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ease within the treated tumors (viable lesion

>50%) are observed, even after changing the che-

motherapeutic agents and/or reanalysis of feed-

ing artery, on response evaluation CT/MRI after

1–3 months following adequately performed

selective TACE [12].

Despite a very long history, there is no stan-

dard technique regarding all aspects of the proce-

dure including drugs, embolic materials, and

microcatheter selection. In the treatment of HCC,

doxorubicin is the most used chemotherapeutic

agent, although several other drugs are also used,

including epirubicin, idarubicin, cisplatin, and

mitomycin C.Concerning the embolic material,

TACE has classically been performed with an

emulsion of Lipiodol and chemotherapeutic

drugs followed by Gelfoam (conventional

TACE). In the late 2000s, drug-eluting beads

(DEB) became available for clinical use and

showed a better safety prole with lower sys-

temic drug-related toxicity, although without sig-

nicant added value on local tumor control over

conventional TACE [1, 6, 7].

In this complex scenario, the role of the multi-

disciplinary team in individualizing treatment

strategy is evident. It has been in fact demon-

strated that MDT discussion improves patient

outcomes and that even when decision is taken in

discordance with guidelines but in a patient-

tailored manner, the results may ultimately be

equal to or even superior to those expected per

tumor stage [13, 14].

2.3 TACE forNon-intermediate-

Stage HCC

1. In clinical practice, not all patients with early-

stage HCC are suitable for curative therapies,

such as LT, surgical resection, or ablation due

to several clinical factors, such as old age,

hepatic dysfunction, tumor location, and

comorbidities [7] (Table2.1).

Despite having early-stage disease, this subset

of patients could be good candidates for

TACE.This treatment stage-migration strategy is

well established and is recommended by interna-

tional guidelines [1, 7]; several studies have

reported a high response rate and good outcomes

after TACE in patients with early-stage HCC [6].

A particular subset of patients where TACE is

often performed is in combination with thermal

ablation in patients with HCC nodules larger than

3cm. Despite not included in current guidelines,

the combination of TACE and radiofrequency

ablation is associated with signicantly higher

overall survival and recurrence-free survival,

than radiofrequency monotherapy, without a sig-

nicant difference in major complications [7]

(Table2.1).

There is not enough evidence in the literature

to support the use of TACE for patients in the

advanced stage, not even in cases with locally

advanced disease such as segmental/sectorial

portal vein invasion, where systemic therapies

are presently indicated and radioembolization

may be discussed as an option at MDT [7].

2.4 TACE forBridging

andDownstaging HCC toLT

Patients with HCC are at high risk of list dropout

due to tumor progression while waiting for LT.

Bridging therapy is intended to prevent dropouts

especially if the estimated waiting time is of

≥6months: in fact, approximately 22% of patients

with HCC drop off the waiting list and patients

who do not receive any bridging treatments have a

1-year drop-out rate greater than 30% [5]. Several

studies have shown that in patients who were

bridged to liver transplantation by means of

TACE, the drop-out rates were of 3%–9.3%, sig-

nicantly lower if compared to the ones of the

pre-bridging therapy era [5] (Table2.1).

The term downstaging describes treatment

used to bring patients whose tumor burden is out-

side accepted criteria for transplantation to within

acceptable criteria. Acceptable criteria are

dened as those criteria achieving an expected

survival after LT equal to patients who meet

transplant criteria without downstaging [5].

According to EASL guidelines, patients are

accepted as LT candidates when their HCC, pre-

senting at an intermediate/advanced stage, is suc-

cessfully down-staged to within the Milan criteria

[7]. Patients with HCC initially exceeding Milan

2 Transarterial Chemoembolization (TACE): Indications

t.me/medicina_free

criteria and down-staged with TACE can achieve

post-transplant survival and HCC recurrence-free

probability at 5years similar to those of patients

within Milan criteria [5, 15, 16] (Table2.1).

Some concerns have been raised about possi-

ble impairment of liver function in cirrhotic

patients treated with TACE, as well as the

increased risk of postoperative hepatic artery

complications in patients undergoing TACE

before liver transplantation [17, 18]. On the con-

trary, two recent retrospective studies conducted

in transplanted patients who were previously

submitted to TACE showed that the incidence of

hepatic artery thrombosis was quite similar in

those who had or had not received TACE and

TACE delivered before liver transplant did not

affect complications, patient death, or graft fail-

ure after transplantation [19, 20].

When TACE is performed as a neoadjuvant

therapy before LT, there is not enough data to

establish if it is preferable to use conventional

TACE (c-TACE) or DEB-TACE.A recent publi-

cation demonstrates that, compared to Lipiodol

TACE, DEB-TACE is better tolerated, allowing

for reduced hospitalization, and is associated

with more durable local tumor control after

complete radiological response. These features

may be of specic importance if applied to a

patient during a possibly long waiting period

before LT [21].

2.5 TACE forLiver-Dominant

Primary Cholangiocellular

andMetastatic Disease

TACE may be considered as a treatment option in

selected patients with other primary tumors

(intrahepatic cholangiocarcinoma, iCCA) or sec-

ondary tumors from colorectal and non- colorectal

carcinomas (neuroendocrine, breast, thyroid can-

cer, melanoma and in oligometastatic disease

controlled with systemic treatment), after discus-

sion in a dedicated multidisciplinary team. In

these cases, careful pretreatment imaging is

needed to conrm the liver only or oligometa-

static disease.

Indications for TACE in iCCA include surgi-

cally unresectable or inoperable liver tumors with

liver-only disease [22].

In the setting of mCRC, patients with liver-

limited disease in whom the available chemother-

apeutic lines have failed, TACE may be also

considered as a treatment option [23].

TACE can also be considered as an alternative

therapy to surgical resection of liver metastasis in

patients with NET and as an alternative to sys-

temic treatment in those patients with NETs with

disease limited to the liver [24].

In all those specic settings, the choice of

embolizing material and drug should be part of

the multidisciplinary discussion according to

liver functional reserve, tumor burden (selective

access/lobar approach), molecular proling of

the disease, and previous response to cytotoxic

drugs [6].

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center evaluation of reduction in tumor size before

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23. Van Cutsem E, Cervantes A, Adam R, Sobrero

A, Van Krieken JH, Aderka D, Aranda Aguilar E,

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L. Crocetti et al.

t.me/medicina_free

Access andMaterial

StavrosSpiliopoulos andLazarosReppas

3.1 Access

TACE can be performed via common femoral

or radial artery access, although brachial artery

or distal transradial access can be also used

[1–3]. A transradial access offers the benet of

immediate mobilization/ambulation with mini-

mal bleeding complications and less patient

discomfort, and is advised in obese patients

with hostile abdomen, those unable to lay at

for a long period of time, or those at high bleed-

ing risk [4, 5]. Both local anesthesia and single-

wall arterial access should be performed under

ultrasound guidance to minimize pain, access

attempts, and complications [6]. For all access

types, standard 4–5 Fr x 10cm sheaths can be

used with the relative angiographic catheter

diameter. Dedicated access kits with 21 G

short-length puncture needles are recom-

mended for transradial access.

Preprocedural study of visceral arteries, vas-

cular anatomy, and tumor supply can minimize

procedural time and decrease the risk of nontar-

geted embolization. Frequent anatomical varia-

tions such as right hepatic artery arising from the

superior mesenteric artery (SMA) and left hepatic

artery arising from the left gastric artery can be

easily noted in preprocedural CTA imaging.

3.2 Materials andTechnique

Celiac axis and SMA are most frequently cathe-

terized from femoral access with 4- or 5-Fr

Cobra, Simmons, or SOS angiographic catheters.

For challenging catheterizations, Yashiro tip

catheter can also be used. For celiac/SM artery

catheterization from transradial access, MPA1,

VANSCIE, vertebral, or headhunter angiographic

catheters can be used.

5 Fr angiographic catheters demonstrate better

steerability than the smaller 4Fr and could be

used in challenging celiac or SMA catheteriza-

tions. An angled 0.035 hydrophilic guide wire is

subsequently and carefully advanced distal into

the right hepatic artery in order to advance the

angiographic catheter in the common hepatic

artery, distal to the origin of the gastroduodenal

artery, for adequate support, when possible.

In cases of challenging anatomy with steep

angulation and/or in cases in which the hepatic

artery originates steeply from the proximal por-

tion of the celiac artery, after catheterization of

the celiac trunk, the guidewire can be advanced

within the splenic artery. Catheter is exchanged

with an angled catheter (VANSCIE, vertebral, or

similar) and the common hepatic artery can now

S. Spiliopoulos (*) · L. Reppas

2nd Department of Radiology, Interventional

Radiology Unit, National and Kapodistrian

University of Athens, “ATTIKON” University

General Hospital, Athens, Greece

e-mail: stavspiliop@med.uoa.gr

P. Lucatelli (ed.), Transarterial Chemoembolization (TACE),

https://doi.org/10.1007/978-3-031-36261-3_3

t.me/medicina_free

be catheterized by simultaneously injecting

contrast, slowly retrieving and turning the angled

catheter just at the origin of the celiac artery.

Recently, the “side-hole technique” has also been

proposed for challenging angulations, in which a

side hole is created at the lesser curvature side of

a 5-Fr Cobra catheter and a micro-wire with a

microcatheter is subsequently advanced through

the side hole [7]. Nevertheless, catheterizing just

the ostium of the celiac artery with the mother

catheter and using the microcatheter to advance

within the feeding vessels always remain a valid

option.

Standard or specically designed for TACE

microcatheters (length: 105–150 cm; diameter:

2.0–2.8 Fr; 0.018-inch guidewire compatible) are

usually required. Digital subtraction angiography

(DSA) of the hepatic arteries should be per-

formed before selective catheterization to depict

the target lesion(s) and document free antegrade

ow of contrast media, conrming that the cath-

eter is not obstructing the ow. Intraprocedural

imaging including 3D angiography with a rota-

tional at panel detector (cone-beam CT, CBCT)

or a combined MDCT angiography system is

highly recommended as it has been correlated

with less complications, increased technical suc-

cess, and optimization of clinical outcomes [8–

10]. Intraprocedural CBCT/MDCTA imaging

enables accurate lesion detection, provides guid-

ance for catheterization, and offers intraproce-

dural treatment assessment and guidance, as in

cases of incomplete tumor embolization, further

feeders can be identied and catheterized [11,

12]. For detailed CBCT advantages and clinical

applications, refer to Chap. 5.

Superselective catheterization is highly rec-

ommended in cases of a single lesion or those

with short number of lesions, and feeding arteries

should be to minimize the risk of nontargeted

embolization, increase the local concentration of

chemotherapeutic agent within the tumor, and

enhance optimization of clinical outcomes [13].

The materials used in a typical TACE procedure

are described in Table3.1.

Embolic agents should be delivered with the

catheter tip beyond the origin of the gastroduode-

nal artery, the right gastric artery (usually arising

from the proper hepatic artery), and the cystic

artery (mainly arising from the right hepatic

artery) to avoid nontargeted embolization of the

bowel, stomach, and gallbladder, respectively.

Once the catheter has been positioned at the

desired feeding vessel and prior to the delivery of

the embolic material, a superselective arterio-

gram (usually 8–10 ml total contrast volume,

4–5 ml/sec rate, 800 psi) performed via the

microcatheter conrms the correct position of the

tip as well as the free antegrade ow of contrast

media within the tumor but could also depict

additional vessels that were not noted during the

previous less selective angiograms. It is impor-

tant that free antegrade ow is demonstrated

before infusion, and the physician should be able

to visualize that both the macro- and the micro-

catheter are positioned within adequately sized

vessels, as to avoid backow and guarantee the

delivery of the materials within the lesion.

Available embolic agents typically used for

TACE are presented in Table 3.2. Luer-lock

syringes and female/male Luer-lock connections

are recommended for safe infusion during DEB-

TACE while dedicated Lipiodol-resistant infu-

sion sets can be used for c-TACE.

In the presence of arterio-portal or arterio-

venous shunts, selective embolization is sug-

gested. Several embolization materials are

Table 3.1 Recommended materials during a typical

TACE procedure

1. Study preprocedural CT (including detailed analysis

of the vascular anatomy).

2. Arterial access (US guided under local anesthesia):

4/5 Fr sheath.

3. Celiac axis catheterization and arteriogram (CBCT

or MDCTA highly recommended).

• 4- or 5-Fr catheter: Cobra Simmons/SOS (femoral

access) or VANSCIE/vertebral/headhunter (radial

access)

• A 0.035 angled hydrophilic guidewire.

4. Superselective catheterization of the feeder(s) and

angiogram:

• Microcatheter.

5. Embolization/drug delivery: See Table3.2.

• DEB-TACE.

• C-TACE (Lipiodol/drug).

6. Hemostasis of vascular access:

• 4 Fr: Manual compression

• 5–6 Fr: Closure device.

S. Spiliopoulos and L. Reppas

t.me/medicina_free

Table 3.2 Embolic agents typically used for TACE

c-TACE: Suspension of Lipiodol and chemotherapy

drugs followed by Gelfoam or 100–300μm embolic

particles

DEB-TACE: Drug-eluting microsphere usually

75μm–300μm:

• DC/LC bead (BTG international, PA, USA).

• Hepasphere/Quadrasphere (merit medical, UT,

USA).

• Tandem/Embozene (Boston Scientic, MA, USA).

• LifePearl (Terumo medical, Japan).

Chemotherapy drugs:

• HCC: Doxorubicin, epirubicin 75–150mg per

session/doxorubicin, epirubicin, cisplatin, and

mitomycin for c-TACE.

Nonionic contrast medium: Usually 5–10mL/liter of

microspheres

available, and the choice should depend on the

specific anatomical details and the experi-

ence of the physician. N-butyl-2-cyanoacrylate

(glue) use has been mainly reported in the

literature. The dilution of Lipiodol/

N-butyl-2-cyanoacrylate depends on the

dimensions and hemodynamic characteristics

of the shunt, and generally low-viscosity mix-

tures are used for high-flow, large shunts,

while balloon occlusion techniques have been

implemented in order to avoid nontargeted

distal embolization [14, 15]. Coils and gelatin

sponge (plain or soaked with ethanol) can also

be used successfully in selected cases [16].

3.2.1 Novel Anti-Reux

Microcatheters. Pressure-

Assisted Embolization

Although typical end-hole microcatheters are

currently the standard of TACE therapy, novel-

anti-reux technology has been implemented,

aiming in preventing retrograde ow and mini-

mize non-target delivery. This novel class of anti-

reux microcatheters (also called “ow-directed”

or “pressure-assisted” microcatheters) uses

micro-balloons, valves, or dynamic ow obstruc-

tion technology to prevent backow of the

embolic material and enhance intratumoral deliv-

ery. Moreover, it has been proposed that pressure-

assisted embolization, enabled by anti-reux

microcatheters, results in reduced both extrahe-

patic and intrahepatic non target embolization,

and therefore improves selective intra-tumor

delivery, due to a signicant reduction in the

blood pressure occurring in the downstream ante-

grade vascular territory and ow redistribution

via intra-hepatic collaterals. [17, 18]

Specically, the Surere® Infusion System

(SIS; TriSalus Life Sciences, USA) is using a

patented valve system that partially collapses

with forward systolic arterial ow and expands

with reversed diastolic ow avoiding reux dur-

ing delivery. SIS is introduced through a 5F guid-

ing catheter with an inner diameter of 1.37mm

(0.054 inches) or greater and is available in 3.7

Fr/3.4 Fr proximal distal tip/outer diameter and

120cm and 150cm (SIS Radial) usable lengths.

Also, two sizes are available (SIS 025M for ves-

sel between -2.0 and 4.0mm and SIS 025L for

vessels between -4.0 and 6.0 mm) [19–21]

The IsoFlow™ dual-balloon anti-reux

microcatheter (Vascular Designs Inc., USA) is

equipped with two compliant balloons (can be

inated from 2 to 6mm), positioned near the dis-

tal end of the catheter. Between the two balloons,

there is a 10 mm long infusion segment (with

multiple side holes). The IsoFlow™ microcathe-

ter has three lumens: one for balloons ination,

one for infusion through the side holes, and a

third to accommodate the guidewire (0.014 inch).

The IsoFlow™ catheter can be inserted via a 5-Fr

guiding catheter, with a 0.056-inch inner diame-

ter. It is available in 150cm length and a proxi-

mal/distal outer diameter of 3.5 F and 2.3 F,

respectively, and can deliver embolic materials

up to 300μm [22].

The Occlusafe® Temporary Occlusion

Balloon Catheter (Terumo, Japan) is a microcath-

eter equipped with a single balloon at the distal

tip that can be inated to occlude vessels measur-

ing from 1mm to 4mm (balloon ination mini-

mum volume 0.02 mL and maximum volume

0.10 mL). It is compatible with a 0.014- inch

guidewire and available in 110 to 150cm length.

The proximal/distal outer diameter is 2.8 Fr and

2.7 Fr, respectively.

Finally, the SeQure® Reux Control

Microcatheter (Guerbet, Princeton, USA) uses

3 Access andMaterial

t.me/medicina_free

Table 3.3 Commercially available anti-reux catheters

indicated for TACE

Brand name Technical characteristics

Surere® precision

infusion system (TriSalus

life sciences, USA)

Expandable basket;

requires specic

angiographic catheters

IsoFlow™ microcatheter

(vascular designs Inc.,

USA)

Dual-balloon technology

Occlusafe® temporary

occlusion balloon catheter

(Terumo, Japan)

Inatable balloon

SeQure® reux control

microcatheter (Guerbet,

USA)

Dynamic ow

obstruction technology

side slits that generate a uid barrier during

infusion impeding reux of the embolic mate-

rial. This ow dynamic technology is based on

the fact that side slits measure <70μm size and

therefore allow the outow of contrast media

without passage of the embolic microspheres. It

is compatible with 0.018- to 0.021-inch guide-

wires and available in 105 to 150cm in lengths.

The SeQure® microcatheter is available in

proximal/distal outer diameters of 2.9/2.4 Fr,

2.9/2.7 Fr, and 3.0/2.8 Fr, delivering embolic

microspheres measuring 70–500 μm,

70–500 μm, and 70–700 μm, respectively, but

also 0.018-inch micro coils [23].

Commercially available anti-reux micro-

catheters indicated for TACE procedures are

summarized in Table3.3.

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3 Access andMaterial

t.me/medicina_free

Preprocedure Workup

ArgiròRenato andGasparriniFulvio

TACE is an established treatment for patients

with intermediate-stage HCC.

The development of new effective diagnostic

procedures such as ultrasound, spiral CT, and

MRI has led to improved preoperative patient

selection and thus improved overall survival.

Correct patient selection and proper prepara-

tion of the procedure in each step play a central

role in the success of the treatment and the nal

outcome.

In this chapter, we discuss the current man-

agement of patients with HCC undergoing TACE.

Particular emphasis is given to the diagnostic

and clinical workup as it should be performed

currently. Standard preprocedure workup and

periprocedure patient management are also

discussed.

4.1 Preprocedure Workup

4.1.1 Outpatient Examination

The outpatient visit is a key step in the pretreat-

ment workup. During the visit, the indications are

assessed, the patient informed, and the treatment

planned in every step, including additional labo-

ratory analyses and imaging studies.

Much has been written about patient selection

and detailed coverage of this area is beyond the

scope of this chapter. However, during outpatient

visit, certain aspects of patient selection must be

recognized, including Child-Pugh classication,

extrahepatic involvement, liver tumor burden,

serology values, and eventually portal vein

patency.

Patients with extrahepatic metastasis may be

candidates if hepatic tumor burden is predomi-

nant and is the main cause of symptoms.

Caution should be exercised in Child-Pugh

class C patients as TACE is poorly tolerated in

this group who are prone to hepatic failure. In

patients with large hepatic tumor burden, the

staging of treatment into two or more sessions

might be necessary to avoid hepatic failure. In

general, no more than 50% of liver volume should

be embolized in a single procedure. Many physi-

cians will not treat tumors that are bigger than

50% of total liver volume. Staged procedures are

usually performed at least 2weeks apart to allow

patients to recover. More time may be needed in

some patients to return to baseline.

In patients with elevated liver enzymes in

addition to increased bilirubin levels, there is a

propensity for hepatic failure and TACE may be

contraindicated.

If the patient is judged to be suitable for treat-

ment, the outpatient clinic visit is the best moment

A. Renato (*) · G. Fulvio

UOSD radiologia interventistica–Dipartimento di

Biomedicina e prevenzione, Azienda Ospedaliera

Universitaria Policlinico Tor Vergata Rome,

Rome, Italy

P. Lucatelli (ed.), Transarterial Chemoembolization (TACE),

https://doi.org/10.1007/978-3-031-36261-3_4

t.me/medicina_free

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