CLINICAL STUDY

Transarterial Chemoembolization with Irinotecan

Beads in the Treatment of Colorectal Liver
Metastases: Systematic Review
Arthur J. Richardson, MBBS, FRACS, Jerome M. Laurence, MBChB, MRCS,
PhD, FRACS, and Vincent W.T. Lam, MBBS, MS, FRACS

ABSTRACT

Purpose: For patients with unresectable colorectal liver metastasis (CRLM), transarterial embolization with the use of drug-
eluting beads with irinotecan (DEBIRI) represents a novel alternative to systemic chemotherapy or local treatments alone. The
present systematic review evaluates available data on the efficacy and safety of DEBIRI embolization.
Materials and Methods: A comprehensive search of medical literature identified studies describing the use of DEBIRI in the
treatment of CRLM. Data describing adverse events, pharmacokinetics, tumor response, and overall survival were collected.
Results: Five observational studies and one randomized controlled trial (RCT) were reviewed. A total of 235 patients were
included in the descriptive analysis of observational studies. Postembolization syndrome was the most common adverse event.
Peak plasma levels of irinotecan were observed at 1–2 hours after administration. Wide variations in tumor response were
observed. The median survival time ranged from 15.2 months to 25 months. In the RCT, treatment with DEBIRI was superior
to systemic chemotherapy with 5-fluorouracil/leucovorin/irinotecan in terms of quality of life and progression-free survival.
Conclusions: For patients with unresectable CRLM, particularly after failure to respond to first-line regimens, DEBIRI
represents a novel alternative to systemic chemotherapy alone, transarterial embolization with other agents, or other local
treatments (eg, microwave or radiofrequency ablation). In these reports, DEBIRI was safe and effective in the in the treatment
of unresectable CRLM. Further RCTs comparing DEBIRI with alternative management strategies are required to define the
optimal role for this treatment.

ABBREVIATIONS

CR = complete response, CRLM = colorectal liver metastasis, DEB = drug-eluting bead, DEBIRI = drug-eluting beads
with irinotecan, 5-FU = 5-fluorouracil, FOLFIRI = 5-fluorouracil/leucovorin/irinotecan, FOLFOX = 5-fluorouracil/leucovorin/
oxaliplatin, OS = overall survival, PFS = progression-free survival, PR = partial response, QoL = quality of life, RCT = randomized
controlled trial, SD = standard deviation

Colorectal cancer is the third most common cancer
worldwide (1). Synchronous colorectal liver metastases
(CRLMs) will be present at the time of diagnosis in
15%–20% of patients, and another 50% of patients will
develop metachronous CRLM (2). Nevertheless,
From the Department of Surgery, Westmead Hospital, Wentworthville; and
Discipline of Surgery, University of Sydney, Sydney, Australia. Received
February 16, 2013; final revision received May 15, 2013; accepted May 22,
2013. Address correspondence to A.J.R., Department of Surgery, West-
mead Hospital, 106b/151 Hawkesbury Rd., Wentworthville, NSW 2145,
Australia; E-mail: aj.richardson@bigpond.com
None of the authors have identified a conflict of interest.
& SIR, 2013
J Vasc Interv Radiol 2013; 24:1209–1217
http://dx.doi.org/10.1016/j.jvir.2013.05.055
although the liver is the sole site of metastatic disease
in as many as 40% of patients, CRLM is resectable in
fewer than 20% of cases (3). Until the past decade,
5-fluorouracil (5-FU) and leucovorin were the stan-
dard chemotherapy for unresectable CRLMs, and this
doubled median survival to approximately 12 months
(4). The use of irinotecan and oxaliplatin have improved
median survival times to approximately 20 months (5),
with a small additional benefit from the addition of
biologic agents such as bevacizumab and cetuximab
(6,7). Nevertheless, many patients are unable to undergo
surgery and have to be treated with other techniques.
Transarterial chemoembolization, combines injection
of drug and embolic material and has mostly been used
in hypervascular tumors such as hepatocellular carci-
noma and neuroendocrine liver metastases (8,9). The use
1210 ’ Irinotecan Beads in Colorectal Liver Metastases
of drug-eluting beads (DEBs), which can be loaded with
irinotecan, allows drug release after the DEBs are
trapped in the tumoral circulation, and was first reported
for the treatment of CRLM in 2006 (10). Although DEB
with irinotecan (DEBIRI) therapy is not currently
approved by the United States Food and Drug
Administration, there is an increasing body of data
from clinical trials. In the present systematic review,
we aim to evaluate the available data on the efficacy and
safety of DEBIRI in the treatment of CRLM.
MATERIALS AND METHODS
Literature Search Strategy
A systematic review was conducted by two authors (A.J.R.
and V.L.). The following electronic databases were
searched: Medline (1950–2012), Embase (1974–2012), the
Cochrane controlled trials register, and the science citation
index. Combinations of Medical Subject Headings as well
as key words including the following were searched: “liver
metastases,” “colorectal cancer,” “chemoembolization,”
“drug-eluting beads,” “DEBIRI,” and “irinotecan.” The
literature search was not restricted by language but was
restricted to human trials. The last search was done
September 25, 2012, and a manual search of all relevant
articles was performed.
Study Selection
The study evaluation was performed by two reviewers
(A.J.R. and V.L.). Reviews, case reports, conference
abstracts, and nonhuman studies were excluded. Abstracts
of the remaining studies were retrieved and then reviewed
for relevance. The full texts of previously selected articles
Potentially relevant records identified and
study abstracts screened for retrieval
n = 249
Full text articles assessed for eligibility
n = 13
Studies included in qualitative analysis
n=6
Studies included in quantitative analysis
n=5
Figure. Flowchart showing the search strategy used to identify studies. (Available in color online at www.jvir.org.)
Richardson et al ’ JVIR
were thoroughly reviewed. Studies from which a decision
could not be made based on the abstract were also reviewed.
When multiple publications were identified from the same or
overlapping patient series, only the most complete or recent
publication was included.
Data Extraction and Critical Appraisal
Two reviewers (A.J.R. and V.L.) independently
appraised each article to extract a predefined dataset
that included the dates during which the treatment was
conducted, the details of the metastatic colorectal cancer
(including size, location in the liver, and extrahepatic
disease), other treatment (including chemotherapy and
surgery), nature of DEBIRI (DEBs used, preparation,
dose and number of sessions), adverse events, treatment
response, survival, and pharmacokinetics. The extracted
data were then cross-checked between the two authors to
rule out discrepancy. In the event of disagreement, a
third reviewer (J.L.) extracted the data. Because of the
lack of a control group in the majority of the included
reports and the heterogeneity present among the selected
studies, a metaanalysis could not be carried out. Qual-
itative systematic review was performed without com-
parator group by full tabulation of the results.
RESULTS
The search strategy is depicted in the Figure. The
publication by Morise et al (11) had only four patients
with incomplete follow-up data and was therefore
excluded from analysis. After exclusion of dual publica-
tions (10,12–17), there were six studies included in the
review (Table 1) (14,15,17–20). The inclusion and exclusion
237 articles excluded for
irrelevance, case reports etc
7 articles excluded as
irrelevant, reviews or dual
publications
 Volume 24
’
Table 1 . Summary of Published Studies Available for Analysis (14,15,17–20)

Number 8
Previous Systemic Tumor Response
Study, Year No. of Pts. Age (y) Inclusion Criteria Exclusion Criteria Chemotherapy Median OS at 6 mo Adverse Events
Eichler et al 11 64 (45–85)* 1–8 unresectable Extrahepatic In 5 pts. NS Intrahepatic Total n ¼ 41†;

’
August
(20), 2012 metastases confined to metastases; tumor progression at 6 pain (63%),
liver; ECOG PS ≤ 1, life involving 4 30% of mo (n ¼ 7), SD nausea (22%),
expectancy 4 6 mo, liver volume; (n ¼ 2), PR (n ¼ 2) vomiting (19.5%);

’
adequate liver/renal/ contraindications to 61% mild, 31%

2013
hematologic function irinotecan; active moderate
bacterial, viral, or
fungal infection;
concurrent
malignancy;
malignancy in past
5y
Martin et al 10 63 (48–84)‡ ≥ 1 measurable liver Eligible for curative None for metastatic 15.2 mo (range, CR (n ¼ ); DOD (n Total n ¼ 99; 98
(18), 2012 metastasis 4 1 cm; treatment (resection disease 6.5–45.5 mo); 4 ¼ 1), not grade 1/2§;
liver-dominant disease or RF ablation) pts. underwent assessed (n ¼ 1) hypertension
(≥ 80% tumor body liver resection (80%), abdominal
burden confined to pain (40%),
liver), o 60% liver nausea (40 %);
replacement by tumor, grade 3 (n ¼ 1
patent main PV, ECOG admission with
PS ≤ 2, life expectancy hypertension)
4 3 mo
Vogl et al 77 61 (36–78)* Unresectable liver Extrahepatic All patients 22.5 mo (range, NS All grade 1/2§
(19), 2012 (irinotecan metastasis, surgical metastases, tumor (oxaliplatin) 7–70 mo), some
and contraindications/ load 4 70% of liver, pts. with residual
mitomycin) refusal; adverse poor general lesions treated
reaction/lack of condition (Karnofsky with laser
response to systemic PS 4 70%), poor thermotherapy
chemotherapy liver/renal function,
ascites, partial/
complete PV throm-
bosis, respiratory/
cardiovascular

1211
failure

(Continued )
 1212
Table 1 . Summary of Published Studies Available for Analysis (14,15,17–20) (continued )

’
Previous Systemic Tumor Response

Irinotecan Beads in Colorectal Liver Metastases

Study, Year No. of Pts. Age (y) Inclusion Criteria Exclusion Criteria Chemotherapy Median OS at 6 mo Adverse Events
Martin et al 55 60 (34–82)‡ Confirmed diagnosis of NS FOLFOX and 19 mo CR (n ¼ 7); PR Total n ¼ 28; 21
(17), 2011 liver-dominant bevacizumab alone (n ¼ 21); SD grade 1/2§; grade
metastatic CRC, defined (n ¼ 17); FOLFOX (n ¼ 19); PD ≥ 3 (n ¼ 7; liver
previous chemotherapy and bevacizumab, (n ¼ 8); DOD dysfunction, n ¼
and reasons for FOLFIRI, cetuximab (n ¼ 5) 3; cholecystitis,
abandoning it (n ¼ 14); ≥ 3 anorexia,
regimens (n ¼ 14) myocardial
infarction causing
death, n ¼ 1 each)
Aliberti 82 61.8 Histologically proven ECOG PS o 2, ≥ 2 lines of systemic 25 mo (range, NS Grade 3§ pain
et al (14), (46–82)* liver metastasis; nutritional chemotherapy with 6–34 mo); 2 pts. (n ¼ 20); grade 1/
2011 primary resected or impairment, poor PD/no response treated with liver 2 events NS
unresectable liver liver/renal function, resection free of
disease; liver-dominant ascites, PV disease at 14 and
tumor (25%–50% of thrombosis 18 mo
liver replaced)
Fiorentini 36 64 (44–77)* Histologically proven Previous liver RT, ≥ 2/3 lines of NS NS Total n ¼ 77
et al (15), unresectable liver embolization, systemic grade 2/3§: pain
2012 metastasis occupying ascites, poor liver/ chemotherapy (30%), vomiting
o 50% of liver renal function (25%), asthenia
parenchyma, no (20%)
extrahepatic disease

CR ¼ complete response, CRC ¼ colorectal cancer, DOD ¼ death of disease, ECOG ¼ Eastern Cooperative Oncology Group, FOLFIRI ¼ 5-fluorouracil/leucovorin/irinotecan, FOLFOX ¼
5-fluorouracil/leucovorin/oxaliplatin, NS ¼ not specified, OS ¼ overall survival, PD ¼ progressive disease, PR ¼ partial response, PS ¼ performance status, PV ¼ portal vein, RF ¼
radiofrequency, RT ¼ radiation therapy, SD ¼ stable disease.
*
Mean (range).
†
Events coded per Medical Dictionary for Regulatory Activities terminology for reporting adverse events.
‡
Median (range).
§
Adverse events graded per Common Terminology Criteria for Adverse Events, version 3.

Richardson et al
’
JVIR
Volume 24 ’ Number 8 ’ August ’ 2013 1213

BSA ¼ body surface area, DC ¼ DC/LC Bead (Biocompatibles, Farnham, United Kingdom), DEBIRI = drug-eluting beads with irinotecan, 5-FU ¼ 5-fluorouracil, FOLFOX ¼ 5-fluorouracil/
criteria for treatment, along with the use of previous

Mean (median)
Sessions per
systemic chemotherapy, are noted in Table 1. With the

2.8 (2.5)

2.3 (2.2)
Patient

1.8 (2)
4 (4)

2 (2)
3.2
exception of one study (18), all patients had received one
or more lines of systemic chemotherapy before being
treated with DEBIRI. DEBIRI was administered as
monotherapy in all but two studies, both by Martin

Dose per Session

150 mg/m2 BSA

et al (17,18). There were five observational studies and

Mean (Median)
one randomized trial (15). The latter was analyzed

(mg)

100

100

156
200
73
separately, leaving a total of 235 patients included in
the descriptive analysis of observational studies.
Technical aspects of DEBIRI (dosage of irinotecan,
DEB preparation, and treatment schedule) are summa-
rized in Table 2 (14,15,17–20). The technical aspects of

Mean Total
Dose (mg)
embolization (initial angiography, selection of emboliza-

293

280

185

352
400
NS
tion target, and embolization endpoint) are summarized
in Table 3 (14,15,17–20).

Concentration
Adverse Events

Irinotecan

(ng/mL)
Adverse events were reported in all studies (14,15,

NS
50

50

25

50
50
17–20). Common Terminology Criteria for Adverse
Events, version 3, were used in all but one study (14,15,

leucovorin/oxaliplatin, NS ¼ not specified, SM ¼ starch microsphere (EmboCept; Pharmacept, Berlin, Germany).

*Standard chemotherapy with FOLFOX6 with bevacizumab at the discretion of the treating medical oncologist.
17–19). Eichler et al (20) used the Medical Dictionary

300–500 and 500–700

100–300 and 300–500
100–300; 300–500;
100–300; 300–500;
100–300, 300–500
for Regulatory Activities terminology for reporting of

Bead Size (μm)

adverse events. The adverse events are summarized in

100–300

100–300
Table 1. There was one death related to the procedure,

NS
which resulted from a myocardial infarction. Post-
embolization syndrome, which involved abdominal
pain, nausea, and vomiting, was the most common
adverse event reported. This was reported as mild in
Bead Type

the studies of Eichler et al (20) and Martin et al (17,18)

Table 2 . Technical Aspects of DEBIRI Treatment in Published Studies (14,15,17–20)

SM
DC

DC

DC

DC
DC
and made up 40%–63% of adverse events. In the study of
Aliberti et al (14), abdominal pain was reported as pre-
sent within 6 hours of the procedure in 40% of patients

Fiorentini et al (15), 2012 Bead monotherapy; 2 doses at 1-mo intervals

and was reported as severe in 25% of patients. In the
Concurrent chemotherapy with capecitabine

study by Vogl et al (19), it was stated that mild abdo-

Standard chemotherapy* on days 0/14,

Bead monotherapy; repeated with ≥ 3

or infusional 5-FU in 16 of 55 pts

minal pain was the most common adverse event

sessions at 4 weekly intervals

reported, but the percentage was not defined.

DEBIRI every 3 wk (≤ 4

DEBIRI on days 7/21

Hypertension was the second most common adverse

Treatment Protocol

Bead monotherapy

event reported. It seems most likely that hypertension was

treatments)

related to pain (the most common complication), as it was

transitory with a temporal coincidence during the post-
procedural course. Its incidence was not reported in the
paper by Vogl et al (19). In the paper by Aliberti et al (14),
it was reported as not occurring in the first 24 hours after
the procedure. Eichler et al (20) reported hypertension as
making up less than 10% of adverse events, and Martin
et al (17,18) reported hypertension as making up 4% of
adverse events. Martin et al (17,18) reported that hyper-
tension made up 80% of adverse events. One patient in
Aliberti et al (14), 2011
Eichler et al (20), 2012

Martin et al (18), 2012

Martin et al (17), 2011

this series required an overnight hospital stay for severe

Vogl et al (19), 2012
Study, Year

hypertension. There was one device-related infection

reported, but no episodes of significant bleeding.

Pharmacokinetics
The pharmacokinetics of DEBIRI were evaluated in the
two of the smaller studies (18,20). Eichler et al (20)
1214 ’ Irinotecan Beads in Colorectal Liver Metastases Richardson et al ’ JVIR

(complete stasis of blood) was achieved before full dose

performed until stasis observed; stasis confirmed via

showed that the plasma half-life of irinotecan was 1.6–

In all patients, vascular occlusion with microspheres

Infusion of beads stopped if embolization endpoint

delivery; no additional embolic agent to achieve

7.2 hours (mean, 4.6 h), with a half-life of 7.6–8.5 hours

Beads infused slowly in 5 min; assessment of

(mean, 12.4 h) for its metabolite SN-38. Martin et al (18)
reported that the plasma levels of irinotecan and SN-38
had mostly cleared by 4 hours, with essentially undetect-
Embolization Endpoint

As Martin et al (18)
able levels at 24 hours. Both studies (18,20) reported that

endpoint NS
the peak plasma levels were seen at 1–2 hours after

angiography
endpoint

administration. Significantly, neither study reported any

NS

NS
toxicity directly relatable to irinotecan administration.

Tumor Response
In four studies (14,17,19,20), the Response Evaluation
Criteria In Solid Tumors (21) were used to evaluate the
efficacy of treatment. Response rates at 6 months are
summarized in Table 1. Eichler et al (20) reported that,
6 months following initial treatment, seven of the initial
11 patients (63%) had intrahepatic progression of
Segmental/subsegmental embolization technique; no

Lobar/highly selective administration lesion feeding

disease. They described a partial response (PR) to

Superselective technique distal to cystic artery

patient underwent global chemoembolization

treatment in two patients (18%), and stable disease was

Lobar/segmental embolization technique

reported in two patients (18%). Vogl et al (19) reported

Selection of Embolization Target

Lobar embolization technique

in close proximity to lesions

that the mean diameter of the liver metastases before

treatment was 3.49 cm (range, 1.3–7.3 cm; standard
As Martin et al (18)

deviation [SD], 1.41), which decreased to 2.92 cm (range,

branches

1–5 cm; SD, 1.41) after the final treatment. This

represented a decrease of 16.3%, which was statistically
significant (P o .001). Martin et al (17), in their group of
55 patients who had been heavily pretreated with
systemic chemotherapy, reported a 3-month complete
Table 3 . Technical Aspects of Embolization Techniques in Published Studies (14,15,17–20)

response (CR) in seven patients (12%) and a PR in 29

patients (53%). A 6-month CR was reported in seven
patients (12%) and a PR in 21 patients (38%). At 12
months, a CR was seen in eight patients (15%) and a PR
in 14 patients (25%). The authors made the point that, if
Introduction of selective catheter through femoral

HA ¼ hepatic artery, GDA ¼ gastroduodenal artery, NS ¼ not specified.

mesenteric angiography to check accessory right

a response was achieved at 6 months, it appeared to be

HA; 4-/5-F Cobra catheter placed in celiac trunk,
Diagnostic angiogram obtained to evaluate HA

4-/5-F pigtail catheter through femoral vessels;

artery; vascular anatomy of HAs determined;
Initial angiogram obtained through femoral/
axillary artery puncture to identify origin of

durable to 12 months (17). Aliberti et al (14) reported

that all 82 patients treated showed a significant (75%–
supply and verify portal patency

catheter advanced beyond GDA

Initial Angiography Technique

100%) reduction of metastatic contrast enhancement at

advanced beyond GDA

1 month. A therapeutic response was noted in 78% of

As Martin et al (18)

patients at 3 months. Additionally, they reported that

right/left HA

75 of 82 patients (90%) declared a general improvement

NS

in quality of life (QoL), which lasted 32 weeks (range,

3–39 wk) (14). In the latest study by Martin et al (18),
four of 10 patients underwent liver resection, at which
time pathologic response rates were reported as being
greater than 95%. It is important to remember that this
group of patients was also receiving 5-FU/leucovorin/
oxaliplatin (FOLFOX). The authors reported overall
response rates of 100% at 3 months, 80% at 6 months,
60% at 9 months, and 50% at 12 months (18).
Fiorentini et al (15), 2012
Aliberti et al (14), 2011
Eichler et al (20), 2012

Martin et al (18), 2012

Martin et al (17), 2011

Vogl et al (19), 2012
Study, Year

Overall Survival
Median survival (Table 1) was estimated in four studies
(14,17–19) and ranged from 15.2 months to 25 months
(range, 6–70 mo). Eichler et al (20) calculated the proba-
bility of disease progression by using the Kaplan–Meier
method. They reported a median time to progression from
Volume 24 ’ Number 8 ’ August ’ 2013
the time of the first treatment of 154 days (95% con-
fidence interval, 17–291 d). Additionally, Martin et al
(17), in a group of 55 patients, reported a median
progression-free survival (PFS) of 11 months, with 55%
of patients being alive at 1 year. For those patients with
liver-only disease, the PFS was 15 months, which
equated to a 1-year overall survival (OS) rate of 75%.
This was the same as the OS for the entire patient
cohort, including patients with liver-only disease and
those with extrahepatic disease.
Randomized Trial
In the randomized controlled trial (RCT) trial by
Fiorentini et al (15), 74 patients were randomized to
receive two cycles of DEBIRI treatment (n ¼ 36) or
eight cycles of 5-FU/leucovorin/irinotecan (FOLFIRI)
systemic chemotherapy (n ¼ 28). The patient groups
were comparable in terms of demographics, disease
extent, and previous treatment. All patients had histo-
logically confirmed unresectable colorectal metastasis,
confined to the liver and occupying less than 50% of its
volume. They had all received at least two or three lines
of systemic chemotherapy before DEBIRI treatment.
The OS rates at 24 months and 30 months, respectively,
were 56% and 34% for the DEBIRI group versus 32%
and 9% for the FOLFIRI group (P ¼ .031). Median
survival and PFS were 22 and 7 months, respectively, in
the DEBIRI group, versus 15 and 4 months in the
FOLFIRI group (15).
Toxicity varied significantly between the two groups.
Neutropenia was seen in 4% of patients in the DEBIRI
group versus 44% in the FOLFIRI group (P o .0001),
diarrhea occurred in 6% of the DEBIRI group versus
18% of the FOLFIRI group (P ¼ .073), and mucositis
occurred in 1% of the DEBIRI group versus 20% of the
FOLFIRI group (P ¼ .00002). The only toxicity more
common in the DEBIRI group was pain (30% vs 0% in
FOLFIRI group). The authors concluded that, in terms
of OS, PFS, and QoL, treatment with DEBIRI was
statistically superior to FOLFIRI (15).
DISCUSSION
Surgical resection of CRLM remains the most effica-
cious treatment, with 5-year survival rates ranging from
29% to 70% (22,23). However, surgical resection is
possible in only approximately 25% of patients. Even
in patients who have undergone resection, the recurrence
rate can be as high as 75% (24). Therefore, there remains
a need for palliative treatments and therapies that can
downstage disease to the extent of resectability.
The results of the present systematic review suggest
that DEBIRI treatment may be associated with a
median survival time of 15–25 months. This is broadly
equivalent to the outcomes achieved for unresectable
CRLM with the use of best-practice systemic chemotherapy
1215
(5). Significantly, conventional first-line chemotherapy
had failed in the majority of patients included in this
review. However, there appeared to be an improvement
in disease-free survival associated with DEBIRI. Based
on Response Evaluation Criteria In Solid Tumors, the
PR and CR rates varied from 36% to 78%. Moreover, it
appeared that, in those patients who had a response at
6 months, this was a durable response to 12 months.
Chemoembolization with the use of modern angio-
graphic techniques make it possible to selectively deliver
the material to the tumor so there is minimal release of
chemotherapy agents into surrounding tissues (25).
Moreover, the procedure can be repeated and is asso-
ciated with minimal morbidity. Two of the studies
reviewed (18,20) showed that plasma levels of irinotecan
and its active agent SN-38 were almost undetectable 24
hours after administration, despite these investigators’
having been able to deliver doses of irinotecan many
times the systemic toxic dose.
Adverse events are uncommon with DEBIRI. The
most common appears to be postembolization syn-
drome. Hypertension appears to be the second most
common adverse event, but is self-limiting. In the present
review, adverse events in the more serious category were
rare, with only one death reported as a result of a
myocardial infarction. In a review of 2,300 transarterial
chemoembolization procedures for a variety of indica-
tions, Sakamoto et al (26) reported 102 complications
(4.4%), of which 39 were related to catheter dissections
or perforations.
There was only one comparative study included in the
present review (15). Although patients were randomly
allocated to treatment groups, there was no information
regarding the methods of sequence generation, blinding (of
participants or those conducting outcomes assessments),
or allocation concealment. There was little information
regarding methods used to ensure the quality of outcome
data reporting or freedom from selective reporting of
outcomes. Despite the fact that the study (15) included
only a small number of participants, DEBIRI was found
to be significantly superior to FOLFIRI in terns of OS,
PFS, QoL, toxicity, and financial cost. However, because
of deficiencies in the methodologic quality of the study, the
conclusions must be interpreted with caution. Confir-
mation of these data in high-quality RCTs is required
before widespread change of practice is undertaken.
The role of DEBIRI as a strategy for downstaging
unresectable CRLM with a view toward resection is
unclear. There is increasing evidence that patients whose
disease is rendered resectable after chemotherapy may
have a survival equivalent to those patients whose
disease was initially resectable (27,28). A recent system-
atic review of conversion chemotherapy for CRLMs (29)
concluded that an objective response was achieved in
64% of cases, and that 22.5% of patients underwent
macroscopically curative resection. Bower et al (16)
looked specifically at the effect of DEBIRI on surgical
1216 ’ Irinotecan Beads in Colorectal Liver Metastases
downstaging and found that 11 of 55 patients (20%)
were able to be treated with liver resection or ablation.
With a median follow-up of 12 months, nine patients
had recurrence. In this cohort (16), the median disease-
free interval was 9 months (range, 6–18 mo), with 80% of
recurrences being extrahepatic. The overall pathologic
response rate was 90% (range, 30%–90%). In a separate
series of 10 patients reported by Martin et al (4), disease
subsequently became resectable. A greater than 95%
pathologic response was seen in this group (18), with the
added benefit that none of these patients developed
significant steatohepatitis. On this basis, a reasonable
approach for treatment with a view to downstaging of
disease would be systemic chemotherapy with FOLFOX
(with or without the addition of bevacizumab) combined
with DEBIRI. Although the main concern with this
approach would be hepatic toxicity, it is likely that this
would be no greater than that of FOLFOX and
bevacizumab alone.
QoL is an important issue for all patients with cancer,
but particularly in those whose disease is not curable and
who are undergoing palliative treatment. It does appear
that DEBIRI is well tolerated and has few side effects.
Fiorentini et al (15) found a significantly improved
QoL for patients undergoing DEBIRI treatment
versus those undergoing treatment with FOLFIRI. The
difference in duration of improvement significantly
favored DEBIRI. This group also addressed the issue
of cost. They compared the cost of two treatments with
DEBIRI (including interventional radiology) to that of
commonly used systemic alternatives. Six months of
treatment with FOLFOX and bevacizumab, 6 months
of treatment with FOLFIRI, and 6 months of treatment
with FOLFIRI and cetuximab cost 11.3, 4.5, and 10.9
times as much as DEBIRI, respectively.
Among the studies analyzed here, there was consid-
erable variability in the efficacy and toxicity outcomes
reported. This heterogeneity is likely a consequence not
only of differences in the dose of irinotecan per treatment
and the number of treatment sessions per patient, but
also outcome assessments and quality of reporting. All
but one study in this review was observational with no
direct comparator group, and the RCT included (15) was
of poor methodologic quality. Systematic investigation of
the optimal treatment protocol in comparison with other
available options will be an essential element of further
studies of DEBIRI treatment.
Another emerging therapy for the treatment of
unresectable liver metastases is the use of yttrium-90
(90Y)–loaded microspheres. These microspheres, made
of resin or glass, are embolized via the hepatic artery and
deliver localized high-dose radiation (30). This type of
therapy does involve more planning—particularly with
regard to radiation dose—and intervention than
DEBIRI, and delivers brachytherapy rather than chemo-
therapy (31,32). There are a number of nonrandomized
observational studies of 90Y with or without chemotherapy
Richardson et al ’ JVIR
(33,34), which have reported a median OS of 10–29
months, not significantly different that the survival times
reported with the use of systemic chemotherapy alone.
We are aware of only one prospective trial of 90Y as
salvage therapy for disease refractory to modern chemo-
therapy with oxaliplatin and irinotecan (35). In this
small study, there was no significant difference in OS
between the two groups, although there was some
improvement in time to progression in the 90Y group
(35). As there are no data comparing 90Y versus
DEBIRI for unresectable CRLM, this question
requires further research.
The present systematic review suggests that DEBIRI
can provide a median survival equivalent to that asso-
ciated with standard systemic chemotherapy, and may
also be useful in downstaging unresectable CRLM to
resectable status with minimal toxicity and acceptable
cost. DEBIRI treatment merits further study in larger
multicenter trials to define its optimal indications.
REFERENCES
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002.
CA Cancer J Clin 2005; 55:74–108.
2. Donadon M, Ribero D, Morris-Stiff G, Abdalla EK, Vauthey JN. New
paradigm in the management of liver-only metastases from colorectal
cancer. Gastrointest Cancer Res 2007; 1:20–27.
3. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM.
Epidemiology and management of liver metastases from colorectal
cancer. Ann Surg 2006; 244:254–259.
4. Thirion P, Michiels S, Pignon JP, et al. Modulation of fluorouracil by
leucovorin in patients with advanced colorectal cancer: an updated meta-
analysis. J Clin Oncol 2004; 22:3766–3775.
5. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled
trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combina-
tions in patients with previously untreated metastatic colorectal cancer.
J Clin Oncol 2004; 22:23–30.
6. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus
irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.
N Engl J Med 2004; 350:2335–2342.
7. Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of
cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure
in patients with metastatic colorectal cancer. J Clin Oncol 2008; 26:
2311–2319.
8. Bruix J, Sherman M. Practice Guidelines Committee, American Asso-
ciation for the Study of Liver Diseases. Management of hepatocellular
carcinoma. Hepatology 2005; 42:1208–1236.
9. Yao KA, Talamonti MS, Nemcek A, et al. Indications and results of liver
resection and hepatic chemoembolization for metastatic gastrointestinal
neuroendocrine tumors. Surgery 2001; 130:677–682.
10. Aliberti C, Tilli M, Benea G, Fiorentini G. Trans-arterial chemoembolization
(TACE) of liver metastases from colorectal cancer using irinotecan-eluting
beads: preliminary results. Anticancer Res 2006;26:3793–2795.
11. Morise Z, Sugioka A, Kato R, Fujita J, Hoshimoto S, Kato T. Transarterial
chemoembolization with degradable starch microspheres, irinotecan, and
mitomycin-C in patients with liver metastases. J Gastrointest Surg 2006;
10:249–258.
12. Fiorentini G, Aliberti C, Turrisi G, et al. Intraarterial hepatic chemo-
embolization of liver metastases from colorectal cancer adopting
irinotecan-eluting beads: results of a phase II clinical study. In Vivo
2007; 21:1085–1091.
13. Fiorentini G, Aliberti C, Benea G, et al. TACE of liver metastases from
colorectal cancer adopting irinotecan-eluting beads: beneficial effect of
palliative intra-arterial lidocaine and post-procedure supportive therapy on
the control of side effects. Hepatogastroenterology 2008; 55:2077–2082.
14. Aliberti C, Fiorentini G, Muzzio PC, et al. Trans-arterial chemoemboliza-
tion of metastatic colorectal carcinoma to the liver adopting DC Bead(R),
Volume 24 ’ Number 8 ’ August ’ 2013
drug-eluting bead loaded with irinotecan: results of a phase II clinical
study. Anticancer Res 2011; 31:4581–4587.
15. Fiorentini G, Aliberti C, Tilli M, et al. Intra-arterial infusion of irinotecan-
loaded drug-eluting beads (DEBIRI) versus intravenous therapy (FOLFIRI)
for hepatic metastases from colorectal cancer: final results of a phase III
study. Anticancer Res 2012; 32:1387–1395.
16. Bower M, Metzger T, Robbins K, et al. Surgical downstaging and neo-
adjuvant therapy in metastatic colorectal carcinoma with irinotecan drug-
eluting beads: a multi-institutional study. HPB 2010; 12:31–36.
17. Martin RC, Joshi J, Robbins K, et al. Hepatic intra-arterial injection of
drug-eluting bead, irinotecan (DEBIRI) in unresectable colorectal liver
metastases refractory to systemic chemotherapy: results of multi-
institutional study. Ann Surg Oncol 2011; 18:192–198.
18. Martin RC II, Scoggins CR, Tomalty D, et al. Irinotecan drug-eluting
beads in the treatment of chemo-naive unresectable colorectal liver
metastasis with concomitant systemic fluorouracil and oxaliplatin: results
of pharmacokinetics and phase I trial. J Gastrointest Surg 2012; 16:
1531–1538.
19. Vogl TJ, Jost A, Nour-Eldin NA, Mack MG, Zangos S, Naguib NN.
Repeated transarterial chemoembolisation using different chemothera-
peutic drug combinations followed by MR-guided laser-induced thermo-
therapy in patients with liver metastases of colorectal carcinoma. Br J
Cancer 2012; 106:1274–1279.
20. Eichler K, Zangos S, Mack MG, et al. First human study in treatment of
unresectable liver metastases from colorectal cancer with irinotecan-
loaded beads (DEBIRI). Int J Oncol 2012, http://dx.doi.org/10.3892/
ijo.2012.1572.
21. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J
Cancer 2009; 45:228–247.
22. Rees M, Tekkis PP, Welsh FK, O’Rourke T, John TG. Evaluation of long-
term survival after hepatic resection for metastatic colorectal cancer: a
multifactorial model of 929 patients. Ann Surg 2008; 247:125–135.
23. Smith MD, McCall JL. Systematic review of tumour number and
outcome after radical treatment of colorectal liver metastases. Br J Surg
2009; 96:1101–1113.
24. Bhattacharjya S, Aggarwal R, Davidson BR. Intensive follow-up after liver
resection for colorectal liver metastases: results of combined serial
tumour marker estimations and computed tomography of the chest
and abdomen—a prospective study. Br J Cancer 2006; 95:21–26.
25. Tang Y, Taylor RR, Gonzalez MV, Lewis AL, Stratford PW. Evaluation of
irinotecan drug-eluting beads: a new drug-device combination product for
1217
the chemoembolization of hepatic metastases. J Control Release 2006;
116:e55–e56.
26. Sakamoto I, Aso N, Nagaoki K, et al. Complications associated with
transcatheter arterial embolization for hepatic tumors. Radiographics
1998; 18:605–619.
27. Baize N, Gerard B, Bleiberg H, et al. Long-term survival of patients
downstaged by oxaliplatin and 5-fluorouracil combination followed by
rescue surgery for unresectable colorectal liver metastases. Gastro-
enterol Clin Biol 2006; 30:1349–1353.
28. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable
colorectal liver metastases downstaged by chemotherapy: a model to
predict long-term survival. Ann Surg 2004; 240:644–657.
29. Lam VW, Spiro C, Laurence JM, et al. A systematic review of clinical
response and survival outcomes of downsizing systemic chemotherapy
and rescue liver surgery in patients with initially unresectable colorectal
liver metastases. Ann Surg Oncol 2012; 19:1292–1301.
30. Seront E, Van den Eynde M. Liver-directed therapies: does it make sense
in the current therapeutic strategy for patients with confined liver
colorectal metastases? Clin Colorectal Cancer 2012; 11:177–184.
31. Kennedy A, Nag S, Salem R, et al. Recommendations for radio-
embolization of hepatic malignancies using yttrium-90 microsphere
brachytherapy: a consensus panel report from the radioembolization
brachytherapy oncology consortium. Int J Radiat Oncol Biol Phys 2007;
68:13–23.
32. Salem R, Thurston KG. Radioembolization with 90yttrium microspheres:
a state-of-the-art brachytherapy treatment for primary and secondary liver
malignancies. Part 1: Technical and methodologic considerations. J Vasc
Interv Radiol 2006; 17:1251–1278.
33. Sharma RA, Van Hazel GA, Morgan B, et al. Radioembolization of liver
metastases from colorectal cancer using yttrium-90 microspheres with
concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemo-
therapy. J Clin Oncol 2007; 25:1099–1106.
34. van Hazel GA, Pavlakis N, Goldstein D, et al. Treatment of fluorouracil-
refractory patients with liver metastases from colorectal cancer by using
yttrium-90 resin microspheres plus concomitant systemic irinotecan
chemotherapy. J Clin Oncol 2009; 27:4089–4095.
35. Hendlisz A, Van den Eynde M, Peeters M, et al. Phase III trial
comparing protracted intravenous fluorouracil infusion alone or with
yttrium-90 resin microspheres radioembolization for liver-limited meta-
static colorectal cancer refractory to standard chemotherapy. J Clin Oncol
2010; 28:3687–3694.