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| Katerina Malagari is
Associate Professor of
Radiology at the University
of Athens, Greece. She is
part of a research team for
the National Referral Center
for Liver Diseases and
Hepatocellular Carcinoma
and a co-investigator
in the Precision V
multicentre study, a
randomised trial comparing
doxorubicin-eluting
beads with conventional
chemoembolization in the
treatment of HCC. She
has contributed several
scientific papers and
abstracts to international
peer-reviewed journals. |
Drug-eluting beads: a new opportunity in the
treatment of hepatocellular carcinoma
Katerina Malagari
Associate Professor of Radiology,
University of Athens, Greece
Address for correspondence:
Dr Katerina Malagari, MD
2nd Department of Radiology
University of Athens, 19 Monis Kyccou
15669 Papagou, Athens, Greece
Tel/Fax: +30-210-651–0340
Email: kmalag@acn.gr
Abstract
Drug-eluting beads represent a new technology in
selective locoregional treatment. Doxorubicin-eluting
beads have been tested in vitro and in vivo and the
first results of clinical series are being released. The
safety and efficacy of doxorubicin-loaded beads
in the treatment of hepatocellular carcinoma are
discussed in detail in this review.
Introduction
Transarterial chemoembolization (TACE) is the
most widely used treatment for hepatocellular
carcinoma in non-surgical patients not suitable for
radiofrequency ablation. There is no fixed or standard
procedure for TACE, but the common denominator is
the selective administration of a chemotherapeutic
agent in an emulsion with iodized oil, followed by
the injection of an embolizing agent into the feeding
vessels of the tumour (Ref: 1). The procedure aims to induce
ischaemic necrosis of the tumour and cell death by
the local effect of the chemotherapeutic agent.
TACE variables include the choice of embolizing
agent, chemotherapeutic agent(s) and embolization
procedure. TACE is a technique widely used in the
past 25 years, interest in which has recently increased
after landmark studies were reported demonstrating
a significant benefit for TACE over systemic
chemotherapy or symptomatic supportive treatment (Ref: 2-5).
DC Bead™ (Biocompatibles International plc, Surrey,
UK) has properties that allow a one-step procedure
and assist in the standardisation of TACE. The
pharmacokinetics and the antitumour effects of this
new treatment are described in this paper.
DC Bead description
DC Bead is a soft deformable device of spherical
shape composed of a polyvinyl alcohol (PVA)
and a hydrophilic monomer known as AMPS
(2-acrylamido-2-methylpropane sulphonic acid)
capable of being loaded with anthracycline drugs
such as doxorubicin (Ref: 6,7). The microspheres are stored
in a phosphate packing solution. During preparation, the beads initially increase in diameter with the
admixture of water for injection and subsequently
shrink again on loading with doxorubicin. Diameter
changes are more pronounced with larger beads (Ref: 7).
Elution kinetics
The ideal TACE should result in high levels of
doxorubicin in the tumour with low plasma levels
to reduce systemic toxicity. Conventional TACE
pharmacokinetic studies have shown that plasma
concentrations are lower than those observed with
systemic chemotherapy and even lower when the
agent is administered with lipiodol (Ref: 8). However, a
significant fluctuation in plasma doxorubicin levels is
observed. Johnson et al. showed that plasma levels of
doxorubicin were identical if the drug is administered
alone or in an emulsion with iodized oil (Ref: 9).
From a pharmacokinetic standpoint, controlled
drug elution with DC Bead occurs only within the
tumour and in a gradual fashion since doxorubicin
is contained within the beads. Doxorubicin loss
on bead suspension and contrast agent mixture
is about 0.2%, minimizing the systemic release of
doxorubicin and hence the side-effects seen with
conventional TACE (Ref: 7). In this respect, DC Bead presents
an opportunity to standardise and improve TACE.
Initial in vivo studies in a rabbit Vx-2 model showed
that, at concentrations per liver weight planned for
clinical trials, the concentration of doxorubicin in the
peripheral blood was low and that the fraction of
non-viable tumour was higher compared with intra-arterial
injection (Ref: 10). Additionally, the systemic plasma
concentration of doxorubicin was significantly
lower than when injected intra-arterially without
the DC Bead (Ref: 10). From a clinical viewpoint, the first
published human study, by Varela et al., showed a
2-log reduction in plasma doxorubicin for the loaded
beads compared with conventional TACE (Ref: 11).
The rate of elution of doxorubicin follows the
Higushi equation and depends on the osmolality
of the tumour and the size of the injected beads
(the larger the beads, the slower the local release) (Ref: 7). In a study by Lewis et al. in Yucatan pigs, doxorubicin
peak concentrations were 15 times higher in animals
treated with smaller beads (Ref: 12).
Other embolizing agents such as gelatine-coated
tris-acryl embospheres, PVA or Bead Block™
(Biocompatibles International plc, Surrey, UK),
are incapable of being loaded with or transferring
doxorubicin molecules and, further, can be unstable:
when lipiodol is added to the loaded bead suspension
all the doxorubicin may be lost in under 4 hours (Ref: 12,13).
Doxorubicin loading range
Overall, the extent of loading with doxorubicin
depends on the osmolality of the bead suspension (Ref: 7).
The maximum loading capacity of the beads with
doxorubicin reaches levels as high as 45 mg/ml of
hydrated beads (irrespective of the size of the beads)
while still maintaining the capability for controlled local
release. The recommended dose range, suggested by
the Precision Study (Ref: 8), is 2537.5 mg of doxorubicin per
ml of hydrated beads (100150 mg per patient). These
concentrations can be achieved by the preparation of
6 ml of beads with 25 mg/ml of hydrated beads or 4 ml
of beads with 37.5 mg of hydrated beads (total 150 mg/
patient) or 4 ml of beads with 25 mg/ml of hydrated
beads (total 100 mg/patient). This range achieves doses
of 5075 mg/m2, which are considered safe treatment
levels. The maximum recommended lifetime dose of
doxorubicin is 450 mg/m2 to avoid cardiac toxicity (Ref: 14).
Choice of beads
As a general rule, the choice of bead diameter
depends on the size and vascularity of the target
lesion. The elution kinetics show that larger beads
release doxorubicin more slowly than smaller beads (Ref: 7).
However, small diameters can be more harmful to the
adjacent liver tissue, and a versatile combination of
bead diameters for each patient is needed. It has to
be noted that larger diameters require longer loading
times compared with small diameters (Ref: 7).
Mechanisms of action: antitumoural effect
The induction of tumour ischaemia is an essential
mechanism in TACE, whether conventional or with DC
Bead. The concept is based on the preferential arterial
flow to the tumour compared with the non-malignant
liver tissue (Ref: 15). Both treatments aim to obliterate the
tumour vasculature while preserving afferent arterial
branches. Selective or superselective administration
of the embolizing agent increases the local ischaemia
and preserves adjacent non-malignant liver tissue.
In conventional TACE the effect of ischaemia is
augmented by lipiodol, which temporarily obliterates
the portal venules and further enhances ischaemia (Ref: 6).
DC Bead enables a more reproducible procedure since
the chemotherapeutic agent is contained within the
embolizing bead, the chemical structure of which
ensures a local and sustained delivery within the
tumour. The toxic effect of doxorubicin is augmented
with ischaemia induced by DC Bead that block the
lumen of the neoplastic vessels.
Conventional TACE pharmacokinetic studies have
shown that the doxorubicin half-life in tumourous
liver is two or three times longer, compared with
intra-arterial administration (Ref: 8), while the total dwell
time of the chemotherapeutic agent in the tumour
may be up to 1 month after TACE (Ref: 17,18). In addition,
TACE achieves local drug concentrations at least
twice the levels achieved by systemic chemotherapy;
Kanematsu et al. showed a nine-fold increase in
retention of the chemotherapeutic agent within the
tumour, compared with adjacent non-malignant liver
tissue (Ref: 16). The length of dwell time and the increased
concentrations of the chemotherapeutic within the
tumour augment the effect of tumour ischaemia
induced by the embolizing agent (Ref: 19). However, the
washout from the tumour is, to a certain extent,
unpredictable while the mechanical obstruction of
the neovascularity varies according to the nature and
size of the embolizing agent.
By contrast, with doxorubicin-loaded DC Bead,
one sole agent (the loaded bead) with defined
characteristics simultaneously induces ischaemia
and releases doxorubicin locally within the
tumour. Further, the procedure can be performed
in a standardised manner. Tumour cell ischaemia
causes tumour cell membrane damage, resulting
in intracellular retention of the chemotherapeutic
drug. Increased retention and sustained release of
doxorubicin after embolization with loaded DC Bead
has been demonstrated by staining and coloration
techniques in Yucatan pigs 28 and 90 days after
liver embolization. Results showed that the local
level of doxorubicin was sustained for 90 days post
embolization (Ref: 12), an observation supported in previous
in vitro studies and in rabbit (Vx-2) models showing
half-lives of doxorubicin release between 60 and
100 days (Ref: 10). In the Vx-2 rabbit model, Hong et al.
found that intratumour doxorubicin levels at
72 hours after embolization were about 400%
higher than after conventional TACE (Ref: 10).
Tumour necrosis was greatest at 714 days after
treatment and, in this period, almost all cells were
damaged or necrotic, while the plasma concentration
of doxorubicin was minimal (Ref: 9). Comparing these results
with necrosis induced in controls through intra-arterial
injection of doxorubicin followed by embolization with
unloaded DC Bead, there was a statistically significant
advantage for the loaded beads (Ref: 10).
Histologically, the results observed in animals embolized
with doxorubicin-loaded beads have been shown to
depend on the size of the beads (Ref: 7). Doxorubicin-loaded
beads of diameters of 100300 µm are shown to inflict
widespread pan-necrosis of the target and adjacent
hepatic tissue, with notable degrees of vasculopathy,
neutrophilic inflammation, moderate portal fibrosis and
arteriovenous and biliary hyperplasia. The patterns of
necrosis in this group tend to radiate outwards centred
on clusters of DC Bead, with extensive liquefactive
and coagulative necrosis suggesting both ischaemic
and toxic causes of cell death. With loaded beads of
larger diameters (700900 µm), necrosis has been
shown to be less extensive compared with the smaller
doxorubicin-loaded beads, and not radiating outwards.
With non-drug-loaded beads of 100300 µm
(inert), changes were shown to represent mostly
non-necrotic vasculopathy without hepatic necrosis (Ref: 12).
These findings are indicative of the added value of
doxorubicin. However, randomized studies are needed
to clearly demonstrate the benefit of loaded beads
over inert embolization with beads alone (Ref: 20,21). The
large extent of the necrosis in 100300 µm loaded
beads has been attributed to damage caused by the
combination of the small size of the beads (smaller
beads lodge more centrally and occlude collateral
circulation) and the local actions of doxorubicin.
The induced cellular necrosis further increases the
diffusion of doxorubicin that is not carried away by
the collateral circulation and is not metabolized by
destroyed liver cells (Ref: 12,22).
Clinical application: embolization procedure
The inclusionexclusion criteria for DC Bead TACE are
the same as for conventional TACE (Ref: 11). Embolization
procedures in the clinical series included selective and
superselective embolization. One practical difference
with the procedure compared with conventional TACE
is that no lipiodol is used with DC Bead. Therefore,
there is no morphologic evaluation of the distribution
of the preparation within the tumour, as there is with
TACE using lipiodol. However, the absence of lipiodol
allows a better depiction of the residual tumour or of
local recurrence.
Results of conventional TACE versus DC Bead
Comparison of various series of TACE is not easy
because of the variation in different techniques and
the heterogeneity of patient and tumour samples.
Additionally, there is the difficulty that in some
studies sequential embolization is adopted, while in
other studies disease progression is the indication to
repeat the treatment.
In the first clinical studies of DC Bead, survival
was not the primary aim due to the short follow-up
time of this new treatment scheme. Apart from
survival, these studies also report tumour responses
that correlate well with survival rates (Ref: 35). Varela
et al., in the first human trial with doxorubicin-loaded
beads, studied 27 patients with cirrhosis-related HCC
and observed a response rate of 75% (66.6% on
intention-to-treat), while survival rates at 1 and
2 years were 92.5% and 88.9%, respectively (Ref: 11).
Overall, TACE achieves a partial response in 1555%
of patients, with a delay in tumour progression, while
systemic doxorubicin provides partial response in 10%
of cases without proven survival advantages (Ref: 25,2325).
Llovet et al. reported 1- and 2-year survival rates of
82% and 63% with objective response sustained for at
least 6 months in 35% of cases and a 3-year survival
rate of between 20% and 50% (Ref: 24). In addition, in the
study arm where TACE was repeated every 2 months,
a tumour response of 35% was observed while 1- and
2-year survival rates were 82% and 63%, respectively.
In the study by Lo et al., the tumour response rate
for conventional TACE was 39% by WHO criteria and
the fetoprotein response rate 72% (Ref: 4). Malagari et al.,
in a study of 62 cirrhosis-related-HCC patients who
underwent sequential embolization with doxorubicinloaded
DC Bead, observed high rates of tumour
necrosis ranging from 77.4% to 83.9% across three
treatment procedures (Ref: 26). In the same study, objective
response according to European Association for the
Study of the Liver (EASL) criteria was observed in
59.6%, 81.8% and in 70.8% of patients across the
three treatments (Figure 1). Complete response was
observed in 4.8% of patients after the first procedure
and 3.6% and 8.3% after the second and third
treatments, respectively. Alpha-fetoprotein levels
showed a mean decrease of 1,123 ng/ml (95% CI=846,
1,399, p=3x10-11) after the first session and remained
stable after the second and third embolizations
(42 and 70 ng/ml decreases, respectively) (Ref: 26).
 |
 |
| Figure 1. (a) Pre-embolization MR image shows a relatively well defined HCC of 5 cm in diameter near the diaphragm. (b) One month after two
superselective embolization sessions with DC Bead, the lesion shows complete necrosis and considerable shrinkage in size. |
Liver function
The protection of non-tumourous liver is an important
issue since HCC develops on a background of cirrhosis,
and patients already have compromised hepatocyte
function.
An increase in liver enzymes following TACE is well
documented (Ref: 27). In a porcine model, increased levels of
aspartate aminotransferase were observed until day 14,
returning to near or below pretreatment levels by days
2890 in the groups treated with loaded beads (Ref: 10). By
contrast, in the group with non-loaded beads, a slight
increase was seen but levels returned to normal by day
7. The increase in liver enzymes was greater with the
smaller beads compared with the larger ones. Similar
patterns of liver enzyme levels were also recorded
for alanine transferase and alkaline phosphatase,
although these increases were not as marked. The
higher elevation of liver enzymes with smaller loaded beads was attributed to the more distal nature of the
embolization and the elimination of collateral flow (Ref: 28).
In a recent human study, Varela et al. showed that the
treatment was well tolerated without impairment
of liver function (Ref: 11). Similarly Malagari et al. (Ref: 26) observed
transient liver enzyme increases with return to baseline
at 1 month following each procedure. Bilirubin levels
remained relatively constant, with no statistically
significant changes compared with baseline (Ref: 26).
Complications
Following embolization, an increase in the
polymorphonuclear and leucocyte counts are observed.
These have been attributed to the administration of
doxorubicin. A postembolization syndrome (Ref: 14) of variable
severity is a common side-effect of TACE. Lo et al.
recorded episodes of fever in 76% of patients and
abdominal pain, with or without vomiting, in 38.5%
of patients (Ref: 4). Malagari et al. observed that all patients
suffered from postembolization syndrome, but the
maximum duration of pain was 3 days (Ref: 26). Fever was
observed in 83%, 80% and 95% of patients after
the first, second and third procedures, respectively.
Apart from the postembolization syndrome, no other
effects that affected quality of life were recorded.
Overall, TACE-related mortality is under 4% (Ref: 1) and
Malagari et al. reported no procedure-related deaths (Ref: 26).
The most common serious adverse events of TACE are
liver abscesses or infarction and cholecystitis, which
each occur in approximately 2% of patients (Ref: 1). The
30-day mortality rate of conventional TACE is 1% (Ref: 1).
Similar rates for these complications were observed
in previous clinical series with DC Bead. Varela et al.
recorded two cases of liver abscess in 27 patients, one
of which was fatal (Ref: 11). Similarly, Malagari et al. observed
liver abscesses and cholecystitis in 3.2% of their
patients despite antibiotic prophylaxis treatment and
the lack of risk factors for abscess formation (Ref: 26).
Conclusion
Clinical results so far show that doxorubicin-eluting
DC Bead results in higher necrosis and
tumour response rates in short-term follow-up in
comparison with TACE. Randomised trials of DC Bead
and conventional TACE procedures are ongoing to
investigate long-term survival rates, recurrence-free
durations and the percentage of new lesions occurring
in non-embolized areas of the liver.
Key Learning
-
Drug-eluting beads represent a new technology in selective locoregional treatment of hepatocellular
carcinoma
-
Controlled drug-elution with DC Bead occurs only within the tumour and in a gradual fashion, the rate of
elution following the Higushi equation
-
While both conventional TACE and DC Bead act in a similar way (tumour ischaemia), DC Bead permits a
more controlled, localised action of the antichemotherapeutic agent compared to TACE
-
The early results using DC Bead with doxorubicin are encouraging higher necrosis and tumour response
rates have been observed compared to TACE
-
Data from ongoing randomised trials are awaited
|
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