ANNALS OF GASTROENTEROLOGY & HEPATOLOGY ORIGINAL ARTICLE

Hepatic Arterial Chemoembolization Adopting Dc Bead†,

Drug-Eluting Bead Loaded with Irinotecan (Debiri) Versus
Systemic Therapy for Hepatic Metastases from Colorectal
Cancer: A Randomized Study of Efficacy and Quality of Life
Giammaria Fiorentini1, Camillo Aliberti2, Giorgio Benea3, Massimo Tilli3, Francesco Graziano1, Paolo Coschiera1, Andrea Mambrini4, Maurizio Cantore4, and
Stefano Guadagni5
Affiliations: 1Department of Oncology and Hematology, Ospedali Riuniti Marche Nord
sede Muraglia, Pesaro, Italy; 2Interventional Radiology Unit Istituto
Oncologico Veneto, Padova, Italy; 3Department of Radiology, Delta Hospital, ferrara, Italy; 4Department of Oncology, General Hospital, Carrara, Italy and
5
Department of Surgery, University of L’Aquila, L’Aquila, Italy

A B S T R A C T

PURPOSE
Hepatic metastases receive most of their blood supply from the hepatic artery; therefore, for patients with hepatic metastases from
colorectal cancer, hepatic arterial chemoembolization adopting DC Bead, Drug-Eluting Bead (n-Fil modified sulphonate spherical embolic
device) loaded with irinotecan (DEBIRI) may improve outcome.

METHODS
In a multi-institutional study, 74 patients were randomly assigned to receive DEBIRI (36) versus systemic irinotecan, fluorouracil, and
leucovorin (FOLFIRI, 38). The primary end point was survival and the secondary end points were response, recurrence, toxicity, quality of life,
cost, and influence of molecular markers.

RESULTS
At 30 months, overall survival was significantly longer for DEBIRI than FOLFIRI (p .044, log-rank). Median survival was 23 months (95%
CI 22
24) for DEBIRI and 15 months (95% CI 12
18) for FOLFIRI. Progression-free survival was 7 months (95% CI 3
11) in the DEBIRI group
compared to 4 months (95% CI 3
5) in the FOLFIRI group, and the difference between groups was statistically significant (p .006,
log-rank). Median time to extrahepatic progression was 13 months (95% CI 10
16) in the DEBIRI group compared to 9 months (95% CI 5
13)
in the FOLFIRI group. A statistically significant difference between groups was not observed (p .064, log-rank). The median time
for duration of improvement to quality of life was 8 months (95% CI 3
13) in the DEBIRI group and 3 months (95% CI 2
4) in the FOLFIRI
group. The difference in duration of improvement was statistically significant (p .00002, log-rank).

CONCLUSION
This study showed a statistically significant difference between DEBIRI and FOLFIRI for overall survival (8 months), progression-free
survival (3 months), and quality of life (5 months). In addition, a clinically significant improvement in time to extrahepatic progression
(4 months) was observed for DEBIRI, a reversal of the expectation for a regional treatment as observed in the past. This data suggest a
benefit to DEBIRI treatment over intravenous FOLFIRI and serve to establish the expected difference between these two treatment options
for planning future large randomized studies.

Keywords: chemoembolization, irinotecan, liver metastases, colorectal cancer, angiography, DC-beads Drug-Eluting Beads, DC Bead,
DEBIRI

Correspondence: Giammaria Fiorentini, MD, Oncology Unit, Department of Oncology and Hematology, Ospedali Riuniti Marche Nord, via
C. Lombroso 1, 61121 Pesaro (PU), Italy. Tel: 0039 0721 364097; Fax: 0039 0721 364094; e-mail: g.fiorentini@alice.it

INTRODUCTION 150,000 patients, who develop metastatic colorectal cancer

The cancer of colon and rectum (CRC) is one of the leading each year.1,2 The liver will remain the only site of metastatic
causes of cancer-related death worldwide. In the United States, disease until end stage in most patients, and a small number of
metastatic spread to the liver occurs in approximately 60% of patients will be candidates for surgical resection. Liver

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Annals of Gastroenterology & Hepatology
involvement is a major source of morbidity and, eventually,
leads to death in the majority of such patients.3
Surgical ablation is the standard treatment in patients with
resectable liver metastases (LM) but results are frequently
disappointing: 5-year survival after resection is 25
35%,
and recurrence is common.3,4 When surgery is not feasible,
chemotherapy,5
9 radiofrequency ablation,10,11 intra-arterial
chemotherapy,12
16 and trans-arterial chemoembolization
(TACE) are possible alternatives to achieve liver control of
the disease.17
20
Palliative chemotherapy is the mainstay of treatment.
Toxicity is common and median survival is about 20 months,
although this slightly increased adding monoclonal when
monoclonal antibodies and angiogenesis inhibitors.7
9 Abla-
tive or trans-arterial techniques allow localized, minimally
invasive therapy without systemic toxicity or morbidity.
Trans-arterial chemoembolization is the administration of
embolic particles mixed with chemotherapeutic drugs. It
produces a shutdown of blood flow and the simultaneous
release of high doses of the drug increasing the drug
concentration and exposure of the drug compared with
standard intra-arterial infusion.21
23
Trans-arterial chemoembolization is currently approved for
the treatment of hepatocellular carcinoma22 but it has been
investigated also in LM from CRC.17
20
Different embolic formulations are available. They have
different diameters and they can be combined with various
drugs, such as mitomycin-C, melphalan, cisplatin, epirubicin,
and irinotecan. Recently, a new n-FIL sulfonate modified
hydrogel spherical embolic device capable to be loaded with
irinotecan (drug-eluting bead) has been developed, showing
interesting properties.23
25
Taylor et al.23 observed that following porcine hepatic artery
infusion of drug-eluting beads preloaded with irinotecan
(DEBIRI), maximum plasma levels were 70
75% lower for
both irinotecan and SN-38, compared to intra-arterial bolus
administration, with peak levels observed at 2 and 5 min after
completion of the infusion procedure. DEBIRI is a combina-
tion of local drug infusion with selective embolization of
the LM feeding arteries. It was reported to be feasible and
safe in a Phase 2 study.17,20 Clinical studies consistently
reported high response rates of TACE in the treatment of
LM from CRC, but randomized studies are lacking and the
impact of this procedure on survival is unknown.26,27 On
the other hand, this technique was shown to be associated
with a variety of side effects, and the most common of them
is the ‘‘postembolization syndrome’’. It consists of pain in
the right upper quadrant (RUQP), nausea, vomiting, fever,
and elevation of liver enzymes and occurs almost in every
patient [17, 20, 22]. Less common complications are liver
abscess, tumor rupture, acute liver failure, infraction, acute
pancreatitis, and acute renal failure; and adequate supportive
therapy is required.28
AGH 2012; 3:(1). March 2012
Because of the uncertainty in drawing any definitive inter-
pretation from these studies, a multicenter trial was designed
to compare DEBIRI treatment with irinotecan, fluorou-
racil, and folinic acid given intravenously. In this design, no
crossover was allowed, so the trial addresses the fundamental
question of whether DEBIRI therapy is more effective than
systemic therapy for the treatment of LM from CRC. The
primary end point of the study was survival, and the secondary
end points were tumor response, toxicity, quality of life (QoL),
and cost-effectiveness. Tumor and LM biopsies from both
groups were analyzed for p53 status, K-Ras, and EGFr to
evaluate the utility of these molecular markers in predicting
outcomes.
MATERIALS AND METHODS
We reported a prospective multiple-institutional double
arms treatment study, which was approved by the institu-
tional review board (IRB) and evaluated from December 2006
to December 2008 in which 74 patients presenting with LM
from CRC were randomized to receive DC Bead† (Biocom-
patibles UK), loaded with irinotecan, DEBIRI or systemic
chemotherapy (FOLFIRI).
The study was conducted in compliance with the protocol
and the principles laid down in the Declaration of Helsinki,
in accordance with the ICH Harmonized Tripartite Guideline
for Good Clinical Practice (GCP). Informed consent was
obtained from the subjects prior to evaluation, screening, and
treatment. The study was initiated to apply the criteria for
appraising the quality of a study. We present a well-reported
patient population with high-quality data and quality control
and with good clinically significant follow-up without loss
of patients.
All patients were required to have histologically confirmed
CRC with unresectable LM occupying less than 50% of
the liver parenchyma and no radiological evidence of
extrahepatic disease. Patients who have previously received
chemotherapy were not excluded if they had completed 3
months before protocol therapy. Patients who had received
radiation to the liver, or had portal vein occlusion or ascites,
were excluded. Patients could not have a previous or
concurrent malignancy and had to have total bilirubin 52x
the upper limit of normal, with normal hematologic and
renal function.
A biopsy was required before registration to document LM
with metastatic disease.
Each patient was asked to complete health-related QoL
instruments before treatment and every 3 months during
participation on the study until 12 months. The following
instrument was used: Edmonton Symptom Assessment
System.29
All patients had received at least two (45) or three (27) lines
of chemotherapy.The percentage of liver involvement was
525% in 52 cases and 550% in 22 cases.
40 www.slm-gastroenterology.com

Drug Doses and Schedule
DEBIRI consists of drug-eluting bead, DC Bead, capable
†
to be loaded with irinotecan (Campto injection solution),
200 mg (50 mg/mL) once a month for two times.
Patients underwent DEBIRI administration using angiogra-
phy. The catheter is placed as selectively as possible in order to
isolate the blood supply to the malignancy and achieve
localized chemotherapy. Selective hepatic embolization in-
volves embolization of the right or left hepatic arteries
separately as they branch from the proper hepatic artery.
Superselective or highly selective embolization involves em-
bolization of branches leading off from the hepatic arteries,
preferably the lesion itself or its feeding branches. The size
of n-Fil sulfonate modified hydrogel spherical embolic device
is chosen according to the particular study, usually with
smaller particles (100
300 mm in diameter).
Patients receiving embolization are monitored closely after
each procedure in case hepatic failure develops or any other
criteria become apparent that would exclude them from
further therapy.
Intravenous hydration, morphine, antiemetic and antibiotic
prophylaxis were provided to reduce post-embolization
effects.
Intravenous hydration started day-1 and continued on day
0, 1, 2 consisting of 2000 ml bag/24 hours infusion
(1000 ml of saline solution, 1000 ml of glucose 5%) with the
addition of Ranitidine 900 mg.
Prophylactic treatment against nausea administered was
Tropisetron 5 mg, one vial intravenously before and one vial
at 6 hours, Prednisone 25 mg orally (or Desamethasone
8 mg intravenously) at 08.00 am and at 08.00 pm day 0, 1,
2, 3, 4, 5.
Prophylactic treatment against pain was based on Morphine
10mg 30 minutes before DEBIRI and 10 mg at 6 hours.
Intra-arterial Lidocaine 5 ml just before DEBIRI was adopted.
Prophylactic treatment against infection was based on
Cefazolin 2000 mg intravenously at 08.00 am and at 08.00
pm day 0, 1, 2. The supportive treatment goes on if
required on day3, 4, 5.
Systemic chemotherapy FOLFIRI consisted of intravenous
†
irinotecan (Campto injection solution) 180 mg/m2 on day 1
with folinic acid 100 mg/m2 as 2-hour infusion, followed
by fluorouracil 400 mg/m2 bolus and fluorouracil 600 mg/m2
as 22-hour infusion on days 1 and 2 every 2 weeks for 8 times
(4 months of treatment). Ondansetron 8 mg, Dexamethasone
12 mg intravenously on day 1, and loperamide 2 mg tabs
if required were provided to control nausea, vomiting, and
diarrhoea.
Molecular Marker Evaluation
The detections of K-Ras activating mutations (most fre-
quently at codon 12 and codon 13) have been performed on
the real-time polymerase chain reaction (real-time PCR).
This technique is based on the PCR, which permits to
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Hepatic Arterial Chemoembolization
amplify and, in ‘‘real time’’, quantify the hotspot mutations
site. In this molecular procedure the amplified DNA frag-
ment is detected, as the reaction progresses, by nonspecific
fluorescent dyes that intercalate with any double-stranded
DNA, or by a fluorescent DNA probe, specific and comple-
mentary for DNA target. Real-time PCR can also be combined
with reverse transcription to quantify mRNA.
p53 protein expression was assessed by immunohistochem-
istry using paraffin sections with DO7 antibody. Patients with
greater than 10% positive nuclei with moderate or strong
staining were considered positive, whereas all others were
considered negative.
Statistical Methods
The study was designed to show an increase of 40% of
median overall survival (MS, primary endpoint) at 2 years
follow-up (HR  .72 by Kaplan
Meier method).
Patients were randomly assigned to DEBIRI or systemic
therapy. Stratification factors included percent liver involve-
ment (525%, 550%); synchronous disease (no versus yes);
type of prior palliative chemotherapy with versus without
irinotecan, weight loss in three months, CEA, K-Ras, p53.
IBM SPSS Statistics was used for all calculations and plots.
A comparison of median survival only compares the single
point in time for each group where the survival probability
reaches 50%; thus, the log-rank (also known as Mantel
Cox)
is used here to evaluate the difference in survival across the
entire study. The other advantage of this method is that no
assumptions need to be made relating to the distribution
of survival times. The log-rank test tests the null hypothesis
that there is no difference between groups and is essentially a
chi-square test at 1 degree of freedom for two groups as in
this study. The test statistic is a function of the actual and
expected number of deaths at each interval in the study,
where an interval is defined by a death occurred (as in the
Kaplan
Meier plot).
The value of p is the probability that the test statistics as
large as that calculated could occur by chance only (i.e. the
probability that the actual difference observed between
groups is not attributable to the treatment).
Differences were tested using Fisher‘s exact test. Toxicity
comparisons were made using the Fisher‘s exact test. All
p values are two-sided.
Calculation of tumor response
Tumor response was calculated using either contrast-
enhanced spiral computed tomography (CT) or magnetic
resonance imaging (MRI) with quantification of tumor
response according to either RECIST or EASL criteria.30
33
Treatment response using RECIST response criteria was
categorized as complete response (CR) or partial response
(PR). CR is defined by the disappearance of measurable
disease, or the absence of arterial phase contrast enhance-
ment as measured by CT, persisting for ]4 weeks without
the appearance of new measurable lesions. PR is defined as a
]30% reduction in the sum of the products of the greatest
41 AGH 2012; 3:(1). March 2012
Annals of Gastroenterology & Hepatology

diameter (length) and the greatest perpendicular diameter
(width) of all measurable lesions compared with baseline,
and no appearance of new measurable lesions. Stable disease
(SD) represents cases in which neither PR nor progressive
disease (PD) criteria are met, taking as reference the smallest
sum of the greatest diameter recorded since the commence-
ment of treatment. Progressive disease (PD) is defined by the
occurrence of one of the following conditions: (i) the sum
of the cross products of all measurable lesions, including
new lesions, increases by 50% compared with the nadir,
or (ii) new measurable lesions occur in any part of the body
outside the liver.
Treatment response assessment using EASL criteria repre-
sented a measure of local tumor response based on tumor
progression with respect to change in necrosis. The greatest
diameter of viable tumor against greatest total tumor
diameter is measured, and initial measurements are com-
pared with those after each chemoembolization treatment.
Overall survival (OS), time to progression (TTP), time to
hepatic progression (THP), time to extrahepatic progression
(TEP), and time to decline in quality of life (DQoL) were
calculated from the time of random assignment using the
Kaplan
Meier method and compared using the log-rank test.
TTP was defined as documented progression of disease at any
site or death as a result of any cause; THP was defined as
documented progression of disease in the liver; TEP was
defined as progression outside the liver; and DQoL was
defined as decline in quality of life. There was intent-to-treat
analyses with the inclusion of all patients registered. Both the
log-rank test and the Cox proportional hazards model were
used to assess the association of OS, TTP, THP, and TEP,
with the clinical and histologic variables.
In the evaluation of molecular markers, K-Ras and p53
expression were measured as a dichotomous variable (posi-
tive or negative). To estimate correlation between markers,
the Spearman’s rank correlation was computed.
The study was designed with primary QoL end points,
which was measured by one scale of Edmonton.
We hypothesized that patients in the DEBIRI arm would
have better physical and social functioning and better health
perceptions than patients in the FOLFIRI arm.29 We report an
analysis at 30 months median follow-up.
RESULTS
Patient Characteristics
From December 2006 to October 2008, 74 patients were
randomly assigned: 36 to DEBIRI and 38 to FOLFIRI (Table 1).
No statistical differences among baseline characteristic were
observed. One patient in DEBIRI arm had disease progression
prior to treatment, three patients in FOLFIRI arm declined
rapidly leaving 35 and 35 treated patients, respectively, for
this report.

Table 1. Patients Characteristics.

DEBIRI (D) FOLFIRI (CT)
Number of patients 36 (35) 38 (35)
Sex (M
F) 20
16 24
14
Age 64 (44
74) 63 (42
73)
Liver involvement ( 5 25% to 5 50%) 26
10 26
12
Synchronous/metachronous disease 0/36 0/38
Number of metastases 4 (3
10) 4 (3
10)
Largest diameter (cm) 4.5 (2.5
8) 4 (2.5
8)
Performance status (0
1 and 2) 32 and 4 34 and 4
Extrahepatic metastases 0 0
Previous chemo (2
3 Lines) 23
13 24
14
Types of previous chemo 13 FUFA 12 FUFA
18 FOLFOX 20 FOLFOX
13 IFL 14 IFL
3 FOLFOXBEVACIZUMAB 5 FOLFOXBEVACIZUMAB
3 FUCETUXIMAB 3 FUCETUXIMAB
Weight loss in 2 months 20 (60%) 24 (63%)
Albumin, g/dl (median) 4 3.9
CEA ng/mL 69 (3.5
473) 77 (2.5
611)
K-RAS (WT-M) 22
14 26
12
P53 (positive
negative) 22
12 20
18

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All patients, except four each arm, received adjuvant
chemotherapy previously; all had metachronous metastatic
disease. All patients underwent primary tumor resection prior
to random assignment. All surgical procedures took place
at least 6 months prior to start of treatment (7
20). Two
sites enrolled patients. The numbers of cycles received were
two and eight for the DEBIRI and systemic treatments arms,
respectively. A total of 70 cycles of DEBIRI with a relative
dose intensity of 99% were administered to 35 patients and
277 FOLFIRI cycles with a relative dose intensity of 90%
were administered to 35 patients.
Survival
At 2 years, survival was 56% for DEBIRI group and 32%
for FOLFIRI group; at 30 months, survival was, respectively,
34% and 9%. At 30 months, OS was significantly longer for
DEBIRI than FOLFIRI (p .044, log-rank). Median survival
was 23 months (95% CI 22
24) for DEBIRI and 15 months
(95% CI 12
18) for FOLFIRI (Figure 1).
A significant difference in PFS was observed: 7 versus 4
months (p .006; Figure 2). Median THP was 7 and 4 months
(p .006; Figure 3), whereas TEP was 13 and 9 months for
DEBIRI and FOLFIRI groups, respectively (p.064; Figure 4).
A multivariate analysis based on the proportional hazards
model was used to determinate the impact of variables
associated with survival, and this variable was considered in
this model. Significant associations were apparent between
percent of liver involvement, albumin, and Lactate dehydro-
genase.
Overall treatment with DEBIRI remains significantly related
to survival when each of these variables is considered
separately with treatment arm.
Figure 1. Overall survival.
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Hepatic Arterial Chemoembolization
Response
Among the 74 registered patients, 70 were included in
response assessment, 35 in each arm. Responses in the liver
in the DEBIRI group included 24 complete and partial
responses in 35 eligible patients (68.6%) compared with 7
of 35 responses (20%) in the systemic treatment group.
Stable disease was observed in 4 (11.4%) and 12 (34.3%)
patients, respectively. Progressive disease was reported in 7
(20%) and 16 (45.7%) patients, respectively (Table 3).
Toxicity
Toxicity profiles differed between the two treatment arms
(Table 2). Neutropenia grade ]3 occurred in 4% and 44%
(pB.0001), diarrhoea occurred in 6% and 18% (p .073), and
mucositis occurred in 1% and 20% of DEBIRI and FOLFIRI
(p .00002), respectively. Liver enzyme elevations more than
¯ NV (58% and 8%; pB.0001), bilirubin elevation (18% and
3x
1%; pB.00002) in the DEBIRI and FOLFIRI groups, respec-
tively. Of the patients in DEBIRI group, with increase of
bilirubin more than 2.5 mg/dL due to treatment, all returned
to normal 3 weeks after treatment.
QoL Assessment
Forty-nine (65.3%) patients completed the entire study
(i.e., completed all QoL assessments: baseline, 1, 3, 6, 9,
and 12 months). The most common reason for patient
dropout was death.
Analyses of data at 1 and 3 months, while most of the
patients were receiving active protocol treatment, demon-
strated that the physical functioning of the DEBIRI patients
was better than that of those receiving systemic therapy at
1 (p .38), 3, (p .025), and 6 months (p .025). Similarly,
43 AGH 2012; 3:(1). March 2012
Annals of Gastroenterology & Hepatology
Figure 2. Period free survival.
the duration time to decline was better for DEBIRI group
compared to FOLFIRI group (Figure 5).
Molecular Markers
In 39 of 69 patients, biopsies from primary tumor and
LM were evaluated for K-Ras (n 27 patients) and p53
(n 22 patients).
Figure 3. Hepatic period free survival.
AGH 2012; 3:(1). March 2012
In DEBIRI arm, 14 of 14 patients with K-Ras WT had
evidences of major response as 9 of 13 patients with K-Ras
mutation present evidences of major response. In DEBIRI the
survival was different, with wild type appearing to have better
OS than mutated 26 and 14 months, respectively (p .17).
Seven of 11 patients in DEBIRI arm with enhanced immu-
nohistochemical expression of p53 (positive) in tumor tissue
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 Hepatic Arterial Chemoembolization

Figure 4. Extra hepatic period free Survival.

had a median OS of 24 versus 18 months for 4 of 11 patients Treatment Costs

with low expression p53 (negative; p.6). As health care costs spiral, the issue of cost-effectiveness of
Eleven in FOLFIRI arm with enhanced immunohistochem- our new treatments is increasingly becoming a major issue.
ical expression of p53 (positive) in tumor tissue had a median Over the past 20 years the US FDA has approved 6 new drugs
OS of 12 versus 8 months for four patients with low for metastatic CRC: irinotecan, oxaliplatin, capecitabine,
expression p53 (negative; p .6). bevacizumab, cetuximab, and panitumumab. In the meta-
static setting, these treatments are mostly palliative. Six
Sites of Progression months of biweekly 5-FU plus leucovorin cost approximately
Liver was the main site of progression in both arms: $1300 (t975 in Europe). Six months of treatment (2-week
DEBIRI, 17 patients, and FOLFIRI 23 patients. More than one cycles) with FOLFOX/bevacizumab, for an average of 1.8 m2,
site has been reported in 18 and 12 patients (Table 4 and 5). the cost per patient can be $120,000 (average selling price
from 2008 plus 5% in the United States and t90,000 in
Chemotherapy at relapse Europe). Six months of FOLFIRI cost $50,000 (t37,000), and
At evidence of progression, 19 patients received further with the addition of cetuximab, this cost can increase to
chemotherapy in DEBIRI and 15 patients in FOLFIRI; $115,000 (t87,000).
palliative medicine and miscellanea in 16 and 20 patients, Drug-eluting beads preloaded with irinotecan given twofold
respectively. in 2010, including interventional radiology expenses cost and
supportive cure, amounts $15,000 (t10,000).
Table 2. Toxicity. FOLFIRI given for 4 months (eightfold), including insertion
DEBIRI (D)% FOLFIRI (CT)% of venous device, antiemetic therapy, and other medications,
Pain 30 0% amounts $33,000 (t24,000).
Vomiting 25 25%
Diarrhoea 2 35% Table 3. Responses Observed.
Asthenia 20 50 DEBIRI 35 patients FOLFIRI 35 patients
Leukopenia 5 35
Anemia 5 35 Complete and partial responses 24 (68.6%) 7 (20%)
Fever 15 3 Stable disease 4 (11.4%) 12 (34.3%)
Alopecia 5 35 Progression 7 (20%) 16 (45.7%)

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Annals of Gastroenterology & Hepatology

Figure 5. Duration of clinical benefit to decline.

In our study, costs are considerably in favor of DEBIRI versus The likelihood of longer survival was greater in patients
FOLFIRI, even if the selling price for off-patent irinotecan was with lower tumor burden and better performance status.
reduced in many European countries like in Italy. Although based on small numbers, primary tumor and liver
biopsies in the DEBIRI arm demonstrated that patients with
DISCUSSION K-Ras WT and positive p53 had the best survival.
A comparison of DEBIRI versus systemic therapy in patients The responses to DEBIRI are better in the K-Ras WT than
with unresectable hepatic metastases from CRC indicates K-Ras mutated, but to our knowledge it has not been
that DEBIRI therapy prolonged the median survival (23 versus reported previously.
15 months) and was associated with a greater likelihood of A criticism of this study is that the systemic chemotherapy
objective tumor response in the liver (68.6% versus 20%), used was FOLFIRI. New randomized studies have demon-
enhanced time to hepatic progression 7 and 4 months (p  strated that the addition of oxaliplatin, bevacizumab, cetux-
.006), whereas time to extrahepatic was 13 and 9 months for imab, panitumumab added to FOLFIRI will increase survival
DEBIRI and FOLFIRI groups, respectively, and improved compared to FOLFIRI alone. This study was planned in
physical functioning during active treatment at 1, 3, 6, 9, 2005, at which time FOLFIRI was the standard of treatment in
and 12 months. second- or third-line chemotherapy, and the use of biologics
The regional approach was not inferior to FOLFIRI in was not as diffuse as now.
preventing extrahepatic metastatic progression (TEP 9.2 In this study, the survival advantage conferred by DEBIRI over
versus 10 months). These data appear to indicate that DEBIRI systemic chemotherapy suggests that DEBIRI may represent
has also a systemic activity and that by controlling the liver a superior clinical treatment modality because both treatment
diseases it is possible to extend the survival. groups had access to new drugs at progression. The significant
Table 4. Sites of Relapses. Table 5. Treatments at Progression.
ARM DEBIRI (D) FOLFIRI (CT) Type of Therapy DEBIRI (D) FOLFIRI (CT)
Number of patients treated 35 35 FU c.i. 8 4
Liver 17 23 FU c.i.Mitomycin 4 4
LiverLung 8 7 Folfoxiri 2 2
LiverLungBones 3 3 Herbal medicineHOLISTICS 2 5
LiverPeritoneal Carcinosis 2 1 FolfiriCetuximab 3 2
LiverLungBrain 1 1 FolfoxBevacizumab 2 3
LymphonodesPeritoneal Carcinosis 2 0 Palliative medicine 14 14

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difference in survival was shown to be attributable to treatment
arm and remained significant even considering that the vast
majority of patients received postprogression therapy. This
study emphasized the importance of the method of drug
delivery and the superiority of locoregional therapy over
systemic therapy even if the treatment was irinotecan-based
for both arms in patients with liver-only metastases.
TEP was similar in both groups. One could postulate that
the use of concurrent systemic therapy with new agents in
the DEBIRI group would have improved results. Studies of
HAI FUDR plus systemic irinotecan and oxaliplatin, even in
previously treated patients, have produced response rates of
]70%12
15 obtaining substantially the same responses that
we had reported.
Both the regional and the systemic treatments were reason-
ably well tolerated. Patients allocated to receive the systemic
FOLFIRI demonstrated a higher likelihood of grade 3
neutropenia, diarrhoea, and stomatitis. Patients allocated to
receive DEBIRI reported higher likelihood of abdominal pain
and elevation of liver enzymes.
This study is the first in literature that provides evidence that
chemoembolization therapy provides superior survival with
better physical functioning when compared with the same
chemotherapeutic compound administered systemically. The
benefits of the chemoembolization in combination with
systemic chemotherapy are minimally explored.34 Whether
this regional strategy can be enhanced further through the
addition of concurrent systemic treatment will be the focus of
future studies.
Disclosure: The authors declare no conflict of interest.
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