A Coliseum with frail foundations: a critical analysis of the state-of-the-art open-abdomen HIPEC technique

a Coliseum with frail foundations
a critical analysis of the state-of-the-art
open-abdomen HIPEC technique
Marco Lotti MD
Advanced Surgical Oncology Unit
Papa Giovanni XXIII Hospital - Bergamo (Italy)
im.marco.lotti@gmail.com

Morbidity and Mortality Analysis of 200 Treatments With
Cytoreductive Surgery and Hyperthermic Intraoperative
Intraperitoneal Chemotherapy Using the Coliseum Technique
Arvil D. Stephens, MD, Robert Alderman, PA-C, David Chang, MD, Gary D. Edwards, PA-C,
Jesus Esquivel, MD, Gilbert Sebbag, MD, Mark A. Steves, MD, and Paul H. Sugarbaker, MD
Background: Peritoneal carcinomatosis from gastrointestinal cancers is a fatal diagnosis without
special combined surgical and chemotherapy interventions. Guidelines for cytoreductive surgery
and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) by using the Coliseum tech-
nique have been developed to treat patients with peritoneal carcinomatosis and other peritoneal
surface malignancies. The purpose of this study was to analyze the morbidity and mortality of
patients undergoing cytoreductive surgery and HIIC by using mitomycin C.
Methods: Data were prospectively recorded on 183 patients who underwent 200 cytoreductive
surgeries with HIIC between November 1994 and June 1998. Seventeen of the 183 patients returned
for a second-look surgery plus HIIC. All HIIC administrations occurred after cytoreduction and used
continuous manual separation of intra-abdominal structures to optimize drug and heat distribution.
Origins of the tumors were as follows: appendix (150 patients), colon (20 patients), stomach (7
patients), pancreas (2 patients), small bowel (1 patient), rectum (1 patient), gallbladder (1 patient),
and peritoneal papillary serous carcinoma (1 patient). Morbidity was organized into 20 categories
that were graded 0 to IV by the National Cancer Institute’s Common Toxicity Criteria. In an attempt
to identify patient characteristics that may predispose to complications, each morbidity variable was
analyzed for an association with the 25 clinical variables recorded.
Results: Combined grade III/IV morbidity was 27.0%. Complications observed included the
following: peripancreatitis (6.0%), fistula (4.5%), postoperative bleeding (4.5%), and hematological
toxicity (4.0%). Morbidity was statistically linked with the following clinical variables: duration of
surgery (P Ͻ .0001), the number of peritonectomy procedures and resections (P Ͻ .0001), and the
number of suture lines (P ϭ .0078). No HIIC variables were statistically associated with the
presence of grade III or grade IV morbidity. Treatment-related mortality was 1.5%.
Conclusions: HIIC may be applied to select patients with peritoneal carcinomatosis from gastroin-
testinal malignancies with 27.0% major morbidity and 1.5% treatment-related mortality. The frequency
of complications was associated with the extent of the surgical procedure and not with variables
associated with the delivery of heated intraoperative intraperitoneal chemotherapy. The technique has
shown an acceptable frequency of adverse events to be tested in phase III adjuvant trials.
Key Words: Morbidity—Mortality—Cytoreductive surgery—Hyperthermia—Intraperitoneal
chemotherapy—Mitomycin C—5-Fluorouracil—Pseudomyxoma peritonei—Colon cancer.
Peritoneal carcinomatosis and sarcomatosis are uni-
formly fatal diagnoses without special combined surgical
and intraperitoneal chemotherapy interventions. Malig-
nancies that present within the abdominopelvic cavity
often cause their great morbidity and mortality through
progressive involvement of the peritoneal surfaces. Ex-
amples of this can be seen in patients with appendiceal
Received March 5, 1999; accepted August 18, 1999.
From the Washington Cancer Institute, Washington, DC.
Annals of Surgical Oncology, 6(8):790–796
Published by Lippincott Williams & Wilkins © 1999 The Society of Surgical Oncology, Inc.
Hyperthermic intraoperative intraperitoneal chemo-
therapy was first added to cytoreductive surgery at the
Washington Hospital Center in March 1992. Sixty pa-
tients were enrolled in an Institutional Review Board-
approved phase I/II clinical trial. Informed consent was
obtained from all patients before surgery. This trial com-
bined cytoreductive surgery with heated intraoperative
mitomycin C administered by a closed abdominal tech-
nique. The techniques,2 pharmacokinetics,3,4 safety con-
siderations,5 and morbidity and mortality6 of the closed
intraoperative intraperitoneal chemotherapy technique
have been reported. Deficiencies were noted in the dis-
tribution of methylene blue dye with the closed tech-
nique, which may cause a high frequency of complica-
tions and nonuniform treatment. This prompted the
development of the Coliseum technique for HIIC, which
allowed for manual distribution of heat and drugs.7,8
After the conclusion of the investigative phase, clinical
guidelines combining cytoreductive surgery and HIIC
for biopsy-confirmed peritoneal carcinomatosis from
gastrointestinal malignancies were used. These data were
prospectively recorded for 200 treatments in 183 patients
that occurred between November 1994 and June 1998.
The techniques of cytoreductive surgery have been
9
dialysis solution containing 12.5 mg/m2
of mitomycin C
for males (maximum dose, 25 mg) or 10.0 mg/m2
for
females (maximum dose, 20 mg) was heated and infused
at approximately 1 liter/minute. Temperatures were mea-
sured with a Labcraft digital thermometer (Curtin Mathe-
son Scientific, Jessup, MD). The temperature at the in-
flow line was approximately 44°C. The Tenckhoff
temperature probe was maintained between 42°C and
43°C, and a distant intra-abdominal site averaged
39.6°C. Throughout the perfusion, the surgeon continu-
ously manipulated the viscera to distribute both heat and
chemotherapy.
All bowel anastomoses were constructed with hand-
sewn two-layer closures with two exceptions. Low colo-
rectal anastomoses were performed with a 33-mm-diameter
intraluminal stapler and esophagojejunal anastomoses with
a 29-mm-diameter intraluminal stapler (Ethicon Endo-
surgical, Cincinnati, OH). If a pyloroplasty was per-
formed, it was a full-thickness incision closed with a
single layer of interrupted silk sutures.
TABLE 1. Patient characteristics
No. of patients receiving 1 cytoreduction ϩ HIIC 166
No. of patients receiving 2 cytoreductions ϩ HIIC 17
The Coliseum technique was developed
to overcome the uneven distribution of
the perfusion fluid that was observed
with the closed-abdomen technique.
The key concept of the Coliseum
technique is the manual distribution of
heat and chemotherapy.
Marco Lotti MD

It has been 30 years since the first HIPEC was delivered by
ratt et al5 in 1979 at the University of Louisville to a male patient
h pseudomyxoma peritonei. During these 3 decades, there have
en significant changes on how to deliver the heated perfusate,
different sites of the circuit and the intraperitoneal cavity: heat
generator, heat exchanger, inflow and outflow catheters and some
centers add temperature probes to the liver and bladder. During the
Milan consensus, it was agreed that the desirable intra-abdominal
temperature range that needs to be maintained during HIPEC should
be between 41.5°C and 43°C. This temperature is usually accom-
6
FIGURE 2. Open “colisuem” technique for HIPEC.
GURE 1. Concentration of mitomycin C in plasma versus
ritoneal fluid.
The
“Coliseum”
Open Abdomen HIPEC
22
Smoke evacuator tubing
Plastic sheet
Self retaining
retractor
Technical Handbook for the Integration of Cytoreductive
Surgery and Perioperative Intraperitoneal Chemotherapy
into the Surgical Management of Gastrointestinal and
Gynecologic Malignancy
4th
Edition
Paul H. Sugarbaker, MD, FACS, FRCS
Contents
I. Background and rationale
II. Quantitative prognostic indicators
III. Peritonectomy
IV. Sugarbaker retractor
V. Heater circulator apparatus
VI. Heated intraoperative intraperitoneal chemotherapy
VII. Early postoperative intraperitoneal chemotherapy
VIII. Clinical pathway for postoperative care
IX. Results of treatment
X. Current indications for cytoreductive surgery plus perioperative intraperitoneal
chemotherapy
XI. Conclusions
XII. Appendix
Foundation for Applied Research in
Gastrointestinal Oncology
December 5, 2005

It has been 30 years since the first HIPEC was delivered by
ratt et al5 in 1979 at the University of Louisville to a male patient
h pseudomyxoma peritonei. During these 3 decades, there have
en significant changes on how to deliver the heated perfusate,
different sites of the circuit and the intraperitoneal cavity: heat
generator, heat exchanger, inflow and outflow catheters and some
centers add temperature probes to the liver and bladder. During the
Milan consensus, it was agreed that the desirable intra-abdominal
temperature range that needs to be maintained during HIPEC should
be between 41.5°C and 43°C. This temperature is usually accom-
6
FIGURE 2. Open “colisuem” technique for HIPEC.
GURE 1. Concentration of mitomycin C in plasma versus
ritoneal fluid.
22
Smoke evacuator tubing
Plastic sheet
Self retaining
retractor
4th
Edition
Contents
III. Peritonectomy
chemotherapy
XI. Conclusions
XII. Appendix
December 5, 2005
We have:
• a plastic barrier
• a forced air flow
• a basin filled with fluid and
viscera
• a hand-shaped impeller

A single inflow and four outflow tubes are placed through the lateral aspect of the
abdominal wall for hyperthermic peritoneal irrigation. The inflow catheter is secured to a
temperature probe within the mid-abdomen. During the hyperthermic chemotherapy irrigation
the inflow catheter is placed beneath the right hemidiaphragm. After the skin edges are elevated
by monofilament suture, a lid, also made of stainless steel, closes off the space above the
peritoneal cavity except for an access site. An impermeable disposable drape covers the entire
operative field with a cruciate cut in its central portion to open the access site. The surgeon’s
double-gloved arm is placed through the access site to continuously mix the heated
chemotherapy solution (Figure 33). If desired to further seal off the open abdomen, the access
site may be secured to the surgeon’s arm by hand assist laparoscopy equipment. If the access
4th
Edition
Contents
III. Peritonectomy
chemotherapy
XI. Conclusions
XII. Appendix
Behind the Coliseum technique is
the trust that hand mixing leads to
the homogeneous distribution of
heat and chemo.
Marco Lotti MD

“have the homogeneous distribution”
González-Moreno S et al. HIPEC: Rationale and Technique
of drugs are in micrograms, so that it is not possible to
have a major spill; (13) Cleaning the operating room after
10
11
12
13
14
15
Figure 1 Administration of HIPEC by the coliseum (open) technique.
Constant manipulation of the perfusate ensures a homogeneous distribution of
the heated chemotherapy within the peritoneal cavity. Note that elbow-length
double gloving, goggles and an impervious gown are used.
A single inflow and four outflow tubes are placed through the lateral aspect of the
abdominal wall for hyperthermic peritoneal irrigation. The inflow catheter is secured to a
temperature probe within the mid-abdomen. During the hyperthermic chemotherapy irrigation
the inflow catheter is placed beneath the right hemidiaphragm. After the skin edges are elevated
by monofilament suture, a lid, also made of stainless steel, closes off the space above the
peritoneal cavity except for an access site. An impermeable disposable drape covers the entire
operative field with a cruciate cut in its central portion to open the access site. The surgeon’s
double-gloved arm is placed through the access site to continuously mix the heated
chemotherapy solution (Figure 33). If desired to further seal off the open abdomen, the access
site may be secured to the surgeon’s arm by hand assist laparoscopy equipment. If the access
4th
Edition
Contents
III. Peritonectomy
chemotherapy
XI. Conclusions
XII. Appendix
“mix the solution”
This trust has been readily shared by many…
Marco Lotti MD

gical staff. Thus, the following factors must be taken into account: (1) the per-
ceived risk of environmental chemotherapy exposure (the real risk is negligi-
ble if proper safety measures are followed); (2) concerns regarding possible
differences in uniform distribution of the chemotherapeutic agent or heat
throughout the peritoneal cavity, which may result in visceral thermal injury;
and (3) possible differences in dosage and perfusate volume inherent to the
closed method.
Table 10.2 Choosing the hyperthermic intraperitoneal chemotherapy (HIPEC) procedure
Feature Open Closed Semiopen
Uniform heat and chemotherapy distribution
Minor heat dissipation
No direct contact of surgeon with chemotherapeutic agent
Minimize risk of chemotherapeutic agent exposure to
operating-room staff
Minimize risk of thermal injury
User friendliness
37Journal of Gastrointestinal Oncology Vol 7, No 1 February 2016
Table 4 Credits and debits of two different technologies for hyperthermic intraperitoneal chemotherapy
Features Open abdomen manually distributed Closed abdomen
Efficiency Allows continued cytoreduction of bowel and
mesenteric surfaces
No surgery possible during chemotherapy
Environmental hazard No aerosols detected Perception of increased safety
Distribution Uniform distribution of heat and chemotherapy
solutions, tissues close to skin edge not immersed
Possible poor distribution to dependent sites and
closed spaces
Pressure No increased intraabdominal pressure Increased intraabdominal pressure may increase
chemotherapy penetration into tissue
Pharmacology Allows pharmacokinetic monitoring of tumor and
normal tissue
Tissue uptake of chemotherapy cannot be
determined
Abdominal incision
and suture lines
Treated prior to performing the suturing Risk of recurrence in abdominal incision and suture
lines
Diaphragm perforation
with peritonectomy
Pleural space treated by hyperthermic chemotherapy
may prevent seeding of pleural space
Diaphragm closed prior to hyperthermic intraperitoneal
chemotherapy so pleural space is not treated
Intestinal perforation Detected by observing immersed bowel loops Not detected
Hyperthermia Increased heat necessary to maintain 42 ℃ Less heat required to maintain 42 ℃
Surgical technology and pharmacology of hyperthermic perioperative
chemotherapy
Paul H. Sugarbaker1
, Kurt Van der Speeten2
1
Center for Gastrointestinal Malignancies, MedStar Washington Hospital Center, Washington, DC, USA; 2
Department of Surgical Oncology,
Ziekenhuis Oost-Limburg, Genk, Belgium
Contributions: (I) Concept and design: All authors; (II) Administrative support: Foundation for Applied Research in Gastrointestinal Oncology;
(III) Provision of study materials or patient: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All
authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Correspondence to: Paul H. Sugarbaker, MD, FACS, FRCS. MedStar Washington Hospital Center, 106 Irving St., NW, Suite 3900, Washington, DC
20010, USA. Email: Paul.Sugarbaker@medstar.net.
Abstract: Although cytoreductive surgery (CRS) and hyperthermic perioperative chemotherapy (HIPEC)
have not been shown to be effective by themselves, as a combined treatment they are now standard of care for
peritoneal metastases from appendiceal cancer and from colorectal cancer as well as peritoneal mesothelioma.
The timing of the HIPEC in relation to the CRS is crucial in that the HIPEC is to destroy minimal residual
disease that remains following the CRS and prevent microscopic tumor emboli within the abdomen and
pelvis from implanting within the resection site, within fibrinous clot, or within blood clot. Proper selection
of chemotherapy agents is crucial to the long-term benefit of CRS and HIPEC. One must consider the
response expected with the cancer chemotherapy agent, its area under the curve (AUC) ratio indicating the
amount of dose intensity within the peritoneal space, and the drug retention within the peritoneal space
for a prolonged exposure. Hyperthermia will augment the cytotoxicity of the cancer chemotherapy agents
and improve drug penetration. Irrigation techniques should not be overlooked as an important means of
reducing the cancer cell burden within the abdomen and pelvis. Multiple technologies for HIPEC exist and
these have advantages and disadvantages. The techniques vary from a totally open technique with a vapor
barrier over the open abdominal space to a totally closed technique whereby the HIPEC is administered at
the completion of the surgical procedure. The open techniques depend on a table-mounted retractor for
suspension of the skin edges allowing a reservoir to occur within the abdomen and pelvis. There are nearly
a dozen commercially available hyperthermia pumps, all of which seem to perform adequately for HIPEC
although there is a variable degree of convenience and documentation of the HIPEC procedure. As the
management of peritoneal metastases has progressed over three decades, early cases are now seen in which
a laparoscopic CRS and HIPEC may be appropriate. Also, prophylactic use of laparoscopic HIPEC with
perforated appendiceal malignancies and T4 colon cancers may be appropriate.
Keywords: Peritoneal metastases; carcinomatosis; peritoneal mesothelioma; irrigation; laparoscopy; laparoscopic
cytoreductive surgery; hyperthermic perioperative chemotherapy (HIPEC)
Submitted Jun 27, 2015. Accepted for publication Aug 20, 2015.
doi: 10.3978/j.issn.2078-6891.2015.105
Updates in Surgery
Treatment
of Peritoneal
Surface
Malignancies
Angelo Di Giorgio
Enrico Pinto Editors
In collaboration with
Paolo Sammartino and Franco Roviello
State of the Art and Perspectives
…and definitely credited to
the Coliseum technique
Marco Lotti MD

The image of the Surgeon
who acts with her/his hands
to distribute heat and chemo
is very powerful.
It is a suggestion that
influenced many operators,
who became mirrors
of the belief that hand mixing
entails the homogeneous
distribution of the desired
therapy.
Marco Lotti MD

“Constant manipulation of the perfusate ensures
a homogeneous distribution of the heated
chemotherapy within the peritoneal cavity”
“In the methodology described by Sugarbaker,
access to the abdomen and pelvis is maintained
during the chemotherapy treatment so that the
surgeon can distribute the heat and the
chemotherapy solution uniformly. This resulted
in a decreased morbidity associated with the
procedure and is likely to improve its
effectiveness”
“The main benefit of the Coliseum technique is
that heated chemotherapy is adequately
distributed throughout the abdominal cavity and
there is no pooling of temperature or
chemotherapy”
Annals of Surgical Oncology, 9(2): 186-191
Published by Lippincon Williams & Wilkins 9 2002 The Society of Surgical Oncology, Inc.
Safety Monitoring of the Coliseum Technique for Heated
Intraoperative Intraperitoneal Chemotherapy With Mitomycin C
O. Anthony Stuart, BS, Arvil D. Stephens, BS, Laura Welch, MD, and Paul H. Sugarbaker, MD
Background: Treatment of carcinomatosis may involve the use of heated intraperitoneal che-
motherapy; the cytotoxic solution is administered in the operating room with the abdomen open so
that manual distribution results in uniform treatment. The potential risk of this procedure to the
operating room personnel has not been previously investigated.
Methods: Mitomycin C was perfused through the peritoneal cavity, which was partially covered
by a plastic sheet. Large volumes of air were suctioned from 5 and 35 cm above the abdominal skin
edge. Urine from the surgeon and from the perfusionist were assayed. Sterile gloves worn in the
operating room for manipulating the viscera during treatment were assayed for their permeability to
mitomycin C. All samples were analyzed by high-performance liquid chromatography.
Results: Analysis of samples of operating room air and urine from 10 procedures showed no
detectable levels of mitomycin C. Six tests of three different types of gloves showed a 10-fold range
of mitomycin C penetration. The least permeable gloves leaked a mean of 3.8 parts per million over
90 minutes.
Conclusions: No detectable safety hazard to the surgeon or other operating room personnel was
demonstrated.
Key Words: Safety monitoring--Operating room--Hyperthermia--Intraperitoneal chemothera-
py--Mitomycin C---Latex gloves.
Gastrointestinal and gynecologic malignancies fre-
quently disseminate to the peritoneal surfaces. Preven-
tion or adequate treatment of disease at this anatomical
site would improve the survival of patients if dissemina-
tion did not occur elsewhere in the body. For patients
with distant metastases, eradication of cancer on abdom-
inal and pelvic surfaces would result in a quality of life
advantage because intestinal obstructions would occur
much less frequently. 1One method currently used at this
institution in >450 patients to treat the peritoneal surface
component of these malignancies is heated intraoperative
intraperitoneal chemotherapy. 2 Heat synergizes the cyto-
toxic effects of chemotherapy. 3 In addition, heat in-
creases the penetration of chemotherapy solution into
cancer nodules, 4 To improve penetration of tumor nod-
ReceivedAugust 9, 2000; acceptedSeptember20, 2001.
From the WashingtonCancer Institute, Occupationaland Environ-
mental Medicine,WashingtonHospitalCenter,Washington,DC.
Addresscorrespondenceand reprintrequeststo: PaulH. Sugarbaker,
MD, WashingtonCancer Institute, WashingtonHospital Center, 110
IrvingSt., N.W.,Washington,DC 20010;Fax: 202-877-8602;E-mail:
paul.sugarbaker@medstar.net.
ules by chemotherapy, the size of tumor nodules is
maximally cytoreduced before the heated chemotherapy
treatments. In the methodology described by Sugarbaker
et al.,2 access to the abdomen and pelvis is maintained
during the chemotherapy treatment so that the surgeon
can distribute the heat and the chemotherapy solution
uniformly. This resulted in a decreased morbidity asso-
ciated with the procedure and is likely to improve its
effectiveness. 5 With an increasing number of institutions
adopting this strategy to treat and prevent peritoneal
surface malignancy, there has been a growing concern
regarding the safety of this technique for operating room
personnel.
The most common chemotherapy agent used in heated
intraoperative intraperitoneal chemotherapy procedures
is mitomycin C. It was suitable for this study because it
is highly soluble in methanol and because it is rapidly
absorbed and excreted unchanged in the urine, 6 Mitomy-
cin C can also be accurately assayed by established
high-performance liquid chromatography (HPLC) tech-
niques. 7-9 The purpose of this study was to assay in 10
patients for any detectable level of mitomycin C in the
186
Santiago González-Moreno, Luis A González-Bayón,
Gloria Ortega-Pérez, Peritoneal Surface Oncology Program,
Department of Surgical Oncology, Centro Oncológico MD
Anderson International España, 28033 Madrid, Spain
Author contributions: González-Moreno S, Ortega-Pérez G,
and González-Bayón LA designed, discussed the paper contents
and collected pertinent information; González-Moreno S wrote
the paper.
Correspondence to: Santiago González-Moreno, MD, PhD,
Peritoneal Surface Oncology Program, Department of Surgical
Oncology, Centro Oncológico MD Anderson International
España, Calle Arturo Soria 270, 28033 Madrid,
Spain. sgonzalez@mdanderson.es
Telephone: +34-91-7878600 Fax: +34-91-7680681
Received: July 2, 2009 Revised: January 11, 2010
Accepted: January 18, 2010
Published online: February 15, 2010
Abstract
The combination of complete cytoreductive surgery
and perioperative intraperitoneal chemotherapy
provides the only chance for long-term survival for
selected patients diagnosed with a variety of peritoneal
neoplasms, either primary or secondary to digestive or
gynecologic malignancy. Hyperthermic intraperitoneal
chemotherapy (HIPEC) delivered in the operating room
once the cytoreductive surgical procedure is finalized,
constitutes the most common form of administration
of perioperative intraperitoneal chemotherapy. This
may be complemented in some instances with early
postoperative intraperitoneal chemotherapy (EPIC).
HIPEC combines the pharmacokinetic advantage
inherent to the intracavitary delivery of certain cytotoxic
drugs, which results in regional dose intensification,
with the direct cytotoxic effect of hyperthermia.
Hyperthermia exhibits a selective cell-killing effect
in malignant cells by itself, potentiates the cytotoxic
effect of certain chemotherapy agents and enhances
the tissue penetration of the administered drug. The
chemotherapeutic agents employed in HIPEC need
to have a cell cycle nonspecific mechanism of action
and should ideally show a heat-synergistic cytotoxic
effect. Delivery of HIPEC requires an apparatus that
heats and circulates the chemotherapeutic solution
so that a stable temperature is maintained in the
peritoneal cavity during the procedure. An open
abdomen (Coliseum) or closed abdomen technique
may be used, with no significant differences in efficacy
proven to date. Specific technical training and a solid
knowledge of regional chemotherapy management
are required. Concerns about safety of the procedure
for operating room personnel are expected but are
manageable if universal precautions and standard
chemotherapy handling procedures are used. Different
HIPEC drug regimens and dosages are currently in use.
A tendency for concurrent intravenous chemotherapy
administration (bidirectional chemotherapy, so-called
“HIPEC plus”) has been observed in recent years, with
the aim to further enhance the cytotoxic potential
of HIPEC. Future trials to ascertain the ideal HIPEC
regimen in different diseases and to evaluate the
efficacy of new drugs or drug combinations in this
context are warranted.
© 2010 Baishideng. All rights reserved.
Key words: Hyperthermia; Intracavitary chemotherapy;
Peritoneal neoplasms; Peritoneal carcinomatosis;
Cytoreductive surgery
Peer reviewer: Akihiko Tsuchida, MD, PhD, Associate Professor,
Department of Surgery, Tokyo Medical University, 6-7-1 Nishi-
Shinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
González-Moreno S, González-Bayón LA, Ortega-Pérez G.
Hyperthermic intraperitoneal chemotherapy: Rationale and
technique. World J Gastrointest Oncol 2010; 2(2): 68-75
Available from: URL: http://www.wjgnet.com/1948-5204/full/
v2/i2/68.htm DOI: http://dx.doi.org/10.4251/wjgo.v2.i2.68
Online Submissions: http://www.wjgnet.com/1948-5204office
wjgo@wjgnet.com
doi:10.4251/wjgo.v2.i2.68
World J Gastrointest Oncol 2010 February 15; 2(2): 68-75
ISSN 1948-5204 (online)
© 2010 Baishideng. All rights reserved.
68 February 15, 2010|Volume 2|Issue 2|WJGO|www.wjgnet.com
Hyperthermic intraperitoneal chemotherapy: Rationale and
technique
Santiago González-Moreno, Luis A González-Bayón, Gloria Ortega-Pérez
TOPIC HIGHLIGHT
Antonio Macrì, MD, Professor,Series Editor
Updates in Surgery
Treatment
of Peritoneal
Surface
Malignancies
Angelo Di Giorgio
Enrico Pinto Editors
In collaboration with
Paolo Sammartino and Franco Roviello
State of the Art and Perspectives
Marco Lotti MD

but what is the desired therapy?
Marco Lotti MD

the desired therapy is called HIPEC
• Exposure of the WHOLE peritoneal surface to HEAT and CHEMO
• An adequate volume of PERFUSION FLUID is needed
• The perfusion fluid should be maintained at 41-42°C
• And FREELY recirculate through the abdomen for 30-90 min
Marco Lotti MD

As far as HEAT is concerned,
one can argue that the statement
that hand mixing entails the
homogeneous distribution of the
desired therapy is not supported
by sound evidence.
Moreover,
when it comes to physical laws,
that claimed homogeneous
distribution is very unlikely to
occur.
Marco Lotti MD

The Level of Evidence affair
Marco Lotti MD

could be extended to the clinical ground; (2) what is the impact of the
duration of the procedure when we used high temperature?
The duration of hyperthermia. There is clinical data demon-
strating the safety of hyperthermia with different schemes established
on empirical bases, but not from systematic experimental studies.
These schemes are the following: to use a temperature of 418C but
during 90 min, or to use 438C but during 30–40 min. Also, some teams
use a temperature of 428C during 60 min. Long duration hyperthermia
needs to use cooling systems to decrease the body’s temperature.
Unfortunately, there is no systematic study about the escalation of the
level and also of the duration of hyperthermia in animals or in human.
However, it appears that low hyperthermia allows long duration of the
procedure and that high hyperthermia do not allow it. At that time
nobody knows if it more efficient to privilege high temperature or long
duration. If they were equivalent, the first should be cheaper.
Also, it is necessary to obtain a thermal homogeneity in the whole
abdominal cavity to be sure that every site of the diffuse peritoneal
disease will receive the optimal treatment. It is well accepted in the
literature that only the coliseum technique with a continuous stirring of
the viscera, allows to obtain it. Even with this continuous stirring, and a
high flow rate in the pumps (2 L/min), and with a moderate volume of
perfusate (2 L/m2
), in the experience of Elias et al., to obtain
a minimum of 428C in the out-drains, it is necessary to have between
44 and 458C in the in-drains.
The Different Parameters Impacting on
Pharmacokinetics and Efficacy of HIPEC
Journal of Surgical Oncology 2008;98:247–252
Drugs, Carrier Solutions and Temperature in
Hyperthermic Intraperitoneal Chemotherapy
SHIGEKI KUSAMURA, MD, PhD,1
ELIAS DOMINIQUE, MD, PhD,2
*,{
DARIO BARATTI, MD,1
RAMI YOUNAN, MD,3
AND MARCELLO DERACO, MD
1
1
Department of Surgery, National Cancer Institute of Milan, Italy
2
Department of Surgical Oncology, Institut Gustave Roussy, Villejuif, France
3
Department of Surgery-Surgical Oncology Unit, CHUM, University of Montreal Health Centre, Montreal, Canada
Fifth International Workshop on Peritoneal Surface Malignancy, in Milan, the consensus on technical aspects of cytoreductive surgery
for peritoneal surface malignancy was obtained through the Delphi process. Conflicting points concerning drugs, carrier solution and
l temperature for hyperthermic intraperitoneal chemotherapy (HIPEC) were discussed.
g. Oncol. 2008;98:247–252. ß 2008 Wiley-Liss, Inc.
KEY WORDS: peritoneal carcinomatosis; hyperthermic intraperitoneal chemotherapy; consensus
INTRODUCTION
December 4–6, 2006, the National Cancer Institute of Milan
zed a consensus statement on the management of peritoneal
malignancy (PSM). This conference brought together experts
field of local–regional therapy in an effort to discuss current
ches to this PSM.
Eligible Drugs for Hyperthermic
Intraperitoneal Chemotherapy
eral drugs are available for intraperitoneal use, as outlined in
. Theoretically, only cell cycle phase non-specific agents are
ed for this single-shot cancer treatment. In other words cell
hase specific agents should be not suitable for HIPEC.
the concentration of agents in the perfusate, the volume of the carrier
solution should also be taken in consideration [1,2].
In Table III different types of carrier solution and their respective
main characteristics are outlined.
Intraperitoneal Temperature During HIPEC
There is two different but synergic points to consider: the suitable
temperature to obtain and the duration of hyperthermia.
What is the theoretical optimal temperature? Different levels
of target temperatures have been reported in the literature: from 40 to
418C [3], from 41 to 438C [4], from 41.5 to 42.58C [20], 428C [5], from
42 to 438C [6] and from 42 to 458C [7].
The establishment of the optimal temperature level during the per-
fusion requires the consideration of several aspects regarding the inter-
Journal of Surgical Oncology 2008;98:242–246
Hyperthermic Intraperitoneal Chemotherapy:
Nomenclature and Modalities of Perfusion
OLIVIER GLEHEN, MD, PhD,1,2
* EDDY COTTE, MD,1,2
SHIGEKI KUSAMURA, MD, PhD,3
MARCELLO DERACO, MD,3
DARIO BARATTI, MD,3
GUILLAUME PASSOT, MD,1,2
ANNIE-CLAUDE BEAUJARD, MD,2,4
AND GILLY FRANCOIS NOEL, MD, PhD,1,2
1
Department of Oncologic surgery, Centre Hospitalo-Universitaire Lyon Sud, Pierre Beńite Cedex, France
2
EA 3738, UCBL, Faculte´ de me´dicine Lyon Sud, Oullins Cedex, France
3
Fondazione IRCCS Istituto Nazionale dei Tumori Milano, Milan, Italy
4
Department of Anesthesiology, CHLS—HCL, Pierre Beńite Cedex, France
Following international consensus, HIPEC should be the acronym used in the scientific literature to refer to the hyperthermic intraperitoneal
chemotherapy. Several modalities of perfusion are used to deliver HIPEC: open abdominal technique (Coliseum), closed abdominal technique,
peritoneal cavity expander, semi-opened abdominal technique. There is no sufficient evidence in literature confirming the superiority of one
technique over the others in terms of outcome, morbidity and safety to the personnel of the operating theatre. Each option has its own operational
advantages and disadvantages and future prospective studies must be conducted to establish which one is the best alternative. Today, the best
technique is the one which is routinely used and improved into each specialized institution involved in the management of peritoneal surface
malignancy.
J. Surg. Oncol. 2008;98:242–246. ß 2008 Wiley-Liss, Inc.
KEY WORDS: hyperthermia; peritoneal carcinomatosis; techniques; intraperitoneal chemotherapy
INTRODUCTION
Patients with peritoneal carcinomatosis have long been considered
as a terminal condition with no curative options. Over the past decade,
novel therapeutic approaches to peritoneal surface malignancies
have emerged. Loco-regional treatments including cytoreductive
surgery and peritonectomy procedures for the macroscopic disease in
combination with perioperative intraperitoneal chemotherapy for
the microscopic residual disease have been developed for this loco-
regional disease. There are different modalities for perioperative
intraperitoneal chemotherapy administration. Most of peritoneal
surface malignancy treatment centers exclusively use hyperthermic
intraperitoneal chemotherapy (HIPEC), some others only early post-
operative administration and others use both sequentially. Several
devices or technologies of HIPEC have been described and are
Modalities of Perfusion
Early postoperative intraperitoneal chemotherapy. Early post-
operative intraperitoneal chemotherapy (EPIC) is delivered by a
Tenckhoff catheter or by a subcutaneous port placed through the
abdominal wall in the approximate area at the greatest risk of
recurrence after cytoreductive surgery. Closed suction drains are
placed in dependant areas in the pelvis and below each hemi-
diaphragm. Intraperitoneal chemotherapy is administered postoper-
atively on postoperative days 1–5, but can be initiated immediately
postoperatively and continued in the outpatient setting [3].
EPIC has the advantages to administer multiple cycles of
chemotherapy. During each treatment, the chemotherapeutic drug is
not drained for at least 24 hr, to increase the duration of exposure of
tumor cells to therapy.
results to a longer bathing duration with decreased drug concentration.
The best duration is not known and depends on the protocol used [8,9].
Among the different devices reported into scientific literature we will
discuss advantages and inconvenient of open abdomen (coliseum)
technique, closed abdomen technique, peritoneal cavity expander and
semi-open technique.
Open abdomen technique. The open abdominal technique has also
been referred to as the ‘‘Coliseum technique’’. A silastic sheet is
sutured over a Thompson retractor and to the patient’s skin over the
abdominal incision. This suspends that abdominal wall creating a
‘‘Coliseum’’ or ‘‘soup bowl-like’’ container for instillation of the
peritoneal perfusate. An incision is made in the middle of the sheet
to allow manual manipulation of the intra-abdominal contents
to prevent stasis of the heated perfusate. A smoke evacuator is
used to clear aerosolized chemotherapy liberated during the procedure
(Fig. 1).
Elias et al. [14] did a prospective phase II trial testing seven
different techniques in 32 patients. They found that complete closure of
the abdominal wall before the perfusion restricted the volume of the
perfusion, decreased spatial diffusion of the instillate, and resulted in
lack of thermal homogeneity. Use of the a peritoneal cavity expander
o
G
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r
g
H
t
t
i
Journal of Surgical Oncology
T
C
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E
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treated with cytoreductive surgery combined with perioperative
intraperitoneal chemotherapy [5]. Its efficacy is limited by adhesions
that can result in pooling of the chemotherapeutic drugs in
intraperitoneal loculations. Not only does this sequester the treatment
from tumor cells, loculations also result in exposure of normal tissue
to high concentrations of drug, thereby adding to the morbidity of the
therapy [6].
EPIC do not involve hyperthermia. However heat has been shown to
be cytotoxic in vitro at 42.58C [7], and hyperthermia has been shown to
enhance the antitumor effect of agents such as oxapliplatin, mitomycin,
doxorubicin, and cisplatin, by augmenting cytotoxicity and increasing
the penetration of drugs into tissue [8–10]. Moreover, Elias et al.
recently compared two groups of patients with colorectal carcinoma-
tosis with characteristics as similar as possible. One was treated with
EPIC using 5-FU and mitomycin C and one with HIPEC using
oxaliplatin at 438C. All results were in favor of HIPEC group:
mortality, morbidity, rate of peritoneal recurrence which was twice in
EPIC group and overall survival [11].
Thus, EPIC may be used in the treatment of microscopic residual
peritoneal disease, but following HIPEC which seems to be more
efficient, with an increased risk of postoperative complications.
HIPEC. To take advantage of the synergistic effect of chemo-
therapy and hyperthermia, several different HIPEC devices to enable
intraoperative perfusion of the peritoneal cavity with hyperthermic
chemotherapy have been developed. Constant hyperthermia is ob-
tained by a closed continuous circuit, with pump, heater, heat
exchanger, and real-time temperature monitoring. Open circuit without
recirculation and reheating of the instillate should be avoided [8,9]. To
avoid systemic hyperthermia during the perfusion procedure, core
temperature have to be not more than 34–358C at the beginning of the
allowed an immediate thermal homogeneity, but the expander
isolated the abdominal wall from the instillate, resulting in early
parietal peritoneal recurrence. The use of coliseum technique was
identified into this single institution as the best technique in terms of
thermal homogeneity and spatial diffusion. Because the surgeons can
manipulate the intra-abdominal viscera during perfusion, all peritoneal
surfaces are equally exposed to therapy. Furthermore, excessive
heating of normal tissue that can exacerbate post-operative ileus and
increase the incidence of postoperative perforation or fistula formation
is avoided [15].
Disadvantage of this technique is that the open abdomen naturally
Fig. 1. The coliseum apparatus. [Color figure can be viewed in the
online issue, available at www.interscience.wiley.com.]
…
…
Marco Lotti MD

the claimed evidence is based on two articles:
1. Elias D, Antoun S, Goharin A, Otmany AE, Puizillout JM, Lasser P. Research on the best
chemohyperthermia technique of treatment of peritoneal carcinomatosis after complete
resection. Int J Surg Investig. 2000;1(5):431-9.
2. Stephens AD, Alderman R, Chang D, Edwards GD, Esquivel J, Sebbag G, Steves MA,
Sugarbaker PH. Morbidity and mortality analysis of 200 treatments with cytoreductive
surgery and hyperthermic intraoperative intraperitoneal chemotherapy using the
coliseum technique. Ann Surg Oncol. 1999 Dec;6(8):790-6.
Marco Lotti MD

Elias D, Antoun S, Goharin A, Otmany AE, Puizillout JM, Lasser P.
Research on the best chemohyperthermia technique of treatment of
peritoneal carcinomatosis after complete resection.
Int J Surg Investig. 2000;1(5):431-9.
• The International Journal of Surgical Investigation
started in 1999 and ended in 2001. It is not to be
found on the web. I could not find any link to the
journal website available by Google search. My
librarian was not able to retrieve the article.
• I tried to request the article on ResearchGate and
Mendeley, without success.
• I could just make some considerations about the
Abstract.
Marco Lotti MD

BACKGROUND:
AIMS:
METHODS:
RESULTS:
Abstract
The complete or almost complete resection of peritoneal carcinomatosis (PC)
followed by intraperitoneal chemohyperthermia (IPCH) is potentially capable of curing some
patients presenting with disease confined to the peritoneum.
The aim of this prospective phase I-II study was to develop an efficient IPCH procedure
with good thermal homogeneity and good spatial diffusion, that would be reproducible (and thus
could be standardized and exported), and to evaluate patient tolerance and its efficiency in
eradicating tumor tissue.
Seven IPCH procedures were tested successively in 32 patients (up to a total of 35
IPCH). Each procedure was tested in at least 4 patients before modifications for technical
reasons or due to inacceptable tolerance. Five of them were followed by early postoperative
intraperitoneal chemotherapy (EPIC) lasting 4 days. Thermal homogeneity was measured with 6
thermal probes placed in different positions inside the abdominal cavity. Spatial diffusion was
studied in the last patients by adding methylene blue to the IPCH liquid. The mean follow-up was
23.85 months for the series.
From the technological point of view, we have progressively shown that procedures
with closure of the abdomen are not satisfactory: it was impossible to obtain thermal
homogeneity when the entire parietal wound was closed, but markedly improved when only the
skin was closed. However, these "closed" procedures did not allow us to treat all surfaces at risk.
The peritoneal cavity "expander" did not permit treatment of the parietal wound and an
indeterminate amount of the perfusion oozed out at its periphery. The open technique with
traction of the skin upwards was superior. Using different procedures successively undermined
the quality of the postoperative results. Three patients (8.6%) died and morbidity (albeit minimal)
Author information
BACKGROUND:
AIMS:
METHODS:
RESULTS:
Research on the best chemohyperthermia technique of treatment
of peritoneal carcinomatosis after complete resection.
Elias D , Antoun S, Goharin A, Otmany AE, Puizillout JM, Lasser P.
Abstract
Format: Abstract
1
Author information
PubMedThe Level of Evidence affair
7 procedures tested
in 32 patients
Each procedure
tested in 4 (maybe 5)
patients
6 thermal probes
used to measure
thermal homogeneity
Marco Lotti MD

BACKGROUND:
AIMS:
METHODS:
RESULTS:
Abstract
Format: Abstract
1
Author information
PubMed
7 procedures tested
in 32 patients
Each procedure
tested in 4 (maybe 5)
patients
6 thermal probes
used to measure
thermal homogeneity
As far as Statistics is concerned and sample size
calculation is considered, only huge differences
between techniques can be found to be significant
by means of so small samples.
Otherwise, the differences found between samples
cannot be credited to any of the techniques and are
likely to be subject to the opinion of the Researchers.
Marco Lotti MD

BACKGROUND:
AIMS:
METHODS:
RESULTS:
Abstract
homogeneity when the entire parietal wound was closed, but markedly improved when only the
skin was closed. However, these "closed" procedures did not allow us to treat all surfaces at risk.
The peritoneal cavity "expander" did not permit treatment of the parietal wound and an
indeterminate amount of the perfusion oozed out at its periphery. The open technique with
traction of the skin upwards was superior. Using different procedures successively undermined
the quality of the postoperative results. Three patients (8.6%) died and morbidity (albeit minimal)
Author information
BACKGROUND:
AIMS:
METHODS:
RESULTS:
Abstract
Format: Abstract
1
Author information
PubMedThe Level of Evidence affair
I am concerned that
this is opinion more
than evidence
Marco Lotti MD

Hyperthermic intraoperative intraperitoneal chemo-
therapy was first added to cytoreductive surgery at the
Washington Hospital Center in March 1992. Sixty pa-
tients were enrolled in an Institutional Review Board-
approved phase I/II clinical trial. Informed consent was
obtained from all patients before surgery. This trial com-
bined cytoreductive surgery with heated intraoperative
mitomycin C administered by a closed abdominal tech-
nique. The techniques,2 pharmacokinetics,3,4 safety con-
siderations,5 and morbidity and mortality6 of the closed
intraoperative intraperitoneal chemotherapy technique
have been reported. Deficiencies were noted in the dis-
tribution of methylene blue dye with the closed tech-
nique, which may cause a high frequency of complica-
tions and nonuniform treatment. This prompted the
development of the Coliseum technique for HIIC, which
allowed for manual distribution of heat and drugs.7,8
After the conclusion of the investigative phase, clinical
guidelines combining cytoreductive surgery and HIIC
for biopsy-confirmed peritoneal carcinomatosis from
gastrointestinal malignancies were used. These data were
prospectively recorded for 200 treatments in 183 patients
that occurred between November 1994 and June 1998.
The techniques of cytoreductive surgery have been
dialysis solution containing 12.5 mg/m2
of mitomycin C
for males (maximum dose, 25 mg) or 10.0 mg/m2
for
females (maximum dose, 20 mg) was heated and infused
at approximately 1 liter/minute. Temperatures were mea-
sured with a Labcraft digital thermometer (Curtin Mathe-
son Scientific, Jessup, MD). The temperature at the in-
flow line was approximately 44°C. The Tenckhoff
temperature probe was maintained between 42°C and
43°C, and a distant intra-abdominal site averaged
39.6°C. Throughout the perfusion, the surgeon continu-
ously manipulated the viscera to distribute both heat and
chemotherapy.
All bowel anastomoses were constructed with hand-
sewn two-layer closures with two exceptions. Low colo-
rectal anastomoses were performed with a 33-mm-diameter
intraluminal stapler and esophagojejunal anastomoses with
a 29-mm-diameter intraluminal stapler (Ethicon Endo-
surgical, Cincinnati, OH). If a pyloroplasty was per-
formed, it was a full-thickness incision closed with a
single layer of interrupted silk sutures.
TABLE 1. Patient characteristics
No. of patients receiving 1 cytoreduction ϩ HIIC 166
• the Authors were disappointed by
the closed-abdomen technique
• their disappointment brought
them to develop the Coliseum
technique
• They describe their experience
and the results of 200
treatments
Marco Lotti MD

Fistula
Fistulas were observed in nine patients (4.5%). Exten-
sive lysis of fibrous and cancerous adhesions between
small bowel surfaces may have caused seromuscular
tears that later developed into fistula. Jacquet et al.6
reported a spontaneous fistula of the small bowel after a
patient underwent cytoreductive surgery and HIIC with a
closed abdominal technique. This fistula was thought to
result from the patient experiencing continuous high
intra-abdominal inflow temperatures at a single site. We
did not observe a statistical association with the occur-
rence of combined grade III/IV morbidity and any intra-
peritoneal chemotherapy parameter despite higher
Tenckhoff temperatures during HIIC with manual distri-
bution of the heated chemotherapy. We attribute the lack
of association to the change from a closed abdominal
procedure to the Coliseum technique described above.
The Coliseum technique allows the surgeon to move the
Tenckhoff catheter around the abdominopelvic cavity,
thus improving the distribution of both heat and drug.
Postoperative Bleeding
not
All
stra
cel
thr
pan
adm
bee
mi
tien
(72
dos
W
tali
the
clo
HI
rep
stra
Fo
ies
Th
nia
I tried to follow their
reasoning
Marco Lotti MD

Fistula
not
All
stra
cel
thr
pan
adm
bee
mi
tien
(72
dos
W
tali
the
clo
HI
rep
stra
Fo
ies
Th
nia
3
2
1
1. Jacquet reported a fistula of the
small bowel due to scald injury.
2. We used higher temperatures and
didn’t observe an increase in fistula
rate.
3. Therefore we conclude that the
Coliseum technique with manual
distribution of the heated chemo is
better.
Marco Lotti MD

Fistula
not
All
stra
cel
thr
pan
adm
bee
mi
tien
(72
dos
W
tali
the
clo
HI
rep
stra
Fo
ies
Th
nia
One can reasonably argue that this is
just an arbitrary assertion and not a
demonstration.
But their latter assertion is even
more interesting.
Let’s go deeper in… Marco Lotti MD

The Thermal Probe affair
Marco Lotti MD

The Thermal Probe affair
44°C
39.6°C
Stephens AD et al. assumed that a 44°C inflow temperature and an average 39.6°C
outflow temperature was indicative of a mean abdominal temperature of 42°C.
But there are several ways to arrange the thermal probes inside the abdominal cavity.
But what happens if we move the inflow catheter?
Marco Lotti MD

Probe 1
Probe 2
Probe 3
By moving the inflow catheter we unconsciously give demonstration of the
Heisenberg’s uncertainty principle.
Our action is altering the measurements. Unconsciously, of course.
Marco Lotti MD

So we can give a different
reading:
Probe 1
Probe 2
Probe 3
The Coliseum technique allows the
surgeon to move the inflow catheter
around the abdominopelvic cavity,
thus unconsciously affecting the
temperature measurements and
bringing them to the desired values.
Postoperative bleeding requiring transfusion of more
than 4 U or reoperation occurred in nine patients (4.5%)
and was associated with increased intraoperative blood
loss (P ϭ .0083). Two of these nine patients underwent
cytoreduction and HIIC during a period in which
hetastarch was given intraoperatively to expand plasma
volume. Hetastarch is a chemically modified complex
polysaccharide with a molecular mass of approximately
4.5 ϫ 105
daltons. Hetastarch has been reported to cause
coagulopathy in a dose-related manner by three mecha-
tients absorbed an average of 14.34 mg of mitomycin C
(72.6% of the dose), and excreted 0.887 mg (4.2% of the
dose), during the 90-minute HIIC administration.
We have compared the published morbidity and mor-
tality of cytoreduction and early postoperative chemo-
therapy18 versus cytoreduction and HIIC by using a
closed abdominal technique6 versus cytoreduction and
HIIC by using the Coliseum technique. This comparison
represents a critical review of the evolution of treatment
strategies for patients with peritoneal carcinomatosis.
Forty-three patients underwent 45 cytoreductive surger-
ies with EPIC. Severe morbidity was reported in 37.7%.
The most prominent causes of morbidity were pneumo-
nia (13.3%), fistula (9%), and postoperative bleeding
(9%). No deaths were reported among this group of
patients. Jacquet et al. reported on 60 patients who un-
derwent 60 cytoreductive surgeries with HIIC performed
with a closed abdominal technique.6
Morbidity was
35.0% and was caused by anastomotic leak (10%), fis-
tula (8.3%), hematological toxicity (6.7%), and bile leak
(5.0%). Mortality in this group of patients was 5%. In
patients who had cytoreduction plus HIIC with the Col-
iseum technique, the morbidity was 27.0% and the treat-
ment-related mortality was 1.5%.
Marco Lotti MD

Probe 1
Probe 2
Probe 3
When you can influence the measurements of the thermal probes,
you can’t assume that the temperature at the tip of the probe is the
temperature of the entire region.
It is when you are far from there that the measurements become
more reliable.
Marco Lotti MD

The “Mix the Fluid” affair
Marco Lotti MD

Fluid mixers consist of a Tank and an Impeller
As the Engineers who design fluid mixers know well,
effective mixing requires:
• a proper shape of the Tank
• a proper shape of the Impeller
• a proper positioning of the Impeller
• a proper rotational speed of the Impeller
Marco Lotti MD

RPM (Rounds Per Minute)
Turbulence is created at high rotational speed
Marco Lotti MD

Propellers generate a different flow pattern than
Radial Flow Turbines
hands are
much more
like this
Marco Lotti MD

Effective mixing requires:
• Adequate rotational speed
• Proper positioning of the
impeller
• Proper shape of the tank
I want to show you a link to a
video that I found on Youtube
(please go to the next slide)
Marco Lotti MD

The abdomen is not a properly shaped tank.
It is like a maze with multiple
compartments.
The hand is not a properly
shaped impeller, it is not a
propeller and does not rotate.
With the wrong tank and the
wrong impeller, effective fluid
mixing is an illusion.
Marco Lotti MD

manipulation of the perfusate plays a negligible role in the distribution of heat
therefore, when concerned about the movements of the perfusion fluid,
we can get inspired by weather forecasts
and movements of the ocean currents,
and consider…
Marco Lotti MD

The Temperature Gradient affair
Marco Lotti MD

The Temperature Gradient affair (it’s Physics)
The next one is one of my videos
(please go to the next slide)
HOT WATER
is lightweight
and GOES UP
COLD WATER
is heavy and
GOES DOWN
There is no doubt:
Marco Lotti MD

The
temperature
gradient is the
most powerful
engine that
shapes the
distribution of
the perfusion
fluid
Marco Lotti MD

In the Coliseum
technique, a
powerful thermal
gradient is
created between
a broad cooling
surface and a
very small
heating area
Marco Lotti MD

this temperature
gradient
is maintained
during the entire
perfusion period
Marco Lotti MD

all the physical
modalities of
heat dissipation
are promoted
by the intrinsic
architecture of
the Coliseum
Marco Lotti MD

The heating
source is
forced to work
with full power,
to deliver a
huge amount
of heat in a
relatively small
area
Marco Lotti MD

this need was
well
acknowledged
by the proposers
of the Coliseum
technique
Marco Lotti MD

The temperature
gradient is
unavoidable in
the Coliseum
technique, and
the temperature
of the fluid can
never reach
equilibrium
Marco Lotti MD

35 - 40°C Normothermia
41 - 44°C Hyperthermia
45 - 48°C Irreversible cellular damage after 45 min
50 - 52°C Coagulation necrosis in 4-6 min
In the hottest
areas there is risk
of scald injuries to
the loops of the
bowel
Marco Lotti MD

random
measurements
confirm that
the distribution
of heat is not
homogeneous
Marco Lotti MD

distribution of the HIPEC solut
temperature remained constant a
output temperature varied by <1
temperature of 41.48C. Heat loss w
during the open technique than d
CO2 technique. To address this pr
studies have used the closed tec
fluid administered at very high inp
(#488C).18
Similarly, Kusamura e
a phase II clinical trial that includ
with peritoneal carcinomatosis o
using an input temperature of
studies,18-20
mortality ranged fro
and morbidity ranged from 12 t
owing to digestive complications, s
fistulas, perforations, and sutu
which represented 70% of all rec
tions in the study by Kusamura et
The lack of uniform distributio
Fig 4. Thermographic images. A, Closed CO2 technique.
The upper images represent ventral views, and the lower
images represent lateral views. B, Open technique. The
Experimental development of an
intra-abdominal chemohyperthermia
model using a closed abdomen
technique and a PRS-1.0 Combat CO2
recirculation system
Susana Sanchez-Garcıa, MD,a
David Padilla-Valverde, MD, PhD,a
Pedro Villarejo-Campos, MD, PhD,a
Jesus Martın-Fernandez, MD, PhD,a
Marcial Garcıa-Rojo, MD, PhD,b
and
Marta Rodrıguez-Martınez, MD,c
Ciudad Real, Spain
Background. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is the best operative
treatment currently available for patients with peritoneal carcinomatosis of ovarian origin. The open
abdomen technique is the classic technique for hyperthermic intraperitoneal chemotherapy. We developed
a closed abdomen model that improves temperature control and increases exposure of peritoneal surfaces
to the drug by recirculating the perfusate.
Methods. We used a porcine model with 12 female, Large White pigs---4 in the open technique group and
8 in the closed technique CO2 group. We performed cytoreductive surgery and hyperthermic intraperi-
toneal chemotherapy for 60 minutes using paclitaxel (175 mg/m2
) at an input temperature of 428C.
Perfusate recirculation was performed under controlled pressure (range, 12–15 mmHg). The infusion of
0.7 L of CO2 via a separate intraperitoneal infusion catheter mixed the perfusate within the peritoneal
cavity. Intra-abdominal temperature was assessed using 6 intra-abdominal temperature probes and
2 temperature probes in the inflow and outflow circuits. Drug distribution was assessed using methylene
blue staining.
Results. Intra-abdominal temperatures remained constant and homogeneous in all intra-abdominal
quadrants with a constant input temperature of 428C and a minimum output temperature of 41.48C.
The infused CO2 caused the fluid to bubble and created agitation inside the abdominal cavity to
facilitate a homogeneous distribution of the drug-containing perfusate.
Conclusion. The closed recirculation hyperthermia with intraperitoneal chemotherapy technique developed
in this study is safe and feasible, and may provide a more homogeneous delivery of heated chemotherapy to
the peritoneal cavity in patients with peritoneal malignancies. (Surgery 2014;155:719-25.)
From the General Surgery Department,a
Pathology Department,b
and Pharmacy Department,c
University
General Hospital, Ciudad Real, Spain
OPTIMAL OPERATIVE DEBULKING in association with
intraperitoneal chemotherapy increases overall
survival and progression-free survival in women
with advanced ovarian cancer.1
The use of hyper-
thermia with intraperitoneal chemotherapy (HI-
PEC) further increases the therapeutic benefit of
the chemotherapeutic drug.2
In addition, heat
has a direct cytotoxic effect on the tumor cells.
Experimental animal studies demonstrated that tu-
mor cells are killed by a temperature of 438C,
whereas normal cells can withstand temperatures
up to 458C.3-5
Hyperthermia enhances the penetra-
tion of drugs administered intra-abdominally into
the peritoneum from 3 to 5 mm, thereby
increasing their effect of drug-induced apoptosis,6
leading to greater effectiveness of HIPEC at tem-
Fig 1. A, Schematic diagram of the te
abdominal cavity with the perfusate so
for irrigation of the abdominal cavity w
inal cavity via a gas exchanger. 5, Cath
exchanger. Roller-pump A, Used to preh
Surgery
Volume 155, Number 4
“thermographic image analysis
in the open procedure group
revealed heterogeneity in the
distribution of the hyperthermic
solution“
…and the floating bowel is actually being treated with
DRY HYPOTHERMIA
Marco Lotti MD

all these considerations made me convinced that the Coliseum technique
cannot be considered an adequate technique for the delivery of
Hyperthermia
no sound evidence exists that the distribution of heat is improved
the claimed superior temperature homogeneity is not tenable when it
comes to the laws of Physics
Marco Lotti MD

all these considerations pushed me to search for a different modality
for the delivery of HIPEC
and brought me to the concept of
the Laparoscopy-Enhanced HIPEC technique
You can find further information at:
https://www.slideshare.net/MarcoLotti3/lotti-marco-md-the-laparoscopyenhanced-hipec-concept
Marco Lotti MD

A Coliseum with frail foundations: a critical analysis of the state-of-the-art open-abdomen HIPEC technique

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