Langenbecks Arch Surg

DOI 10.1007/s00423-015-1308-9

REVIEW ARTICLE

Transarterial chemoembolization (TACE) for colorectal liver

metastases—current status and critical review

Alexander Massmann 1 & Thomas Rodt 2 & Steffen Marquardt 2 & Roland Seidel 1 &
Katrina Thomas 3 & Frank Wacker 2 & Götz M. Richter 3 & Hans U. Kauczor 4 &
Arno Bücker 1 & Philippe L. Pereira 5 & Christof M. Sommer 3,4

Received: 9 May 2015 / Accepted: 24 May 2015

# Springer-Verlag Berlin Heidelberg 2015

Abstract are discussed. The role of TACE as a valuable adjunct to surgery

Background Transarterial liver-directed therapies are currently
not recommended as a standard treatment for colorectal liver
metastases. Transarterial chemoembolization (TACE), howev-
er, is increasingly used for patients with liver-dominant colo-
rectal metastases after failure of surgery or systemic chemother-
apy. The limited available data potentially reveals TACE as a
valuable option for pre- and post-operative downsizing, mini-
mizing time-to-surgery, and prolongation of overall survival
after surgery in patients with colorectal liver only metastases.
Purpose In this overview, the current status of TACE for the
treatment of liver-dominant colorectal liver metastases is present-
ed. Critical comments on its rationale, technical success, compli-
cations, toxicity, and side effects as well as oncologic outcomes
is addressed regarding pre- and post-operative downsizing, con-
version to resectability as well as improvement of the recurrence
rate after potentially curative liver resection. Additionally, the
concept of TACE for liver-dominant metastatic disease with a
focus on new embolization technologies is outlined.
Conclusions There is encouraging data with regard to techni-
cal success, safety, and oncologic efficacy of TACE for colo-
rectal liver metastases. The majority of studies are non-
randomized single-center series mostly after failure of system-
ic therapies in the 2nd line and beyond. Emerging techniques
including embolization with calibrated microspheres, with or
without additional cytotoxic drugs, degradable starch micro-
spheres, and technical innovations, e.g., cone-beam computed

* Christof M. Sommer
c.sommer@klinikum-stuttgart.de; Arno Bücker
christof.sommer@med.uni-heidelberg.de arno.buecker@uks.eu
Alexander Massmann Philippe L. Pereira
alexander.massmann@uks.eu philippe.pereira@slk-kliniken.de
Thomas Rodt
rodt.thomas@mh-hannover.de 1
Clinic for Diagnostic and Interventional Radiology, Saarland
Steffen Marquardt University Medical Center, Kirrberger Straße, Geb. 50.1,
marquardt.steffen@mh-hannover.de 66421 Homburg Saar, Germany
Roland Seidel 2
Department of Diagnostic and Interventional Radiology,
roland.seidel@uks.eu
Hannover Medical School, Carl-Neuberg-Strasse 1,
30625 Hannover, Germany
Katrina Thomas
3
k.thomas@klinikum-stuttgart.de Clinic for Diagnostic and Interventional Radiology, Klinikum
Stuttgart, Kriegsbergstrasse 50-55, 70174 Stuttgart, Germany
Frank Wacker
wacker.frank@mh-hannover.de 4
Clinic for Diagnostic and Interventional Radiology, University
Götz M. Richter Hospital Heidelberg, INF 110, 69120 Heidelberg, Germany
g.richter@klinikum-stuttgart.de 5
Clinic for Radiology, Minimally-Invasive Therapies and Nuclear
Hans U. Kauczor Medicine, SLK Kliniken Heilbronn GmbH, Am Gesundbrunnen
hu.kauczor@med.uni-heidelberg.de 20-26, 74078 Heilbronn, Germany

tomography (CT) allow a new highly standardized TACE
procedure. The real efficacy of TACE for colorectal liver me-
tastases in a neoadjuvant, adjuvant, and palliative setting has
now to be evaluated in prospective randomized controlled
trials.
Keywords Transarterial chemoembolization (TACE) .
Embolization . Hepatic artery infusion (HAI) . Colorectal liver
metastases . Surgical resection
Key points
& TACE is a minimal-invasive image-guided transarterial
catheter-directed therapy, which has been used for the
treatment of colorectal liver metastases applying embolic
materials and cytotoxic drugs. Therapy-associated com-
plication rates are low.
& New TACE technologies lead to a highly increased cyto-
toxic drug concentration in the treated liver metastases by
significantly reducing systemic toxicity compared with
systemic treatments.
& A repeated TACE procedure seems to be necessary to
improve the tumor response.
& TACE may potentially represent a valuable tool in the
management of surgical candidates in a neoadjuvant set-
ting for downsizing and for early conversion to resectabil-
ity without adverse effects, e.g., sinusoidal obstruction syn-
drome (SOS) or non-alcoholic steato-hepatitis (NASH) as
observed in some systemic chemotherapy regimens.
& TACE could be potentially performed in the adjuvant set-
ting to prevent recurrence after surgery or ablative thera-
pies with the aim to improve the overall survival without
major side effects.
Background
Colorectal liver metastases represent the fourth most common
malignant tumor entity, and the second most common cause of
cancer-related death in Western countries. The presence and
extent of liver metastases is a major prognostic factor for the
overall survival. The prevalence is 25–50 % at the time of
diagnosis, and about 80 % of patients will suffer from liver
metastases during follow-up. Since the microstructure of the
liver is an effective tumor cell barrier, early distant metastasis
due to hematogenous spreading is rare. The variety of avail-
able therapies for colorectal liver metastases—e.g., surgical
resection, systemic chemotherapy, molecular substances, and
local ablative treatments—challenges the selection of the best
treatment strategy with regard to tumor stage, mutation status,
sequence and pattern of metastases, performance status, and
Langenbecks Arch Surg
patients’ preference [1–3]. Basically, there are four different
clinical settings of disease’s presentation: (I) primarily resect-
able liver metastases without extrahepatic disease (accepted
treatment strategy: primary surgical resection with or without
additive systemic therapy or peri-operative systemic therapy
with secondary resection), (II) primarily non-resectable liver
metastases with or without extrahepatic disease (accepted
treatment strategy: pre-operative systemic therapy with sec-
ondary resection (if not successful palliative systemic therapy
and/or liver-directed therapies with palliative intention)), (III)
primarily resectable liver metastases with extrahepatic disease
(accepted treatment strategy: peri-operative systemic therapy
with secondary resection (if not successful palliative systemic
therapy and/or liver-directed therapies with palliative inten-
tion), and (IV) non-resectable diffuse liver metastases (pallia-
tive systemic therapy (if not successful liver-directed therapies
with palliative intention)). Surgical resection is currently ac-
cepted as the curative first-line treatment. According to the
published literature, feasibility of resection with curative in-
tention can be characterized by ≤5 isolated metastases per
liver lobe, at least two tumor-free adjacent liver segments as
well as a volume of the liver remnant >20 % by reference to
the initial liver volume [4, 5]. In experienced centers, howev-
er, there are extended resection criteria. Applying the standard
criteria, curative resection can be realized in less than 20 % of
patients resulting in a 5-year overall survival rate of 20–40 %
[6–8]. Of the patients, 60–80 % of those with liver resection
will develop recurrent colorectal metastases at follow-up, of
which half have a recurrence within the liver [9, 10]. At the
time of initial diagnosis, at least more than 80 % of patients are
non-surgical candidates due to the extent of liver and/or extra-
hepatic disease or due to general conditions [11]. Such pa-
tients are treated routinely with systemic therapy according
to the current available European guidelines. Despite the con-
siderable improvements of the systemic regimens inclusive
with combined chemotherapeutics and molecular substances,
the nature of this approach remains palliative. The former
standard of care with systemic chemotherapy based on 5-
fluoro-pyrimidine achieved a response rate of about 20 %
and a mean overall survival of 12 months. Combined systemic
chemotherapies with 5-fluoro-uracil, irinotecan, and/or
oxaliplatin (e.g., FOLFOX, FOLFIRI, and FOLFOXIRI) have
dramatically improved both response rates and the mean over-
all survival to 40–57 % and 15–20 months, respectively, but
the reported 5-year overall survival rates are still close to 0 %
[12–16]. On average, the mean overall survival of stage IV
colorectal cancer patients can be estimated as follows:
6 months without systemic chemotherapy, 12 months with
systemic mono-chemotherapy (5-fluoro-uracil), 15 months
with systemic dual-chemotherapy (5-fluoro-uracil plus
irinotecan ), and 21 m onths with systemic poly-
chemotherapy (5-fluoro-uracil (infusion) plus irinotecan/
oxaliplatin). The introduction of molecular substances such
Langenbecks Arch Surg
as growth receptor inhibitors (anti-EGFR (epidermal growth
factor receptor) antibodies (cetuximab; Erbitux, Imclone Sys-
tems, Bristol Meyers Squibb, New York, USA or
panitumamab; Vectibix, Amgen, Thousand Oaks, USA) and
inhibitors of neoangiogenesis (anti-VEGF (vascular endothe-
lial growth factor) antibodies (bevacizumab; Avastin, Roche,
Basel, Switzerland and regorafenib; Stivarga, Bayer, Berlin,
Germany) have further improved the results of systemic ther-
apies. In controlled trials in the 2nd and 3rd line, overall sur-
vivals of more than 24 months have been reported with a
combination of systemic poly-chemotherapy (5-fluoro-uracil
(intravenous or oral) plus irinotecan/oxaliplatin) with antibod-
ies. Up to now, there is no clear evidence for a survival benefit
and the long-term quality of life [7, 8, 17, 18]. Anti-EGFR
antibodies (cetuximab) in the 3nd line have a survival benefit
in mutation status Bk-ras wildtype^ patients [19]. The high
objective response rates to cetuximab along with systemic
chemotherapy in patients with colorectal liver metastases
makes it an effective downsizing protocol. With this optimal
management using k-ras testing, cetuximab and systemic che-
motherapy can result in a 28 % R0 resection rate in patients
with initially unresectable colorectal cancer liver metastases
[20]. Current evidence suggests that systemic chemotherapy
for downsizing followed by rescue liver resection is safe and
effective for selected patients with initially unresectable colo-
rectal liver metastases [21]. Nevertheless, compared with all
systemic therapies, transarterial liver-directed therapies have
the potential advantage of a markedly higher concentration of
the drugs within the liver metastases and at the same time, a
decrease of systemic toxicity and adverse effects [19].
Transarterial liver-directed therapies
Rationales
Due to its specific architecture, normal liver parenchyma is
largely supplied by the portal vein whereas hepatic arterial
branches predominantly supply malignant liver tumors [22].
Transarterial drug delivery into the liver allows, therefore, a
considerably increased local therapeutic concentration com-
pared with intravenously applied systemic chemotherapeutics.
At the same time, healthy non-affected liver parenchyma can
be spared with selective or superselective transarterial
chemoembolization (TACE), and the liver toxicity that is ob-
served after systemic applications is avoided or at least mini-
mized. Chemotherapy-associated liver injury (CALI)—e.g.,
sinusoidal obstruction syndrome (SOS) and non-alcoholic
steato-hepatitis (NASH)—are relevant limitations after cyto-
toxic therapy and should have implications for treatment plans
prior to surgical resection. Hepatic steatosis without inflam-
mation (simple steatosis) may occur with chemotherapy. SOS
may occur with oxaliplatin treatment and appears to increase
in severity with prolonged treatments (>6 cycles).
Bevacizumab can be used safely when discontinued >5 weeks
before liver resection and seems to decrease the incidence and
severity of sinusoidal injury after oxaliplatin therapy [23]. At
least, for patients with unresectable liver-only metastasis, a
response to chemotherapy could establish resectability and
should be considered as an initial treatment goal. In patients
with unresectable colorectal liver metastases, oxaliplatin or
irinotecan represent standard regimens. The addition of
bevacizumab may increase response and possibly reduce the
risk of CALI [24]. In tumors without k-ras mutations, anti-
EGFR antibodies are also reasonable choices for higher re-
sponse and improved survival outcomes [24]. Since chemo-
therapeutics are metabolized by a first-pass in the liver,
transarterial application goes along with decreased systemic
toxicity and side effects [25]. Since angiogenesis and
neoangiogenesis are crucial steps in the complex cascade of
hematogenous spreading as well as growth of distant metas-
tases, EGFR, VEGF, angiopoietin, and cyclooxygenase are
relevant pathways to control the arterial blood supply of colo-
rectal metastases. The definite role of such pathways in terms
of molecular targets, however, is not clearly defined. Apart
from the safe transarterial use of anti-EGFR antibodies
(cetuximab) in a patient with recurrent ependymoma (with a
dose of 100 mg/m2 body surface) as well as anti-VEGF anti-
bodies (bevacizumab) in a patient with glioblastoma (with a
dose of 15 mg/kg body weight), the authors could not identify
any study with transarterial application of those molecular
substances for colorectal liver metastases.
Overview and results of hepatic artery infusion—a
trailblazer?
Transarterial administration of different chemotherapeutics di-
rectly into the liver is associated with a significantly improved
tumor response rate and at least with a trend to improved
survival in patients with colorectal liver metastases [26, 27].
In the surgical literature, the concept is published as hepatic
artery infusion (HAI) and realized by using an implanted ar-
terial portcatheter system. Table 1 gives a synopsis of the key
studies for HAI for colorectal liver metastases. Accordingly,
tumor response rates and median survival are 22–62 % and
12.6–24.4 months for HAI compared with 9–42 % and 7.5–
20.0 months for systemic chemotherapy and/or best medical
treatment (BMT), respectively. In one randomized study, a
significant survival benefit is reported for patients undergoing
continuous HAI with 5-fluoro-deoxy-uridine (FUDR) com-
pared with the control arm (5-fluoro-uracil (5FU)/BMT)
(13.5 versus 7.5 months; p=0.03)) [28]. Recent results of a
non-controlled trial promote HAI in combination with system-
ic chemotherapy including bevacizumab [29]. The overall re-
sponse rate was 76 % (inclusive of 4 complete responses), and
23 patients (47 %) achieved conversion to resection at a
 Langenbecks Arch Surg

Table 1 Key studies with HAI for colorectal liver metastases (controlled trials)

Study/reference Year Study group (hepatic Therapy (5-fluoro-deoxy- Patients Tumor Median Significance (first
artery infusion (HAI), uridine (FUDR), 5-fluoro- (n) response survival row: tumor response
systemic chemotherapy uracil (5FU), leucovorin (LV), rate (%) (months) rate, second row:
(CTx)) best medical treatment (BMT) median survival)

Kemeny et al./[67] 1987 HAI FUDR 48 53 17 Yes

CTx FUDR 51 21 12 n.s.
Chang et al./[68] 1987 HAI FUDR 32 62 17 Yes
Ctx FUDR 32 17 12 n.s.
Hohn et al./[69] 1989 HAI FUDR 67 42 16.5 Yes
CTx FUDR 76 9 10.5 n.s.
Martin et al./[70] 1990 HAI FUDR 39 48 12.6 Yes
CTx 5FU + LV 35 21 10.5 n.s.
Wagman et al./[71] 1990 HAI FUDR 31 55 13.8 Yes
CTx 5FU 10 20 11.6 n.s.
Rougier et al./[72] 1992 HAI FUDR 81 41 15 Yes
CTx 5FU/BMT 82 9 11 n.s.
Allen-Mersh et al./[28] 1994 HAI FUDR 51 n.a. 13.5 n.s.
CTx 5FU/BMT 49 n.a. 7.5 Yes
Lorenz et al./[73] 2000 HAI FUDR 54 43 12.7 n.s.
HAI 5FU + LV 57 45 18.7 n.s.
CTx 5FU + LV 57 27 17.6 n.s.
Kerr et al./[74] 2003 HAI 5FU + LV 145 22 14.7 n.s.
CTx 5FU + LV 145 19 14.8 n.s.
Kemeny et al./[26] 2006 HAI FUDR 68 47 24.4 Yes
CTx 5FU + LV 67 24 20 n.s.
Fiorentini et al./[75] 2006 HAI + CTx 5FU + LV 38 48 20 n.s.
CTx 5FU 38 42 14 n.s.

Yes significant differences, n.s. no significant differences (significant differences in italicized characters)
HAI hepatic artery infusion

median of 6 months from initial treatment. Median overall
survival and progression-free survival for all the patients
were 38 and 13 months, respectively. While bevacizumab
did not impact the surgical outcome, the conversion to
resectability was the only factor associated with prolonged
overall survival and progression-free survival. Patients who
had undergone resection had a better overall survival than
those who did not (3-year overall survival of 80 versus 26 %).
Ten of 49 (20 %) of the patients with surgical resection had no
evidence of disease at a median follow-up of 39 months (32–
65 months) [29]. Procedure-related specific complications of
HAI such as hepatic artery dissection and thrombosis,
portcatheter occlusion as well as pump failure and infection
are reported in up to 21, 5, 2, and 3 %, respectively [30]. In
summary, the oncologic results—especially response rates—
for HAI are excellent. Main drawbacks, however, are the lack
of impact on overall survival and the relatively high rate of
technical failure, which may explain why HAI is not well
accepted in clinical standard practice. Instead of HAI, repeti-
tive TACE could be used combining an excellent oncologic
effectiveness, a low rate of technical failure, and a high level
of patient satisfaction.
Transarterial chemoembolization—an
underestimated option?
Rationales
TACE is a minimal-invasive image-guided transarterial liver-
directed therapy. After selective and superselective injection
of one or more chemotherapeutic drugs and one or more em-
bolic agents into the liver metastases, combined anti-tumoral
effects (chemotoxicity and ischemia) are observed. The use of
an embolic agent before and/or after transarterial drug appli-
cation results in a reduction of the arterial flow, combining
reduced chemotherapeutic clearance and decreased tumor per-
fusion [31]. For an optimal outcome, it is recommended to
inject the chemoembolics directly into the tumor-feeding ar-
teries until stasis or at least flow reduction as the embolization
Langenbecks Arch Surg
endpoint [32, 33]. According to the current guidelines, and in
contrast to hepatocellular carcinoma, TACE is still not recom-
mended as a standard therapy for colorectal liver metastases.
Nevertheless, there is new evidence of a significantly in-
creased and effective use of repetitive TACE in patients with
liver-dominant colorectal metastases after failure of surgical,
ablative, and/or systemic therapies.
Technique
According to good clinical practices, TACE is indicated in
patients with a life expectancy >3 months and an appropriate
health status (ECOG (Eastern Cooperative Oncology Group)
status ≤2) [34, 35]. Adequate liver function is a prerequisite:
bilirubin should be <3 mg/dl, albumin >3 g/dl, and the INR
(international normalized ratio) >1.6; however, those numbers
must be assessed together with the specific health status of
each patient. Pre-interventional staging with contrast-
enhanced CT or dynamic magnetic resonance imaging
(MRI) before conventional catheter angiographies are neces-
sary to assess precisely the tumor extent and the arterial anat-
omy inclusive of its variants. Especially in case of large sub-
capsular tumors, evaluation of the celiac trunk and superior
mesenteric artery but also of the phrenic, intercostal, lumbar,
and internal thoracic arteries is recommended. A few centers
consider tumor invasion into the large portal vein branches as
a relative contraindication. Peri-interventional medication in-
cludes analgetics and antiemetics. In case of large tumor vol-
umes, cortison can be very efffective to treat the tumor edema
after TACE (e.g., dexamethasone 250 mg). Additionally, an-
tibiotics are recommended only in high-risk patients [34]. The
correct choice of the catheter position for embolization as well
as the embolization endpoint are relevant key factors for safe
and effective treatments, and both must consider size, loca-
tion, and vascularization of the liver metastases. Treatment via
the right or left hepatic artery is used for a selective targeting
of one liver lobe. A more distal catheter position is applied for
superselective treatments of single-liver segments [32, 33]. A
microcatheter should be used to obtain the superselective em-
bolization position at persistent antegrade arterial flow. For
sufficient stability even in complex catheterizations, a
transfemoral guiding catheter (4 or 5 French) is positioned in
the celiac trunk or the common hepatic artery. The
microcatheter (e.g., 2.4 French) is then advanced into the tar-
get region applying high-resolution fluoroscopy. Diagnostic
angiographies and intraoperative cone-beam CTs help to iden-
tify the exact anatomy of all tumor-feeding arteries and to
navigate the microcatheter accordingly. The selection of the
adequate chemoembolics is another key and depends on sev-
eral parameters (see below). It is recommended to treat each
tumor site for at least three times with selective/superselective
TACE to cover also satellites and micrometastases [33]. After
TACE, therapy control includes clinical examination, blood
sampling, and contrast-enhanced imaging.
Although there is no official standard of practice, repetitive
TACE procedures should be scheduled (e.g., with intervals of
4–6 weeks) according to tumor response and performance
status. Between the different TACE cycles, interdisciplinary
re-evaluation within the tumor board is recommended. Offi-
cial recommendations such as the BStandards of Practice
Guidelines^ of the Cardiovascular and Interventional Radio-
logical Society of Europe (CIRSE) will help to further stan-
dardize TACE for colorectal liver metastases (http://www.
cirse.org/?pid=412).
Chemoembolics
Due to the lack of an evidence-based treatment standard, mul-
tiple chemotherapeutics, and embolic agents are used in dif-
ferent combinations and doses [35, 36]. In order to give a
better insight, interventional oncologists begin to classify in
three different categories: conventional (c) TACE (cTACE),
degradable starch microsphere (DSM) TACE (DSM-TACE),
and drug-eluting bead (DEB) TACE (DEB-TACE).
cTACE was introduced in 1963 and established in the
1980s for the treatment of primary liver tumors. Historically,
a cytotoxic agent was dissolved in iodized oil (Lipiodol;
Laboratoire Guerbet, Aulnay-sous-Bois, France), and injected
directly into the liver artery under fluoroscopy [37]. Today,
different hydrophilic chemotherapeutics (e.g., 5-fluoro-uracil)
in combination with iodized oil and/or permanent embolic
agents (e.g., polyvinyl alcohol (PVA) particles) are used [38,
39]. Gelatine sponge can be added to enforce the grade of
temporary vessel occlusion until degradation after a few days.
Size-calibrated microspheres are permanent embolic agents,
which allow occlusion of a pre-defined arterial level [40].
For DSM-TACE, one or more chemotherapeutics (e.g., mi-
tomycin C, gemcitabine, and/or irinotecan) can be mixed with
DSMs [32]. Since human serum amylase dissolves this em-
bolic agent, vascular occlusion is temporary. In Europe, the
available type of DSM (EmboCept S; PharmaCept, Berlin,
Germany) has a mean microsphere size of 50 μm and a recan-
alization time of about 60 min.
The recent innovation of DEB-TACE is a widely increas-
ing embolization technique. The concept is based on perma-
nent microspheres, which are loaded with a cytotoxic drug (at
the moment there are CE marks for doxorubicin- and
irinotecan-loaded microspheres). After injection of DEBs,
there is a controlled drug-release over several hours, and even
days, within the treated tissue (Fig. 1) [41]. Since type and
dose of the chemotherapeutic can be selected individually and
combined with a particular microsphere size and volume,
DEB-TACE is considered as the most standardized procedure
among TACE technologies.

Fig. 1 Drug-eluting beads (DEBS) as a chemoembolic for DEB-TACE
(DEBIRI) - controlled local drug-release over time. Typical in vitro drug-
release profile (UV absorption with standard deviation versus time) of
irinotecan-loaded TANDEM microspheres (100 μm; 50 mg irinotecan
hydrochloride per ml microspheres) using isotonic saline at 37 °C as
release medium with a flow of 5 ml/min in an USP 4 type elution appa-
ratus. Inset: optical micrograph of Embozene TANDEM (100 μm) (with
permission of CeloNova BioSciences, San Antonio, USA)
Tables 2 and 3 give an overview of chemotherapeutics (in-
cluding molecular substances) available for transarterial use and
embolic agents used for TACE. In terms of tumor response, it is
still unclear which specific combination of drug and embolic
agent should be used for an optimal treatment result. The pre-
defined calibration of microsphere size allows an exact control
of the embolization depth, whereby the occluded vessel diam-
eters correspond more or less to the nominal size of the micro-
sphere. Only randomized controlled studies can determine
which chemoembolics result in the best tumor response rates.
In contrast to the permanent embolic agents, DSMs should
reduce ischemic effects and, therefore, avoid neoangiogenesis.
In that light, issues such as cTACE and DEB-TACE with or
without the use of neoangiogenesis inhibitors (e.g., anti-VEGF
antibodies (bevacizumab)) should be addressed.
Technical success, complications, and adverse effects
In key studies with TACE for colorectal liver metastases, the
technical success—defined as successful catheterization with
subsequent selective/superselective deposition of the
chemoembolic within the target region—is close to 100 %
[42, 43]. Dissection or thrombosis of the hepatic artery is
extremely rare [30]. Temporary vasospasm during catheteri-
zation is common but can be treated effectively with vasodi-
lators (e.g., repetitive transarterial bolus injections of nitro
0.25 mg). Arterio-portal and arterio-venous shunts should be
occluded to avoid the risk for non-target embolization. After
one or more TACE cycles, the chemoembolics can alter the
larger tumor-feeding arteries. Then, very small microspheres
(e.g., irinotecan-loaded microspheres with a diameter of 40±
10 μm) help to embolize the diffuse tumor vasculature, if
necessary applying protective embolization of the non-target
Langenbecks Arch Surg
liver tissue (e.g., DSMs) [44]. The so-called Bpost-emboliza-
tion syndrome^ is a relatively frequent side effect after TACE,
which is characterized by one or a combination of fatigue,
nausea, vomitus, mild fever, and elevated laboratory signs
indicating tumor necrosis.
In a recent review, relevant toxicities of cTACE, DEB-
TACE, systemic chemotherapy (CTx), and HAI are compared
[30]. For cTACE, cited toxicities are nausea/vomitus (18–
83 %), fever (13–83 %), fatigue (24–60 %), abdominal pain
(82–100 %), liver dysfunction/failure (13–33 %), gastritis
(17 %), neurotoxicity (45 %), diarrhea (9–31 %), hematolog-
ical toxicity (13–33 %), and renal failure (4 %).
For DEB-TACE, cited toxicities are nausea/vomitus (2–
55 %), hypertension (4–80 %), liver dysfunction/failure
(6 %), cholecystitis (1 %), gastritis (1 %), anorexia (3 %),
abdominal pain (0–57 %), hematologic toxicity (9–90 %), fa-
tigue (60 %), and alopecia (5–35 %).
For CTx and HAI, cited toxicities are chemical hepatitis
(7–15 and 4–79 %, respectively), biliary sclerosis (not report-
ed (n.r.) and 4–21 %, respectively), peptic/duodenal ulceration
(0–3 and 0–17 %, respectively), gastritis/duodenitis (1–7 and
1–21 %, respectively), diarrhea (16–70 and 1–44 %, respec-
tively), nausea/vomitus (35–46 and 21–61 %, respectively),
and stomatitis (14–87 and 0–76 %, respectively).
Major complications such as liver abscess or tumor rupture
are rare. Non-target embolization (e.g., pancreatitis or cholecys-
titis) can be avoided after sufficient evaluation of the arterial
anatomy (e.g., by using high-resolution angiography or intra-
operative cone-beam CT) and by using dedicated embolization
techniques (e.g., flow-mediated embolization or balloon protec-
tion) [45]. In experienced centers, the overall major and minor
complication rates during and after TACE are generally very
low [32, 46, 47]. The procedure can be regarded as a safe and
well-tolerated procedure as long as standardized catheterization
and modern imaging techniques are used as well as the peri-
procedural supporting medication is implemented consistently.
Oncologic outcomes in patients with irresectable liver
metastases
A systematic literature review of the published studies with
TACE for colorectal liver metastases has been performed
(search strategy: MEDLINE as database and Btransarterial
embolization^ plus Bcolorectal liver metastases^ as search
term for primary selection and cross references for additional
selection). A total of 30 appropriate original studies were iden-
tified (Table 4). In summary, TACE for colorectal liver metas-
tases is always performed after failure of at least one and more
often more systemic and/or surgical therapies. According to
Table 4, the different types of TACE can show a tumor re-
sponse rate of 89 %, a progression-free survival rate of
13.6 months and an overall survival of >28 months. The re-
ported TACE data are to be compared with the other treatment
Table 2 Chemotherapeutics (including molecular substances) available for transarterial use

Type Maximum single dose Major indications Major toxicity and side effects Reference study for Reference study for
transarterial use colorectal liver
metastases

Bevacizumab (anti-VEGF) 15 mg/kg body weight Colorectal cancer, lung cancer, breast Hypertension, fatigue, diarrhea, proteinuria, Burkhardt et al. 2012 [76] Glimelius et al. 2012 [77]
cancer, ovarian cancer, renal cancer thromboembolia, hemorrhage, bowel
Langenbecks Arch Surg

perforation
Carboplatin (AUC 5) 300 mg/m2 body surface Lung cancer, breast cancer, ovarian Nausea and vomitus, tinnitus, allergy, Barletta et al. 2006 [78] Shimonov et al.2005 [79]
cancer, testicular cancer abdominal pain, diarrhea, constipation,
neurotoxicity, nephrotoxicity, bone
marrow suppression
Caelyx (liposomal 30 mg/m2 body surface See doxorubicin See doxorubicin Gonzalez Cao et al. 2006 [80] Moroney et al. 2012 [81]
doxorubicin)
2
Cetuximab (anti-EGFR) 100 mg/m body surface Colorectal cancer, head and neck cancer Acne-like skin reaction, pruritus, Rajappa et al. 2010 [82] Glimelius et al. 2012 [77]
hypomagnesemia, fever, shivering,
vertigo, dyspnea
Cisplatin 100 mg/m2 body surface Head and neck cancer, lung cancer, Bone marrow suppression, anemia, Mancini et al. 2003 [83] Gruber-Routh et al. 2014 [84]
ovarian cancer, cervix carcinoma, hyperuremia, fever, heart arrhythmia,
chorion carcinoma, testicular dyspnea, pneumonia, allergy
cancer, bladder cancer
Doxorubicin 50 mg/m2 body surface Lung cancer, breast cancer, ovarian Bone marrow suppression, nephrotoxicity, Liu et al. 2015 [85] Albert M et al. 2011 [39]
cancer, lymphoma cardiotoxicitya, skin ulceration
2
Docetaxel 75 mg/m body surface Head and neck cancer, lung cancer, Bone marrow suppression, fever, Nakanishi et al. 2012 [86] Seki et al. 2011 [87]
breast cancer, ovarian cancer, neurotoxicity, diarrhea, alopecia,
prostate cancer, gastric cancer hepatotoxicity, heart arrhythmia
Epirubicin 75 mg/m2 body surface Lung cancer, breast cancer, ovarian Bone marrow suppression, alopecia, Tawada et al. 2015 [88] Fiorentini et al. 2004 [89]
cancer, gastric cancer, bladder stomatitis, abdominal pain, nausea,
cancer, lymphoma, sarcoma and vomitus, diarrhea, anorexia
Fotemustin 100 mg/m2 body surface Melanoma, lymphoma Bone marrow suppression, fatigue, Edelhauser et al. 2012 [90] Hartmann et al. 1997 [91]
nausea, vomitus, and alopecia
Gemcitabine 1000 mg/m2 body surface Lung cancer, breast cancer, ovarian cancer, Bone marrow suppression, skin reaction, Vogl et al. 2008 [92] Gruber-Routh et al. 2014 [84]
pancreatic cancer, cholangiocellular alopecia, stomatitis, hepatotoxicity,
carcinoma, bladder cancer, lymphoma neurotoxicity, nephrotocicity
Irinotecan 200 mg/m2 body surface Lung cancer, cervix carcinoma, esophagus Bradycardia, lacrimation flush, diarrhea, Tsuchiya et al. 2007 [93] Gruber-Routh et al. 2014 [84]
cancer, gastric cancer, pancreatic cancer, hyperhidrosis, bone marrow suppression,
cholangiocellular carcinoma, sacroma alopecia, nephrotoxicity, hepatotoxicity
Mitomycin C 10 mg/m2 body surface Colorectal cancer, head and neck cancer, Skin necrosis, lung fibrosis, nephrotoxicity, Vogl et al. 2008 [92] Gruber-Routh et al. 2014 [84]
lung cancer, breast cancer, cervix bone marrow suppression, skin reaction,
carcinoma, esophagus cancer, nausea and vomitus, cardiotoxicity
gastric cancer, pancreatic cancer,
hepatocellular carcinoma, bladder
cancer
Mitoxantrone 14 mg/m2 body surface Breast cancer, prostate cancer, lymphoma, Nausea and vomitus, anorexia, alopecia, Boulin et al. 2011 [94] Link et al. 2001 [95]
multiple sclerosis stomatitis, bone marrow suppression,
cardiotoxicity
Oxaliplatin 60–80 mg/m2 body surface Colorectal cancer Diarrhea, nausea and vomitus, bone Chen et al. 2014 [96] Nordlinger et al. 2008 [59]
marrow suppression, stomatitis,
nephrotoxicity, neurotoxicity
 Langenbecks Arch Surg

(1. folin acid (=leucovorin), 2. 5-fluoro-uracil, and 3. irinotecan), FOLFOXIRI (1. folin acid (=leucovorin), 2. 5-fluoro-uracil, 3. oxaliplatin, and 4. irinotecan), FOLFIRINOX (1. folin acid (=leucovorin), 2.

irinotecan); molecular substances are frequently used: the anti-EGFR antibodies cetuximab (Erbitux; Imclone Systems, Bristol Meyers Squibb, NY, USA) and panitumamab (Vectibix; Amgen, Thousand
5-fluoro-uracil, 3. irinotecan, and 4. oxaliplatin), XELOX (1. capectitabine (Xeloda; Roche, Basel, Switzerland) and 2. oxaliplatin) and XELIRI (1. capectitabine (Xeloda; Roche, Basel, Switzerland) and 2.

neoangiogenesis. For colorectal liver metastases, all relevant chemotherapeutics and molecular substances are available either for transarterial use (oxaliplatin and irinotecan as well as cetuximab (Erbitux;
Imclone Systems, Bristol Meyers Squibb, NY, USA) and bevacizumab (Avastin; Roche, Basel, Switzerland)) or for oral use (leucovorin, 5-fluoro-uracil, capecitabine (Xeloda; Roche, Basel, Switzerland)
Oaks, USA) to block the growth receptor cascade as well as the anti-VEGF antibodies bevacizumab (Avastin; Roche, Basel, Switzerland) and regorafenib (Stivarga; Bayer, Berlin, Germany) to block
According to the guidelines, chemotherapeutic standards in the different lines for colorectal liver metastases include FOLFOX (1. folin acid (=leucovorin), 2. 5-fluoro-uracil, and 3. oxaliplatin), FOLFIRI
Tsimberidou et al. 2011 [98]
options beyond the 2nd line. There are two strategic controlled
trials comparing two different systemic regimens for colorec-
tal liver metastases in the 3nd line: sequential systemic therapy
Reference study for

versus combined systemic therapy. In the study of Amado

colorectal liver

et al., tumor response rate, progression-free survival, and over-

metastases

all survival are 8 %, 13.2 months, and 16.4 months for the
sequential systemic chemotherapy arm as well as 9 %,
12.9 months, and 16.2 months for the combined systemic
chemotherapy arm, respectively [48]. In the other study (CAI-
RO trial), tumor response rate, progression-free survival, and
Koga et al. 2003 [97]

overall survival are 4 %, 10.3 months, and 16.3 months for the
Reference study for

sequential systemic chemotherapy arm as well as n.r., n.r., and

transarterial use

17.4 months for the combined systemic chemotherapy arm,

respectively [49]. Studies with anti-EGFR antibodies beyond
the 2nd line show a tumor response rate of 0–22.9 %, a
progression-free survival of 1.5–4.1 months and an overall
survival of 4.4–9.5 months [19]. At least one of those studies
Bone marrow suppression, neurotoxicity,

could detect a survival benefit: 9.5 months for cetuximab in

myalgia, alopecia, diarrhea, nausea

combination with BMT versus 4.5 months for BMT only in

mutation status Bk-ras wildtype^ patients [19]. The authors
Major toxicity and side effects

concluded that with the multiple therapeutic options in the

1st and 2nd line and beyond, subsequent lines of systemic
therapy should be performed as a multi-line strategy, and spe-
and vomitus

cific strategic trials are indicated to better understand tumor

biology and predictive factors for response [19].
Currently, six review articles with TACE for colorectal liv-
and the anti-VEGF antibody regorafenib (Stivarga; Bayer, Berlin, Germany)) (see also Tables 4 and 5)

er metastasis have been published over the last few years [30,
47, 50–54]. Based on the similar referral time (review articles
published between 2011 and 2015), the conclusions drawn are
Lung cancer (NSCLC), breast cancer,

somewhat heterogeneous at first glance. On the one hand,

ovarian cancer, prostate cancer

some authors stress an increased reported survival benefit in

the literature and conclude that TACE should be implemented
Dexrazoxane can be used as cardio-protective medication in palliative patients

earlier in the treatment regimes after failed 1st and 2nd line
systemic therapy [50]. On the other hand, authors focus on the
Major indications

existing randomized trials only and concluded that no signif-

icant survival benefit or benefit on extrahepatic recurrence
was found for TACE in comparison to palliation [54]. These
authors also state that from their point of view TACE cannot
be recommended outside randomized clinical trials [54].
However, on second glance, the key points are similar in be-
175 mg/m2 body surface
Maximum single dose

tween most of the reviews. Authors state that the evolving

new TACE techniques have an appealing mode of action but
prospective clinical data from randomized trials is unfortu-
nately still lacking [30, 47, 50–54]. Toxicity and side effects
during and after the different types of TACE seem to be ac-
ceptable. In terms of oncologic long-term efficacy, however, it
is still unclear which approach—cTACE, DEB-TACE, or
DSM-TACE—is superior. In this context, standardization of
Table 2 (continued)

the interventional techniques as with DEB-TACE is mandato-

ry, and targeted drugs should be included in the treatment
regimes. Finally, based on the current data from the literature,
Paclitaxel

studies should implement TACE earlier on in the treatment

Type

regimes as opposed to a pure salvage approach [30, 47,

a
Langenbecks Arch Surg

Table 3 Embolic agents used for TACE

Product Material Type of TACE Sizes (μm)

(cTACE, DSM-TACE,
DEB-TACE)

Bead block (BTG, London, Great Britain) Polyvinyl alcohol (PVA) cTACE 100–300 or 300–500
Contour-SE (Boston Scientific, Malborough, PVA cTACE 45–150, 150–250, or 250–355
USA)
DC Bead (BTG, London, Great Britain) PVA loaded with irinotecan or DEB-TACE ≈75, 100–300, or 300–500
doxocubucin
EmboCept S (PharmaCept, Berlin, Germany) Starch DSM-TACE ≈50
EmboSphere (Merit Medical, South Jordan, Tris-acryl gelatin cTACE 40–120, 100–300, or 300–500
USA)
Embozene Microspheres (CeloNova Hydrogel core with a biocompatible cTACE 40, 75, 100, 250, or 500
BioSciences, San Antonio, USA) nanocoat consisting of Polyzene-F
Gelatine sponge (Spongostan; Johnson Gelatin cTACE Dependent on its formulation
& Johnson, New Brunswick, USA) (pieces of ≈500, ≈1000,
or ≈2000)
Gelfoam (Pfizer, NY, USA) Gelatin powder cTACE ≈50
HepaSphere (Merit Medical, South Jordan, PVA loaded with irinotecan or DEB-TACE 30–60, 50–100, 100–150, or 150–200
USA) doxocubucin
Lipiodol (Laboratoire Guerbet, Iodized poppy seed oil cTACE Dependent on its formulation
Aulnay-sous-Bois, France) (droplets of 15–200)
LifePearl (Terumo, Tokyo, Japan) Polyethylene glycol with sulfonide DEB-TACE 100, 200, or 300
bonding loaded with irinotecan
or doxocubucin
PVA (Cook, Bloomington, USA) PVA cTACE 90–180, 180–300, or 300–500
Spherex (Pharmacia AB, Stockholm, Sweden) Starch DSM-TACE ≈40
TANDEM (CeloNova BioSciences, San Hydrogel core with a biocompatible DEB-TACE 40, 75, or 100
Antonio, USA) nanocoat consisting of Polyzene-F
loaded with irinotecan or
doxocubucin

The smaller and the better size-calibrated the permanent embolic agents are, the more distal the vascular occlusion is, and the more effective the
therapeutic effects in terms of tumor penetration should be; however, the risk of bile duct ischemia, post-embolization syndrome, and non-target
embolization (e.g., via shunts) is also increased when the smallest particles are used. Iodized oil, gelatine sponge, and DSMs can be regarded as non-
permanent embolic agents with different recanalization times. For some embolic agents, the listed sizes change after preparation for transarterial use (e.g.,
increase or decrease of the nominal size after drug-load or dilution with iodinated contrast material) which has to be considered for the TACE strategy
TACE transarterial chemoembolization

50–53]. Especially the new DEB-TACE (DEBIRI) shows
very encouraging results, most likely due to the prolonged
intratumoral delivery of drugs combined with tumor
devascularization. In the vast majority of reported patients,
TACE is used in the 2nd line, and very often beyond, means
after failure of systemic therapy and surgery (since local or
systemic toxicity and/or tumor progression). To describe the
real efficacy of TACE in the 1st, 2nd, and 3rd line and beyond,
randomized controlled trials are urgently warranted.
The multi-disciplinary approach—TACE in combination
with systemic chemotherapy and/or surgery
According to our literature review, there are very few studies
reporting outcomes of patients with colorectal liver metastases
after TACE in combination with surgical resection. In the
1990s, Ceelen et al. performed the only controlled trial with
cTACE before resection [55]. In one group, 14 patients
underwent Bneoadjuvant^ cTACE before surgical resection
and in the control group, 9 patients were treated with liver
resection only. Reported overall survival and tumor recurrence
were 93 and 8 % (mean follow-up of 15.5 months) versus 67
and 67 % (mean follow-up of 17.5 months) in favor of the
Bneoadjuvant^ TACE approach. In this context, it is worth to
mention that cTACE was not associated with increased oper-
ating time, transfusion requirement, and peri-operative com-
plication rates. The authors concluded that Bneoadjuvant^
TACE reduces recurrence after curative liver resection in the
first post-operative year and may improve the overall survival.
A limitation of this study is the lack of randomization since all
treatments were indicated on an Bat random^ basis. Jones et al.
published two studies with DEB-TACE prior to surgical re-
section with a radiologic-pathologic correlation. In the first
study, a case-control series, three patients were treated with
DEB-TACE (DEBIRI; 200 mg irinotecan loaded in a particle
volume of 2 ml (particle size of 100–300 μm) (DC Bead;
Table 4 Original studies with TACE for colorectal liver metastases
Study/year/ Patients Therapy stage Extrahepatic Chemoembolics Tumor response (%) Progression-free Median 1-, 2-, 3-, 4-,
reference (n) (1st line, 2nd line, disease (%) (embolic agents + survival survival and 5-year
3rd line, beyond chemotherapeutics) (months) survival (%)
3rd line)

Ceelen et al./1996/[55] 14 versus 9a n.r. n.r. Lipiodol and gelfoam + cisplatin n.r. 92 % 15.5±12.5 93 versus 67b
(1 mg/kg body weight) 33.3 % 17.5±10 n.r.
n.r.
n.r.
n.r.
Tellez et al./1998/[33] 30 n.r. n.r. Bovine collagen material + n.r. n.r. 8.6 n.r.
cisplatin, doxorubicin, and n.r.
mitomycin C n.r.
n.r.
n.r.
Leichman et al./1999/ 31 n.r. n.r. Collagen suspension + doxorubicin, CR 1 8 months 14 85
[99] mitomycin C, and cisplatin PR 8 n.r.
(subsequent systemic therapy OR 29 n.r.
with continuous infusion of n.r.
5-fluorouracil and leucovorin) n.r.
Müller et al./2001/[100] 103 2nd linec n.r. Days 1–4: HAI 550 mg/m2 CR 2.7 7 months 17 n.r.
5-fluoro-uracil (trans-arterial; PR 32.4 8 months >28 (p=0.0095) n.r.
days 1–4) and 80 μg/m2 MR 21.6 n.r.
GM-CSF (transarterial; days 1 + 2) SD 12.7 n.r.
Day 5: TACE Lipiodol and NR 16.2 n.r.
Gelfoam+25 mg/m2 CR 1.0
melphalan versus days PR 42.4
1 + 2: HAI 1400 mg/m2 MR 24.2
5-fluoro-uracil (transarterial), SD 18.2
60 mg/m2 leucovorin NR 12.1
(intravenous) and 80 μg/m2
GM-CSF (transarterial)
Day 3: TACE Lipiodol and
Gelfoam+25 mg/m2 melphalan
Salman et al./2002/[101] 26 2nd line 36 PVA PR 15.4 n.r. Liver-only metastases n.r.
24 PVA and 750 mg/m2 5-fluoro-uracil PR 20.8 15 months (10–17) n.r.
and 9 million units interferon Extra-hepatic disease n.r.
8 months (6–10) n.r.
n.r.
Müller et al./2003/[38] 66 2nd lined Days 1 + 2: HAI 1400 mg/m2 CR 1.0 8 months >28 n.r.
5-fluoro-uracil (transarterial), PR 42.4 66d
60 mg/m2 rescuvolin MR 24.2 n.r.
(intravenous) and 80 μg/m2 SD 18.2 n.r.
GM-CSF (transarterial) NR 12.1 n.r.
Day 3: TACE Lipiodol and
Gelfoam+25 mg/m2 melphalan
Aliberti et al./2006/[102] 10 n.r. n.r. DEBIRI (100 mg irinotecan) n.r. n.r. n.r. n.r.
every 3 weeks n.r.
n.r.
n.r.
n.r.
Tsuchiya et al./2007/ 27 n.r. n.r. DSMs + irinotecan and 59 n.r. n.r. n.r.
[93] mitomycin C n.r.
20e
n.r.
n.r.
Langenbecks Arch Surg
Table 4 (continued)
Study/year/ Patients Therapy stage Extrahepatic Chemoembolics Tumor response (%) Progression-free Median 1-, 2-, 3-, 4-,
reference (n) (1st line, 2nd line, disease (%) (embolic agents + survival survival and 5-year
3rd line, beyond chemotherapeutics) (months) survival (%)
3rd line)

Martin et al./2009/[103] 30 2nd line n.r. DEBs (100–700 μm) 66 n.r. n.r. n.r.
n.r.
Langenbecks Arch Surg

n.r.
n.r.
n.r.
Martin et al./2009/[104] 55 2nd line n.r. DEBs (100–900 μm) EASL response (defined as 6.6 months 11.4 n.r.
CR, PR, and SD) 89 n.r.
(3 months), 80 (6 months), n.r.
and 54 (12 months) n.r.
RECIST response 71 n.r.
(3 months), 56
(6 months), and
40 (12 months)
Vogl et al./2009/[32] 463 2nd line n.r. Lipiodol and DSMs + mitomycin PR 14.7 n.r. 14 62
C alone (52.5 %), mitomycin SD 48.2 28
C and gemcitabine (33.0 %) PD 37.1 n.r.
or mitomycin C and irinotecan n.r.
(14.5 %) n.r.
Martin et al./2010/[105] 84 2nd line n.r. DEBs (100–700 μm) n.r. n.r. n.r. n.r.
n.r.
n.r.
n.r.
n.r.
Martin et al./2011/[42] 55 2nd line 55 DEBs (100–700 μm) EASL response CR 12 11 months 19 n.r.
(3 months), 12 (6 months), n.r.
and 15 (12 months) n.r.
RECIST response PR 53 n.r.
(3 months), 38 (6 months), n.r.
and 25 (12 months)
Aliberti et al./2011/[43] 82 2nd line DEBIRI n.r. 8 months (4–16) 25 months (6–34) n.r.
n.r.
n.r.
n.r.
n.r.
Albert et al./2011/[39] 121 2nd–6th line 46 Lipiodol and PVA (50–250 μm)+10 mg n.r. 3 (extrahepatic progression) TACE in the 2nd or 3rd 2nd line
mitomycin C, 50 mg doxorubicin, 5 (liver) line 9 (11–12) 41 %
and 100 mg cisplatin (in sterile TACE in the 4th line and 16 %
contrast (8.5 ml) diluted with beyond 6 (p=0.03) 3rd line
1.5 ml sterile normal saline 42 %
emulsified in a 1:1 ratio with 13 %
the Lipiodol) >3rd line
12 %
0%
Seki et al./2011/[87] 1 5th line n.r. DEBs (docetaxel) in combination n.r. n.r. n.r. n.r.
with HAI of cisplatin (20 mg) n.r.
n.r.
n.r.
n.r.
Fiorentini et al./2012/ 36 versus 38f n.r. n.r. DEBIRI n.r. 7 months (3–11) (extrahepatic 22 n.r.
[106] progression 13 months (21–23) n.r.
(10–16)) 15 n.r.
Table 4 (continued)
Study/year/ Patients Therapy stage Extrahepatic Chemoembolics Tumor response (%) Progression-free Median 1-, 2-, 3-, 4-,
reference (n) (1st line, 2nd line, disease (%) (embolic agents + survival survival and 5-year
3rd line, beyond chemotherapeutics) (months) survival (%)
3rd line)

4 months (3–5) (p=0.006) (12–18) n.r.

(extrahepatic progression (p=0.031) n.r.
9 months (5–13) (p=0.064))
Martin et al./2012/[107] 10 During the off week n.r. DEBIRI (100 mg irinotecan, CR 20 PR 80 n.r. 15 n.r.
of FOLFOX 100–300 μm) n.r.
n.r.
n.r.
n.r.
Jones et al./2013/[57] 22 Easily resectable n.r. DEBIRI n.r. 13.6 months n.r. n.r.
colorectal liver (4.7–22.5) n.r.
metastases were n.r.
treated with n.r.
TACE 4 weeks n.r.
prior to resection
Ghanaati et al./2012/ 45 2nd line n.r. Lipiodol + mitomycin and n.r. n.r. n.r. n.r.
[108] doxorubicin n.r.
n.r.
n.r.
n.r.
Eichler et al./2012/[109] 11 2nd line 0 DEBIRI (100–500 μm) n.r. 5.1 n.r. n.r.
n.r.
n.r.
n.r.
n.r.
Jones et al./2013/[56] 3 Easily resectable DEBIRI n.r. n.r. n.r. n.r.
CRLM were n.r.
treated with n.r.
TACE 4 weeks n.r.
prior to resection n.r.
Jones et al./2013/[110] 10 n.r. n.r. DEBIRI (200 mg irinotecan) n.r. n.r. n.r. n.r.
as part of PARAGON II n.r.
n.r.
n.r.
n.r.
Li et al./2013/[111] 15 n.r. n.r. Gelatin sponge + lobaplatin CR 6.7 n.r. n.r. n.r.
(50 mg) PR 73.3 n.r.
SD 20.0 n.r.
n.r.
n.r.
Narayanan et al./2013/ 28 n.r. n.r. DEBIRI CR 15 n.r. 13.3 n.r.
[112] PR 30 (6.8–19.8) n.r.
SD 20 n.r.
PD 35 n.r.
n.r.
Nishiofuku et al./2013/ 24 Beyond 2nd line n.r. DSMs + cisplatin powder n.r. 8.8 months 21.1 n.r.
[113] (4.1–13.5) (8.4–33.8) n.r.
n.r.
n.r.
n.r.
Gruber-Roth et al./2014/ 564 n.r. n.r. Lipiodol and DSMs + mitomycin PR 16.7 SD 48.2 PD 16.7 n.r. 14.3 62
[84] C (43.1 %), mitomycin 28
Langenbecks Arch Surg
Table 4 (continued)
Study/year/ Patients Therapy stage Extrahepatic Chemoembolics Tumor response (%) Progression-free Median 1-, 2-, 3-, 4-,
reference (n) (1st line, 2nd line, disease (%) (embolic agents + survival survival and 5-year
3rd line, beyond chemotherapeutics) (months) survival (%)
3rd line)

C and gemcitabine (27.1 %), 7

mitomycin C and irinotecan n.r.
Langenbecks Arch Surg

(15.6 %), or mitomycin n.r.

Cand irinotecan and cisplatin
(15.6 %)
Huppert et al./2014/[46] 29 Beyond 2nd line 35 DEBIRI (35–400 mg irinotecan) EASL response (defined as 5 months 8 n.r.
CR, PR, and SD) 72 % n.r.
(3 months), 32 % (6 months), n.r.
and 0 % (12 months) n.r.
RECIST response (defined as n.r.
CR, PR, and SD) 86 %
(3 months), 48 % (6 months)
and 8 % (12 months
Kekez et al./2014/[114] 7 n.r. n.r. DEBIRI n.r. n.r. n.r. n.r.
n.r.
n.r.
n.r.
n.r.
Akinwande et al./2014/ 22 versus 149g n.r. n.r. DEBIRI + capecitabine 3- and 6-month disease control n.r. 22 n.r.
[66] DEBIRI only rate not different between both n.r. 13 n.r.
study groups, 12-month disease (n.s.) n.r.
control better in DEB-TACE + n.r.
capecitabine versus DEB-TACE n.r.
only (p=0.03)

n.r. not reported, CR complete response, PR partial response, OR overall response, MR minor response, SD stable disease, NR no response, PD progressive disease, EASL European Association for the
Study of the Liver, RECIST Response Evaluation Criteria for Solid Tumors, DEBIRI drug-eluting beads loaded with irinotecan
a
TACE + surgery versus surgery alone
b
No statistically significant difference between the treatments
c
In 57 % of patients
d
In 54 % of patients
e
No statistically significant difference between chemonaive patients and patients pre-treated with any kind of systemic therapy
f
TACE versus systemic therapy
g
TACE + capecitabine versus TACE only
TACE transarterial chemoembolization
 Langenbecks Arch Surg

Table 5 Oral systemic chemotherapeutics as well as molecular substances as potential adjunct to TACE for colorectal liver metastases

Therapy Type Mechanism Use

Bevacizumab (Avastin, Roche, Basel, Switzerland) Molecular substance Anti-VEGFA Intravenous, transarterial
Capecitabine (Xeloda; Roche, Basel, Switzerland) Chemotherapy Prodrug of 5-fluoro-uracil, anti-metabolite Oral
Cetuximab (Erbitux, Imclone Systems, Molecular substance Anti-EGFR Intravenous, transarterial
Bristol Meyers Squibb, NY, USA)
5-fluoro-uracil Chemotherapy Anti-metabolite Oral
Leucovorin Chemotherapy Detoxicant for 5-fluoro-uracil Oral
Panitumamab (Vectibix, Amgen, Thousand Oaks, USA) Molecular substance Anti-EGFR Intravenous
Regorafenib (Stivarga; Bayer, Berlin, Germany) Molecular substance Anti-VEGF Oral

TACE transarterial chemoembolization

BTG, London, Great Britain)). The pathologic analysis of the
surgical specimen proved 0 % tumor viability for all targeted
liver metastases [56]. Interestingly, the further detected and
non-targeted liver metastases showed also a response: 2 in
the non-treated contralateral liver lobe (30 and 45 % tumor
viability, respectively) as well as 3 in the ipsilateral liver lobe
(0, 0, and 60 % tumor viability, respectively). Such data sup-
port the hypothesis that TACE has the potential to treat also
non-targeted liver metastases and micrometastases. In the sec-
ond study, 22 patients were treated with DEB-TACE (protocol
comparable with the first study) 4 weeks prior to liver resec-
tion [57]. Thereby, the overall disease-free survival was
13.6 months. The used radiological response criteria
(RECIST), however, were rated as ineffective for accurate
prediction of the pathologic response, and the clinical out-
come. Accordingly, new concepts for response assessment—
such as cone-beam CT, angio-CT, hybrid-imaging, and bio-
markers—should be implemented for clinical studies and set-
tings. Regarding conversion to resectability, Kemeny et al.
demonstrated impressively the potential of a combined

Fig. 2 Clinical case - DEB-TACE (DEBIRI) for recurrence after resec-
tion of colorectal liver metastases and failure of palliative systemic ther-
apy. Ten months after resection of multiple liver metastases (S II and VI)
from colorectal carcinoma, the patient developed recurrence within the
liver (a CT, arterial phase, transverse reconstruction); after significant
progression of the liver metastasis during palliative systemic therapy in
the 1st line, DEB-TACE (DEBIRI) was indicated as palliative 2nd line in
the interdisciplinary tumor board (b selective digital subtraction angiog-
raphy, late arterial phase; c cone-beam CT (DynaCT; Siemens,
Forchheim, Germany); d radiography of the tumor feeding arteries after
injection of 3-ml TANDEM (75 μm) loaded with 150-mg irinotecan
(CeloNova BioSciences, San Antonio, USA)). One day after DEB-
TACE, a non-enhanced CT (e transverse reconstruction) showed accu-
mulation of the chemoembolic within the liver metastasis; 10 days after
DEB-TACE, contrast-enhanced CT documented necrosis of the liver me-
tastasis (f CT, arterial phase, transverse reconstruction). To destroy also
satellites and micrometastases, two further DEB-TACE procedures were
indicated (images with permission of the Siemens European Reference
Site for Interventional Radiology and Oncology, Klinikum Stuttgart,
Stuttgart, Germany)
Langenbecks Arch Surg
strategy consisting of transarterial and systemic therapies
[58]. Fifty-three patients with primarily irresectable colorectal
liver metastases (53 % in the 2nd line or beyond) were treated
with 5-fluoro-deoxy-uridine and dexamethasone as HAI as
well as oxaliplatin and irinotecan as systemic chemotherapy.
Tumor response was 92 %, and the conversion rate was 47 %
in a group of high-risk patients (>5 liver metastases in 73 %,
bilobar disease in 98 %, ≥6 involved segments in 86 % of
patients). Multiple studies have shown the safe use of peri-
operative chemotherapy. For example, Nordlinger et al. dem-
onstrated that FOLFOX4 is compatible with major liver re-
section [59]. Basically, patient selection as well as timing,
dose, and type of the systemic therapy are the relevant pre-
dictors for the outcome. In controlled trials, the conversion
rate after systemic chemotherapy (FOLFOX, FOLFIRI, or
FOLFOXIRI) is published with 4–22 % [60]. In single-arm
studies, the conversion rate is listed with 10–33 % after
FOLFIRI (Douillard regimen), 40 % after FOLFOX4, and
82 % after FOLFIRINOX [61–65]. Akinwande et al. have
subsequently introduced the concept of DEB-TACE in com-
bination with oral systemic therapies [66]. In the controlled
trial, DEB-TACE plus oral capecitabine (Xeloda; Roche, Ba-
sel, Switzerland)—a prodrug of 5-fluoro-uracil—was com-
pared with DEB-TACE only. Although not statistically sig-
nificant, there was a prolonged survival (but no additional
toxicity) in patients undergoing the combined treatment com-
pared with patients undergoing DEB-TACE only (22 versus
13 months). Further available oral systemic
chemotherapeutics/molecular substances with relevance for
colorectal liver metastases are leucovorin, 5-fluoro-uracil,
and the anti-VEGF antibody regorafenib (Table 5). The
multi-disciplinary treatment strategy consisting of modern
DEB-TACE concepts, systemic therapies with low toxicity,
and dedicated surgical techniques may decrease the number
of recurrences and improve the overall survival without rele-
vant procedure-related adverse events. Figure 2 shows a clin-
ical case with DEB-TACE (DEBIRI) as salvage therapy in
the 2nd line. As presented, the data for TACE in combination
with surgical resection for colorectal liver metastases is still
very poor. On the basis of three published non-randomized
small mono-center series for Bneoadjuvant^ TACE with very
encouraging results, and a phase I study for HAI with a high
rate of conversion to resectability, randomized controlled
multi-center trial trials are now justified. Such trials should
also include TACE with and without systemic therapies
for the adjuvant setting after curative liver resection with
the aim to prevent recurrence and to improve the overall
survival. For optimization of the study design as well as
for adequate implementation and accomplishment of the
interventions and operations under consideration of the
multiple specific facets, the randomized controlled multi-
center trials require the leadership of oncologists, interven-
tional oncologists, and surgeons.
Conclusion
In the last few years, there is evidence of a significantly in-
creased use of repetitive TACE in patients with therapy-
refractory colorectal liver metastases. Emerging techniques
such as calibrated microspheres, DSMs, and DEBs now allow
performing TACE as a highly standardized setting. The ade-
quate chemotherapeutics and the adequate embolic agents can
be combined individually to obtain improved therapeutic ef-
fects (cytotoxic and ischemic tumor necrosis) in each patient.
In the vast majority of published studies, TACE is used either
in patients with failure in the 1st or 2nd line under study
conditions or in salvage patients with failure of multiple pre-
vious surgical, ablative, and/or systemic therapies. Although
the specific original studies with very encouraging results with
regard to safety and oncologic efficacy, there is a lack of ran-
domized controlled trials. TACE may be a valuable tool in the
neoadjuvant setting for downsizing and earlier for conversion
to resectability without systemic toxicities and adverse effects
on the surgical outcome or in the adjuvant setting after surgery
to prevent recurrence and to improve the overall survival. In
non-surgical candidates with liver-dominant metastases, palli-
ative TACE in combination with systemic therapy (chemo-
therapeutics and/or molecular substances with low toxicity)
should be evaluated. To determine the real efficacy of the
new TACE technologies for patients with colorectal liver me-
tastases in the 1st, 2nd, and 3rd line and beyond, randomized
controlled trials are now justified.
Conflicts of interest Götz M. Richter declares the following potential
conflicts of interest regarding this article: technical study support and
grants from Siemens Medical Solutions. Hans U. Kauczor declares the
following potential conflicts of interest: consultant, honorars, grants, and
advisory boards for Siemens Medical Solutions, Boehringer Ingelheim,
Bayer, Novartis, Almirall, and GlaxoSmithKlein. Philippe L. Pereira de-
clares the following potential conflicts of interest regarding this article:
consultant, honorars, grants, and advisory boards for Terumo,
Pharmacept, Celonova BioSciences, Bayer, Microventure, BTG, and Sie-
mens Medical Solutions. Christof M. Sommer declares the following
potential conflicts of interest regarding this article: technical study support
and grants from Celonova BioSciences, PharmaCept, and Siemens Med-
ical Solutions. All other authors declare that there is no conflict of interest
regarding this article.
Human and animal rights and informed consent This article does
not contain any studies with human participants or animals performed by
any of the authors. Informed consent is not applicable for this study.
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