Critical Reviews in Oncology/Hematology 88 (2013) 530–549
Use of Lipiodol as a drug-delivery system for transcatheter arterial
chemoembolization of hepatocellular carcinoma: A review
Jean-Marc Idée a,∗ , Boris Guiu b
b
a Guerbet, Research and Innovation Division, BP 57400, 95943 Roissy-Charles de Gaulle cedex, France
INSERM U866, Department of Diagnostic and Interventional Radiology, CHU Le Bocage, 14 rue Paul Gaffarel, BP 77908, 21079 Dijon, France
Accepted 9 July 2013
Contents
1.
2.
3.
4.
5.
6.
7.
8.
9.
∗
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Lipiodol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hepatocellular carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Transarterial chemoembolization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2. Cytotoxic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3. Embolic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4. Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6. Clinical efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.7. Drug-eluting beads . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.8. Selective internal radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Lipiodol distribution following intra-hepatic arterial injection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1. Tumour uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.1. Preclinical data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.2. Hepatocellular carcinoma microvascularization and rationale for Lipiodol embolization . . . . . . . . . . . . . . . . . . . . . . .
5.2. Parameters influencing tumour uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.1. Lipiodol-cytotoxic drug emulsion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.2. Type of emulsion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.3. Droplet size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.4. Viscosity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3. Drug-delivery properties of Lipiodol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4. Role of Lipiodol in modulating the pharmacokinetics of associated chemotherapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Effects of Lipiodol per se on hepatocellular carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.1. Pharmacological management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.2. Thermochemoembolization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.3. Immunoembolization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.4. Gene therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Corresponding author. Tel.: +33 01 45 91 50 77; fax: +33 01 45 91 51 23.
E-mail address: [email protected] (J.-M. Idée).
1040-8428/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.critrevonc.2013.07.003
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Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
Hepatocellular carcinoma (HCC) remains a major public health problem. Transarterial chemoembolization (TACE) is recognized as the
standard of care for patients with unresectable, asymptomatic, noninvasive and multinodular HCC. This procedure is based on percutaneous
administration of a cytotoxic drug emulsified with Lipiodol followed by embolization of the tumour-feeding arteries. The standard procedure
involves Lipiodol, an oily contrast medium which consists of a mixture of long-chain di-iodinated ethyl esters of poppy seed fatty acids.
The aim of this review is to discuss the physical properties, tumour uptake behaviour and drug delivery effects of Lipiodol, the parameters
influencing tumour uptake and future prospects.
Lipiodol has a unique place in TACE as it combines three specific characteristics: drug delivery, transient and plastic embolization and
radiopacity properties. Substantial heterogeneity in the physicochemical characteristics of Lipiodol/cytotoxic agent emulsions might reduce
the efficacy of this procedure and justifies the current interest in Lipiodol for drug delivery.
© 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Lipiodol; Transcatheter arterial chemoembolization; Hepatocellular carcinoma; Drug delivery; Theranostics; Cytotoxic drugs; Interventional
radiology
1. Introduction
Interventional radiology can be defined as all medical procedures performed by radiologists using medical imaging
guidance to treat diseases under minimally invasive conditions. Image-guided procedures result in more rapid recovery,
fewer complications and reduced medical costs [1]. Interventional radiology has become an essential aspect in oncology
and the subject of very active research involving distinct fields
such as drug delivery, pharmacology, medical devices and
medical imaging [1].
Transarterial chemoembolization (TACE) plays an essential role in the management of unresectable hepatocellular
carcinoma (HCC) [2–5]. Since its inception in the early 80s,
this technique has been based on the use of the iodinated
oil Lipiodol. In TACE, Lipiodol is used not only for its
radiopacifying properties but also for its drug delivery and
tumour-seeking properties and its ability to induce plastic
(adapted to the size of the vessels) and transient embolization of the tumour microcirculation [6–8]. However, many
uncertainties remain unresolved. The aim of this review is
to critically discuss the physical properties, tumour uptake
behaviour and drug delivery effects of Lipiodol for the intraarterial treatment of HCC as well as future prospects.
Lipiodol is also widely used in many other interventional procedures, for example mixed with surgical glues
(cyanoacrylates) or with ethanol for various fluoroscopyguided embolization procedures [9]. These indications will
not be discussed here.
2. Lipiodol
2.1. Characteristics
Lipiodol is an oily contrast medium consisting of a mixture
of long-chain (C16 and C18) di-iodinated ethyl esters of fatty
acids from poppy seed (Papaver somniferum var. nigrum) oil,
which contains 98% unsaturated fatty acids [10]. The predominant fatty acid is linoleic acid (70%). Lipiodol is a pale
yellow to amber, clear liquid, containing 37% (w/w) iodine
(i.e. an iodine concentration of 480 mg/mL). The viscosity of
Lipiodol Ultra-Fluid at 37 ◦ C is approximately 25 mPa·s (and
50 mPa·s at 20 ◦ C) and its density is 1.28 [11,12]. Lipiodol is
marketed as a solution for injection in 10 mL glass ampoules.
Throughout this article, Lipiodol Ultra Fluid® is referred to
as Lipiodol. Historically, Lipiodol was called “Ethiodol® ” in
the USA until 2012.
2.2. History
Lipiodol was first synthesized by the French pharmacist
Marcel Guerbet (1861–1938), early in 1901 in the Paris
School of Pharmacy Chemistry Laboratory and was first
presented by his friend and colleague Laurent Lafay at the
May 1901 meeting of the French Society of Dermatology
and Syphilography [13]. Lipiodol was first marketed for
therapeutic purposes. The clinical indications were syphilis,
pulmonary (asthma) and cardiovascular (angina, pericarditis)
diseases, impetigo, rheumatism, etc. [14]. Its X-ray opacifying properties were discovered in 1921 by Jean-Athanase
Sicard, professor of radiology in Paris, and his resident,
Jacques Forestier. The first myelography was performed on
13th October 1921 in a patient suffering from paralysis,
probably caused by a spinal cord tumour [15]. Epidural
injection of Lipiodol had no adverse effects and X-ray imaging performed on the days following the procedure showed
that Lipiodol did not remain at the injection site, but travelled along the spinal canal. Many radiological applications
for Lipiodol were subsequently developed (bronchography
in 1922, dacryography in 1923, hysterosalpingography in
1924, sialography and fistulography in 1928, lymphography
in 1960), and even urethrography and cystography [16], to the
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J.-M. Idée, B. Guiu / Critical Reviews in Oncology/Hematology 88 (2013) 530–549
point that radiological indications subsequently outnumbered
therapeutic indications. The notable exception is prophylaxis
and treatment of endemic goitre [10,17], based on the use of
Lipiodol as a long-lasting source of iodide [10,18]. Tubal
flushing with Lipiodol has been proposed for the treatment
of unexplained infertility [19].
The use of Lipiodol for chemoembolization of HCC by
Toshimitsu Konno and coworkers in the early 1980s was
a major step forward and the dawn of a new life for this
venerable compound [20–22]. Lipiodol-based TACE is classically used as the gold standard for comparative studies with
other TACE procedures (using drug-eluting beads), radioembolization or targeted therapy (sorafenib) in intermediate
or advanced HCC patients.
Treatment of HCC by the polystyrene co-maleic acidconjugated neocarzinostatin (SMANCS)/Lipiodol method
has been approved in Japan since 1995 [23]. Lipiodol is
also approved for TACE in Italy and Mexico. Although
widely used worldwide, the use of Lipiodol for TACE is not
registered in other countries according to local marketing
authorization in force.
3. Hepatocellular carcinoma
In 2008, the worldwide prevalence of liver cancer was
750,000 cases with an estimated 695,000 deaths. Due to its
high mortality rate, liver cancer is the third most common
cause of death from cancer worldwide [24,25]. Five-year
prevalence is 613,000 cases [24]. HCC has a high prevalence in Southeast Asia and sub-Saharan Africa. Cirrhosis
is present in 80–90% of cases and is therefore considered
to be the single most important risk factor. Other risk factors are chronic viral hepatitis B, hepatitis C (both diseases
account for the vast majority of HCC worldwide), exposure to toxins such as aflatoxin B1, or diethylnitrosamine, as
well as diabetes and obesity (non-alcoholic steatohepatitis)
[26].
In 2002, 82% of cases of liver cancer occurred in developing countries, with 55% in China alone [27]. HCC rates also
change over time, at least in certain countries: incidence rates
tripled in the US between 1975 and 2005 (1.6 and 4.9/100,000
respectively). This growth has been attributed to an epidemic
of hepatitis C virus during the 1960s and rising rates of obesity
and diabetes [27].
Hepatocellular carcinoma (HCC) represents about 80% of
all primary liver cancers [28]. The presence of underlying cirrhosis makes the treatment of HCC very challenging, due to
the intricate association of two different diseases with a poor
prognosis. The 5-year cumulative risk for the development of
HCC in patients with cirrhosis ranges between 5% and 30%,
depending on the cause, region or ethnic group and the stage
of cirrhosis [29].
The Barcelona Clinic Liver Cancer (BCLC) classification
[3] (Fig. 1) is widely acknowledged and used for the management of HCC in Europe and the USA. In Japan, a different
algorithm was proposed in 2007 [30] and revised in 2010
[31].
4. Transarterial chemoembolization
4.1. Definition
Chemoembolization is classically defined as “percutaneous introduction of a substance to occlude a vessel in
combination with a chemotherapeutic agent, used in the
treatment of cancer to deliver sustained therapeutic levels
of the agent to a tumour” [32]. TACE is recognized as the
primary treatment for BCLC stage B, asymptomatic, noninvasive and multinodular HCC [3,5]. It is also used to
treat cholangiocarcinoma and metastases of colorectal cancer, neuroendocrine tumours, breast cancer or melanoma
[33].
The rationale for TACE (as for all hepatic intra-arterial
therapies) is the preferential blood supply of liver malignancies derived from the hepatic artery (∼95%), thereby
allowing local chemotherapy and embolization without damaging the surrounding healthy parenchyma, which receives
three quarters of its blood volume from the portal vein, and
thus only one quarter from the hepatic artery [34–36].
TACE must be distinguished from other procedures:
transarterial oily chemoembolization (TOCE) (or “chemolipiodolization”), in which the cytotoxic agent is mixed
with Lipiodol without an embolic agent; bland transarterial
embolization (TAE), in which no cytotoxic agent is delivered
and transarterial chemotherapy (TAC), in which Lipiodol is
not used and no embolization is performed [3] (Table 1).
It is often recommended to repeat the TACE procedure
3–4 times per year [3]. However, the optimal schedule in
terms of clinical benefit/risk (liver failure, vascular lesions)
remains unclear [37] and is generally based on the individual response to treatment. This variable frequency of TACE
also accounts for the considerable heterogeneity of treatment
schedules between centres.
4.2. Cytotoxic drugs
Basically, the TACE procedure consists of transcatheter
hepatic arterial administration of one or several cytotoxic
drugs.
In a recent review of the literature, the agents most
commonly used were, in decreasing order of frequency:
doxorubicin, cisplatin, epirubicin, mitoxantrone, mitomycin
C (these drugs are sometimes diluted in a water-soluble
contrast medium (CM) to adjust densities) and (in Japan)
SMANCS, and subsequently emulsified with an equivalent
volume of Lipiodol [37] or, sometimes, a smaller volume with
the objective of administering a water-in-oil (W/O) emulsion. Other drugs, such as pirarubicin [38], nemorubicin [39]
miriplatin [40] or idarubicin [41], are or have been used. It
is worth mentioning that cytotoxic agents are not approved
J.-M. Idée, B. Guiu / Critical Reviews in Oncology/Hematology 88 (2013) 530–549
533
Fig. 1. Updated Barcelona Clinic Liver cancer (BCLC) staging system and treatment strategy. CLT, cadaveric liver transplantation; LDLT, living donor
liver transplantation; OS, overall survival; PEI, percutaneous ethanol injection; PS, performance status; RF, radiofrequency ablation; TACE, transarterial
chemoembolization.
From [3] with permission.
by health authorities for the loco-regional treatment of HCC
(except SMANCS and miriplatin in Japan).
The Lipiodol/drug emulsion is usually prepared extemporaneously. In their princeps articles, Konno et al. dispersed
and solubilized the high-molecular weight (15 kDa) and
lipophilic agent SMANCS [42,43] in Lipiodol [20–22]. The
highly lipophilic agent SMANCS is soluble in a number of
organic solvents (such as pyridine or acetone) and in water
and Lipiodol [21,42]. Miriplatin is suspended in Lipiodol at a
concentration of 20 mg/mL [40]. Successful attempts of solubilization of the lipophilic molecule paclitaxel in Lipiodol
have also been reported [44,45].
Unfortunately, there are no evidence-based data regarding
the optimal selection of cytotoxic molecule(s) and dosages
[37]. The lipophilic anthracycline, idarubicin, was recently
found to be more cytotoxic in vitro on three HCC cell lines
(including the chemoresistant SNU-449 cell line) than all
other cytotoxic molecules classically used in TACE [46].
Idarubicin was reported to be safe and effective in a pilot
clinical study [41].
Most cytotoxic molecules used in TACE procedures are
metabolized by the liver [47,48].
Considerable heterogeneity of TACE procedures is
observed between centres and interventional radiologists
with respect to the cytotoxic drug, and the dose of this drug
also varies considerably (some clinicians use a fixed dose,
while others base the dosage on the body surface area, tumour
size, bodyweight or bilirubin level) [37]. For example, the
dose of doxorubicin used for TACE ranges between 50 and
150 mg among centres, without evidence-based pharmacological rationale [37]. Such heterogeneity is uncommon in
oncology. The absence of the studies that are usually conducted to determine the dose-limiting toxicity and then the
optimal dose for TACE could explain this lack of rationale for
the dose used. The issue of the choice of drug for TACE can be
even more complex, as some US authors use a combination
Table 1
Main transarterial techniques for the treatment of HCC.
Procedure
Acronym
Cytotoxic agent
Lipiodol
Embolization agent
Transarterial chemoembolization (conventional)
Transarterial oily chemoembolization (chemo-Lipiodolization)
Transarterial embolization (bland, transcatheter embolization)
Transarterial chemotherapy
DEB-Transarterial chemoembolization
TACE
TOCE
TAE
TAC
DEB-TACE
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes or no
No
No
Yes
No
Yes
No
Yes
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of doxorubicin, cisplatin and mitomycin C [49]. A recent randomized clinical trial (RCT) performed in 365 HCC (BCLC
stages B and C) patients demonstrated that the choice of
chemotherapy may affect survival outcomes: a significantly
better survival was observed in patients receiving triple-drug
(lobaplatin, epirubicin and mitomycin C) chemolipiodolization with embolization than in patients treated by single-drug
(epirubicin) chemolipiodolization with embolization [50].
However, the clinical value of adding drug-induced
cytotoxicity to embolization-induced ischaemia during
locoregional procedures remains debated [37]. Some authors
speculate on a potentiation of drug-induced cytotoxicity by
tumour ischaemia [4]. On the contrary, it must be underlined
that there was no statistical evidence of a better survival
associated with TACE compared with bland embolization
(TAE) in a prospective RCT that was prematurely stopped
because of higher survival rate associated with TACE compared with best supportive care [51]. Similarly, no difference
was reported between (cisplatin-based) TACE and TAE (Lipiodol and gelfoam) in terms of survival rates, in a small
RCT [52]. Additional studies are warranted to better understand the respective roles of tumour ischaemia (including
pro-angiogenic factors) and drug-induced cytotoxicity.
4.3. Embolic agents
Chemoembolization is commonly followed by transient
embolization of the tumour-feeding vessels with agents such
as gelatin sponge particles, polyvinyl alcohol (PVA) or calibrated microspheres (trisacrylgelatin, PVA, etc.) to induce
or enhance tumour ischaemic necrosis and prevent washout
of the drug, thereby maintaining a high local concentration [4,49,53]. These embolic agents can be spherical or
non-spherical, resorbable or non-resorbable, calibrated or
non-calibrated (Table 2).
None of these agents has been demonstrated to be clinically superior to any of the others [37], although no RCT
have been specifically conducted to date.
Fig. 2. Principle of conventional transarterial chemoembolization.
the right or left hepatic artery is achieved [49] (Fig. 3). Based
on retrospective multivariate analysis of 219 patients with
HCC who underwent TACE, the optimum dose of Lipiodol
(mL) has been proposed to be 1–1.5 times the absolute value
of the tumour diameter (expressed in cm) [54]. However, this
approach is rarely used in clinical practice.
Injection of the solution or emulsion/suspension is followed by intra-arterial injection of a mixture of an embolic
agent and a water-soluble contrast medium in order to retain
the drug in the tumour and to exert embolic effects.
The cytotoxic drug/Lipiodol extemporaneous mixture
described above is unstable (except for SMANCS and
miriplatin). Various techniques have been used in preclinical studies, basically blending [6] or ultrasonication
[55], to improve the stability of the emulsion/suspension.
4.4. Procedure
TACE is carried out after performing a complete vascular radiological investigation. In general, catheterization
is performed via a femoral artery followed by selective
embolization of the hepatic artery branches feeding the
tumour (Fig. 2). The radiologist extemporaneously prepares a
solution (for lipophilic drugs) or an emulsion of the drug and
Lipiodol. The emulsification procedure is therefore operatordependent. One of the most commonly used techniques
consists of approximately 15–20 pushes and pulls through
a three-way stopcock between two syringes. Some clinicians
first push the cytotoxic drug solution into Lipiodol in order
to form a W/O emulsion. Depending on the tumour size, vascularity, and fluoroscopic findings, a total volume of about
10–15 mL of Lipiodol is injected. In general, the mixture is
injected until stasis in the second- or third-order branches of
Fig. 3. 54-year old woman with multifocal HCC, thereby justifying lobar
TACE (right liver). This image was obtained during injection of the emulsion
drug/Lipiodol through a microcatheter positioned in the right hepatic artery.
Note the typical aspect of lipid droplets progressing through arteries.
J.-M. Idée, B. Guiu / Critical Reviews in Oncology/Hematology 88 (2013) 530–549
535
Table 2
Main embolic agents.
Embolic agents
Non-spherical
Spherical
Gelatin
Polyvinyl alcohol
Acrylic
Polyvinyl alcohol
Spongel®
Ivalon®
Embosphere®
Bead Block®
Contour®
(trisacryl gelatin)
EmboGold®
Contour SE®
1975
Proximal
Yes (month)
Various size ranges
available (45–1180)
1990s
Distal
No
Various size ranges
available (45–1200)
2000s
Distal
No
Various size ranges
available (100–1200)
Trade names
Available on the market since
Level of occlusion
Resorbable
Size (␮m)
Gelfoam®
Curaspon®
1960s
Proximal
Yes (day/week)
Irregular (sponge cut
extemporaneously)
Modified from [53].
Conceptually, enhanced stability of the drug/Lipiodol emulsion could result in increased accumulation of the drug in
the oily phase, thereby improving Lipiodol vectorization
properties [56]. Interestingly, one study reported that ultrasonication achieved a stable suspension of doxorubicin and
Lipiodol with very small droplets (mean diameter 7 nm) (calculated half-life 25 ± 3 days). A retrospective analysis of
clinical data suggested the superiority of this formulation
over conventional TACE in terms of survival [57]. However,
no prospective RCT have been conducted so far to support
the benefit of these techniques.
Of note, Lipiodol may cause cracks in certain types of plastics and rubber stoppers, and is therefore always packaged in
sealed ampoules. In a comparative study in which four types
of stopcocks were soaked in Lipiodol for 6 h and were then
checked for damage and subsequently used for the ‘pumping’ procedure under the usual conditions of use, crazing
and cracking occurred only on polycarbonate three-way stopcocks, while polypropylene, polyamide, and polysulphone
three-way stopcocks had a high durability [58].
4.5. Safety
TACE is generally considered to be well tolerated, with
major complications occurring in only 4–7% of procedures
and a 30-day mortality rate of approximately 1% [7]. The
most common serious complications of TACE are liver
abscess or liver infarction and cholecystitis (about 2% of
patients) [7]. However, the so-called postembolization syndrome [59] occurs in almost all patients (90%) and consists
of a combination of fever, nausea, vomiting and abdominal
pain. It may last up to three days. Other serious complications
may occur: nontarget embolization (i.e. inadvertent reflux of
cytotoxic drugs and/or embolic material into unintended territories); liver failure; tumour rupture (<1% of cases) or biloma
[33]. Pulmonary Lipiodol embolism is a rare and sometimes
fatal complication of TACE [60]. The amount of Lipiodol
injected constitutes one of the main risk factors, especially
when a volume of more than 20 mL is injected [61].
4.6. Clinical efficacy
The survival benefit associated with TACE has been a
controversial issue for a long time, as contradictory results
have been reported [51,62,63]. In a RCT involving 112
patients, 1- and 2-year survival probabilities were 75% and
50% for bland transarterial embolization with gelatin sponge
particles, 82% and 63% for TACE (using doxorubicin as cytotoxic agent) and 63% and 27% for control (symptomatic
treatment), respectively (p = 0.009 for TACE vs. control).
This study was terminated prematurely because of the significant benefit associated with TACE over symptomatic
treatment [51]. A second RCT based on 80 patients with
unresectable HCC compared TACE (emulsion of cisplatin in
Lipiodol, embolization with gelatin particles) versus symptomatic treatment (control group). Survival was better in
the TACE arm (estimated 1-year, 2-year and 3-year survival rates were 57%, 31% and 26% in the TACE group and
32%, 11% and 3% in the control group, p = 0.002) [63]. Two
meta-analyses demonstrated the clinical benefit of TACE for
unresectable HCC. The first analysis [64] was based on RCTs
published between 1980 and 2000 and concluded on a significant improvement of 2-year survival for TACE compared
with conservative management (18 RCTs were pooled, odds
ratio was 0.54 [0.33–0.89, p = 0.015). A subsequent metaanalysis assessing overall survival for primary treatment of
HCC (core group of 6 RCTs, 503 patients) showed a significant 2-year survival benefit associated with TACE compared
with conservative management (odds ratio 0.53 [0.32–0.89],
p = 0.017) [65]. According to the European guidelines, levels of evidence for chemoembolization are 1 (strength of
evidence) and A (clinical endpoints) [3].
4.7. Drug-eluting beads
Alternatively, non-resorbable, embolic microspheres
loaded with cytotoxic drugs [66] can be selectively administered into the lesions. These spherical, deformable particles,
usually referred to as drug-eluting beads (DEB) have a
calibrated diameter (in the 40–900 ␮m range). They were
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developed with the goal of overcoming the difficulty in
obtaining reproducible Lipiodol/doxorubicin emulsions with
standard droplet size. DEBs are composed of a hydrophilic,
ionic polymer that can bind anthracyclines via an ion
exchange mechanism [66]. DEBs are loaded extemporaneously with the cytotoxic agent (the loading procedure takes
20–90 min, depending on the size of the beads) [67]. They
allow simultaneous embolization and administration of the
cytotoxic drug. DEBs can also be loaded with irinotecan for
the treatment of colon cancer liver metastases [68]. In patient
liver explants, doxorubicin was found to impregnate an area
of at least 1.2 mm in diameter around the occluded vessel.
Doxorubicin was detected in the tissue surrounding the beads
at all time-points of liver surgical explantation after DEBTACE (i.e. TACE in which the cytotoxic drug is loaded into
DEBs instead of being mixed with Lipiodol) (from 8 h to 36
days) [69].
One study compared the doxorubicin pharmacokinetic profiles following injection of DEBs loaded with
doxorubicin versus conventional TACE protocol (i.e.
Lipiodol + doxorubicin + bland beads), doxorubicin + bland
beads and doxorubicin administered intra-arterially, in
the rabbit VX2 model [70]. Cmax values of doxorubicin and its principal metabolite, doxorubicinol, were
significantly lower when the drug was administered with
DEBs than when it was administered intra-arterially. The
order of plasma doxorubicinol concentrations was intraarterial > conventional TACE > doxorubicin + embolic bland
beads > DEBS. However, this difference was only transient,
as no differences between groups were observed 2 h after
the procedure. The tumour doxorubicin concentration was
almost undetectable following intra-arterial administration,
low in the TACE (12–36 nmol/g) and doxorubicin + bland
beads (5–25 nmol/g) groups but high in the DEBs group
(413.5 nmol/g at 3 days). Interestingly, at day 3, tumour
necrosis was identical in the DEBs and TACE groups, suggesting that necrosis cannot be exclusively attributed to
doxorubicin [70].
In a clinical study comparing the pharmacokinetic profile
of doxorubicin in patients undergoing TACE (n = 5 patients
with Lipiodol + gelatin sponge particles and n = 2 patients
with Lipiodol + doxorubicin but no gelatin sponge particlebased arterial occlusion) or DEB-TACE (500–700 ␮m)
(n = 13 patients), doxorubicin Cmax and AUC values were
significantly lower in DEB-TACE patients than in conventional TACE patients [71]. However, no comparative clinical
endpoints were studied to investigate whether this difference
in pharmacokinetic profiles had a toxicological or clinical
impact.
No significant evidence of a difference in clinical efficacy between DEB-TACE and TACE has yet been published,
based on prospective RCT [72]. The phase II PRECISION
V trial (212 patients) compared doxorubicin-loaded DEBs
and conventional TACE (the primary endpoint was tumour
response according to the amended EASL criteria [73]). At
6 months, the complete response rate was 27% vs. 22% with
conventional TACE; the objective response rate was 57% vs.
44% and the disease control rate was 63% vs. 53%, p = 0.11
[74]. However, it is worth noting that, in a recent retrospective
study of consecutive patients referred for TACE for metastatic
neuroendocrine tumours (n = 120) or HCC (n = 88), the occurrence of biloma (i.e. encapsulated collection of bile)/liver
infarct was found to be significantly associated with DEBTACE irrespective of tumour type. At least one liver/biliary
injury was observed after 30.4–35.7% of DEB-TACE sessions versus only 4.2–7.2% of conventional (Lipiodol-based)
TACE sessions (p < 0.001) [75]. Subsequently, an unexpectedly high incidence of biloma in DEB-treated patients led
to forced interruption of a clinical trial [76]. Clinical use
of DEBs is relatively recent and knowledge on their safety
is, logically, maturing. Lipiodol-based TACE remains the
standard of care for patients meeting the criteria for the intermediate stage of the BCLC staging classification [3].
4.8. Selective internal radiotherapy
Incorporation of a radionuclide with Lipiodol was rapidly
considered to be an interesting approach for the local treatment of HCC [77]. The ␤-emitting radionuclide 131 I was
selected. However, the long physical half-life of this radionuclide (8.04 days) and the high ␥-ray emission constitute a
serious drawback for radiotherapy with 131 I-Lipiodol because
patients must be kept in isolation for at least 8 days [49,78].
However, the absence of particle embolization following
injection of 131 I-Lipiodol allows this procedure to be performed in the presence of portal vein thrombosis [49].
Radioembolization with resin or glass microspheres
coated with the ␤-emitting radioisotope 90 Y (half-life 64 h) is
becoming an attractive approach to treat intermediate-stage
HCC [5,49,79], The radioisotope 188 Re has also been used to
label Lipiodol (as [188 Re] 4-hexadecyl 1,2,9,9-tetramethyl4,7-diaza-1,10-decanethiol (HDD)-labelled Lipiodol) [80].
In conclusion, the potential benefits associated with selective
internal radiotherapy justify the numerous ongoing clinical
trials.
5. Lipiodol distribution following intra-hepatic
arterial injection
In normal rats, following slow injection into the hepatic
artery, Lipiodol rapidly appeared in the portal venules,
through the peribiliary plexus [81]. The first oily droplets
typically appeared in the portal venules only a few seconds
after the start of injection. When sufficiently small, Lipiodol
droplets rapidly passed through the terminal portal venules
into the sinusoids. Following filling of peripheral portal
branches, patchy sinusoidal congestion occurred, and was
associated with necrotic areas surrounded by inflammatory
cells. It was also observed that Lipiodol could pass through
the sinusoids from portal veins into the hepatic veins.
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Lipiodol has a “plastic” (as it adjusts to the size of the
microvessel) and transient embolic effect [6,81].
In the event of overdosage, Lipiodol may possibly appear
in the systemic circulation, and is therefore associated with
a risk of systemic embolization. In rats, arterial circulation
resumed relatively soon after intrahepatic Lipiodol injection.
The oil cleared from the portal vessel in 2–3 days and from
the sinusoids in 7 days. By the 15th day following selective injection, no oil could be detected in the portal venules
and only a few droplets remained in the sinusoids [81]. The
amount of oil observed in the portal vein was dose-dependent.
This effect was confirmed in other animal species [82,83].
The hepatic arterial blood washed Lipiodol into the portal
vein through the peribiliary plexus and not directly into the
sinusoids. It is generally admitted that opacified vessels in
Lipiodol-treated HCC are portal veins or venules, since the
oil does not remain for a sufficiently long time in the tumour
arterial branches [48].
Phagocytosis by activated Küpffer cells is probably
involved in Lipiodol clearance [83]. The presence of oil
droplets in Küpffer cells has been demonstrated by electron microscopy. In rats, Lipiodol was completely cleared
in 30 days (0.1 mL/kg) or 60 days (0.2 mL/kg). At these
time-points, the microcirculation recovered and the number
of Küpffer cells returned to normal [48].
In healthy pigs, extensive necrosis of the hepatic
parenchyma was observed after re-embolization of the
restored arterial flow with gelatin particles. Hepatic artery
embolization performed with gelatin particles alone did not
produce any necrotic changes in the liver parenchyma [83].
As in pigs, combined administration of Lipiodol and gelatin
beads into the rat hepatic artery severely affected the normal hepatic microcirculation (decrease in blood flow velocity
through terminal portal venules [TPV] and terminal hepatic
venules). However, hepatic artery embolization with Lipiodol alone, which was associated with oil accumulation in
the TPV, did not adversely affect the hepatic microcirculation
[84].
5.1. Tumour uptake
5.1.1. Preclinical data
Following the early observation of Lipiodol globules in
HCC cells of patients [85], it was reported that Lipiodol
droplets accumulate in both fibroblasts and a human HCC
cell line (Hep cells) and bind to cell membranes, suggesting a non-specific phenomenon. However, the final amount
of Lipiodol accumulated in Hep cells was greater than that
in fibroblasts and the proportion of Lipiodol-laden cells was
higher with tumour cells than with fibroblasts [86]. Uptake
has been reported for both the HepG2 cell line and endothelial
HUVEC (human umbilical endothelial cells) line [87], thus
confirming the absence of specificity for cell loading. The
uptake of Lipiodol by HUVEC is of interest, as the incorporation of Lipiodol in endothelial cells of HCC vessels in
patients has been reported [87]. It has been suggested that
537
a cell membrane pump may be involved in the absorption
of Lipiodol by tumour cells [7]. The presence of membranebound Lipiodol-filled vesicles suggests that pinocytosis is the
most likely mechanism of uptake [87].
Membrane cell fluidity of HCC cells is lower than
that of normal hepatocytes because of an increase in the
phospholipids/cholesterol level [88]. The addition of both
dexamethasone and tamoxifen concentration-dependently
increased the membrane fluidity of rat tumour N1S1 cells in
vitro. In rats, pretreatment with these molecules was found to
increase the tumour uptake of 99m Tc-SSS-Lipiodol (i.e. super
six sulphur Lipiodol composed of a lipophilic complex of
99m Tc-PhCS2 (PCS3)2 solubilized into Lipiodol) compared
to controls, while no effect was observed on the distribution
of the radiotracer in the lungs [89].
5.1.2. Hepatocellular carcinoma microvascularization
and rationale for Lipiodol embolization
HCC is typically a highly angiogenic cancer [90]. The
expression of biomarkers for microvessel density is associated with development and progression of the disease [91].
HCC microvasculature is typically less dense than normal
liver vasculature. Tumour microvessels have an abnormal
blood flow and are very leaky. These characteristics lead to
hypoxia and/or necrosis [90]. Schematically speaking, blood
from the hepatic artery goes through the veno-portal compartment before it perfuses the tumour.
Basically, arterio-portal communication occurs at four levels: (a) peribiliary plexus (a dense microvascular network
surrounding the bile ducts); (b) terminal arteriosinus twigs
(i.e. small branches arising from the hepatic arterioles to
connect the sinusoids at their origin); (c) vasa vasorum on
the wall of the portal vein and (d) functional arterio-portal
anastomoses (the least frequently reported of the four types)
[92]. These shunts are typically located at the margin of the
tumour (Fig. 4).
In healthy liver, the inner diameter of portal venules is
50–100 ␮m, that of terminal portal venules is 15–50 ␮m, that
of the sinusoid network is 5–8 ␮m, that of the post-capillary
terminal venules is ∼25 ␮m [92] and that of the hepatic arterioles is 35–45 ␮m [93].
Tumour vasculature communicates with surrounding portal venules and sinusoids. Importantly, the hepatic arterial
blood accesses the tumour via the portal venules and sinusoids surrounding the lesion [92]. As demonstrated after
injection of a fluorescent tracer in animal models, arterial
blood enters the tumour through the portal venules without resistance, while blood from the portal vein meets great
resistance at the tumour margins, thereby accumulating in
the sinusoids surrounding the tumour [48]. Interruption of
either the hepatic arterial or portal venous blood flow (e.g.
by embolization) does not eliminate tumour blood perfusion
[92]. A likely explanation for this phenomenon is that a high
pressure in the peribiliary plexus prevents portal blood flow
from entering the tumour. Following arterial embolization, as
arterial blood flow is impaired, the peribiliary plexus blood
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Fig. 4. Arterioportal communications in liver without (A) or with (B) tumour.
Modified from [81].
pressure drops, thus allowing portal perfusion of the tumour
[92].
Because of it oily nature, Lipiodol allows transient dual
(arterial and portal) embolization of HCC [48], unlike
DEBs which only block hepatic arterioles. These results
could favour Lipiodol-based TACE, as they demonstrate that
embolization of only the hepatic artery without concomitant
embolization of the portal vein is insufficient. This is clinically important in extracapsular infiltrative tumour and in
surviving frontier regions, as the majority of local sinusoids
are perfused via the portal vein [92].
When sinusoidal spaces are filled beyond a certain threshold, any additional volume of oil may flow back into the portal
vein via arterio-portal communications [92,94–96]. Although
encapsulated liver tumours are almost exclusively perfused
by arterial blood, infiltrative lesions and daughter nodules
are perfused via peripheral sinusoids, i.e. with portal blood
[92,94,96] (Fig. 5).
Apart from rats, many studies have also been performed
in rabbits implanted with the VX2 tumour [97]. Table 3 summarizes the results of distribution of Lipiodol in this rabbit
model.
In the VX2 rabbit model, 3 days after selective injection
of SMANCS/Lipiodol solution, the ratio of Lipiodol concentration in the lesion to that in plasma was >3000 (∼10 in liver
adjacent to the tumour, ∼30 in liver parenchyma distant from
the tumour and ∼100 in lung, brain and kidney) [98].
A clinical study conducted in patients treated by transarterial injection of Lipiodol alone or Lipiodol + doxorubicin
followed by gelatin sponge particles and subsequent hepatectomy, compared dynamic computed tomography (CT)
findings (within 3 weeks before TACE and within 4
weeks before surgery) with pathological findings of resected
tumours. Tumour specimens and the necrosis rate measured
on CT showed a significant correlation, an effect consistent
with the retention of Lipiodol in the necrotic area of the
tumour [102].
It was subsequently shown that complete Lipiodol uptake
without enhancement by water-soluble contrast medium on
serial helical CT (Fig. 6) was predictive of complete necrosis in the explanted liver treated by TACE followed by liver
transplantation [103]. The volume of Lipiodol deposited in
the tumour observed on CT 24 h after TACE was significantly
correlated with subsequent necrosis and with the reduction in
total tumour volume. Furthermore, a significant association
was observed between Lipiodol volume measured on CT and
survival time since diagnosis and since treatment [104]. In a
retrospective analysis of 84 HCC patients, Mondazzi et al.
reported that the early degree of Lipiodol labelling of the
tumour was an independent prognostic parameter for survival
[105]. This was confirmed in other studies [106–108].
Histological analysis of HCC surgically resected or discovered incidentally after transplantation in TACE-treated
patients, revealed the presence of oily droplets both in
endothelial cells and in tumour cells surrounding these vessels [87]. In one explant liver perfused ex vivo with Lipiodol
shortly after surgery and immediately fixed thereafter, Bhattacharya et al. [87] observed brown intracellular vesicles
of Lipiodol in ballooned, foamy tumour cells as well as
in endothelial cells. The presence of oily droplets in HCC
tumour cells within 15 min after resection (at this time point,
cells were still considered viable) suggests that Lipiodol cellular uptake is a very rapid (and possibly active) process
[87].
The distribution of Lipiodol or 131 I-Lipiodol was evaluated (CT scan or gamma-camera) in 6 patients with HCC who
underwent hepatic lobectomy or segmentectomy. Lipiodol
was retained in the tumour in all cases, for as long as 3 months
post-infusion. One- to two-thirds of the tumour mass was
necrotic. Most necrotic areas were replaced by inflammatory
tissue, as well as fibrosis in some cases. Only a few oily globules were observed in cirrhotic nodules and in the connective
tissue septa. Intracellular lipid globules were located in the
cytoplasm of tumour cells. Tumour cells were enveloped by
non-globular lipid along the cell membrane, giving the HCC
a honeycomb-like appearance. It is noteworthy that, in this
study, Lipiodol and 131 I-Lipiodol were administered in the
absence of any cytotoxic drug [85].
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539
Fig. 5. Embolization of HCC and daughter nodules (A) with Lipiodol and gelatin sponge particles: stable emulsion: B or unstable emulsion: C.
Modified from [11,92,96].
5.2. Parameters influencing tumour uptake
Basically, the rationale for local treatment of the tumour is
to achieve a high and selective concentration of the cytotoxic
agent associated with embolization-induced ischaemia. It
is also crucial to release the cytotoxic agent locally under
standard conditions. These goals are obviously closely
related. Anatomical (size, density and architecture of tumour
microvessels, tumour size, ischaemia, necrosis, etc.), physiological (local flow, shear stress, blood pressure, permeability,
etc.), and physicochemical parameters associated with the
drug itself [22] or the emulsion, are all involved in tumour
uptake [4,6,109].
In terms of anatomical parameters, Lipiodol (pure or as
an emulsion) tends to follow large diameter arterial branches
at each bifurcation [6]. This phenomenon probably plays a
crucial role in the selectivity of Lipiodol for HCC.
Although each parameter cannot be interpreted independently of the others, an extensive body of work has been
published in the past 25 years and is summarized below.
5.2.1. Lipiodol-cytotoxic drug emulsion
Most cytotoxic molecules are more soluble in water than
in Lipiodol, which is why emulsions (mixture of two phases
that are insoluble in each other) are usually used. However,
depending on their hydrophilic–lipophilic balance (HLB),
cytotoxic molecules may present different distribution ratios
in aqueous or oily phases. When the cytotoxic drug can
be directly suspended in Lipiodol, the suspension may be
used without the need to prepare an emulsion. A considerable heterogeneity of the physicochemical characteristics
of the emulsion is observed when emulsions are used for
TACE, as the type of emulsion (water-in-oil [W/O] or oil-inwater [O/W]) and the size of the emulsion depend on many
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Table 3
Distribution of Lipiodol following selective intra-tumour injection in the rabbit VX2 model.
Author
Lipiodol dose
Follow up
Iwai et al., 1984 [98]
0.2 mL of
14 C-Lipiodol
15 min, 3 and 7 days
Akashi et al., 1993
[99]
0.3 to 1.2 mL/rabbit
Up to 7 days
De Baere et al., 1996
[100]
0.1 mL/kg
Up to 4 days
Hamuro et al., 1999 [101]
0.5 mL/rabbit
Up to 14 days
parameters which are mostly beyond the control of the clinician. Examples of these parameters are: the water vs. Lipiodol
volume ratio [109], the pressure exerted on both fluids during the extemporaneous preparation of the emulsion, the
number of times the emulsion is pushed through the threeway stopcock, or the nature and amount of excipients in the
cytotoxic drug used. The importance of these parameters
may be overlooked by clinicians, who may tend to believe
that pushing the aqueous solution of cytotoxic agent into
Lipiodol systematically results in a W/O emulsion. Furthermore, since an emulsion is not described by thermodynamic
Fig. 6. Computed tomography scan performed 1 h after the TACE procedure,
showing a strong Lipiodol uptake by multiple HCC nodules. Lipiodol uptake
by the right liver parenchyma not affected by the tumour is obvious and
demonstrates where the treatment was delivered (since the left liver does not
take up the iodinated oil).
Results
Accumulation of radio-labelled Lipiodol in tumour tissue
∼1000-fold higher at 15 min and ∼100-fold higher at 3 days than
the levels observed in most other organs or plasma
Selective deposition of Lipiodol in the tumour confirmed by
histology and autoradiography. Deposition in tumour vessels and
the extracapillary space
Accumulation around the tumour immediately after injection
Scattered distribution in the intact parenchyma
Tumour retention significant at 7 days, while few oil deposits
remained in healthy parenchyma: confirms tropism of Lipiodol for
the VX2 tumour
18 days following implantation, tumour = 0.9–1.2 cm in diameter.
No intrahepatic disseminated nodules or pulmonary metastases.
Minimal focal necrosis
Selective injection of large droplet diameters (30–120 ␮m
with > 70% of 70–100 ␮m) water-in-oil iodized emulsions: higher
tumour/non-tumour uptake of Lipiodol than with all other
conditions or pure iodized oil
Accumulation in connective tissue in Glisson’s sheath, portal vein
walls, and their surrounding sinusoids. LUF remained in Glisson’s
sheath at 2 days, but was absent at 7 days. At 5 min, Lipiodol was
concentrated in the margin of the tumour, mainly in blood vessels.
Retention in the tumour was still evidenced at 14 days
equilibrium laws, the type of emulsion (W/O or O/W) may
not be reproducible even when it is prepared under similar
conditions. This is particularly true when a 1:1 ratio is used to
mix the aqueous phase and Lipiodol. Lastly, the ideal emulsion for TACE procedures has not been clearly defined. Most
emulsions used in TACE, without the addition of surfactant,
are characterized by highly polydispersed sizes that certainly
evolve very rapidly in vivo because of their poor stability.
5.2.2. Type of emulsion
De Baere et al. [6] compared the stabilities of four types
of Lipiodol and doxorubicin emulsions: small (10–40 ␮m)
droplet water-in-oil (W/O); large (30–120 ␮m) droplet-W/O;
small droplet O/W and large droplet O/W. Emulsion type
and size were evaluated by light microscopy. The stability of
all emulsions tested was considered to be good: no changes
were observed in emulsion appearance, both in vitro (silicone
model of the arterial tree) and in vivo (rat cremaster muscle
model). The poorest embolic effect was achieved with small
droplets of the O/W type. As expected, W/O emulsions had
a similar, high embolic effect, close to that of pure Lipiodol.
This effect can be attributed to their oily external phase [6].
Kan et al. [109] demonstrated that a W/O (1:2 ratio) emulsion in rats exhibited a higher doxorubicin carriage capacity
(estimated on the basis of the water droplets in oil drops) and
a longer release time than an O/W (2:1 ratio) emulsion.
5.2.3. Droplet size
In general, emulsification provides a polydispersed
system in which large and small droplets coexist [110].
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This is particularly true for extemporaneous emulsions of a
cytotoxic agent with Lipiodol. Intuitively, it can be assumed
that if Lipiodol-based emulsion droplets are too small, they
will be trapped by both healthy and tumour tissues and will
pass through the sinusoids to reach extrahepatic organs.
Conversely, if they are too large, they will accumulate
proximal to the tumour microvascular bed. This is also true
for DEBs: DEB-induced biloma and necrosis of the liver
parenchyma were recently attributed to the relatively large
size of the beads used (500–700 ␮m) [75]. In fact, tumour
vascular architecture probably influences droplet distribution. The distribution of six different Lipiodol + doxorubicin
O/W mixtures (shaken for 5, 10, 15 and 30 min) within and
around hypovascular liver metastases of human colorectal
tumour was compared in mice following either intra-arterial
or intra-portal injections. All droplets found within the
centre of hypovascular tumours measured less than 20 ␮m.
Larger droplets aggregated in and occluded microvessels
surrounding the tumour, but did not enter the tumour.
Interestingly, microdroplets first adhered to the vascular
endothelium and then advanced towards the centre of the
tumour where they accumulated [111]. However, because of
their small size, these droplets can be easily entrapped by
the lung, thereby resulting in pulmonary toxicity.
In rabbits bearing the VX2 liver tumour, the highest
tumour/healthy liver parenchyma uptake 4 days after selective injection into the hepatic artery was achieved with a
“large” (30–120 ␮m with >70% of droplet diameters in the
range 70–100 ␮m) droplet W/O emulsion, compared with all
other emulsions tested. The highest lung uptake was observed
with pure Lipiodol and small droplets (10–40 ␮m with > 70%
of droplet diameters in the range 20–30 ␮m), O/W emulsion
[100].
A clinical study investigating the influence of the
droplet size of Lipiodol and epirubicin water-in-oil-in-water
(W/O/W) emulsions (average diameter of 30 vs. 70 ␮m), concluded that tumour necrosis (estimated from the decline in
serum ␣-foetoprotein (AFP) levels in the first week) was
greater in patients who received the 70 ␮m emulsion than
in those who received the 30 ␮m emulsion [112].
In summary, no clear conclusion can be drawn concerning
this important issue. Further studies are definitely needed,
with rigorous investigation of the in vivo behaviour of various
types of well-characterized emulsions.
5.2.4. Viscosity
The type of emulsion (W/O or O/W) is the main parameter determining their viscosity. Droplets of the discontinuous
phase can be considered to be particles in solution that
increase the initial viscosity of the continuous phase. The
viscosity of W/O emulsions was found to be higher than that
of Lipiodol alone which, in turn, was higher than that of O/W
emulsions [6].
Lipiodol exhibits Newtonian behaviour (i.e. viscosity
does not depend on shear stress) [6]. In this situation,
viscosity only depends on temperature and pressure, not
541
on the forces acting on the emulsion. However, Lipiodol/doxorubicin O/W and W/O emulsions were found to be
non-Newtonian (i.e. the viscosity alters with shear rate) below
a shear stress value of 40 s−1 . Viscosity was, in descending
order: W/O > Lipiodol > O/W. No correlation was observed
between viscosity and the embolic effect of the emulsion in
rats and rabbits [6].
However, based on the assumption that increased viscosity of Lipiodol would increase its tumour retention, the
biodistribution of various formulations of radiolabelled Lipiodol mixed with stearic acid to increase viscosity (up to
67 mPa·s) was subsequently investigated in rats bearing N1S1
liver tumour. At 72 h, the optimum tumour uptake was
observed with the formulation incorporating 0.8% stearic
acid (54 mPa·s) [113].
5.3. Drug-delivery properties of Lipiodol
In vivo studies have demonstrated that the most distal
release of doxorubicin from Lipiodol was observed for W/O
emulsions [109], corresponding to the optimal site of release.
This effect was actually observed when droplets reached
arteries corresponding to their own diameter [6]. Water-in-oil
type emulsions are superior to O/W type emulsions in terms
of drug delivery capacity, as shown in both mice and rats bearing liver tumours. Furthermore, they result in a longer contact
time than O/W emulsions following selective injection of
various types of Lipiodol/doxorubicin emulsions [109]. Intuitively, these results make sense, as the aqueous solution
which represents the dispersed, discontinuous phase in which
the cytotoxic agent must be solubilized, can be delivered to
a more distal and selective level than an O/W emulsion, in
which the aqueous continuous phase containing the cytotoxic
drug could be easily flushed away by local arterial blood
flow.
An important issue is the distribution of droplets in
the microvascular network. Various types of Lipiodoldoxorubicin emulsions (large droplet O/W or W/O and small
droplet W/O) have a propensity to pass through the largest
arteries in bifurcations (like pure Lipiodol), with virtually
no passage through narrower arteries [6]. This phenomenon
may facilitate the selectivity of oily droplets to the tumour,
as it is generally accepted that tumour vessels are usually
larger than healthy vessels at a similar level of bifurcation
[6]. Two possible explanations can be proposed for this phenomenon: (a) when the artery diameter/particle diameter ratio
is less than 30, particle distribution is not proportional to flow
in microvascular bifurcations and distribution preferentially
occurs through the vessel with the largest diameter [114]; (b)
the combination of the high surface tension of Lipiodol-based
droplets and the low shear rate in narrow microarteries [6].
The mechanism by which cytotoxic drugs are retained
within the tumour tissue to allow sustained impregnation is
unclear and most probably depends on the physicochemical
properties of the molecule itself, notably its HLB, charge
and molecular weight (MW). The drug-delivery potential of
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iodinated poppy seed oil should therefore be characterized
on a case-by-case basis.
The enhanced permeability and retention (EPR) effect is
a universal phenomenon by which macromolecular agents
are passively retained in the interstitial space of tumours as
the consequence of high microvascular density and permeability and the absence of lymphatic drainage [23,115–117].
The EPR effect is applicable to macromolecules with MW
higher than 40 kDa [117]. Despite its relatively low MW,
SMANCS accumulates in HCC via the EPR effect because
it binds to albumin and consequently reaches a MW value of
about 80 kDa [23]. Arterial infusion of a SMANCS/Lipiodol
mixture is therefore an excellent targeting method, as shown
in the rabbit VX2 model of HCC [98].
Compared with Lipiodol-based emulsions, DEBs seem
to release doxorubicin at a slower rate [118]. In a pig
model, doxorubicin-loaded DEBs eluted 43% of their initial cytotoxic agent load 28 days after left lobe hepatic artery
embolization, and this effect was not complete after 90 days
(89% elution), regardless of the DEBs size [118].
Indeed, DEBs are less prone to inter- and intra-operator
variability compared with conventional TACE [66]. However,
these characteristics have not been shown to be associated
with a significant, evidence-based clinical benefit (response
rate or survival) [74]. It may be possible that the release
of the drug from DEBs is too slow to achieve sufficiently
high cytotoxic concentrations, as in the case of metronomic
chemotherapy.
5.4. Role of Lipiodol in modulating the
pharmacokinetics of associated chemotherapies
The primary objective of TACE is to locally deliver the
drug and minimize systemic toxicity by decreasing drug levels in non-tumour tissue. Only two prospective, comparative
clinical studies with conflicting results have investigated the
effect of Lipiodol on circulating doxorubicin concentrations.
Johnson et al. [119] did not observe any difference in the
pharmacokinetic behaviour of doxorubicin or its principal
metabolite doxorubicinol in 9 patients receiving two courses
of a bolus injection of doxorubicin into the common hepatic
artery, in one of which the drug was mixed with 10 mL of Lipiodol. Furthermore, mixing doxorubicin with Lipiodol had
no significant effect in terms of toxicity. A potential drawback of this study may be the disproportionate volume of
saline used to dissolve doxorubicin (25 mL) compared with
that of Lipiodol (10 mL), making it an O/W emulsion [8]. In
a subsequent study [120], the biodistribution of doxorubicin
was investigated in 18 patients who received either doxorubicin alone into the hepatic artery (Group 1) or emulsified
in Lipiodol without (Group 2) or with (Group 3) gelatin
sponge particle embolization. In this study, a W/O emulsion was prepared (doxorubicin was dissolved in 2.5 mL of
water-soluble contrast medium and the Lipiodol volume was
10 mL). The doxorubicin peak plasma concentration was significantly higher in Group 1 (no Lipiodol) than in Groups 2
or 3. The area under the curve was also higher for Group
1 compared with Groups 2 and 3. This study confirmed the
preferential concentration of cytotoxic drug in the tumour
measured after surgical resection observed with multiple
cytotoxic agents in several studies [11,21,55,121]. However,
no local correlation between iodine (used as a marker of Lipiodol uptake) and doxorubicin concentrations was recently
reported in the VX2 tumour in rabbits [122]. Indeed, determination of this relationship would elucidate the controversial
[37] value of Lipiodol as a drug delivery matrix and would
distinguish between drug-induced cytotoxicity and Lipiodolinduced ischaemia. Noteworthy, an O/W emulsion was used
in this study [122]. As mentioned above, it may be speculated
that this type of emulsion may have had less efficient drug
delivery properties than W/O emulsion.
6. Effects of Lipiodol per se on hepatocellular
carcinoma
In vitro, both clonogenic assay and Trypan blue test
demonstrated that Lipiodol increased the cytotoxicity of
doxorubicin on HepG2 tumour cells [123]. Lipiodol-induced
cytotoxicity was greater for tumour cell lines (HepG2 and
MCF-7 [human breast cancer]) than for human hepatocytes
in one study [124]. However, no toxic effects were found in
other studies [86,87].
In vivo, Lipiodol may induce direct pro-necrotic effects
in liver tumours, depending on the experimental model. This
type of effect has been suggested for a long time.
Although rat models of HCC are widely used to investigate the pharmacodynamic effects of Lipiodol, either alone
or associated with cytotoxic drugs, the size of the rat
hepatic artery branches makes superselective embolization
virtually impossible. Therefore, most authors injected the
Lipiodol + cytotoxic drug by catheterization of the common
hepatic artery via the gastroduodenal artery. Overall, a therapeutic effect for Lipiodol alone is controversial (two studies
supported this effect, one in VX2 tumour-bearing rabbits [44]
and one in rats [125], while two studies in rats did not show
any significant effect [126,127]). If it exists, this therapeutic
effect is probably modest.
Interestingly, in one study comparing the pharmacokinetics of doxorubicin after conventional or DEB-TACE in
rabbits, a doxorubicin-independent necrotic effect was found
in the conventional TACE group and ascribed to the combination of the cytotoxic effects of both Lipiodol and embolic
material [70].
In patients, a therapeutic effect (dramatic decrease in blood
AFP levels and tumour necrosis) has been reported with both
131 I-Lipiodol and non-radiolabelled oil [85]. However, in
another study, Lipiodol alone had practically no therapeutic
effect [128].
Typically, HCC is a highly hypoxic tumour [90]. The
transcriptional regulator factor HIF-1␣ (hypoxia-induciblefactor 1) regulates the adaptive response to lack of oxygen.
J.-M. Idée, B. Guiu / Critical Reviews in Oncology/Hematology 88 (2013) 530–549
HIF-1 ␣ translocates to the nucleus and forms the HIF-1 complex that initiates vascular endothelial growth factor (VEGF)
transcription [129]. The pro-ischaemic effect of TACE may
induce HCC cells to secrete more VEGF. This effect has
been observed in patients [130]. In rabbits, selective injection of Lipiodol alone (without the addition of embolic agent)
induced VEGF expression and an increase in microvessel density (MVD). MVD was significantly correlated with
VEGF expression [131]. In patients, a transient increase in
plasma VEGF levels was observed (day 1 post-TACE) and
the change in plasma VEGF levels (1 month after TACE) was
significantly associated with Lipiodol retention by the tumour
[132]. In a prospective study in 71 patients undergoing
TACE, below-median VEGF plasma levels were a significant predictor of a longer survival [133]. Taken together,
these data support the potential value of the combination
of anti-angiogenic drugs with TACE in HCC. However, the
most appropriate time window for the administration of such
agents, respective to the TACE procedure, has yet to be
established. Investigations designed to improve the synergy
between TACE and targeted therapies are a priority in the
field of HCC treatment.
7. Perspectives
7.1. Pharmacological management
There is considerable ongoing research to improve the
pharmacological management of unresectable HCC. The
multikinase inhibitor sorafenib, is the only targeted therapy
approved by health authorities (Europe, US, Japan, etc.) for
the first-line treatment of unresectable HCC in patients who
are not candidates for TACE, based on a 2.8-month survival advantage over best supportive care in the Sorafenib
Hepatocellular carcinoma Assessment Randomized Protocol (SHARP) study [134]. However, sorafenib-induced side
effects may seriously affect the patient’s quality of life [135].
Combination therapy associating sorafenib and TACE may be
a promising approach in patients with advanced/intermediate
HCC [136,137]. However, so far, it is unclear whether this
agent combined with TACE has additive or synergistic effects
compared with TACE alone [137]. Phase II and III clinical trials evaluating sorafenib combined with locoregional
therapies are ongoing [137]. Although molecular targeted
therapies in HCC are definitely an interesting and active
area of research [138], a promising future can reasonably be
expected for interventional procedures and combination of
these approaches in selected patients. Combination of TACE
and radiofrequency ablation seems also to be a promising
approach for the control of HCC [139].
7.2. Thermochemoembolization
Thermochemoembolization is a technique based on
targeted deposition of magnetic nanoparticles into the
543
tumour, followed by application of an alternating current magnetic field inducing focused heating (39–49 ◦ C).
Superparamagnetic iron oxide (SPIO) nanoparticles may
sensitize the tumour to the effects of hyperthermia. The
presence of both iodine and iron oxide may allow dual
(CT and magnetic resonance imaging, MRI) imaging.
Highly selective targeting of VX2 tumours in rabbits with
therapeutic temperatures has been demonstrated using
SPIO nanoparticles suspended in Lipiodol [140]. However,
further investigation of the tissue reaction showed ischaemic
necrosis of healthy liver parenchyma [141]. Furthermore, a
suspension of SPIO (diameter 150 nm) in Lipiodol was found
to be extensively phagocytosed in the liver of healthy pigs
and was followed by extensive necrosis. No hepatic clearance of the suspension was observed 28 days after injection.
Microvascular occlusions were also observed [142]. Despite
these early negative results, thermochemoembolization
remains a field of extensive research.
7.3. Immunoembolization
Immunoembolization is another interesting field of
investigation. This technique refers to the injection of
granulocyte-macrophage colony-stimulating factor (GMCSF) emulsified with Lipiodol (associated with gelatin
sponge particles) into the hepatic artery [2]. Promising
results have been reported for immunoembolization with
GM-CSF in patients with liver metastases from primary uveal
melanoma [143].
7.4. Gene therapy
Interventional therapy procedures provide unique opportunities for the delivery of gene therapy vectors into HCC or
other cancer. Several approaches can be anticipated [144]:
(a) restoration of tumour suppressor genes. Promising results
on tumour growth were obtained following selective administration of adenovirus (Ad)-p53 gene mixed with Lipiodol
in rabbit VX2 tumour [145]; (b) inhibition of oncogenes (e.g.
Ras, pituitary tumour transforming gene-1 or PTTG1, telomerase reverse transcriptase or TERT, etc.); (c) gene-directed
enzyme/prodrug therapy (i.e. transfer of exogenous genes
which convert a non-toxic prodrug into a cytotoxic molecule);
(d) genetic immunotherapy; (e) antiangiogenic gene therapy
(an approach which may be of particular interest in HCC);
(f) delivery of oncolytic viruses.
8. Discussion
Selectivity of Lipiodol uptake by HCC nodules and its
long-lasting capture is of great clinical relevance. The mechanism for tumour uptake and long-lasting stagnation remains
debated. Several hypotheses (not mutually exclusive) have
been proposed and are summarized in Table 4. Direct capture
by tumour and endothelial cells is quantitatively limited.
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J.-M. Idée, B. Guiu / Critical Reviews in Oncology/Hematology 88 (2013) 530–549
Table 4
Current hypotheses for the uptake of Lipiodol by hepatocellular carcinoma.
Hypothesis
Basis for the hypothesis
Propensity of oily droplets to pass through the largest microvessel
at each bifurcation
Tumour vascularity improves Lipiodol uptake
Almost complete absence of a reticulo-endothelial system in the
tumour: no degradation and absorption of the oil
Direct capture by tumour and endothelial cells
Lack of lymphatic system in HCC: no drainage
Difference between normal liver tissue and HCC
Larger diameter vessels preferentially supply the tumour [6]
HCC is one of the most hypervascular solid tumours [90,91]
Kupffer cells are responsible for eliminating Lipiodol from the healthy
liver parenchyma [146]
Demonstrated in numerous studies [85,87,123]
Suggested in [147]
Dual blood supply (hepatic artery and portal vein) probably induces more
rapid washout from the normal parenchyma
The major advances in “omics”, medical imaging, nanotechnologies and pharmacology pave the way for a
drastically new approach to treat patients. This new process
is based on an in-depth knowledge of pathophysiological
mechanisms of diseases and has led to the birth of a new,
target-centred era based on a specific biological hypothesis for the identification and development of new molecular
entities (NME) to interact with the target [148].
The concept of “theranostics” was coined in 1998 by the
US consultant John Funkhouser to describe a material that
allows the combined diagnosis, treatment and follow-up of
a disease [149]. This approach allows the selection of a subpopulation of patients most likely to benefit from targeted
therapy or, conversely, those at higher risk of adverse effects.
From the clinician’s viewpoint, personalized medicine has
obvious major consequences in terms of patient management.
The revolutionary concept of theranostics has evolved over
time, integrating two distinct approaches that both encompass
all steps of patient management:
(a) The biomarker approach to diagnose the disease, determine the best course of treatment, follow the patient’s
response and detect potential recurrence of the disease.
(b) Guidance and follow-up of therapeutic interventions (e.g.
local drug delivery, medical device or cell therapy). Medical imaging is the prerequisite for such approaches.
The concept of theranostics perfectly applies to Lipiodolbased chemoembolization and this technique is probably the
first example of the validity of theranostics [117]. Given the
radiopacity and drug delivery capacity of Lipiodol, several
perspectives (summarized above) can now be considered.
These properties are consistent with the two conceptual
approaches of theranostics.
The prognostic benefit associated with early tumour
labelling by Lipiodol [105–108] confirms its potential value
as a biomarker, while the relationship with the behaviour of
Lipiodol in the stroma and cell compartments requires further
investigation.
DEBs are an interesting approach to standardize HCC
embolization. Table 5 compares and summarizes the main
properties of Lipiodol and DEBs for TACE.
DEBs cannot be directly imaged by fluoroscopy during the
procedure and must be mixed with a water-soluble iodinated
CM to indirectly monitor delivery of the embolic material.
The dilution ratio is empirical. Furthermore, visualization
of the CM does not provide any information on the site of
beads in the lesion. Over recent years, extensive research
has been conducted to develop imageable beads for MRI,
logically based on iron oxide nanoparticles [151,152], fluoroscopy based on Lipiodol [150,153] or both techniques (i.e.
multimodal approach) [154]. Signal intensity as a surrogate
biomarker for local drug delivery would be clinically and
pharmacologically meaningful. This goal has not yet been
achieved with either DEBs or Lipiodol.
The stability of Lipiodol-based emulsions and hence
their drug-delivery capacities is greatly influenced by the
ratio between Lipiodol and saline or water-soluble contrast
medium used to solubilize the cytotoxic drug. This ratio determines the O/W or W/O type of the emulsion. W/O emulsions
of adequate size will probably allow the cytotoxic drug to
enter the portal compartment before phase separation [11],
as deemed desirable based on non-clinical studies [6,48].
It has been suggested that a Lipiodol/doxorubicin volume
Table 5
Conventional (Lipiodol-based) TACE vs. drug-eluting bead-based TACE.
Proven benefit on survival
Real-time fluoroscopy-guided delivery
Tumour labelling on CT (prognostic value)
Embolization effect
Vascular selectivity for the tumour
Release of cytotoxic agent
Systemic release of the cytotoxic drug
Incidence of biloma and liver infarct
Cost
Conventional TACE
Drug eluting bead-based TACE
References
Yes
Yes
Yes
Transient plastic embolization
Yes (depends on vessel size)
Fast
Moderate
Low
Low
Yes
No
No
Non-plastic embolization
Yes if small (<300 ␮m)
Slow
Low
High
High
[3,5,73]
[7,21,149]
[105–108]
[7,49,66,69,81,96,118]
[6,100,118]
[118]
[66,69,71,120]
[75,76]
–
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2–3:1 ratio would optimize the local bioavailability of the
drug [8].
Many preclinical and clinical studies have compared
various types of emulsions or suspensions comprising
cytotoxic drugs and Lipiodol. Unfortunately, these emulsions/suspensions are often inadequately characterized,
thereby making it hazardous to define any clear conclusions.
Tailored emulsion technology is a rapidly evolving field in
drug-delivery technologies, notably for anti-cancer drugs
[154]. A growing knowledge in the field of formulation
(selection of emulsifiers, additives, and drug incorporation
methods) and the basic knowledge of lipid chemistry and
cytotoxic drug solubility in emulsion systems suggest
a bright future for Lipiodol-based emulsions. However,
the small number of approved and marketed cytotoxic or
cytostatic molecules remains a major constraint in linking
physicochemical parameters of these drugs to stability,
formulability, clinical efficacy and tolerability of lipid-based
emulsions [155]. This issue cannot be resolved without close
collaboration between drug companies, clinicians and health
authorities.
545
The findings and conclusion in this compilation are those
of the individual authors and do not necessarily state or reflect
those of Guerbet. They may not be used for advertising or
product endorsement purposes.
Reviewers
Professor Byung Ho Park, Department of Radiology,
Dong-A University Hospital, Busan, Republic of Korea.
Professor Alban Denys, CHUV – Centre Hospitalier Universitaire Vaudois, Department of Radiology, Rue du Bugnon
46, CH-1011 Lausanne, Switzerland.
Acknowledgements
The authors warmly thank Drs. Anthony Saul and
Dominique Debize-Henderson for reviewing the English version of the manuscript, Drs. Claire Corot and Sébastien Ballet
for helpful discussions, Miguel Soares for the drawings,
Catherine Gicquel, Martine Robert and Camille Ferrer for
their help with the literature search.
9. Conclusion
The benefits associated with the use of Lipiodol for TACE
are widely acknowledged and have led to a huge number of
preclinical and clinical studies over the last 25 years, with
continuing interest in this field. Its unique combination of
properties as a tumour-seeking, drug-delivery, embolic and
X-ray opaque agent explains why it is used worldwide for
chemoembolization procedures for many clinical indications,
beyond hepatic malignancies. The use of Lipiodol is acknowledged in international and national guidelines [2,3]. As it is
performed today, TACE has the drawback of being a heterogeneous technique (type of cytotoxic drug, type of embolic
agent, emulsion, timing, selectivity, schedule, etc.), making
it a field of intense and challenging research. Two additional
drawbacks are worth mentioning: firstly, no cytotoxic agents
are specifically authorized for TACE procedures in Western countries; secondly, shortages of many cytotoxic drugs,
primarily generic drugs, are becoming common and raise a
serious problem for clinicians [156].
In addition to its radiopaque properties, Lipiodol has the
unique property of transiently reducing intra-tumour portal
perfusion and locally delivering the drug of interest. Future
research is expected to improve the efficacy of Lipiodol as
a versatile drug delivery system. Despite its venerable age,
Lipiodol remains the topic of a very active research associated
with promising perspectives.
Conflict of interest
Jean-Marc Idée is employee of Guerbet.
Boris Guiu declared no conflict of interest.
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Biographies
Jean-Marc Idée, PharmD, M.S., is a senior pharmacologist at Guerbet research centre, Aulnay-sous-Bois, France.
He graduated at School of Pharmacy, Paris Descartes University and Pierre and Marie Curie University, both in
Paris, France. His main research interests cover the pharmacology and toxicology of contrast agents for X-ray
medical imaging (including interventional radiology) and the
structure-toxicity relationship of gadolinium chelates used as
contrast agents for magnetic resonance imaging.
Boris Guiu, M.D., Ph.D. graduated at Dijon University
Medical School in 2004 and attended the residency in diagnostic and interventional radiology at University of Dijon,
France. He spent 6 months at the department of interventional radiology in Institut Gustave Roussy, Villejuif, France,
and one year at the department of interventional radiology of the University Hospital of Lausanne, Switzerland. In
2014, he will gain a position of Professor in radiology and
will become the head of the department of radiology at the
University Hospital of Montpellier, France. His main clinical and research interests cover intra-arterial therapies of
liver tumours and more generally, interventional radiology in
digestive tumours.