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Journal of Visceral Surgery (2017) xxx, xxx—xxx

Available online at

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ORIGINAL ARTICLE

A new animal model for hyperthermic

intraperitoneal chemotherapy (HIPEC) in
tumor-bearing mice in the treatment of
peritoneal carcinomatosis of ovarian origin
G. Miailhe a,c,1, A. Arfi a,c,1, M. Mirshahi c, C. Eveno b,c,
M. Pocard b,c, C. Touboul a,c,∗

a
Service de gynécologie obstétrique, hôpital intercommunal de Créteil, université Paris Est,
Paris XII, 40, avenue de Verdun, 94000 Créteil, France
b
Service de chirurgie digestive et cancérologique, hôpital Lariboisière Fernand-Widal,
université Paris VII, 49, boulevard de la chapelle, 75010 Paris, France
c
UMR Inserm U965, angiogenèse et recherche translationnelle, hôpital Lariboisière, 49,
boulevard de la chapelle, 75010 Paris, France

KEYWORDS Summary
Hyperthermic Aim of the study: We set out to develop and evaluate the morbidity of a non-invasive hyper-
intraperitoneal thermic intraperitoneal chemotherapy (HIPEC) procedure in mice. HIPEC has been shown to
chemotherapy; improve overall survival in treating ovarian cancer with peritoneal carcinomatosis. However,
Peritoneal related complications, toxicity and the lack of randomized trials limits its widespread use. To
carcinomatosis; improve the surgical technique, there is a need for animal models that allow teams to work on
Ovarian cancer; large groups without burdensome logistics.
Murine model; Materials and methods: To develop the model, we first determined optimal HIPEC conditions
Oxaliplatin in 20 Black Six mice without carcinomatosis. To evaluate HIPEC morbidity, peritoneal carcino-
matosis cells of ovarian origin were injected into the peritoneum of 10 pathogen-free Nude
mice. The mice underwent HIPEC 21 days later under general anesthesia. An inflow catheter
was introduced into the left hypochondria and an outflow catheter was introduced into the left
iliac fossa. Bath infusion was oxaliplatin (920 mg/m2 ) at 43 ◦ C for 12 minutes. The mice were
monitored and sacrificed two weeks after the procedure.
Results: No deaths were observed during the procedure and infusion was well tolerated
throughout the HIPEC. One mouse died the day after the procedure. No major dehydration,
hemoperitoneum or evisceration was observed.
Conclusion: This mouse model of closed abdomen HIPEC has limited morbidity and could be a
useful model to study HIPEC regimens and its effects on peritoneal carcinomatosis.
© 2017 Elsevier Masson SAS. All rights reserved.

∗ Corresponding author.
E-mail address: cyril.touboul@gmail.com (C. Touboul).
1 These authors contributed equally to this work.

https://doi.org/10.1016/j.jviscsurg.2017.10.008
1878-7886/© 2017 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Miailhe G, et al. A new animal model for hyperthermic intraperitoneal chemotherapy
(HIPEC) in tumor-bearing mice in the treatment of peritoneal carcinomatosis of ovarian origin. Journal of Visceral Surgery
(2017), https://doi.org/10.1016/j.jviscsurg.2017.10.008
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JVS-750; No. of Pages 7 ARTICLE IN PRESS
2 G. Miailhe et al.
Introduction
Epithelial ovarian cancer (EOC) is the leading cause of death
from gynecological cancer in northwestern Europe and in
northern America [1]. Most women are diagnosed only after
peritoneal dissemination has occurred. EOC tends to be
chemosensitive and confine itself to the surface of the
peritoneal cavity for much of its natural history. Though
these features make it an obvious target for intraperitoneal
chemotherapy, standard treatment is complete cytoreduc-
tive surgery followed by five to eight cycles of intravenous
taxane chemotherapy [2]. Even though initially effective,
drug-resistant cancer or relapse from residual disease
reduces the 5-year survival rate to about 20% [3].
Cisplatin is a DNA damaging chemotherapeutic used
to treat solid tumors including EOC. However, resistance
to cisplatin in this setting limits clinical success. Three
large randomized clinical trials have shown the benefit
of hyperthermia when administering chemotherapy agents
intraperitoneally to target small remnant tumor load and
putative malignant cells in the abdominal cavity, a tech-
nique known as hyperthermic intraperitoneal chemotherapy
(HIPEC) [4—6]. Hyperthermia is tumoricidal alone [7] and
has been shown to enhance cisplatin inhibition of peritoneal
tumor growth [8]. A recent Cochrane database [9] has shown
that HIPEC increases overall survival and progression-free
survival in women with advanced ovarian cancer. However,
the potential for catheter-related complications and toxic-
ity needs to be taken into account. Efforts to define the
role of HIPEC in a large randomized trial failed to attain the
required number of patients because of patient dissatisfac-
tion with randomization [10]. Moreover, optimal treatment
modalities remain to be defined and targeted therapies
developed in order to increase efficacy and decrease tox-
icity. Animal models are therefore needed.
While animal models have already been developed in rats
and pigs to study HIPEC procedures [11], these are burden-
some in terms of logistics and limit the possibility of working
on large groups. Mice models are more accessible but pub-
lished data are scarce and existing reports fail to include
animal survival or postoperative complications because the
mice were sacrificed immediately after the HIPEC procedure
[12—14].
The objective of our study was to develop a new non-
invasive HIPEC procedure using mice as a miniaturized
animal model, and to evaluate the morbidity of the pro-
cedure.
Materials and methods
Animals
Twenty female C57BL/6 mice between 6—8 weeks old
(Charles River, Arbesle, France) were used to build the
experimental procedure and determine optimal conditions.
Ten female pathogen-free Nude mice (without thymus,
T-lymphocyte free), weighing 20 to 27 g (average: 25.3 g)
and between 7—9 weeks old (Charles River, Arbesle, France)
were used to perform the HIPEC procedure on a peritoneal
carcinomatosis model.
The animals were housed in filter-topped cages (5 mice
per cage) under clean, non-sterile, standardized conditions
(temperature 20—24 ◦ C, relative humidity 50—60 percent,
12 h light/12 h dark cycle). They were fed with standard
laboratory diet and tap water ad libitum.
Please cite this article in press as: Miailhe G, et al. A new animal model for hyperthermic intraperitoneal chemotherapy
(HIPEC) in tumor-bearing mice in the treatment of peritoneal carcinomatosis of ovarian origin. Journal of Visceral Surgery
(2017), https://doi.org/10.1016/j.jviscsurg.2017.10.008
Maintenance and care of all experimental animals were
carried out according to the guidelines of the local Ani-
mal Protection Commission and in compliance with national
guidelines (Saisine n◦ 02095, Animal Protection Committee,
French Ministry of Agriculture).
Cells and cell culture
We used the human epithelial ovarian cancer cell (OCC) line
OVCAR-3. OCCs were transfected with a plasmide expressing
luciferase. The OCCs were cultivated in an incubator at 37 ◦ C
and 5% CO2 in monolayer cultures in 20 mL complete medium
of Dulbecco’s Modified Eagle’s Medium (DMEM), 10% heat-
inactivated fetal bovine serum, 1% Penicillin/Streptomycin,
and 1% L-glutamate (Gibco, Saint-Aubin, France).
Establishment of intraperitoneal metastatic
ovarian tumors in mice
The OVCAR-3 cell suspension (6.0 × 106 cells in 500 ␮L of
serum-free DMEM media) was injected into the peritoneum
in the left iliac fossa of mice using an 18-gauge needle.
Evaluation of carcinomatosis
To assess the peritoneal carcinomatosis before surgery, the
mice were monitored twice a week by bioluminescence
after intraperitoneal injection of 0.2 mL of Luciferine (150
ug/mL), 10 minutes before acquisition. Almost 3 weeks after
injection (by day 19), the mice had developed disseminated
intraperitoneal tumors.
Chemicals
Oxaliplatine (Onco-TainTM , Hospira), was chosen as
chemotherapy for its peritoneous absorption qualities. The
administered dose was 920 mg/m2 according to the results
of Piché et al. [15].
Experimental design
To develop the model, we first tested the procedure HIPEC
in the 20 Black Six mice without carcinomatosis and deter-
mined optimal conditions. The following parameters were
tested without chemotherapy in the bath liquid:
• safety and operative morbidity of open or closed abdomen
intraperitoneal infusion;
• thermic control using a heat mattress: optimal tempera-
ture of the mattress and length of the procedure.
Before surgery, the mice were administered a subcuta-
neous injection of 0.5 mL buprenophine. They were then
anesthetized with 4% isoflurane (2L/mn) in an inhalation
chamber (Fig. 1A). The body temperature was monitored
using a rectal temperature probe (Fig. 1B). The use of a
warmed mattress to limit body heat loss was evaluated in
four mice:
• mouse No. 1: no warmed mattress;
• mouse No. 2: warmed mattress at 35◦ C;
• mouse No. 3: HIPEC procedure without warmed mattress;
• mouse No. 4: HIPEC procedure with warmed mattress at
35 ◦ C:
◦ Inflow catheter: thermic control and optimal flow;
◦ Outflow catheter: optimal flow.
In the second study, we tested HIPEC using oxaliplatin on
mice with ovarian peritoneal carcinomatosis to evaluate the
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A new murine model for HIPEC 3

Figure 1. Pictures of the HIPEC procedure. A. Anesthesia. B. Introduction of the rectal temperature probe. C. Introduction of the inflow
catheter. D. Introduction of the outflow catheter. E. Final aspect of the installation. F. Skin closure.

feasibility and morbidity of the procedure. Ten mice were

injected with 6 × 106 OVCAR-3 cells 21 days before HIPEC.
Only one HIPEC procedure was performed per mouse and the
mice were monitored for 14 days before sacrifice. Engraft-
ment with OVCAR-3 was checked by bioluminescence 19 days
after the cell injection, 2 days before HIPEC and each week
until sacrifice.

Evaluation of the mice

The mice were inspected daily for side effects and were
weighed on days 2 and 7 after the HIPEC procedure or if
signs of dehydration were observed. Mice displaying major
dehydration with a weight loss of more than 20% of the
initial weight were sacrificed. Mice with moderate dehy-
dration were hydrated with subcutaneous saline (1 mL)
daily until disappearance of the skin fold. The mice were
given water-soaked food in a container and kept under
standard conditions before sacrifice after general anesthesia
by isoflurane 2% 14 days after the HIPEC procedure.
Results
Choice of the technique of the intraperitoneal
infusion
Open abdomen
We first tested open-abdomen laparotomy on five mice. This
model quickly revealed limitations in terms of heat loss,
bath liquid leakage and bleeding. Furthermore, two mice
(40%) displayed evisceration after the procedure. We then
tested closed abdomen infusion.
Closed abdomen
This technique was achieved in four mice under general
anesthesia. Two catheters were introduced through two dis-
tinct dials on the abdomen. The inflow catheter allowed
infusion of the hyperthermic solution and the outflow
Figure 2. Graph showing tests to determine the optimal body
temperature of the mice.
catheter its evacuation. The main problem encountered was
intraabdominal hyperpressure responsible for intestinal loop
collapse and catheter kinking. To fix this problem, a 14G mul-
tiperforated outflow catheter was introduced tangentially to
the abdominal wall. The outflow catheter operated in free
flow to ensure good flow quality. To avoid pre-peritoneal
infusion an 18G inflow catheter was inserted perpendicu-
larly into the abdomen wall. On the final model, the inflow
catheter was positioned into the left hypochondria and
outflow catheter into the right iliac fossa, thus allowing
homogenous diffusion and then aspiration of the liquid. No
complication was observed postoperatively.
Stabilization of body temperature
We tested four conditions to maintain the body tempera-
ture of the mice stable. The temperature of mouse No. 1
(no warmed mattress) rapidly decreased leading to lethal
hypothermia several minutes after general anesthesia began
(Fig. 2). The temperature of mouse No. 4 (HIPEC procedure
with warmed mattress at 35 ◦ C) rapidly increased leading to
lethal hyperthermia several minutes after general anesthe-
sia began (Fig. 2). For mouse No. 3 (HIPEC procedure without

Please cite this article in press as: Miailhe G, et al. A new animal model for hyperthermic intraperitoneal chemotherapy
(HIPEC) in tumor-bearing mice in the treatment of peritoneal carcinomatosis of ovarian origin. Journal of Visceral Surgery
(2017), https://doi.org/10.1016/j.jviscsurg.2017.10.008
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4 G. Miailhe et al.

Figure 3. Diagram of the experimental HIPEC circuit.

Figure 4. Graph of the temperature course during HIPEC in the abdomen and in the rectal cavity.

warmed mattress), the temperature rapidly decreased dur-
ing the first 3 minutes during installation of the catheters
and the temperature reached 36 ◦ C only 8 minutes after infu-
sion. We therefore decided to use a warmed mattress during
the preparation and the first 3 minutes of hyperthermic infu-
sion.
HIPEC procedure
Two catheters were introduced into the abdominal cav-
ity through the flanks as represented in Fig. 3. The inflow
catheter (18 Gauge) was inserted into the left hypochondria
perpendicularly to the abdominal wall with the help of a
prehension clamp (Fig. 1C and D). The perfusate, consisting
of 100 mL of normal saline solution with added oxaliplatin
at a concentration of 920 mg/m2 , was heated to 53 ◦ C by
emerging the saline bag into a heated water bath. Although
the target temperature for the perfusate was 43 ◦ C, an ini-
tial temperature of 53 ◦ C was required because of a heat
loss of 10 ◦ C during administration. Once the perfusate had
reached 53 ◦ C a tube was connected to the inflow catheter
and infusion was performed at a rate of 0.08 mL/sec for
12 min using a Masterflex pump (Cole-Palmer Instrument Co,
Cat # 07524-50). After a few seconds the abdomen had
bulged enough to facilitate the introduction of the outflow
catheter in the left iliac fossa. This 14G multi-perforated
catheter was positioned so that the perfusate was drained
by declivity in free flow without negative pressure
(Fig. 1E).
During the HIPEC procedure, the abdomen was mas-
saged gently to achieve a uniform heat distribution. After
12 minutes of infusion, the inflow catheter was removed.
A light pressure on the abdomen was applied to extract
the surplus solution before removing the perfusate outflow

Please cite this article in press as: Miailhe G, et al. A new animal model for hyperthermic intraperitoneal chemotherapy
(HIPEC) in tumor-bearing mice in the treatment of peritoneal carcinomatosis of ovarian origin. Journal of Visceral Surgery
(2017), https://doi.org/10.1016/j.jviscsurg.2017.10.008
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A new murine model for HIPEC
Figure 5. Course of mice weight after HIPEC procedure.
®
catheter. The skin was closed using Monocryl 5-0 (Ethicon)
(Fig. 1F).
Infusion characteristics
The mean volume of the chemotherapy bath per mouse was
45 mL. During the HIPEC procedure, the mean intraabdom-
inal temperature was 43 ◦ C. The mean rectal temperature
at the start of the procedure was 37.0 ◦ C. It increased to
38.5 ◦ C after 3 minutes at which point the warmed mattress
was taken away and the mice were maintained at 38.5 ◦ C
until the end of the procedure. The course of the rectal and
intraabdominal temperatures during the HIPEC procedure is
shown in Fig. 4.
Morbidity and mortality
No death was observed during the procedure and infusion
was well tolerated until the end of the HIPEC. The 10 mice
were monitored for 14 days after which they were sacrificed.
One mouse died the day after the procedure for unknown
reasons. We observed no major dehydration and one mouse
suffered from moderate dehydration on day 1. No cases of
hemoperitoneum or evisceration were observed. The aver-
age weight loss per mouse was 1.6 g; the mice regained their
original weight on day 14 just before the sacrifice (Fig. 5).
Discussion
Our work is the first experimental animal study to evaluate
the effectiveness of HIPEC and its complications in a repro-
ducible model of peritoneal carcinomatosis of ovarian origin
that resembles the clinical situation. The closed abdomen
HIPEC mouse model we developed results in limited mor-
bidity and would facilitate the study of different HIPEC
regimens and its effects.
The standard front-line therapy for ovarian cancer is
cytoreductive surgery followed by intravenous platinum-
taxane chemotherapy. However, this approach is not
curative and approximately 60% of all patients with ovar-
ian cancer experience recurrence [16—19]. A major limiting
factor of clinical success is acquired or inherent resistance
Please cite this article in press as: Miailhe G, et al. A new animal model for hyperthermic intraperitoneal chemotherapy
(HIPEC) in tumor-bearing mice in the treatment of peritoneal carcinomatosis of ovarian origin. Journal of Visceral Surgery
(2017), https://doi.org/10.1016/j.jviscsurg.2017.10.008
5
to platinum. The combination of cytoreductive surgery
and HIPEC has been introduced as a means to overcome
this issue in the treatment of patients with peritoneal
carcinomatosis [20,21]. HIPEC represents a considerable
pharmacokinetic advantage over systemic treatment as it
achieves high concentrations of cytotoxic drugs locally and
minimizes systemic absorption, thus limiting potential side
effects.
The Gynecologic Oncology Group (GOG) [22—24] assessed
the efficacy and safety of intraperitoneal chemotherapy
in advanced ovarian cancer in three randomized trials.
Improved survival data were observed in the women under-
going surgery plus HIPEC compared to those undergoing
conventional systemic chemotherapy alone. However, the
patient cohorts were heterogeneous, differing in age, pre-
vious systemic therapy, tumor size and timing (primary OC,
consolidation treatment and recurrent/persistent disease)
[25]. Furthermore, there was a lack of homogeneity in
the way HIPEC was administered, such as variation in the
perfusate temperature, chemotherapy protocols, surgical
approach (open or closed technique) and HIPEC devices,
which further influences outcomes. Finally, the nature and
small number of the patients reported in these studies are
not enough to increase the level of evidence for HIPEC in OC
treatment.
Therefore, a reproducible, non-morbid animal model is
needed to improve HIPEC and test new therapies on human
cell lines. Although an HIPEC mouse model already exists,
the various studies involved in developing them [12—14]
did not report on post-treatment effects as the mice were
sacrificed immediately after the procedure. As seen above,
HIPEC complications are a major limiting factor that must
be improved.
Hyperthermia and the drugs used during HIPEC proce-
dures have a limited penetration depth [26]. Therefore,
HIPEC can only be effective in patients with minimal residual
disease after extensive cytoreductive surgery.
In our study, HIPEC could be conducted without difficulty
in all cases and none of the animals died during infusion. The
abdominal cavity was closed during the procedure and the
abdomen massaged to ensure stirring of the perfusate and a
more homogeneous distribution of the heated drug solution
throughout the entire abdominal cavity.
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6 G. Miailhe et al.
Our model consists of a closed abdomen procedure due to
the difficulties encountered during open abdomen surgery:
heat loss, bath liquid leakage and bleeding. Other advan-
tages of a closed procedure include less risk of exposure
of the chemotherapy for the operating staff, a homogenous
distribution of the drug (better diffusion on the diaphrag-
matic dome, and a constant intra-abdominal temperature
(no loss). A limitation of this model, however, is that the
abdominal peritoneal perfusate cannot be manually stirred
as in open infusion.
In Muenyi’s mice model [12], HIPEC infusion lasted
60 minutes as opposed to 12 minutes in our model beyond
which time signs of poor tolerance appeared. We there-
fore chose a high-dose chemotherapy with a high peritoneal
absorption potential over a shorter duration.
We used oxaliplatin in our HIPEC model for several rea-
sons [15]. Oxaliplatin is a platinum compound that acts as
an alkylating agent known to create DNA adducts leading to
apoptosis and impaired cell replication. Intravenous admin-
istration of oxaliplatin has shown success in the treatment of
colorectal cancer [27,28]. This has led many surgical teams
to use oxaliplatin by the intra-peritoneal route to treat
peritoneal carcinomatosis [20]. Intraperitoneal oxaliplatin
leads to high concentrations of the drug in peritoneal tis-
sues in proportion to the dose administered. Furthermore,
heat enhances peritoneal tissue concentration of oxaliplatin
while reducing its systemic absorption. This latter effect
may possibly lead to lower systemic toxicity.
No major complications were observed after HIPEC in our
experimental mouse model. Although data on side effects
remain limited, available studies have reported acceptable
morbidity and mortality rates [29,30]. These data, together
with the results of the present study, show that HIPEC could
be a safe therapy for peritoneal carcinomatosis.
Conclusion
The mouse model of closed-abdomen HIPEC we developed
in this study shows limited morbidity and could represent
a useful model to study different HIPEC regimens and its
effects on peritoneal carcinomatosis and survival. Further
animal studies are now mandatory to increase the effec-
tiveness and safety of HIPEC in women with ovarian cancer.
Disclosure of interest
The authors declare that they have no competing interest.
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Please cite this article in press as: Miailhe G, et al. A new animal model for hyperthermic intraperitoneal chemotherapy
(HIPEC) in tumor-bearing mice in the treatment of peritoneal carcinomatosis of ovarian origin. Journal of Visceral Surgery
(2017), https://doi.org/10.1016/j.jviscsurg.2017.10.008