Transcatheter Treatment of Hepatocellular Carcinoma with Doxorubicin-loaded DC Bead (DEBDOX): Technical Recommendations.

Abstract

Tranarterial chemoembolization (TACE) has been established by a meta-analysis of randomized controlled trials as the standard of care for nonsurgical patients with large or multinodular noninvasive hepatocellular carcinoma (HCC) isolated to the liver and with preserved liver function. Although conventional TACE with administration of an anticancer-in-oil emulsion followed by embolic agents has been the most popular technique, the introduction of embolic drug-eluting beads has provided an alternative to lipiodol-based regimens. Experimental studies have shown that TACE with drug-eluting beads has a safe pharmacokinetic profile and results in effective tumor killing in animal models. Early clinical experiences have confirmed that drug-eluting beads provide a combined ischemic and cytotoxic effect locally with low systemic toxic exposure. Recently, the clinical value of a TACE protocol performed by using the embolic microsphere DC Bead loaded with doxorubicin (DEBDOX; drug-eluting bead doxorubicin) has been shown by randomized controlled trials. An important limitation of conventional TACE has been the inconsistency in the technique and the treatment schedules. This limitation has hampered the acceptance of TACE as a standard oncology treatment. Doxorubicin-loaded DC Bead provides levels of consistency and repeatability not available with conventional TACE and offers the opportunity to implement a standardized approach to HCC treatment. With this in mind, a panel of physicians took part in a consensus meeting held during the European Conference on Interventional Oncology in Florence, Italy, to develop a set of technical recommendations for the use of DEBDOX in HCC treatment. The conclusions of the expert panel are summarized.

Full text

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REVIEW
Transcatheter Treatment of Hepatocellular Carcinoma
with Doxorubicin-loaded DC Bead (DEBDOX): Technical
Recommendations
Riccardo Lencioni•Thierry de Baere•Marta Burrel•James G. Caridi•
Johannes Lammer•Katerina Malagari•Robert C. G. Martin•Elizabeth O’Grady•
Maria Isabel Real•Thomas J. Vogl•Anthony Watkinson•Jean-Francois H. Geschwind
Received: 23 February 2011/Accepted: 27 September 2011
? The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract
been established by a meta-analysis of randomized con-
trolled trials as the standard of care for nonsurgical patients
with large or multinodular noninvasive hepatocellular
carcinoma (HCC) isolated to the liver and with preserved
liver function. Although conventional TACE with admin-
istration of an anticancer-in-oil emulsion followed by
embolic agents has been the most popular technique, the
introduction of embolic drug-eluting beads has provided an
alternative to lipiodol-based regimens. Experimental stud-
ies have shown that TACE with drug-eluting beads has a
safe pharmacokinetic profile and results in effective tumor
killing in animal models. Early clinical experiences have
Tranarterial chemoembolization (TACE) has
confirmed that drug-eluting beads provide a combined
ischemic and cytotoxic effect locally with low systemic
toxic exposure. Recently, the clinical value of a TACE
protocol performed by using the embolic microsphere DC
Bead loaded with doxorubicin (DEBDOX; drug-eluting
bead doxorubicin) has been shown by randomized con-
trolled trials. An important limitation of conventional
TACE has been the inconsistency in the technique and
the treatment schedules. This limitation has hampered the
acceptance of TACE as a standard oncology treatment.
Doxorubicin-loaded DC Bead provides levels of consis-
tency and repeatability not available with conventional
TACE and offers the opportunity to implement a
R. Lencioni (&)
Division of Diagnostic Imaging and Intervention, Pisa University
Hospital, University of Pisa, Building No. 29, 2nd floor,
Via Paradisa 2, 56124 Pisa, IT, Italy
e-mail: riccardo.lencioni@med.unipi.it
T. de Baere
Department of Interventional Radiology, Institut Gustav-Roussy,
114 rue E´douard-Vaillant, 94805 Villejuif Cedex, France
M. Burrel ? M. I. Real
Department of Radiology, Barcelona Clinic for Liver Cancer,
Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain
J. G. Caridi
Division of Interventional Radiology, University of Florida,
P.O. Box 100374, Gainesville, FL 32610-0374, USA
J. Lammer
Department of Interventional Radiology, Medical University
of Vienna, Guertel 18-20, 1090 Vienna, Austria
K. Malagari
Department of Radiology, University of Athens,
Papadiamandopoulou Street, Ilisia, 11528 Athens, Greece
R. C. G. Martin
Division of Surgical Oncology, University of Louisville,
315 East Broadway, Suite 312, Louisville, KY 40202, USA
E. O’Grady
Department of Radiology, University Hospital Aintree,
Longmoor Lane, L9 7AL Liverpool, UK
T. J. Vogl
Department of Radiology, University of Frankfurt, Frankfurt
Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
A. Watkinson
Department of Interventional Radiology, Royal Devon and
Exeter Hospital, Barrack Road, EX2 5DW Exeter, UK
J.-F. H. Geschwind
Division of Interventional Radiology, Johns Hopkins University,
600 North Wolfe Street, Baltimore, MD 21287, USA
123
Cardiovasc Intervent Radiol
DOI 10.1007/s00270-011-0287-7

Page 2

standardized approach to HCC treatment. With this in
mind, a panel of physicians took part in a consensus
meeting held during the European Conference on Inter-
ventional Oncology in Florence, Italy, to develop a set of
technical recommendations for the use of DEBDOX in
HCC treatment. The conclusions of the expert panel are
summarized.
Keywords
Drug-eluting bead ? Hepatocellular carcinoma
Chemoembolization ? Doxorubicin ?
Introduction
Hepatocellular carcinoma (HCC) is the sixth most common
cancer and the third leading cause of cancer-related death
[1]. Unlike most solid cancers, future incidence and mor-
tality rates for HCC were projected to largely increase in
several regions around the world over the next 20 years
[2, 3]. A careful multidisciplinary assessment of tumor
characteristics, liver function, and physical status is
required for proper therapeutic management of HCC [4, 5].
Transarterial chemoembolization (TACE) has been
established by a meta-analysis of randomized controlled
trials as the standard of care for nonsurgical patients pre-
senting with large or multinodular noninvasive tumor iso-
lated to the liver and preserved liver function [6]. TACE is
also used in patients with early-stage HCC when curative
therapies—including liver transplantation, hepatic resec-
tion, and image-guided ablation—are precluded as well as
in the setting of combination strategies including trans-
catheter and percutaneous treatments [7–12].
The ideal TACE scheme should allow maximum and
sustained concentration of the chemotherapeutic drug
within the tumor with minimal systemic exposure com-
bined with calibrated tumor vessel obstruction [13].
Although conventional TACE with administration of an
anticancer-in-oil emulsion followed by embolic agents has
been the most popular technique, the introduction of
embolic, drug-eluting beads has provided an attractive
alternative to lipiodol-based regimens [11, 14, 15].
Experimental studies have shown that TACE with drug-
eluting beads has a safe pharmacokinetic profile and results
in effective tumor killing in animal models [16–18]. Early
clinical experiences have confirmed that drug-eluting beads
provide a combined ischemic and cytotoxic effect locally
with low systemic toxic exposure [19–24].
Recently, the clinical value of a TACE protocol
performed by using the embolic microsphere DC Bead
(Biocompatibles, UK) loaded with doxorubicin (DEBDOX;
drug-eluting bead doxorubicin) has been shown by ran-
domized controlled trials. In particular, in a multicenter
studyincluding201Europeanpatients(PRECISIONV),use
of DEBDOX resulted in a marked and statistically signifi-
cant reduction in liver toxicity and drug-related adverse
events compared with conventional TACE with lipiodol and
doxorubicin [25, 26]. Contrary to the observation in the
conventional TACE arm, high-dose doxorubicin treatment
could be applied according to the planned schedule in the
whole DEBDOX group, resulting in consistently high rates
of objective response and disease control in all preplanned
subgroup analyses [25]. Two other trials reported higher
rates of tumor response and longer time to progression for
the loaded DC Bead as compared to a bland embolic
microsphere with similar characteristics [27, 28]. As a result
of these investigations, DEBDOX has been increasingly
used as the first-line transcatheter treatment for HCC [29–
32].
An important limitation of conventional TACE has been
the inconsistency in the technique and the treatment
schedules. This limitation has greatly hampered the
acceptance of TACE as a standard oncology treatment.
DEBDOX provides levels of consistency and repeatability
not available with conventional TACE, and offers the
opportunity to implement a standardized approach to HCC
treatment. With this in mind, a panel of physicians took
part in a consensus meeting held during the European
Conference on Interventional Oncology in Florence, Italy,
to develop a set of technical recommendations for the use
of DEBDOX in HCC treatment. The conclusions of the
expert panel are summarized here.
Technical Recommendations for the Use of DEBDOX
in HCC Treatment
The technical recommendations that are presented in this
document represent the consensus of a panel of experts, all
of whom have experience with the use of DEBDOX in
HCC treatment. However, although these recommenda-
tions may be used as general guide to the use of DEBDOX
in HCC treatment, the interventional radiologist treating
the patient is the only physician who can decide how to
approach the unique combination of patient and tumor
characteristics that he or she is facing at the time of the
procedure.
Pretreatment Imaging
Obtaining a triple-phase computed tomography (CT) or
magnetic resonance imaging of the liver is required to
integrate clinical and laboratory data to evaluate the indi-
cation to transcatheter treatment of HCC with DEBDOX in
each individual patient by the local multidisciplinary liver
tumor board. Additional imaging examinations to exclude
extrahepatic disease should be performed as appropriate.
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Periprocedure Medication
Pain medication should be provided according to standard
hospital protocols. Antibiotic prophylaxis and gastric pro-
tection should be administered at the physician’s discretion.
Loading Dose of Doxorubicin
Each vial of DC Bead (2 ml of beads) should be loaded
with 50–75 mg doxorubicin (loading dose, 25–37.5 mg
doxorubicin/ml of beads).
Planned Dose of Doxorubicin
The planned dose of doxorubicin should depend on the
extent of the liver tumor burden. We acknowledge, how-
ever, that absolute recommendations cannot be issued in
this regard, as individual patient- and tumor-related factors
play an important role in the decision. As a general rule,
different doses are recommended for patients with limited
disease (defined as HCC within Milan criteria for liver
transplantation: single tumor B5 cm or multiple tumors
(up to 3) B3 cm each, or more advanced disease.
For disease within the Milan criteria, as a general rule,
each single treatment should include a planned dose of up
to 75 mg doxorubicin loaded into one vial of DC Bead. For
disease beyond the Milan criteria, as a general rule, each
single treatment should include a planned dose of up to
150 mg doxorubicin loaded into two vials of DC Bead.
In bilobar tumors, the two hepatic lobes can be treated in
separate treatment sessions 2–4 weeks apart, in the absence
ofcomplicationsrequiringalongertimeintervalbetweenthe
two sessions. Obtaining confirmation that the liver enzymes
have returned to baseline before performing the second
treatment session is recommended. Treatment of both
hepatic lobes in the same treatment session is possible in
properly selected candidates if adequate interventional and
clinicalexpertiseisinplace.Inthiscase,thedosewillbesplit
according to the extent of the tumor burden in each lobe.
In very large tumors, even if unilobar, the same
approach including two sessions should be followed, as a
general rule. Indication to transcatheter treatment with
DEBDOX in patients with tumor replacing more than 50%
of the liver parenchyma, however, should be carefully
evaluated. Adequate interventional and clinical expertise is
required to manage patients with such advanced disease.
Choice of DC Bead Size
Use of 100–300 lm beads is recommended for a standard
procedure. This choice is based on the demonstration that
such small particles are delivered inside the tumor or in
close proximity to the tumor margin and thus are ideal for
drug delivery or precise embolization [33]. However,
individual patient and tumor characteristics, particularly
the identification of arteriovenous shunting, should be
taken into account when the safety of the treatment and the
choice of DC Bead size are determined. In the case of
significant arterioportal or hepatic venous shunting,
embolization of the shunt with gelfoam pledgets is rec-
ommended before proceeding with DEBDOX administra-
tion. Angiographic confirmation that the shunt is no longer
present must be obtained before DEBDOX injection can be
performed, and a larger bead size may be preferred.
DC Bead Dilution
Loaded DC Bead should be mixed with a nonionic contrast
medium. At least 5–10 ml of nonionic contrast should be
used per 1 ml of DC Bead (i.e., 10–20 ml are required to
dilute one vial of DC Bead) before injection. A good sus-
pension of DC Bead in the contrast should be ensured
before delivery.
Catheter Positioning
A
approach should be used whenever possible by using
a microcatheter. Use of 3D multiplanar reconstructions
(MPR) obtained from C-arm rotational angiography with a
flat-panel detector system (cone-beam CT) is recom-
mended, if available, to improve the accuracy in identify-
ing tumor-feeding arteries [34–36]. In addition, repeat cone
beam CT is recommended after successful delivery of the
DC Bead to confirm adequate targeting and saturation of
the tumor(s).
For the segmental/subsegmental approach, the micro-
catheter is placed distally in the segmental/subsegmental
tumor feeding vessel while ensuring that there is sufficient
flow to the tumor. The clinician should avoid wedging the
catheter to prevent reflux along the catheter shaft.
For the lobar approach, the catheter should be placed as
selectively as possible in the right or left hepatic artery,
with the clinician paying attention to identifying the origin
of the cystic artery as well as other arteries supplying flow
to extrahepatic organs. If identified, these vessels must be
either embolized using coils or avoided by placing the
catheter tip well beyond the origin of these vessels. In
addition, forward flow into the desired vessel must be
maintained because inadvertent administration or reflux
of DC Bead into these extrahepatic vessels would be
undesirable.
superselective(i.e.,segmental orsubsegmental)
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Injection Rate
The injection must be very slow. An injection rate of 1 ml of
the contrast agent—DC Bead suspension per minute is rec-
ommended. Care should be taken to avoid sedimentation of
the beads in the syringe by rotating the syringes or using a
three-waystopcocktogentlysuspendthebeadsinthesolution.
Embolization End Point
Injection should be continued until near stasis is observed in
the artery directly feeding the tumor (i.e., the contrast col-
umn should clear within 2–5 heartbeats). At that point,
injection must be stopped, regardless of the amount of beads
that have been actually administered, to avoid reflux of
embolic material. Once the embolization end point has been
achieved, no additional embolic material shouldbe injected.
If the near-stasis end point is not obtained after injection
of the scheduled volume of loaded beads, two different
options are possible. One option is to inject additional
unloaded beads until the embolization end point has been
reached. Another option is to not inject additional unloaded
beads and to schedule the patient for a repeat course of
treatment after imaging follow-up. This second option was
supported by most panelists. However, there are insuffi-
cient data to mandate one strategy over the other.
Posttreatment Imaging
Obtaining a triple-phase CT or magnetic resonance imaging
of the liver 2–4 weeks after treatment is recommended to
assess tumor response and to plan further action. The panel
recommends the use of the modified Response Evaluation
Criteria in Solid Tumors (mRECIST) for HCC guideline for
response classification [37]. Tumor response measured by
mRECIST after transcatheter or systemic therapy has been
shown to be associated with survival [38, 39].
In patients with residual viable tumor—including partial
response,stabledisease,andprogressivediseaseaccordingto
mRECIST—further treatment with DEBDOX can be sched-
uled after 4–8 weeks in the absence of contraindications.
Obtaining confirmation that the liver enzymes have returned
to baseline before repeating treatment is recommended.
In patients with no evidence of residual viable disease—
i.e., with complete response according to mRECIST—
imaging follow-up should be scheduled every 2–3 months.
Treatment Discontinuation
Treatment with DEBDOX should be discontinued—even
iftechnicallyfeasible—in patientspresentingwith
untreatable progression [40]. Untreatable progression is
defined as failure to achieve objective response in the tar-
geted tumor after at least two DEBDOX treatments. The
emergence of new intrahepatic tumor foci remote from the
treated territory, although clearly representing tumor pro-
gression according to mRECIST for HCC, does not con-
traindicate further treatment with DEBDOX. In cases of
clinical or functional deterioration, treatment should be
discontinued in patients who have clinical progression to
ECOG performance status[2 or who experience evolu-
tion to sustained hepatic decompensation (not merely after
therapy).
Final Remarks
The technical recommendations that we summarize here
represent the consensus of a panel of experts and are aimed
at defining standards for an appropriate and consistent use
of DEBDOX in the treatment of HCC. However, given the
many patient- and tumor-related variables that play a role
in the decision-making process, this is intended as no more
than a general guideline. We fully acknowledge that, given
the complexity of HCC, individual patient and tumor
characteristics may require a different approach. Interven-
tional radiologists should not follow these technical rec-
ommendations if, in their opinion, a different approach is
required for the individual patient.
Finally, despite the improved tolerability profile of
DEBDOX with respect to conventional TACE, it is
imperative that interventional radiologists are fully aware
of the spectrum of potential adverse events associated with
the procedure to prevent complications or manage them
properly [41].
Acknowledgment
for assistance in the literature review and in the preparation and
revision of the article, based on our detailed feedback. Editorial
assistance was supported by Biocompatibles UK Limited.
The authors thank the Research Analysis Library
Conflict of interest
of interest.
The authors declare that they have no conflict
Open Access
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
This article is distributed under the terms of the
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