%) patients had liver
cirrhosis out of which 2 had hepatitis C virus (HCV)-related cirrhosis, 8 had
hepatitis B virus (HBV)-related cirrhosis, 1 had alcohol-induced cirrhosis and
4 had cryptogenic cirrhosis. The patients were also staged according to the
Barcelona Clinic Liver Cancer (BCLC) Staging system with 4 (21.1%) of 19
patients presenting with early stage (A) and the rest (78.9%) presenting with
intermediate stage (B) .
Seven of the 19 patients presented with single tumour
while the rest had multicentric disease. Of the 12 patients that presented
with multicentric disease, 9 patients had less than 5 lesions, 2 had 5 to
10 lesions and 1 patient had 12 lesions. The total number of lesions was 62 and
the mean tumour diameter was 4.0 � 1.8 cm. Eleven (57.9%) patients were found
to have unilobar disease with right lobe involvement seen in 10 of them. The rest
(42.1%) of the patients presented with bilobar disease.
A total of 30 embolisations were performed. All procedures
were technically successful with no intraprocedural complication encountered.
Ten patients (52.6%) received single embolisation, 7 patients completed 2
embolisations and 2 patients completed 3 sessions. A total of 32 vials of
DC beads were used (mean, 1.7 vials per patient) with a maximum dose of 150 mg
(range: 50 mg to 150 mg) per session. Radiofrequency ablation (RFA) was performed
on 8 patients following embolisation for residual or recurrent tumour. Two
patients received 2 RFA sessions after embolisation. A total of 10 RFA sessions
Periprocedural laboratory test showed no statistically
significant change in the level of bilirubin and gamma-glutamyl transferase
after the procedure compared to the baseline. However, there was significant
rise of alanine aminotransferase (p = 0.03) and aspartate
aminotransferase (p = 0.002) 1 to 3 days after embolisation which
returned to baseline 3 to 5 weeks after the procedure.
Table 2 reports the tumour response according to the EASL
assessment criteria of patients treated with only DEB TACE at 1-month, 6-month
and 12-month follow-up. Figure 1 and 2 illustrate a case of complete response
and partial response, respectively.
At 1-month follow-up, complete response was seen in 4 of
the 19 patients (21.1%) and partial response was documented in 6 patients
(31.5%). Five patients (26.3%) showed stable disease and 4 patients (21.1%)
showed progressive disease. Objective response was seen in 52.6% of patients.
There was no mortality recorded within 30 days of the embolisation.
At 6-month follow up, 1 patient was lost to follow up
(patient 12) and 4 patients underwent RFA (patient 3, 6, 10, 16). Hence, 14
patients were available for the 6‑month follow up. Six patients had
completed 2 sessions of embolisation, with a treatment-related death
recorded in one of the patients (patient 2). The death, which occurred 3 weeks
after the second embolisation, was caused by cardio-circulatory collapse due to
a ruptured pancreatic pseudocyst. Another patient died 2 months after one
embolisation believed to be caused by tumour rupture (patient 11). The ruptured
tumour showed partial response at the 1-month follow up CT scan. Objective
response was documented in 6 (42.8%) of 14 patients with complete response
seen in 3 patients and partial response recorded in 3 patients. One of the
patients (patient 15) classified as having progressive disease by EASL criteria
showed partial response of the initial target lesion but developed new lesion
in the non targeted part of the liver.
At 12-month follow-up, another patient (patient 7)
defaulted follow up and an additional 3 patients (patient 15, 18 and 19)
underwent RFA. Sustained complete response was seen in 3 (30%) of 10 patients
and sustained partial response seen in 2 (20%) patients. Survival at 12 months
One patient underwent liver resection of new tumour lesion
at 13 months (patient 13). One patient (patient 4) died at 18 months due to
disease progression. No patient was available for the 24-month follow up. The
mean duration of follow-up for patients who received DEB TACE only was 12.9 months
� 6.1 (range, 1 - 18 months).
Seven patients (36.8%) in this series received RFA after
the first embolisation while 1 patient (5.2%) was ablated after the second
embolisation, for residual or recurrent tumour. For these patients, the 1- and
2-year survival rate following the first embolisation was 85.7% (6 of 7) and
100% (1 of 1), respectively. One patient (patient 12) who underwent 2 sessions
of RFA post embolisation succumbed to the disease 11 months from the time of
embolisation. There was no treatment-related complication in this group of
patients. The mean duration of follow up was 17 months � 5.9 (range, 8 to 27.5 months).
Side effects and complications
Pancreatitis resulting in treatment-related mortality was
observed in one patient (patient 2) with intermediate HCC, after the second
embolisation. The pancreatitis, which occurred 5 days after the embolisation
and managed conservatively, was complicated by pseudocysts. Unexpectedly, one
of the pseudocysts ruptured causing the patient to go into cardio-circulatory
collapse. The death was the only 30-day mortality in this series. Another
patient (patient 14) was retrospectively diagnosed to have pancreatitis after
the 6-month follow up MRI revealed a 5 cm pancreatic pseudocyst. On further
questioning, the patient gave a history of having intermittent
�indigestion-like� symptoms 3 months after the embolisation, which gradually
worsened in the subsequent months. The pancreatic pseudocyst was then
percutaneously aspirated under ultrasound guidance and the patient was
completely asymptomatic following the aspiration.
One death (patient 11) occurred 8 weeks after
embolisation, believed to be caused by rupture of the largest tumour, giving a
treatment-related death of 10.5%. The tumour that ruptured measured 6 cm in
diameter and was radioablated 5 times before the DEB TACE procedure.
Liver abscess was recorded in 1 patient (patient 13), 2
months after the second embolisation. The collection was successfully drained
percutaneously but the patient underwent a resection 4 months later after a
follow up CT revealed a recurrence at the margin of the resolving liver
abscess. Overall, the total number of complications was 4 out of 19 patients
Post embolisation syndrome defined as fever, nausea,
vomiting or abdominal pain was observed in all patients following the first
procedure and 4 of 9 patients following the second session. The maximum
hospital stay for post embolisation syndrome was 7 days. The median hospital
stay was 1 day. There was no doxorubicin systemic toxicity (alopecia, marrow
suppression or cardiac failure) documented in these patients.
HCC is the fifth most common cancer globally with over
600,000 new cases diagnosed worldwide each year . The incidence in
developing countries is two to three times higher than in developed countries
. In Malaysia, HCC is among the ten most common cancers in the male
population with a distinct predilection for Chinese [15, 16]. It is the leading
cause of death in cirrhotic patients. Surgery, as a curative option carries significant
perioperative mortality and morbidity in patients with cirrhosis and is
indicated only in patients with single HCC without portal hypertension and
preserved liver function [17, 18]. In patients with HCC that is not suitable
for curative treatment, TACE represents the first-line approach that can
improve 1- and 2-year survival [3, 11, 19]. The choices of chemotherapeutic
agent and embolisation material may vary from centre to centre, however, the
common denominator of this procedure is the intra-arterial injection of
emulsified chemotherapeutic agent with viscous agent. The aim of the procedure
is to deliver chemotherapeutic agents to the tumour selectively, and at the
same time to induce ischaemic necrosis of the tumour.
Drug-eluting beads are new embolic agents for TACE that
can be loaded with chemotherapeutic agent and designed to allow gradual release
of chemotherapeutic agent locally and reduce the systemic toxicity of
chemotherapeutic agent. In vivo study has documented that animals
treated with DEB showed significantly lower plasma concentration of doxorubicin
compared with control animals treated with doxorubicin intraarterially. This
suggests higher tumour retention of doxorubicin in animals treated with DEB
. The high affinity for doxorubicin and the slow-release mechanism are
unique properties of DEB that were not observed with other commercially
available embolisation agents . Varela et al conducted the first
human trial on doxorubicin loaded DC Beads, on Child-Pugh A cirrhotic patients
with large or multifocal HCC. They confirmed that peak plasma doxorubicin level
was lower with DEB compared with that of doxorubicin-lipiodol emulsion .
As with previous DEB TACE studies, there was no systemic
toxicity from doxorubicin observed in this study [9, 10, 20, 21]. The total
incidence of complication observed in this series was 12.5% per procedure or
21.1% per patient, comprising of 2 pancreatitis, 1 liver abscess and 1 tumour
rupture. Two of the complications resulted in 10.5% of treatment-related death.
The incidence of serious treatment-related complication and treatment-related
death following conventional TACE had been reported to be 27.5% and 9.4%,
respectively [4, 22]. Earlier investigators of DEB TACE had documented major
complication rate of 7.4% and 42.9% and treatment-related death of 14.3% in
their series [8, 23]. Overall, the complications encountered in this cohort are
known complications of TACE that are reported to range from 0% to 50% .
Fatal outcome due to tumour rupture following TACE has
been documented, usually in patients with large subcapsular tumours, as was the
case in the authors' patient [25, 26]. Increased intratumoural pressure as a
result of tumour necrosis or vascular injury secondary to embolisation has been
thought to be the mechanism of tumour rupture following TACE .
Pancreatitis is an uncommon complication following
embolisation, but has a significant morbidity and mortality potential if
associated with local or systemic complications . Clinically evident acute
pancreatitis after embolisation occurs at an incidence between 1.7% and 4% but
typical laboratory findings consistent with pancreatitis is shown in 40% of
patients [28, 29]. The diagnosis of acute pancreatitis following embolisation
can be missed as it can clinically mimic postembolisation syndrome, as was the
case in the authors' patient. Hence, careful monitoring of serum pancreatic
enzymes should be employed in cases of abdominal pain following TACE . The
proposed mechanism of pancreatitis following TACE is inadvertent embolisation
through collateral vessels or regurgitation of embolic particles or
chemotherapeutic agents to the non targeted arteries [30, 31]. Similar
causative factors are used to explain a variety of other complications related
to hepatic intra-arterial treatment especially to the gastroduodenal region.
Acute cholecystitis attributed to inadvertent embolisation of the cystic artery
was reported following DEB TACE . In order to avoid serious adverse effects
or damage to the gastroduodenal territory due to misdistribution of embolic or
chemotherapeutic agents, embolisation of the gastroduodenal artery can be
performed prior to embolisation [32, 33]. Prophylactic embolisation of
nontarget arteries is a well-established approach to protection of non target
organs in 90Y SIR-Spheres embolisation . In view of the high
chemoembolic mechanism of action of DEB and documented incidence of fatal
pancreatitis in this series, similar preventive measures may be taken to avoid
repeat incidence of fatal complications of non target organs, especially in
cases where superselective injection are not possible.
Liver abscess is a well known DEB TACE related
complication which had contributed to treatment-related mortality [2, 10, 23].
The 5.3% incidence of liver abscess in this series is comparable to previous
studies which ranged between 1.6% to 14.2% [10, 20, 23]. The most important
predisposing factor for this complication is the presence of biliary
abnormality prone to ascending biliary infection such as bilio-enteric
anastomosis, bilio-enteric fistula, endoscopic papillotomy and percutaneous
biliary drainage . These risk factors were was not present in the authors'
patient (patient 13). Abscess formation after conventional TACE of 1.2% to 2%
seems lower than after DEB TACE [1, 35, 36]. The reason for this observation
could be due to the fact that unlike gelfoam particles used in conventional
TACE, the beads used in DEB TACE are non-reabsorbable and can cause permanent
ischemic damage to the liver .
The authors adopted the EASL criteria as their choice of
monitoring treatment response as they take into account the development of
necrosis, which better describe the effect of treatment. The parameter of
necrosis is not taken into account in the Response Evaluation Criteria in Solid
Tumours (RECIST), which measures the size of treated lesion. It is acknowledged
that it is common for liver tumours to liquefy without significant change in
total lesion diameter within short follow-up periods and that extensive tumour
necrosis may not be paralleled by a reduction in the diameter of the lesion
The authors observed an objective response that ranged
from 42.8% to 57.9% across 1 year (Table 2). Sustained objective response was
recorded in 5 (50%) at 12-month follow up. These values are slightly lower than
previous DEB TACE studies but higher than conventional TACE clinical trials of
16-35% [2, 4, 10, 20, 22, 38, 39, 40]. Malagari et al in their DEB TACE
trials on unresectable HCC reported objective response rate of 59.6% to 80.7%
. However, unlike the authors' series where patients with multicentric
disease make up 63.2% of the study population, only patients with solitary
tumour were included in their study . One patient with complete response of
the initial target lesion developed new lesions at the non targeted part of the
liver at 6-month follow up and, hence, classified as having progressive disease
(patient 19). These new lesions were either microscopic foci undetected by
imaging at the time of recruitment or new multicentric tumours. Such lesions
were probably not covered during treatment due to the selective delivery of DEB
The 1-year survival rate of 80% in this study is similar
if not higher than that of conventional TACE. In TACE studies where lobar
embolisation was performed in 49% of the cases, the 1-, 2-, and 3-year survival
rates were reported at 57, 31 and 26%, respectively . In another paper where
segmental TACE was applied in relatively small cancers which are potentially
suitable for RFA, survival was 80%, 43%, and 23% at 1, 3 and 5 years, respectively
. Comparatively, the survival rate of patients who presented with single
small HCC (< 4 cm) in the authors' series was 100% at 1-year.
These were patients who had refused surgery, or who presented with new lesion
after a successful RFA. Not surprising this small cohort of patients also
achieved 100% objective response across 1 year.
A total of 42% of patients in the authors' series
underwent RFA after DEB TACE. In view of the considerably high rate of patients
in this group the authors have also included the survival analysis of this
cohort. The 1-year survival rate of 85.7% (following the first embolisation)
was slightly higher than that of the DEB TACE only group. At the time of
writing, only 1 death was recorded at 11 months after the first
embolisation. The longest surviving patient in this study belonged in this
group. The patient survived 27.5 months after embolisation and was in partial response
at 24‑month follow up. Improved survival time had been reported in
patients with early HCC treated with resection or TACE followed by RFA as
compared to patients receiving TACE alone . Early literature on patients
with unresectable HCC treated with RFA after TACE reported promising mid-term
clinical success with projected 1- and 2-year survival rate of 89.7% and 67.1%,
respectively . However, the overall usefulness of this combined therapy has
yet to be established by large series and risk-benefit analysis.
In summary, the review of the authors' early experience
shows that DEB TACE is well tolerated and effective in treating patients with
early and intermediate HCC. When combined with other treatment modality, the
survival time can be prolonged.
Figure 1 Multiphase CT in arterial phase showing a focal enhancing lesion in segment 6 (A). Angiogram before embolisation shows tumour (arrows) supplied by the branch of right hepatic artery (B). Multiphase CT in arterial phase 1 month after embolisation reveals complete disappearance of tumour, in keeping with complete response (C).
Figure 2 Multiphase CT in arterial phase showing a heterogenously enhancing lesion in the right lobe of liver (A). 1-month follow up CT in arterial phase shows tumour necrosis of most of the tumour with a small residual nodule at the periphery, in keeping with partial response (B).
Table 1 Baseline characteristics, response and survival of patients.
Table 2 Tumour response based on EASL criteria at 1-, 6- and 12-month follow up.
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|Received 16 August 2009; received in revised form 24
November 2009, accepted 24 November 2009
Correspondence: Department of Biomedical Imaging, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. Tel.: +603-79492069; Fax: +603 7873 9590; E-mail: email@example.com (Ouzreiah Nawawi).
Please cite as: Nawawi O, Hazman MN, Abdullah BJJ, Vijayananthan A, Manikam J, Mahadeva S, Goh KL,
Transarterial embolisation of hepatocellular carcinoma with doxorubicin-eluting beads: single centre early experience, Biomed Imaging Interv J 2010; 6(1):e7