Journal of Surgical Oncology 2008;98:215–216
GUEST EDITORIAL
Building on a Consensus
PAUL H. SUGARBAKER,
Washington Cancer Institute, Washington Hospital Center, Washington, District of Columbia
Thanks to Drs. Kusamura, Deraco, and Delphi Technology, this
supplemental issue of the Journal of Surgical Oncology records a
current consensus for the use of cytoreductive surgery and periopera-
tive intraperitoneal chemotherapy in the management of peritoneal
dissemination of cancer within the abdomen and pelvis. This consensus
came from the world’s experts in peritoneal surface oncology.
These experienced clinicians and investigators should have the best
judgments regarding the balanced application of this emerging
technology.
Verwaal and colleagues discussed the eligibility for these
treatments. Not surprisingly, they suggest that the oncologist has a
great responsibility to select patients for treatment who are candidates
for long-term benefit. Yan and colleagues focused on the proper
preoperative investigations. The CT of chest, abdomen, and pelvis with
maximal oral and intravenous contrast was the preferred radiologic test
of consensus voters. One must remember that no radiologic test is
reliable for the detection of small volume of cancer that is layered out
on a peritoneal surface. Identification of patients for the combined
treatment often occurs in the operating theater. Portilla and colleagues
focused on the four intraoperative assessments of cancer volume. The
consensus voters were most comfortable with the peritoneal cancer
index. However, the Gilly staging system (Lyon), the simplified
peritoneal cancer index (Amsterdam), and the Japanese staging system
of P1, P2, and P3 continue to have merit. Kusamura and colleagues
focused on the technical aspects of cytoreductive surgery. Periton-
ectomy and visceral resections should include surfaces involved by the
malignancy. In order to prevent suture line recurrence anastomoses
should occur following completion of the HIPEC. Gonzalez-Moreno
and colleagues focused on assessments to quantitate postoperative
residual disease. The completeness of cytoreduction score as obtained
by an experienced surgeon’s visual assessment of the abdomen and
pelvis was voted to be the preferred scoring system. Completeness of
cytoreduction indicates cancer control with surgery and perioperative
chemotherapy working together; it needs to be quantitated differently
for a particular disease state (compare papillary mesothelioma or
pseudomyxoma peritonei with gastric cancer and colon cancer).
Glehen and colleagues focused on the technology of HIPEC delivery.
Open, closed, semi-open, or expanded abdomen techniques all have
been reported. The superiority of one technique over the other in terms
of outcome, morbidity, and preservation of a safe operating room
environment were not apparent to the consensus voters. Kusamura
and colleagues focused on the technical aspects of hyperthermic
intraperitoneal chemotherapy. The consensus was that no consensus
exists. Younan and colleagues focused on systems for classification of
morbidity, mortality, and cancer chemotherapy toxicity. Although
protocol-specific and institution-specific assessments have been used
with great value, the consensus voters suggested that the Common
Terminology Criteria for Adverse Events (CTCAE) version 3 as
proposed by the National Institutes of Health is the current standard.
ß 2008 Wiley-Liss, Inc.
MD, FACS, FRCS*
Esquivel and colleagues focused on carcinomatosis from colon cancer.
Support for a new standard of care for carcinomatosis from colorectal
cancer comes from the randomized controlled data of Verwaal et al.,
the multi-institutional study of Glehen et al., and at least a dozen phase
II single institution studies reported from around the world [1–3].
Consensus voters agreed that early referral of these patients when the
peritoneal cancer index was less than 20 would be a crucial step
forward in the management of carcinomatosis. Bozzetti and colleagues
focused on gastric cancer. Systematic reviews and meta-analyses of
perioperative intraperitoneal chemotherapy in stage III and resectable
stage IV gastric cancer show benefit [4,5]. In the much more
difficult problem of gastric cancer with established carcinomatosis
the consensus was less optimistic. However, new approaches with
neoadjuvant combined intraperitoneal and systemic chemotherapy
may present the optimal palliation with a ray of hope for cure with
patients who have a durable response. Baratti and colleagues discussed
the cytoreductive surgery and perioperative intraperitoneal chemo-
therapy for peritoneal mesothelioma. Combined treatment at an
experienced center must be considered as a standard of care. Historical
controls show that best palliative care or systemic chemotherapy offers
little to these patients in comparison to cytoreductive surgery and
perioperative intraperitoneal chemotherapy as administered by an
experienced group. Moran and colleagues thought that similar
conclusions could be made for mucinous appendiceal carcinomatosis.
For ovarian cancer no consensus was reached. Clinical investigation
and phase I/II trials are currently active at many institutions.
Several reports strongly suggest benefit in selected patients. Rossi
and colleagues focused on abdominal sarcomatosis. Although
little evidence exists to recommend cytoreduction and HIPEC for
sarcomatosis there are selected patients who are likely to benefit.
Finally, Bijelic and colleagues focused on treatment failures
after cytoreductive surgery and intraperitoneal chemotherapy. Their
experience with reoperative surgery with HIPEC was extremely
positive in appendiceal malignancy but less favorable with colon
cancer. Only approximately 10% of patients experienced long-term
survival with second look cytoreduction in patients with colon
carcinomatosis.
Where are we currently with this new technology applied to a large
number of cancers that disseminate themselves within the peritoneal
cavity? First, a new standard of care has been achieved and recognized
by the consensus group for peritoneal mesothelioma and appendiceal
*Correspondence to: Dr. Paul H. Sugarbaker, MD, FACS, FRCS, 106 Irving
Street NW, Suite 3900, Washington, DC 20010, USA; Fax: (202) 877-8602
E-mail: paul.sugarbaker@medstar.net
Received 1 April 2008; Accepted 3 April 2008
DOI 10.1002/jso.21078
Published online in Wiley InterScience
(www.interscience.wiley.com).
216 Sugarbaker
mucinous neoplasms. It is possible that death from pseudomyxoma
peritonei can be eliminated with this new combined treatment
modality. Serial debulking procedures should not be used.
In colon cancer it is hard to deny that patients with low volume of
peritoneal seeding are likely to benefit with long-term survival. A
peritoneal cancer index of less than 10 show a 50% or greater survival
at 5 years. Systemic chemotherapy alone is not going to match this
great benefit.
The total lack of consensus regarding technology requires
prospective comparisons of different surgical technologies and
different perioperative intraperitoneal chemotherapy technologies.
Although hyperthermic intraperitoneal chemotherapy in the operating
room is the standard of care there is no standard treatment regimen.
For example, several groups are now using 5-fluorouracil systemically
as a sensitizer for the intraperitoneal drugs. Also, early postoperative
intraperitoneal administration of this cell cycle-specific drug may help
eradicate small volume residual disease. The use of early postoperative
intraperitoneal paclitaxel may improve the local control of patients
with peritoneal mesothelioma and ovarian cancer.
Recently, thoughts regarding long-term bidirectional chemotherapy
in ovarian cancer have been revised; it should be currently a standard
of care in the United States [6]. One should not think that cancer
control on peritoneal surfaces can be maintained by a single surgery
and a single hyperthermic intraperitoneal chemotherapy treatment.
Long-term sequential treatments using both intravenous and intra-
peritoneal chemotherapy (bidirectional) need to be incorporated into
the management of many of these peritoneal surface diseases.
The challenges to the oncologist for control of peritoneal surface
malignancy remain large. Even with current improvements in
technology, the most common site for progression of all the diseases
that were discussed in the consensus is at the peritoneal surface.
Although systemic disease is occasionally a problem, peritoneal
Journal of Surgical Oncology
recurrence of carcinomatosis remains the number one focus for
improved management. Current needs are optimization of cytoreduc-
tion through surgical workshops, an increased intensity of HIPEC and
EPIC, and protocols to investigate long-term bidirectional chemo-
therapy. As clinical and laboratory projects move forward, the broad
application of this consensus to the community of oncologists remains
the greatest challenge.
REFERENCES
1. Verwaal VJ, van Ruth S, de Bree E, et al.: Randomized trial of
cytoreduction and hyperthermic intraperitoneal chemotherapy
versus systemic chemotherapy and palliative surgery in patients
with peritoneal carcinomatosis of colorectal cancer [see comment].
J Clin Oncol 2003;21:3737–3743.
2. Glehen O, Kwiatkowski F, Sugarbaker PH, et al.: Cytoreductive
surgery combined with perioperative intraperitoneal chemotherapy
for the management of peritoneal carcinomatosis from colorectal
cancer: A multi-institutional study. J Clin Oncol 2004;22:3284–
3292.
3. Yan TD, Black D, Savady R, et al.: Systematic review on the
efficacy of cytoreductive surgery combined with perioperative
intraperitoneal chemotherapy for peritoneal carcinomatosis from
colorectal carcinoma. J Clin Oncol 2006;24:4011–4019.
4. Xu DZ, Zhan YQ, Sun XW, et al.: Meta-analysis of intraperitoneal
chemotherapy for gastric cancer. World J Gastroenterol 2004;10:
2727–2730.
5. Yan TD, Black D, Sugarbaker PH, et al.: A systematic review and
meta-analysis of the randomized controlled trials on adjuvant
intraperitoneal chemotherapy for resectable gastric cancer. Ann
Surg Oncol 2007;14:2702–2713.
6. Armstrong DK, Bundy B, Wenzel L, et al.: Intraperitoneal cisplatin
and paclitaxel in ovarian cancer. N Engl J Med 2006;354:
34–43.
 Journal of Surgical Oncology 2008;98:217–219

REVIEWS

The Delphi Approach to Attain Consensus in Methodology of Local Regional

Therapy for Peritoneal Surface Malignancy

1
SHIGEKI KUSAMURA, MD, PhD, DARIO BARATTI, MD,1 RAMI YOUNAN, MD,
2
AND MARCELLO DERACO, MD
1
*
1
Department of Surgery, National Cancer Institute of Milan, Milan, Italy
2
Department of Surgery, Surgical Oncology Unit, CHUM, University of Montreal Health Centre, Montreal, Canada

At the Fifth International Workshop on Peritoneal Surface Malignancy (PSM), held in Milan, December 2006, the consensus on technical aspects
of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was obtained through the Delphi process. The following
topics were discussed: pre-operative workup; eligibility to CRS þ HIPEC; intra-operative staging system; technical aspects of surgery; residual
disease classification systems; HIPEC: nomenclature and modalities; drugs, carrier solution and optimal temperature; morbidity grading systems.
Conflicting points regarding above-mentioned topics were elaborated and voted in two rounds by a panel of international experts in local-regional
therapy. The purpose of this manuscript is to describe the organization and the methodology of the consensus statements and to interpret and
discuss the implications of the most striking results.
J. Surg. Oncol. 2008;98:217–219. ß 2008 Wiley-Liss, Inc.

KEY WORDS: peritoneal carcinomatosis; cytoreductive surgery; hyperthemic intraperitoneal chemotherapy; consensus

INTRODUCTION accumulate theoretical and practical resources and explore how to

About three decades have passed since the first experience on
hyperthermic intraperitoneal chemotherapy conducted by Spratt et al.
[1]. In this period the treatment of peritoneal surface malignancies
(PSM) with cytoreductive surgery (CRS) and intraperitoneal che-
motherapy (IC) has gained an enormous popularity, changing
positively the expectations toward a clinical condition that in
former times was considered incurable. Promising results in terms of
survival have been reported according to phase II studies in the
treatment of peritoneal mesothelioma, pseudomyxoma peritonei, and
peritoneal carcinomatosis from ovarian cancers [2–4]. Moreover, a
phase III study confirmed the efficacy of the CRS þ HIPEC in the
treatment of peritoneal carcinomatosis from colorectal cancer [5].
However the body of literature addressing the local regional therapy
of PSM is growing chaotically. There is a lack of uniformity in the
indications, in the methodology of the procedure and in the instruments
to assess results in terms of side effects and outcome after the
treatment.
Accordingly, there are at least five available intra-operative staging
systems for peritoneal surface malignancy; at least four post-operative
residual disease classification systems; more than six acronyms for
hyperthermic intraperitoneal; more than four side effects grading
criteria.
A panel of experts named Peritoneal Surface Oncology Group
International (PSOGI) has been organizing a biannual meeting since
1998 to share strategies, experiences, tactics and best practices to reach
a consensus pertaining to several conceptual and technical aspects
regarding the treatment of PSM.
The last version of this meeting was held in Milan, in December
2006. It was entitled ‘‘5th International workshop on PSM.
Integrating Cytoreductive Surgery and Hyperthermic Intraperito-
neal Chemotherapy into the management of Peritoneal Malignancies.’’
Following the same policy of the previous meetings, the PSOGI
aimed to bring together a broad expertise to generate new hypothesis,
build an international network for the design of future prospective
controlled studies. Surgeons, medical oncologists, anesthesiologists,
biologists, nutrition specialists, pathologists, nurses and psychologists
were involved in this process.
The present meeting opened the debate in three grounds: the
methodology and the technique of the local-regional therapy, disease
specific consensus and the state of the art of the disciplines related to
local regional therapy.
The purpose of this paper is (1) to describe the organizational steps
and the methodology that guided the consensus achievement process of
5th International Workshop on PSM; (2) to discuss critically the main
results of this consensus statement regarding the methodological and
technical aspects of CRS þ HIPEC.
MATERIALS AND METHODS
Approach
The Delphi technique consists of a consensus method designed to
synthesize information. It allows the inclusion of a large number of
individuals across diverse locations and expertise and avoids the
Special Issue: Dedicated to the 5th International Consensus Meeting on
Peritoneal Surface Malignancies Treatment.
The authors have no financial interest related to the contents of this article to
disclose.
*Correspondence to: Marcello Deraco, MD, Fondazione IRCCS Istituto
Nazionale dei Tumori Milano, Via Venezian 1, 20133 Milan, Italy.
Fax: þ39-02-23902404. E-mail: marcello.deraco@istitutotumori.mi.it
Received 19 March 2008; Accepted 21 March 2008
DOI 10.1002/jso.21059
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.

218 Kusamura et al.
situation where a specific expert might be anticipated to dominate the
consensus process [6,7]. It has been frequently used in health care and
is liable to use a wide range of study types to be considered than is
usual in statistical reviews. Moreover, it allows a major role for the
qualitative assessment of evidence [8].
Panel Selection and Flowchart of Scientific Boards
An Italian scientific organizing committee (ISOC) set up in the
National Cancer Institute (NCI) of Milan was vested with the function
to launch the discussion and take the first steps to structure the
consensus achievement process. The organization of the consensus
statement started with the establishment of a International Scientific
Committee (ISC). Components of ISC were chosen according to their
involvement in the area of local-regional therapy of PSM assessed by
their clinical and scientific background and participation in previous
biannual meetings. The role of this board was to guide the scientific
activities for the maturation and establishment of common concepts
related to specific issues regarding the management of PSM.
Literature Search and Identification of
Main Conflicting Points
Parallel to the ISC formation, a Scientific Secretariat (SS) was
structured with the participation of three components, experts in local
regional therapy, as well. The role of this board was to assist the ISC by
means of three main tasks: (1) to identify the principal conflicting
points regarding the methodological aspects of local regional therapy;
(2) to elaborate a list of possible solutions for each conflicting point;
(3) to elaborate related document for each conflicting point, fully
explaining the dimension of the problematic issue.
The following issues were chosen by ISC and SS as the main not
consensual topics:
. Eligibility to the procedure of CRS þ HIPEC.
. Pre-operative workup.
. Intra-operative staging system.
. Technical aspects of surgery.
. Residual disease classification systems.
. HIPEC: nomenclature and modalities.
. Drugs, carrier solution and optimal temperature.
. Morbidity grading systems.
The conflicting points related with each of the above-mentioned
topics were formulated as multiple choice questions. The possible
solutions for each conflicting point should have been formulated,
clearly, neutrally, comprehensively, accompanied by references from
the literature. The above-mentioned eight conflicting points were split
into 61 multiple choice questions.
For the elaboration of related documents the SS reviewed medical
literature over the past 20 years, summarized the most relevant papers
in different grids and tables and attempted to provide the evidence for
each conflicting point, whenever it was appropriate.
The Voting
The whole material including the conflicting points, their respective
possible solutions and related documents were made available online
on a WEB based voting system. The panel of experts comprising
the ISC, ISOC, SS expressed their opinion according to the Delphi
approach. The following elements were present in this discussion:
(1) Voting in two rounds. In the first round the expert were asked to
select the option he/she believes was the most appropriate for each
conflicting point. In the second round, the experts were asked to
vote again, having the opportunity to see the previous rating of the
Journal of Surgical Oncology
other experts. The purpose of the voting was not to conduct a
simple survey to take a static photograph of the general knowledge
among the experts. The final intention was to trigger a discussion
and to suggest to each expert to do a self-reflection of own
convictions and attitudes in light of the current published evidence
and the opinion of other experts.
(2) The time elapsed between the two rounds was 18 days. The experts
had 16 days to participate in each round of voting.
(3) Anonymity. Each expert did not have an access to the opinion of
his colleagues. Only during the second round he was expected to
vote knowing the general opinion of the entire group.
(4) During the last week of each voting period the respondents
received self-generated reminder emails every other day to
enhance the response rate of the entire panel.
(5) Consensus was defined as the agreement of 51% of the voters
[9,10].
RESULTS
In total 42 experts, coming from 17 different countries participated
in the consensus statement on methodological aspects of the
locoregional therapy. The response rates were 74% and 76% in the
first and second rounds, respectively. The consensus was achieved in
66% and 72% in the first and second rounds, respectively.
The results of voting process related to each of the above-mentioned
methodological topics is outlined elsewhere in this same issue of the
present journal.
Significant change of opinion between first and second rounds
succeeded into four sub topics:
. Residual disease classification systems, in particular the R
classification in pseudomyxoma peritonei.
. Technical aspects of the surgery, timing for bowel anastomosis.
. Ideal carrier solution for HIPEC.
. Optimal temperature at HIPEC.
The topic in which there was a higher rate of disagreement was
drugs to use in intraperitoneal chemotherapy.
Other classic conflicting topics such as intra-operative staging
system and residual disease classification and modality of HIPEC
(open vs. closed vs. etc.) were solved.
DISCUSSION
Most of coined conflicting points regarding the methodology of
LRT were solved. However, this fact does not mean that the right
answer was found nor that future studies are precluded. The
Delphi technique does not substitute the scientific method. Points that
remained open as well as the those not included in the present debate
are expected to be approached in the upcoming meeting of 2008.
Another open question to be cleared is how willing each participant of
the Consensus statement would be to change their everyday practice in
base of these results.
One of the criticisms raised against the locoregional therapy of PSM
is the low level of evidence that characterizes the major part of the
studies on the topic. Several reasons account for this fact. First,
several difficulties surrounds the conduction of prospective rando-
mized studies in the LRT field [11]. Second, the disomogeneity of
the nomenclature, techniques and methodological instruments to
assess the side effects and outcome. The achievement of the present
consensus allowed the establishment of a common language concern-
ing basic concepts among the various centers devoted to LRT in
the world. Moreover, it strengthened the PSOGI as an international
network representing a forum to maturate ideas, design and implement
future prospective trials.

REFERENCES
1. Spratt JS, Adcock RA, Muskovin M, et al.: Clinical delivery
system for intraperitoneal hyperthermic chemotherapy. Cancer
Res 1980;40:256–260.
2. Deraco M, Baratti D, Inglese MG, et al.: Peritonectomy and
intraperitoneal hyperthermic perfusion (IPHP): A strategy that
has confirmed its efficacy in patients with pseudomyxoma
peritonei. Ann Surg Oncol 2004;11:393–398.
3. Deraco M, Casali P, Inglese MG, et al.: Peritoneal mesothelioma
treated by induction chemotherapy, cytoreductive surgery, and
intraperitoneal hyperthermic perfusion. J Surg Oncol 2003;83:
147–153.
4. Ryu KS, Kim JH, Ko HS, et al.: Effects of intraperitoneal
hyperthermic chemotherapy in ovarian cancer. Gynecol Oncol
2004;94:325–332.
5. Verwaal VJ, van Ruth S, de Bree E, et al.: Randomized trial of
cytoreduction and hyperthermic intraperitoneal chemotherapy
versus systemic chemotherapy and palliative surgery in patients
Journal of Surgical Oncology
Consensus in Local Regional Treatment 219
with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol
2003;21:3737–3743.
6. Jairath N, Weinstein J: The Delphi methodology (Part one): A
useful administrative approach. Can J Nurs Adm 1994;7:7–
20.
7. Jairath N, Weinstein J: The Delphi methodology (Part two): A
useful administrative approach. Can J Nurs Adm 1994;7:29–42.
8. Jones J, Hunter D: Consensus methods for medical and health
services research. BMJ 1995;311:376–380. Review.
9. Loughlin KG, Moore LF: Using Delphi to achieve congruent
objectives and activities in a pediatrics department. J Med Educ
1979;54:101–106.
10. Keeney S, Hasson F, McKenna H: Consulting the oracle: Ten
lessons rom using the Delphi technique in nursing research. J Adv
Nurs 2006;53:205–212.
11. Elias D, Delperro JR, Sideris L, et al.: Treatment of peritoneal
carcinomatosis from colorectal cancer: Impact of complete
cytoreductive surgery and difficulties in conducting randomized
trials. Ann Surg Oncol 2004;11:518–521.
 Journal of Surgical Oncology 2008;98:220–223

The Eligibility for Local-Regional Treatment of

Peritoneal Surface Malignancy

1
VIC J. VERWAAL, MD, PhD, SHIGEKI KUSAMURA, MD, PhD,2 DARIO BARATTI, MD,
2
2
AND MARCELLO DERACO, MD *
1
Department of Surgery, The Netherlands Cancer Institute, Amsterdam, The Netherlands
2
Department of Surgery, National Cancer Institute of Milan, Milan, Italy

At the Fifth International Workshop on Peritoneal Surface Malignancy, held in Milan, the consensus on technical aspects of cytoreductive surgery
(CRS) for peritoneal surface malignancy was obtained through the Delphi process. General conflicting points concerning the eligibility to the
local-regional therapy were discussed and voted.
J. Surg. Oncol. 2008;98:220–223. ß 2008 Wiley-Liss, Inc.

KEY WORDS: eligibility; local-regional therapy

INTRODUCTION
The local-regional treatment of peritoneal surface malignancies
has gained an increasing popularity thanks to the favourable results
in terms of outcome in various tumour histologies. However the
procedure carries a significant morbidity and is time and resource
consuming. This confirms the need for the establishment of a clear
eligibility criteria defining the potential indications of the method to
assure a maximisation of the prognostic gain, improvement of quality
of life and minimisation of the side-effects.
The purpose of this manuscript is to approach some general con-
flicting situations concerning the eligibility criteria for the combined
treatment of cytoreductive surgery (CRS) and hyperthermic intraper-
itoneal chemotherapy (HIPEC).
In General
Eligibility for a treatment of CRS þ HIPEC should be seem in the
light of therapeutic alternatives for those eventually selected patients.
Unfortunately, the data that show results of alternative treatments for
peritoneal carcinomatosis are scarce.
Taking one example from colorectal cancer. There are several
studies concerning the treatment of stage IV colorectal cancer with
systemic chemotherapy. These studies include patients with metastatic
colorectal cancer (metastasis of any location). However, to enable
proper response evaluation most studies include only those patients
who have measurable disease. For practical reason measurements are
most often made on liver metastasis (LM) or lymph nodes. Thus, the
data of stage IV colorectal trials are dominated by the results found in
the treatment of liver and lung metastases. The contribution of the
results of the patients with other sided metastasis is limited in these
studies.
This fact hampers the extrapolation of results from studies on
metastatic colorectal cancer treated with systemic chemotherapy to
cases affected with peritoneal carcinomatosis from the same origin.
Liver Metastasis (LM)
Cytoreduction combined with hyperthermic intraperitoneal chemo-
therapy is a treatment for peritoneal surface involvement. The main
issue in this treatment is the high concentration of chemotherapy in the
abdominal cavity and a limited systemic concentration [1]. Besides the
selective effect of the chemotherapy there is also a selective effect of
the heat [2]. This treatment has a curative intent and has a reasonable
5-year survival.
LM have been treated with curative intent and a 5-year survival of
40% was obtained in selected patients. In these patients selection
criteria are mostly absence of local-regional disease [3].
It is questionable if the combined treatment of resectable LM and
operable peritoneal carcinomatosis can be successfully curative as well.
Elias et al. [4] conducted a prospective study on 24 patients with
LM and moderate PC from colorectal origin. Liver resection plus
CRS were combined with a curative intent. One postoperative death
occurred and postoperative morbidity was 58%. Three-year overall and
disease-free survival rates were respectively 41.5% (95% confidence
interval [CI]: 23–63) and 23.6% (95% CI: 11–45). Seven patients are
disease-free with a mean follow-up of 27.8 months after their last
surgery, 3 having a repeated hepatectomy. Three patients developed a
peritoneal recurrence and 13 had recurrence in the liver. The combined
treatment of LM plus PC was shown to be feasible, and beneficial in
selected patients presenting three or fewer metastases.
In any case the real impact of the CRS and heated intraperitoneal
chemotherapy on survival of patients with PC and LM would be
defined only by a prospective controlled trial.
Intestinal Obstruction
The detection of intestinal obstruction in the preoperative CT scan
evaluation has been considered a predictive factor of incomplete
cytoreduction and thus it could represent a parameter precluding an
aggressive and curative surgical approach [5,6].
Patient with an internal obstruction has poorer results then patients
without internal obstructions.
Shen et al. conducted an analysis of prognosis in patients with PC
submitted to CRS and intraperitoneal hyperthermic chemotherapy.
The authors have no financial interest related to the contents of this article to
disclose.
*Correspondence to: Marcello Deraco, MD, Fondazione IRCCS Istituto
Nazionale dei Tumori Milano, Via Venezian 1, 20133 Milano, Italy.
Fax: þ39-02-23902404. E-mail: marcello.deraco@istitutotumori.mi.it
Received 19 March 2008; Accepted 21 March 2008
DOI 10.1002/jso.21060
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.

 Consensus Statement in Peritoneal Surface Malignancy Treatment
Although intestinal obstruction was correlated with a poor prognosis
by univariate analysis, it was not found to be a independent predicting
factor of survival after multivariate analysis (HR 1.71 (95% CI: 0.93–
3.16; P-value 0.09)) [7].
On the other hand it is more difficult to treat patients affected
by bowel obstructions with systemic chemotherapy. Up to date there
are no selective data available on the results of these patients in
chemotherapy studies.
In general practice patient with bowel obstructions should be
operated on before any other treatment can be started.
Averbach and Sugarbaker [8] have evaluated short- and long
term results of management of recurrent intraabdominal malignancy
causing intestinal obstruction using surgery and intraperitoneal
chemotherapy. Forty-two consecutive patients with PC were treated
by CRS with or without intraperitoneal chemotherapy. There were
20 patients with primary tumours of appendix, 13 with cancer of colon
or rectum and 9 patients with cancer of other origins. Surgery included
bowel resections and peritonectomy procedures. In 30 patients early
postoperative intraperitoneal chemotherapy was administered. The
overall morbidity was 55% while mortality was 7.14%. The projected
3-year survival for this group of patients was 32.7%. As a result of
treatment patients’ performance status improved in 47.6% of cases.
They concluded that an aggressive reoperative approach may be
considered for palliation of selected patients with recurrent cancer
causing intestinal obstruction.
Preoperative CT Findings
Due to the fact peritoneal carcinomatosis is a surface disease it will
always stay relatively undetected by imaging studies that are depended
on tumour volume such as CT MRI and even PET.
Computed tomography represents a powerful instrument in the
preoperative selection of patients for the local-regional treatment.
Studies correlating preoperative CT findings with treatment outcome
has been conducted in peritoneal carcinomatosis from peritoneal
mesothelioma, colorectal or from appendiceal origin [6,9,10].
Yan et al. [6] carried out a study to identify computed tomography
(CT) scan images that would be useful in patient selection for CRS and
perioperative intraperitoneal chemotherapy. An analysis of the
preoperative CT scans of 30 patients with peritoneal mesothelioma
was performed. Characteristic interpretative CT appearances of the
small bowel and its mesentery were categorised into four classes
outlined in the Table I.
. The correlation of these categories with the operability revealed 9 of
11 patients (82%) with the suboptimal cytoreduction and 2 of
19 patients (11%) with adequate cytoreduction had Class III
interpretative findings (P < 0.001).
. Seven patients (64%) in the suboptimal cytoreduction group and two
patients (11%) in the adequate cytoreduction group had a >5 cm
tumour mass in the epigastric region (P ¼ 0.004).
. A patient with a tumour size >5 cm in the epigastric region and with
a Class III appearance of the small bowel and its mesentery has a
probability of 100% for a suboptimal cytoreduction. A patient
TABLE I. Classes of Characteristic Interpretative CT Appearances of the Small Bowel and Its Mesentery
Presence of Small bowel and
Class ascites mesentery involvement
0 No No
I Yes No
II Yes Thickening, enhancing
III Yes Nodular thickening, segmental obstruction
Journal of Surgical Oncology
221
without either of these two preoperative CT scan findings has a 94%
probability of an adequate cytoreduction.
De Bree et al. reported on 25 cases of colorectal cancer. Films of
abdominopelvic CT scans from such patients treated by CRS and
HIPEC were retrospectively analysed by two radiologists separately.
A simplified peritoneal cancer index (SPCI) was used to determine the
extent of peritoneal involvement. Correlation between the preoperative
CT based SPCI-scores as well as number of involved abdominopelvic
areas (N) and survival was examined. The preoperative SPCI- and
N-scores of one of the radiologists had no statistically significant
prognostic value, while for the second radiologist SPCI  7 and N  4
were associated with particularly poor outcome. Additionally, the
presence of ileocaecal region involvement and, depending on the
radiologist, the occurrence of tumour deposits in the left subdiaphrag-
matic area on CT appeared to be unfavourable prognostic signs. They
concluded that the prognostic value of preoperative conventional CT
appeared to be radiologist dependent and therefore may be of limited
value in selecting colorectal cancer patients with peritoneal carcino-
matosis who will not benefit from extensive CRS followed by HIPEC.
Jacquet et al. [11] evaluated retrospectively the CT scans of the
abdomen and pelvis in 45 patients affected by mucinous peritoneal
carcinomatosis who were treated with surgery and intraperitoneal
chemotherapy. The following findings were correlated with complete-
ness of cytoreduction: tumour volume in small bowel mesentery
(P < 0.001), tumour volume in proximal jejunum (P ¼ 0.003), tumour
volume in distal jejunum (P ¼ 0.002), tumour volume in proximal
ileum (P ¼ 0.003), mesentery configuration (P < 0.001) and obstruc-
tion of bowel segments by tumour (P < 0.001).
A statistical approach using a tree-structured diagram showed that
patients with both obstruction of bowel segments by tumour and
tumour diameter greater than 0.5 cm on small bowel surfaces exclusive
of distal ileum on preoperative CT scan, had an 88% probability of
incomplete resection. Patients without these two CT findings had a
92% probability of complete resection. The conclusion was that
patients whose scans show obstruction of bowel segments by tumour
and tumour diameter greater than 0.5 cm on small bowel surfaces
exclusive of distal ileum are unlikely to be candidates for CRS for the
treatment of peritoneal carcinomatosis.
A brief analysis of the studies on CT allow us to make some
observations:
. Most of studies were conducted in not adequately dimensioned
small series of patients.
. For the correlation with treatment outcome only completeness of
cytoreduction and prognosis were taken into account in the various
studies. The appropriate selection of patients for local-regional
treatment should be based not only on survival results but also on
variables representing risk factor for major morbidity and mortality
related to treatment. There is no data in the literature assessing the
value of preoperative CT findings as predictor of eventual treatment
complication.
. Conclusions obtained in one type of malignancy should not be
applied arbitrarily in an another histology. For example, which was
Loss of mesenteric
vessel clarity CT scab interpretation
No Normal appearance
No Ascites only
No Solid tumour present
Yes Loss of normal architecture
222 Verwaal et al.
proven to be valid in peritoneal mesothelioma, not necessary will be TABLE III. Survival of 174 Patients With Peritoneal Dissemination of
valid for gastric cancer or colorectal cancer and so on. Appendiceal Malignancy Having Incomplete Cytoreductive Surgery

HIPEC HIPEC and EPIC No

HIPEC or Early Perioperative Intraperitoneal alone EPIC alone POIC
Chemotherapy (EPIC) in Patients With Median survival time 58.6 37.6 19 12
Suboptimal Cytoreduction (months)
% 2-year survival 79.5 55.8 34.7 33.4
The proportion of patients with peritoneal carcinomatosis that % 3-year survival 66.3 53.3 24.6 21.9
remain with suboptimal residual disease after a maximum surgical % 5-yearr survival 35.4 27.2 7.3 11.7
effort is considerable. In the Table II rates of incomplete cytoreduction
HIPEC, hyperthermic intraperitoneal chemotherapy; EPIC, early postoperative
are outlined according to the histological subtype of the primary.
intraperitoneal chemotherapy; POIC, perioperative intraperitoneal chemotherapy.
Taking into account the substantial difference in terms of survival
according to the completeness of cytoreduction, one can propose not to
perform the local-regional antiblastic therapy (HIPEC or EPIC) after
the surgery. The limited benefit in terms of outcome provided by the morbidity in these patients (up to 52% of the patients had major
intraperitoneal chemotherapy does not outweigh the increase in complications) [14].
morbidity and toxicity that the local-regional antiblastic treatment
could imply, in case of suboptimal residual disease remaining in the
cavity after the tentative cytoreduction. Lymph Node Involvement
However, most of the authors of the literature have reported the Lymph nodes are the typical first side of metastasis of many
performance of perioperative intraperitoneal chemotherapy even in malignancies and remains the most frequently used parameter guiding
those suboptimally cytoreduced cases, despite the limited available the performance of adjuvant treatment. The local-regional approach
evidence supporting this policy. There is only few uncontrolled data in targets the treatment of peritoneal surface. And therefore lymph nodes
the literature giving us an idea of in which extent the performance of are out of reach of this treatment.
HIPEC and/or EPIC could add in terms of survival in patients with In the study of Glehen et al. [15] in which they reviewed the ‘‘world
incomplete cytoreduction. series’’ of CRS combined with perioperative intraperitoneal che-
Glehen et al. [16] analysed the survival of 174 patients with motherapy for peritoneal carcinomatosis of colorectal origin it was
peritoneal dissemination of appendiceal malignancy having incom- found that node positive tumours have a significant poorer survival
plete CRS (Table III). then node negative (18 and 31 months).
Extensive Disease
Sugarbaker et al. evaluated the prognostic value of PCI in patients
MATERIALS, METHODS AND RESULTS
with colorectal cancer. In clinical studies a peritoneal cancer index of In order to achieve a consensus among experts, the Delphi
<10 was associated with a 5-year survival rate of 50%, and index of methodology was employed [18]. Conflicting points were identified
11–20 with a 5-year survival rate of 20%, and an index of >20 with a and related multiple choice questions along with a scientific review
5-year survival rate of 0% (P-value < 0.0001). Based on these data they document on the topic were circulated among a panel of experts
coined a clinical pathway to treat patients with peritoneal carcinoma- on peritoneal surface oncology. Two rounds of web-based voting,
tosis from colon cancer in which the procedure of cytoreduc- the second one after disclosing the results of the first round, were
tion þ HIPEC is contra-indicated in patients with PCI > 20 [12]. carried out. A detailed description of the methodology used for this
Verwaal et al. [13] studied prognostic factors extensively. In their consensus development is available elsewhere in this issue. Results
seven-region system they found not only that the survival benefit is low were presented and discussed at the Fifth International Workshop on
in patients with more than five regions effected but also in increase in Peritoneal Surface Malignancy held in Milan, Italy, December 4–6,
2006.
The contents of the related scientific review document are outlined
TABLE II. Rates of Incomplete Cytoreduction Are Outlined According to in the Introduction Section of this article. The accompanying related
the Histological Subtype of the Primary
question circulated among the experts and the respective results of the
Result of Median survival first and second rounds are outlined below:
Primary tumour cytoreduction Rate (%) (months) The local-regional treatment of peritoneal surface malignancies has
gained an increasing popularity thanks to favourable results in terms of
Gastric cancer Cc 0/1 43.9 19.2 outcome. However the procedure carries a significant morbidity,
Cc-2/3 52.1 7.8 is time and resource consuming. This confirms the need for the
Colorectal cancer CC-0 53.5 32.4
establishment of a clear eligible criteria defining the potential
CC-1 21 24
CC-2 25.5 8.4 indications of the method to assure a maximisation of the prognostic
Appendiceal mucinous Cc 0/1 72.9 gain, improvement of the quality of life and minimisation of the side-
tumour effects. Which one of the following you do judge to be an absolute
Cc-2/3 27.1 20.5 exclusion criteria for the procedure? (more than 1 alternative allowed)
Peritoneal mesothelioma Cc 0/1 69 59%a
Cc-2/3 31 19%a (1) Presence of tumour mass >5 cm in the epigastric region evaluated
Advanced epithelial Cc 0/1 78.4 89  9 by preoperative CT scan in peritoneal surface malignancies
ovarian cancer (except Pseudomyxoma Peritonei); First round: 37.50%—Second
Cc-2/3 21.6 19  9
round: 21.88%.
a 15-19
5-Year overall survival . (2) Class III of small bowel or small bowel mesentery evaluated
The bold characters signify to highlight figures related to suboptimal by preoperative CT scan; First round: 68.75%—Second round:
cytoreduction (cc-2 or cc-3). 93.75%.

Journal of Surgical Oncology

 Consensus Statement in Peritoneal Surface Malignancy Treatment
(3) Obstruction of bowel segments, biliary tract or ureters; First round:
37.50%—Second round: 40.63%.
(4) Tumour diameter greater than 0.5 cm on small bowel surfaces
exclusive of distal ileum in mucinous peritoneal carcinomatosis;
First round: 12.50%—Second round: 0%.
(5) Presence of resectable liver metastases; First round: 9.38%—
Second round: 21.88%.
(6) Peritoneal cancer index >20 in colorectal cancer; First round:
53.13%—Second round: 62.50%.
(7) Residual disease >2.5 mm after the CRS. First round: 46.88%—
Second round: 28.13%.
(8) Gross retroperitoneal lymph node involvement First round:
75.00%—Second round: 90.63%.
DISCUSSION AND COMMENTS
Experts agreed that Class III of small bowel or small bowel
mesentery evaluated by preoperative CT scan, peritoneal cancer index
>20 in colorectal cancer and gross retroperitoneal lymph node
involvement were absolute exclusion criteria for local-regional
therapy. On the other hand the panel did not consider obstruction of
bowel segments, biliary tract or ureters an absolute contra-indication
for the procedure. Experts did not reach a consensus regarding the
indication of HIPEC in case of suboptimal CRS. The panel of experts
did not consider that the presence of preoperative CT findings of
unresectability (presence of tumour mass >5 cm in the epigastrium,
tumour nodules of 0.5 cm in the distal ileum in mucinous peritoneal
carcinomatosis) could be contra-indication for the procedure. The
present article aimed at to identify general eligibility criteria that could
be applicable in most of cases of PSM.
The topic of eligibility is complex and is not only related to some
clinical situations represented by technical unfeasibility to the
procedure. As already noted the analysis of prognostic factors, risk
factors for major morbidity and impact on quality of life should be
globally taken into account in the decision making process of patient
selection.
The purpose of the present article was not to report a comprehensive
debate in order to identify all the possible clinical situations in each
single pathology, that could represent a contra-indications for the
combined treatment of CRS and hyperthermic intraperitoneal chemo-
therapy. This more complex task was accomplished by the disease
specific consensus and the results of such a discussion are outlined in
elsewhere in this issue.
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 Journal of Surgical Oncology 2008;98:224–227

Preoperative Investigations in the Management of Peritoneal Surface Malignancy

With Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy:
Expert Consensus Statement

1
TRISTAN D. YAN, * DAVID L. MORRIS, MD, PhD,1 KUSAMURA SHIGEKI, MD,
BSc (Med), MBBS, PhD, PhD,
2

BARATTI DARIO, MD,2 AND DERACO MARCELLO, MD2

1
Department of Surgery, University of New South Wales, St George Hospital, Sydney, Australia
2
Istituto Nazionale dei Tumori Milano, Milano, Italy

At the Fifth International Workshop on Peritoneal Surface Malignancy, in Milan, the consensus on preoperative investigations for peritoneal
surface malignancy was obtained through the Delphi process. The results showed that 100% of the voters considered that contrast-enhanced multi-
sliced CT was the fundamental imaging modality, whereas MRI, PET, laparoscopy and serum tumor markers were regarded as useful, but not
fundamental investigational modalities.
J. Surg. Oncol. 2008;98:224–227. ß 2008 Wiley-Liss, Inc.

KEY WORDS: preoperative investigations; peritoneal surface malignancy; cytoreductive surgery; intraperitoneal
chemotherapy

INTRODUCTION individual lesions with a diameter greater than 5 cm is 60–90%, in

Cytoreductive surgery (CRS) combined with perioperative intra-
peritoneal chemotherapy (PIC) has been suggested as a treatment
option for patients with peritoneal surface malignancy. On December 4–
6, 2006, the Italian National Cancer Institute convened a consensus
conference on the management of peritoneal surface malignancy in
Milan. This conference was timely in bringing together experts in this
relatively new surgical oncology field in an effort to discuss current
approaches to this disease. The consensus focused on several important
patient selection criteria, preoperative investigations, prognostic
scoring systems, treatment regimens for specific diseases and methods
of prospective data collection. Further emphasis was made on stringent
patient selection utilizing current investigational modalities to identify
appropriate surgical candidates. Currently, these modalities include
contrast-enhanced multi-sliced computed tomography (CT), magnetic
resonance imaging (MRI), positron emission tomography (PET),
laparoscopy and serum tumor markers.
PET provides a functional image, but has the drawback of less
accurate spatial resolution for small lesions when compared with
CT and MRI. The latter imaging modalities have similar diagnostic
accuracy [1–3]. However, availability, simplicity and less movement
artifacts, make multi-sliced CT a more widely used imaging tool for
detection of peritoneal tumors [4]. Some institutions also utilized
laparoscopy to evaluate the extent of disease involvement [5–7].
The aims of this paper were to outline the different preoperative
investigation modalities and report the consensus statements of expert
opinions from the Fifth International Peritonectomy Workshop.
contrast to 10–30% for a tumor smaller than 1 cm [12,14]. There is
also a great degree of variation in sensitivity for tumor detection in
different anatomical regions. The sensitivity for tumor detection in
epigastrium, greater omentum and undersurfaces of the diaphragms
have been reported 60–90% [8,12,13], whilst sensitivity was 50–70%
in retroperitoneum and pelvis [8]. With thin collimation contrast-
enhanced spiral CT, Low et al. [3] demonstrated a sensitivity of 58%, a
specificity of 89%, an accuracy of 79% for parietal peritoneal lesions
and sensitivity of 89% and specificity of 98% in detection of pelvic
disease. In contrast, sensitivity was less than 20% for mesenteric
deposits.
At most institutions, multi-sliced CT remains the dominant imaging
modality for patients with intra-abdominal malignancies. It is
generally easier to perform, with shorter imaging times, less movement
artifacts caused by bowel peristalsis, provides a higher spatial
resolution and is more accessible and familiar to radiologists and
clinicians. It is limited, however, by the difficulty in early nodule
detection in thin patients without ascites. This may be the case in many
patients with early tumor dissemination.
However, in the presence of a reasonable amount of fat, fine
stranding and small nodules could be appreciated with the use of spiral
thin-collimation scanning. The presence of ascites is the most common
CT-manifestation of peritoneal carcinomatosis [15]. Peritoneal thick-
ening and enhancement either smooth or nodular, is another useful CT-
sign. Masses on the parietal peritoneum are best seen in presence of
ascites (Fig. 1). Thickening of the peritoneum has a predilection for the

ABDOMINOPELVIC COMPUTED
TOMOGRAPHY
Using more advanced technology including multi-sliced CT,
superior accuracy in detection of peritoneal implants is expected.
Sensitivity of CT in diagnosing peritoneal carcinomatosis varies from
60% to 90% [8–11]. This rate is dependent upon the quality of CT, the
size of tumor nodules, the abdominopelvic regions examined and the
interpretation from the radiologist [8,12,13]. Sensitivity of detecting
The authors have no financial interest related to the contents of this article to
disclose.
*Correspondence to: Tristan D. Yan, BSc (Med), MBBS, PhD, Department
of Surgery, University of New South Wales, St George Hospital, Sydney,
Australia; Fax: 61-2-9350-3997. E-mail: tristan.yan@unsw.edu.au
Received 24 March 2008; Accepted 27 March 2008
DOI 10.1002/jso.21069
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.


Fig. 1. Abdominal CT of the mid-abdomen showing the presence of
peritoneal tumor implants as the peritoneum appeared to be thickened
and enhanced in the presence of a large volume of ascites.
cul-de-sac, the pericolic gutters and the undersurfaces of the
diaphragms. In clinical practice, most sites of peritoneal tumor
infiltration, including omentum, diaphragms and pelvis can be
satisfactorily managed with peritonectomy procedures. Also ileocecal
involvement can be treated with intestinal resection. Therefore tumor
deposits in these areas, even when missed by pre-operative CT, usually
have limited impact on prediction of successfulness of CRS. Whereas,
disease involving portal hepatis, small bowel and/or mesentery is a
limiting factor for complete cytoreduction. In these regions with low
contrast flow, CT has low sensitivity in distinguishing a tumor from the
surrounding tissue. In most series, small bowel and mesentery
involvement was detected correctly only in 20–50% of the cases.
Secondary CT features may be helpful in identifying the disease and
these include small bowel distortion, obstruction, wall thickening and
enhancement. Unfortunately, when patients present with these CT
features, the disease is usually too far advanced to be salvaged by CRS
and PIC [8,16].
MAGNETIC RESONANCE IMAGING
Recent advances in MRI including faster pulse sequences, breath-
hold imaging, and use of intravenous contrast agents and surface coils,
have improved image quality and shortened examination times. MRI
with its superior contrast resolution is an attractive alternative to multi-
sliced CT scanning. Decision to use CT or MRI in patients with
peritoneal malignancy will also depend on factors like MRI
availability, cost and radiologist’s expertise. An inherent advantage
of MRI compared with CT is its ability to acquire multiple image types,
each of which may be useful for depicting different forms of abdominal
disease.
The depiction of thin peritoneal tumor layers largely depends on the
presence of contrast enhancement. In a series comprising of T2 and T1-
weighted contrast enhanced sequences, Low et al., observed a
sensitivity and specificity for bowel involvement of 73% and 77%
respectively in patients with ovarian carcinoma [17]. Some reports
suggest that tumors of the pelvic floor or gynecological organs are
detected with greater accuracy on sagittal or coronal slices [18]. To
enhance the predictive value, these sequences may be added.
The contrast enhancement in peritoneal carcinomatosis is probably
caused by increased permeability of the peritoneum, similar to the
effect seen in diffuse peritonitis. However, exogenous factors, such as
Journal of Surgical Oncology
Preoperative Investigations 225
previous surgery, chemo- or radiation therapy or intrinsic factors such
as inflammatory disease, may also increase peritoneal permeability,
mimicking the effect of peritoneal carcinomatosis. Hence specific
diagnosis may be impossible in patients presenting under the
conditions described [17]. In addition, small amounts of ascites
also show contrast enhancement after intravenous administration of
Gd-DTPA. In some cases, contrast enhancing ascites may not be
distinguishable from small layers of enhancing tumors.
POSITRON EMISSION TOMOGRAPHY
Anatomic imaging can detect pathologic processes only after they
reach a detectable size, become contour deforming or have abnormal
enhancement after intravenous contrast administration. PET with 2-
[18F]-fluoro-2-deoxy-D-glucose (FDG) has evolved as a useful
technique in clinical oncology, especially for tumor staging and post-
treatment monitoring. It provides metabolic information and may help
detect small metastatic lesions. Viable tumors can be differentiated
more easily from adjacent structures, as glucose metabolism in tumor
cells is often increased beyond normal limits, causing areas of focally
elevated FGD tracer uptake. PET has an overall sensitivity of 97% in
the detection of colorectal metastases in the entire body, according to a
recently published meta-analysis [19]. But, the high (>85%)
sensitivity of FDG-PET for tumor localization and detection is
associated with a lower specificity, due to the normal physiologic
accumulation of FDG in the stomach, bowel and urinary tract.
Therefore, relying solely on functional imaging may result in decrease
overall accuracy due to false-positive lesions.
Accurate anatomic localization of functional abnormalities seen on
PET scans is well known to be challenging because of the lack of
detailed, high-resolution anatomy. Due to its relative scarcity of anato-
mic landmarks, however, standard PET imaging remains frequently
unsatisfactory. This major limitation of PET imaging is overcome by
the availability of integrated whole-body PET/CT imaging systems,
yielding intrinsically fused morphological and functional data sets. An
anatomic image can be helpful in differentiating pathological activity
due to malignant processes from physiological FDG uptake in areas
such as the bladder, stomach or the bowel. It can also help in
identifying mucinous primary and metastatic tumors that have poor
FDG uptake. This may result in a decrease in the number of false-
negative PET studies and improved overall accuracy of combined
PET/CT study for mucinous tumors [20].
Fig. 2. Laparoscopic exploration of the abdomen showing small
tumor deposits layering out on the peritoneum. [Color figure can be
viewed in the online issue, available at www.interscience.wiley.com.]
226 Yan et al.
TABLE I. Advantages and Disadvantages of Current Investigational Modalities for Peritoneal Surface
Malignancy

Modality Advantages Disadvantages

Contrast-enhanced spiral CT Superior spatial resolution Low sensitivity for small tumors
Shorter imaging times Low sensitivity with mesenteric
deposits
Less movement artifacts Lower contrast resolution
Readily available
Clinical familiarity
MRI Superior contrast resolution Low sensitivity for small tumors
Multiple imaging types Longer imaging times
Manipulation of signal intensities Movement artifacts
Lower spatial resolution
PET or PET/CT* Functional activity Low sensitivity for small tumors
Higher sensitivity Lower specificity
Detection of occult metastases Increased cost
Anatomical localization* Limited availability
Mismatched fusion*
Laparoscopy Direct visualization Relatively invasive
High sensitivity for small tumors Technical difficulty with adhesions
Supplement to imaging Failure to assess retroperitoneal
space
Biopsy Risk of port track seeding
Increased cost

*Correlates with PET/CT, not PET.

Despite these advantages, PET/CT may be limited by its high cost,
availability and effects of mismatch between the CT and PET images
due to patient respiration. This mismatch is at maximum when the
clinical CT is acquired with breath hold at full inspiration while
the PET is acquired with the patient breathing normally. Care must
be exercised when diagnosing patients with disease in the anatomic
regions most affected by breathing artifacts. These areas include the
diaphragms, base of the lung and the upper portion of the liver. Given
the spatial resolution of 4–6 mm currently available in PET and PET/
CT systems and the fact that FDG is an unspecific radioactive tracer,
micro-metastases must still be considered a challenge. FDG-PET is
known to have poor sensitivity for small (<1 cm) metastases. Negative
PET/CT results will not exclude micro-metastases. However, positive
findings in PET/CT may help to optimize therapeutic strategies and
reduce unnecessary surgery.
There is little doubt that patient selection is essential to avoid futile
aggressive treatment, but therein lies a major problem. The well
reported benefits of resection of liver metastases have partly emanated
from advances in preoperative imaging, in particular CT, MRI and
PET. These modalities allowed early detection of treatable disease,
with increasingly accurate delineation of the location and the extent of
the metastases. Currently, non-invasive imaging assessing the extent and
potential resectability of peritoneal disease are not reliable. Because
peritoneal deposits usually have a low volume density, all imaging
modalities have major limitations in the assessment of low-volume
disseminated peritoneal disease and may fail to detect early localized
disease at a stage where treatment is most likely to be beneficial.
EXPLORATORY LAPAROSCOPY
A reliable way of assessing tumor severity is to visualize it directly.
Therefore, some patients undergo an exploratory laparotomy, in which
the combined therapy would be abandoned, where the disease is found
to be unresectable. Laparotomy is a simple mean of evaluating tumors
and performing biopsies, but may appear overly aggressive for a
staging-only procedure. Laparoscopic exploration of the abdomen
supplements the information provided by the imaging techniques and
enables direct visual assessment of peritoneal involvement (Fig. 2). It
is associated with less pain, shorter hospitalization, and quicker time to
recovery in comparison to laparotomy. Recent studies show that
laparoscopy is safe to treat and stage early ovarian cancers [5,6,21].
Valle and Garofalo [7] used laparoscopy to stage 97 cases of
peritoneal carcinomatosis and achieved full laparoscopic PCI assess-
ment in 96/97 cases, while only 2/96 cases were understaged. There
was a good correlation between the open successive surgery data and
the laparoscopic PCI. There was no mortality and no trochar port
site metastases. The authors suggested that patients with massive
involvement of their small bowel or mesentery by staging laparoscopy
should not be considered suitable for the combined procedure. Pomel
et al. achieved complete cytoreduction in seven of the eight patients

TABLE II. Consensus Results on Preoperative Investigations for Peritoneal Surface Malignancy, Obtained
Through Delphi Process (Percentages in Black Were the Results From the First Round of Voting; Percentages in
Red Were the Results From the Second Round of Voting)

Investigation modality (a) Fundamental (%) (b) Useful (%) (c) Useless (%)

Multi-slice CT 96.77 3.23 0

100.00 0 0
Total body PET 19.35 64.52 16.13
6.25 84.38 9.38
MRI 12.90 70.97 16.13
3.13 81.25 15.63
Laparoscopy 16.13 70.97 12.90
9.38 78.13 12.50

Journal of Surgical Oncology


who were considered resectable by laparoscopy [6]. In the remaining
patient, there was an underestimation of the extent of the disease.
Despite these advantages, there are some limitations associated
with laparoscopy. It is technically difficult to evaluate patients with
extensive prior surgery and lymph node involvement in the retro-
peritoneal space. The spread of malignant cells through the trochar
tract is another major concern. To avoid this risk, all laparoscopy
trochars should be placed in the mid-line and resected at the time of
cytoreduction [6].
Table I provides a summary of the advantages and disadvantages of
CT, MRI, PET and laparoscopy.
CONSENSUS RESULTS
At the Fifth International Workshop on Peritoneal Surface
Malignancy, in Milan in late 2006, the consensus on preoperative
investigations for peritoneal surface malignancy was obtained through
the Delphi process, which is described elsewhere in this issue [22]. The
results showed that 100% of the voters considered that contrast-
enhanced multi-sliced CT is the fundamental imaging modality,
whereas MRI (84.38%), PET (81.25%), laparoscopy (78.13%) and
serum tumor markers (71.88%) were regarded as useful, but not
fundamental investigational modalities (Table II).
In conclusion, considering these current investigational modalities,
a high quality cross-sectional imaging study, either contrast-enhanced
spiral CT or MRI should be performed to evaluate patients undergoing
CRS and PIC. FDG-PET or preferably PET/CT should be at least
selectively considered as part of preoperative workup in high-risk
patients. Laparoscopic exploration may supplement imaging modal-
ities to allow direct visualization. However, the use of these
investigations should be individualized and planned as part of a
multidisciplinary approach. The role of CT, MRI and more latterly
PET or PET/CT and laparoscopy in refining patient selection and
improving prognosis remain to be closely evaluated.
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 Journal of Surgical Oncology 2008;98:228–231

The Intraoperative Staging Systems in the Management of

Peritoneal Surface Malignancy

A. GOMEZ PORTILLA, MD,1* KUSAMURA SHIGEKI, MD, PhD,2

BARATTI DARIO, MD,2 AND DERACO MARCELLO, MD2
1
Carcinomatosis Peritoneal Program, Hospital San José, Vitoria, Spain
2
IRCCS Istituto Nazionale dei Tumori Milano, Peritoneal Surface Malignancy Program, Italy

The establishment of a rationale guideline for intraoperative staging system the extent of carcinomatosis is warranted. The quantitation of tumor
found at the time of surgical exploration of the abdomen has proven to be of value in assessment of prognosis and treatment planning in patients
with peritoneal carcinomatosis. Four different assessments systems have been employed more frequently, thus far. The advantages and
disadvantages of each classification systems are described and discussed. The results of the Consensus of the last 5th International Workshop on
Peritoneal Surface malignancy of Milan, December 2006 are presented.
J. Surg. Oncol. 2008;98:228–231. ß 2008 Wiley-Liss, Inc.

KEY WORDS: peritoneal cancer index; staging systems; peritoneal surface malignancy; peritoneal carcinomatosis

INTRODUCTION
The careful selection of the patients for the treatment based on the
staging of the disease is mandatory in most of surgical diseases. At
the present time, we lack a universally accepted and easily
reproducible staging/scoring system that addresses the quantity and
location of the peritoneal dissemination and its impact on achieving a
complete cytoreduction.
The quantitation of tumor found at the time of surgical exploration
of the abdomen has proven to be of value in assessment of prognosis
and provides critical information in treatment planning in patients with
peritoneal carcinomatosis.
Four different assessments systems have been employed more
frequently and have been published:
. Gilly’s Peritoneal Carcinomatosis Staging [1];
. Japanese Gastric Cancer P System [2];
. Sugarbaker’s Peritoneal Cancer Index (PCI) [3];
. Dutch Simplified Peritoneal Cancer Index (SPCI) [4].
The advantages and disadvantages of each classification systems are
described and discussed.
The major value of these quantitative prognostic systems is to
exclude patients estimating prognosis and the risk of morbidity/
mortality of the treatment.
The establishment of a rationale guideline for intraoperative staging
system of the extent of carcinomatosis is warranted, major require-
ments are reproducibility and simplicity.
The results of the Consensus of the last 5th International Workshop
on Peritoneal Surface malignancy of Milan, December 2006 are
presented.
THE GILLY’S PERITONEAL CARCINOMATOSIS
STAGING SYSTEM
This staging system first described by Gilly et al. [1], in Lyon in
1994, takes into account only the size of the major malignant implants
and their distribution on the abdominal cavity. The details of this
system are summarized in Table I.
The main advantages of the Lyon staging system are simplicity and
reproducibility. Its utility has been validated and demonstrated in
the EVOCAPE study [5], were the natural history of peritoneal
carcinomatosis from non-gynaecologic malignancies was determined,
with a significant difference in median survival rates from 6 to
3 months, when stages 1 and 2 were compared to stages 3 and 4,
respectively.
It is used also to designate the downstaging after the cytoreduction.
Medical oncologists and radiologists consider it as a valuable tool in
the decision-making process regarding the therapy for the patients
affected by peritoneal surface malignancy.
The main disadvantages are that it is not able to predict resectability
of carcinomatosis, and the failure to quantitate the distribution of
peritoneal surface implants.
THE JAPANESE CARCINOMATOSIS
STAGING SYSTEM
Carcinomatosis from gastric cancer is classified by the Japanese
research society of gastric cancer as described in Table II.
This classification has been used as an useful quantitative pro-
gnostic indicator validated for gastric cancer.
The main advantages of the Japanese staging system are simplicity,
reproducibility. It has been used also to designate the downstaging after
the cytoreduction and it is useful for recurrent gastric cancer.
The main disadvantages are its inability to locate the carcino-
matosis, and the failure to size assessment and quantitate the
distribution of peritoneal surface implants.
None to disclose by any of the authors.
*Correspondence to: A. Gomez Portilla, MD, Director, Carcinomatosis
Peritoneal Program, Hospital San José, Vitoria, C/ Beato Tomás de
Zumárraga 10, 01008-Vitoria, Spain. Fax: 34-945145709.
E-mail: agomezpor@teleline.es
Received 25 March 2008; Accepted 27 March 2008
DOI 10.1002/jso.21068
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.

 Peroperative Staging Systems in Carcinomatosis 229
TABLE I. Gilly’s Peritoneal Carcinomatosis Staging TABLE II. Japanese Staging System

Stage Definitions Code Significance

0 No macroscopic peritoneal carcinomatosis S0 No serosal invasion

1 Regional granulations <5 mm greatest diameter localized in one part S1 Suspected serosal invasion
of the abdomen S2 Definite serosal invasion
2 Diffuse abdominal granulations <5 mm in dimension but diffuse to S3 Adjacent organ invasion
the whole abdomen N1 Perigastric LN
3 Granulations >5 mm to 2 cm in greatest diameter N2 LN around the left gastrci artery, common hepatic artery, splenic
4 Large malignant cakes, >2 cm in greatest dimension artery, and celiac axis
N3 LN in the hepatoduodenal ligament, posterior aspect of pancreas, and
root of mesentery
N4 Paraortic and middle colic LN
SUGARBAKER’S PERITONEAL P0 No peritoneal metastases
CANCER INDEX (PCI) P1 Adjacent peritoneal involvement
P2 A few scattered metastases to distant peritoneum
The PCI was proposed by Jacquet and Sugarbaker, and is P3 Many distant peritoneal metastases
represented by a score that comprises both the peritoneal implant size H0 No liver metastases
and distribution of the nodules on the peritoneal surface. H1 Metastases limited to one lobe
H2 A few bilateral metastases
To arrive at a score, the size of the peritoneal nodules must be
H3 Numerous bilateral metastases
assessed, using the lesion size score (LS): an LS0 score means that no
malignant deposits are visualized; an LS1 score means that tumor
nodules less than 0.5 are present; an LS2 score signifies that tumor shown in Figure 1. The summation of the LS score in each of the
nodules between 0.5 and 5.0 cm are present; an LS3 score signifies the abdomino-pelvic regions is the PCI of the patient, with a maximal
presence of tumor nodules greater than 5.0 cm in any dimension, or in score of 39.
case there is confluence of tumor. In order to assess the distribution of The main advantages of Sugarbaker’s staging system are that it
the peritoneal disease, the abdomino-pelvic regions are utilized as allows to estimate the probability of a complete cytoreduction in colon

Fig. 1. Sugarbaker’s PCI. The PCI (Peritoneal Cancer Index) is a clinical integration of both peritoneal implant size and distribution of
the nodules on the peritoneal surface. To arrived at a score, the size of the peritoneal nodules must be assessed. The Lesion size Score (LS) should
be use. An LS-0 score means that no malignant deposits are visualized. An LS-1 score means that tumor nodules less than 0.5 cm are present. An
LS-2 score signifies that tumor nodules between 0.5 cm and 5.0 cm are present. An LS-3 score signifies the presence of tumor nodules greater than
5.0 cm in any dimension. If there is a confluence of tumor, the lesion is scored as 3 In order to assess the distribution of the peritoneal disease, the
abdominopelvic regions are utilized. The summation of the LS score in each of the abdominopelvic regions is the PCI of the Patient. A maximal
score is 39.

Journal of Surgical Oncology

230 Gómez Portilla et al.
TABLE III. Dutch Simplified Peritoneal Cancer Index simplified peritoneal cancer index, where the size of tumor is recorded
Tumor is recorded as as large, moderate, small or no involvement as describe in Table III and
Large >5 cm the distribution of tumor is recorded in seven abdominal areas: left an
Moderate 1–5 cm right subdiaphragmatic, subhepatic, omentun/transverse colon, small
Small <1 cm intestine/mesentere, ileocecal and pelvic regions.
None The main advantages of the SPCI staging system are that it has been
Seven abdominal regions validated in PMP and in carcinomatosis from colon cancer. It allows a
I Pelvis correlation with the incidence of complications, and it is a valuable
II Right lower abdomen
guide for patient selection.
III Greater omentum, transverse colon and spleen
IV Right subdiaphragmatic area The main disadvantages are that some abdomino-pelvic regions are
V Left subdiaphragmatic area not designated, like the epigastric region, or regions of the descending
VI Subhepatic and lesser omental area and sigmoid colon AR4–AR5 (Table IV).
VII Small bowel and small bowel mesentery A summary of the staging systems is outlined in Table V.

MATERIAL AND METHODS

carcinomatosis, according to Elias et al. [6] the limit is a PCI < 16, and
in Sugarbaker’s experience the limit should be a PCI <20 [7]. It has
also been useful as a guide for sequential re-operative surgery [8] and
represents the most popular preoperative staging system among
surgical teams dealing with peritoneal carcinomatosis.
The main disadvantage is that it has no prognostic implication in
Pseudomyxoma peritonei (PMP) and primary malignant peritoneal
mesothelioma.
In order to obtain the consensus regarding the best preoperative
staging system among those mentioned above, an international panel of
experts in local–regional therapy participated in a web-based voting
system, following the two-step Delphi methodology. Consensus was
defined as the agreement of 51% of the voters [23,24]. Further details
of consensus statement methodology could be found elsewhere in the
same issue. The following question was presented to the experts.
In your opinion which one is the best intraoperative staging system
for patients affected by peritoneal carcinomatosis?

DUTCH SIMPLIFIED PERITONEAL . French system [1]

CANCER INDEX (SPCI) . Japanese system [2]
. Peritoneal cancer Index [3]
Zoetmulder and Verwaal [9], at the Netherlands Institute have used . Dutch Simplified Peritoneal Cancer Index [4]
a quantitative scoring system quite similar to the PCI, known as the . TNM system [25]

TABLE IV. Characteristics of the Main Intraoperative Staging Systems

System Survivorship prediction Advantage Disadvantage

Gilly Peritoneal
Carcinomatosis Staging [1]
Japanese system [2]
Peritoneal Cancer Index [3]
Dutch Simplified Peritoneal
Cancer Index (SPCI) [4]
In 370 patients with peritoneal
carcinomatosis from non-gynecologic
malignancies, a significant difference
observed between stages 1/2 (median
survival ¼ 6 months) and stages 3/4
(median survival 3 months) [5]
Prognostic value proven in other
clinical trials [10–12]
Prognostic value proven in other
clinical trials (gastric cancer) [13–15]
Prognostic value proven in colon cancer
[15–17] and ovarian cancer [18]
Prognostic value proven in
colorectal cancer [4]
Simple and reproducible [19]
Downstaging
Used by Medical Oncologists
and Radiologists
Simple [19]
Can also be applied to patients
with recurrent gastric cancer [19]
Reproducible [19]
Allows to estimate the probability
of a complete cytoreduction [20]
Is a guide for sequential determinations
of volume of carcinomatosis
over time estimating the likelihood
of a complete cytoreduction at
re-operative surgery [8]
Allows a correlation with the incidence
of complications in patients who
receive local-regional therapy [21]
Volume of tumor in each region is to
be scored quantitatively [20]
Should not be designated a ‘‘staging
system’’ because patients can only be
staged once in the course of their
disease at the time of diagnosis of the
primary malignancy [19]
Not able to predict resectability of
carcinomatosis (stage 2 disease could
consist of diffuse peritoneal
carcinomatosis with nodules <5 mm
that are non-resectable [19])
Failure to quantitate distribution of
peritoneal surface implants in the
stages 3 and 4 categories [19]
Inability to accurately locate the
carcinomatosis
It has no size assessment of the
cancerous implants [19]
PCI has no prognostic implication in the
following possible cases:
Non-invasive disease such as
Pseudomyxoma peritonei [22] in
which a high PCI not necessary is
correlated with a poor prognosis
A patient with invasive cancer at a
crucial anatomic site (around the
common bile duct), even if the tumor
elsewhere is of low burden, the
prognosis will be poor [19]
The epigastric region, very important in
determining the completeness of
cytoreduction in some diseases is not
designated separately [19]

Journal of Surgical Oncology


TABLE V. Results of the Panel of Experts Decision
First round of Second round of
Staging system the voting the voting
Gilly’s system 9.68% 6.25%
Japanese system 0% 0%
Sugarbaker’s PCI 83.70% 87.50%
Dutch SPCI 6.45% 6.25%
TNM 0% 0%
RESULTS
The decision of the panel of experts is outlined in Table V, been the
Sugarbaker’s PCI elected as the best intraoperative staging system.
CONCLUSION
According to the opinion of the panel of experts, the Sugarbaker’s
PCI has been elected as the best intraoperative staging system and it is
proposed to be used by all the investigators involved in the treatment of
patients with peritoneal surface malignancies.
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5. Sadeghi B, Arvieux C, Glehen O, et al.: Peritoneal carcinomatosis
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prognosis features. World J Surg 1999;23:23–29.
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9. Zoetmulder FAN, Verwaal V: Hyperthermic intrapoeritoneal
chemotherapy (HIPEC) with mitomycin C significantly improves
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origion (abstract). ASCO Prog Proc 2002;21:147a.
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chemohyperthermia with mitomycin C for digestive tract cancer
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2519.
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with peritoneal carcinomatosis. Anticancer Res 1999;19:1375–
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treated by cytoreductive surgery and intraperitoneal chemo-
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peritoneal metastases. Case reports of survivors and their
implications. Hepatogastroenterology 1999;46:1673–1677.
14. Ouchi K, Sugawara T, Ono H, et al.: Therapeutic significance of
palliative operations for gastric cancer for survival and quality of
life. J. Surg Oncol 1998;69:41–44.
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 Journal of Surgical Oncology 2008;98:232–236

Technical Aspects of Cytoreductive Surgery

SHIGEKI KUSAMURA, MD, PhD,1 SARAH T. O’DWYER, MD, FRCS,2 DARIO BARATTI, MD,1
RAMI YOUNAN, MD,3 AND MARCELLO DERACO, MD1*
1
Department of Surgery, National Cancer Institute of Milan, Milan, Italy
2
Peritoneal Tumour Service, Christie Hospital, Manchester, UK
3
Department of Surgery, Surgical Oncology Unit, CHUM, University of Montreal health centre, Montreal, Canada

At the Fifth International Workshop on Peritoneal Surface Malignancy, in Milan, the consensus on technical aspects of cytoreductive surgery
(CRS) for peritoneal surface malignancy was obtained through the Delphi process. Five conflicting points were discussed: radicality of the
peritonectomy procedure, cytoreduction of neoplastic nodules <2.5 mm, the timing of bowel anastomoses in relation to hyperthermic
intraperitoneal chemotherapy (HIPEC) and indications of protective ostomies. According to the panel of experts a partial parietal peritonectomy
restricted to the macroscopically involved regions could be indicated in all listed clinical conditions with the exception of peritoneal
mesothelioma. No expert was of the opinion that a radical parietal peritonectomy is advisable irrespective of the disease being treated. All the
experts agreed that electrovaporization of small (<2.5 mm) non-infiltrating metastatic nodules in the mesentery would be appropriate, even if
theoretically the HIPEC affords microscopic cytoreduction. The panel also agreed that in the closed technique for HIPEC administration the
intestinal anastomoses should be fashioned after completion of the perfusion. Finally when considering the place for protective ostomies the
experts voted for a flexible approach allowing the surgeon to exercise discretion for individual patients.
J. Surg. Oncol. 2008;98:232–236. ß 2008 Wiley-Liss, Inc.

KEY WORDS: peritoneal carcinomatosis; cytoreductive surgery; consensus

INTRODUCTION
On December 4–6, 2006, the National Cancer Institute of Milan
organized a consensus statement on the management of peritoneal
surface malignancy (PSM). This conference brought together experts
in the field of local-regional therapy in an effort to discuss current
approaches to this PSM.
The purpose of this manuscript was not to trigger a comprehensive
discussion about all the technical variations involved in cytoreductive
surgery but to focus on key controversial aspects of surgical technique.
The fundamental procedures undertaken in CRS have been described
and standardized by Sugarbaker [1], however with increasing number of
surgeons setting up treatment centers for peritoneal surface malignancies
across the world several modifications have been introduced. Further-
more recognition of the potential of CRS and HIPEC applied to
additional disease groups requires the adaptation of the original
techniques with some modification aligned to specific tumor types.
Using an expert panel we explored five areas where there was
known variation in practice of surgical technique in an attempt to gain
consensus and open opportunities for further studies and fertile
discussion in future.
Radicality of the Peritonectomy Procedure
The extent of surgery has a direct and significant impact on the
mortality and morbidity associated with the CRS [2–5]. While a
complete peritonectomy procedure seems appropriate when there is
widespread macroscopic disease (except in colorectal cancer with a
peritoneal cancer index >20), the same does not hold true in case of
limited or localized peritoneal carcinomatosis. The rationale for
complete or partial peritonectomy lies with the histology of the
primary tumor and the pattern of spread within the peritoneal cavity.
The extent of peritoneal carcinomatosis is determined by the ability
of tumor cells to disseminate transcaelomically and to implant into
the peritoneal surface. Three patterns of dissemination have been
described by Sugarbaker and are determined by the histologic grade/
invasive ability and the presence of mucinous acites. For example
moderate and high grade cancers show early local implantation of
the primary tumor to the peritoneal surface due to the presence of
adherence molecules on the surface of the cancer cells. In these cases
implantation can remain confined to a region even when a considerable
quantity of ascites is present and has been described as randomly
proximally distributed (RPD). In contrast low grade tumor cells
express few adherence molecules and demonstrate limited involvement
of the peritoneal surface near the primary tumors. Furthermore, where
there is a high production of mucin a complete redistribution
phenomenon (CRD) can occur in the peritoneal cavity resulting in
few invasive implants and scant epithelial cells, classically character-
ized in diffuse peritoneal adenomucinosis (DPAM) and Pseudo-
myxoma Peritonei. Finally, widespread cancer dissemination (WCD)
characterizes the invasive mucinous tumor that produces high
quantities of mucus, which in itself interferes with cell adherence
[6]. Recent evaluation of adhesion molecules in PMP and colorectal
cancer has demonstrated a distinct profile that helps to explain the
pattern and distribution of disease and offers potential for molecular
targeting to prevent invasion [7]. The patterns of spread of the common
histotypes of peritoneal carcinomatosis are described in the Table I.
Based on these observations one could propose a sparing surgical
approach with partial parietal peritonectomy where there is limited
peritoneal carcinomatosis as seen in the random and proximal
distribution (RPD) disease.
The authors have no financial interest related to the contents of this article to
disclose.
*Correspondence to: Dr. Marcello Deraco, MD, Istituto Nazionale Tumori
Milano, Via Venezian 1, 20133 Milan, Italy; Fax: þ39-02-23902404.
E-mail: marcello.deraco@istitutotumori.mi.it
Received 19 March 2008; Accepted 21 March 2008
DOI 10.1002/jso.21058
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.

 Consensus on Cytoreductive Surgery 233
TABLE I. Hypothesis of Cancer Spread the traditional open abdominal Coliseum technique delay the anasto-
moses until after HIPEC as they believe that manipulation of the bowel
Histologic type RPD CRP WCD
achieves better distribution of heat and drugs throughout the peritoneal
Pseudomyxoma peritonei þ cavity. When the abdomen is closed or sealed during perfusion there
Appendix cancer remains a choice as to whether to anastomose before after the treatment.
Cystoadenocarcinoma G1 þ The key advantages and disadvantages are outlined in Table II.
Cystoadenocarcinoma G2, G3 þ
Adenocarcinoma þ
Carcinoid þ Indications for Ostomies
Colorectal cancer
The incidence of major morbidity associated with CRS/HIPEC is
Mucinous G1, G2, G3 þ
Intestinal þ well documented. Many have raised concern regarding anastomotic
Gastric cancer leaks following bowel resection and have raised questions as to the
Diffuse þ indicators protective proximal/defunctioning ostomies. Key studies to
Intestinal þ be considered in this regard are (Table III):
Ovarian cancer
Serous þ Verwaal et al. evaluated toxicity and complications in 102 patients with
Mucinous þ carcinomatosis of colorectal origin treated with cytoreductive
Diffuse malignant mesothelioma þ surgery and hyperthermic intra-peritoneal chemotherapy. The
median number of small bowel resections was 2 (range: 0–7).
RPD, randomly and proximally distributed; CRP, complete redistribution Cecum, colon and rectal resections were performed in 102, 41, and
phenomenon; WCD, widespread cancer dissemination.
53 patients, respectively with protective ostomy in 42% of the cases.
Despite the stoma bowel complication was reported in 17.6% of the
An aggressive complete peritonectomy could then be reserved for cases [8]. More recently, the same group of investigators conducted
generalized peritoneal carcinomatosis resultant from the complete a similar study in 103 patients with pseudomyxoma peritonei.
redistribution phenomenon (CRP) or widespread cancer dissemination The median number of resections was 4 (range: 0–8) and gastro-
(WCD) processes. For example, patients with malignant mesothelioma intestinal fistula was reported in 19 (18.4%) cases [9].
even in the presence of a localized disease would require a complete Shen et al. despite having found an unacceptable high rate of sepsis
resection of the parietal peritoneum along with any involved structures, correlated with bowel anastomoses, adopted a more flexible policy
based on the understanding that the origin of the disease is the suggesting the performance of protective stoma as an alternative
peritoneum itself and the pattern of distribution is characterized by CRP. [2]. They performed study in 77 (32 female and 45 male)
In pseudomyxoma peritonei the distribution characteristics may support patients with nonappendiceal colorectal cancer treated with
calls for a complete peritonectomy yet the relatively low ability to CRS and HIPEC. Protective ostomy was performed in 13% of the
implant argues for a more conservative approach confining the cases and bowel complication was reported in 17.6% of the
peritonectomy to where there is evidence of more solid disease. cases [10].
In the experience of Moran et al. the preservation of rectum is
Timing of Bowel Anastomoses: Pre- or important, where an anterior resection is required during the pelvic
Post-Hyperthermic Intraperitoneal peritonectomy, a proximal defunctioning stoma is necessary due to the
Chemotherapy (HIPEC) unacceptably high risks of anastomotic leakage. Alternatively if the
rectum can be preserved, a stoma can be avoided [11,12].
There is no consensus concerning the optimal timing for bowel To primarily perform unprotected colorectal anastomoses can be
anastomoses following cytoreductive surgery (CRS). Surgeons adopting considered a feasible option. Younan et al. reported results following

TABLE II. Timing of Bowel Anastomoses in Relation to HIPEC

Timing of
anastomoses Argument for Comment

Before HIPEC
Advantages Reduce costs and operation time [15] This justification is not supported by controlled evidence
Disadvantages Mechanical traction of viscera during the perfusion could impair This justification is not supported by controlled evidence
the integrity of the anastomoses
After HIPEC
Advantages Avoidance of potential adverse effects of heat and chemotherapy The evidence supporting this justification is weak. The influence of
on the suture healing CHT on the suture healing depends on the type of drug. In
animal studies, anastomotic healing can be impaired by
intraperitoneal MMC but not by 5-FU, at normal temperature
[16,17] or paclitaxel [18]. Local hyperthermia in itself has no
adverse effect on rat anastomotic healing [19]
Diminished risk of postoperative bowel complications Rate of bowel complication and or anastomotic leak between the
two approaches (before and after) are not substantially different
according to uncontrolled series (see the next table)
Possibility to treat the bowel margins against eventual implantation There is no data in literature reporting the risk of tumor relapse in
of tumor cells [20] the anastomoses
Disadvantages After the HIPEC all the visceral and parietal tissue are embedded This justification is not supported by controlled evidence
by the perfusate. Performing a suture in a bowel tissue with
edema could be technically more difficult and could also
hamper the quality of the anastomoses

Journal of Surgical Oncology

234 Kusamura et al.
TABLE III. Overview of Studies on Bowel Complications Associated With CRS þ HIPEC

Timing of Bowel
Mean No. of Protective anastomosis in F/A ratio Median Duration complication
References Predominant histology anastomosis/patient ostomy (%) relation to HIPEC (%) of operation (hrs) rate (%)

Jacquet et al. [21] Appendix, colon 1.8 None After 9.3 10.9b 17
Stephens et al. [4] PMP, colon NA NA After NA NA 7.5
Zanon et al. [22] Ovarian, gastric 0.7 NA Before 15 4–6 10
Elias et al. [23] Colon 2.6 8 7.3 18.8
Witkamp et al. [24] PMP 2 39 After 17.4 10b 34
Moran et al. [11] PMP NA NA NA NA 10.5 5
Elias et al. [25] PMP 2.8 NA After 7.2 10 22.2
Glehen et al. [5,26] Colon, PMP, ovarian 0.6 NA Before NA 6.1b 10.7
Elias et al. [27] Colon, PMP 2a NA After NA 8 10.3
Glehen et al. [28] Colon 0.4 NA Before 17.3 5.3b 8
Verwaal et al. [10] Colon 2 ¼ 69 42 After NA 7.5 17.6
>2 ¼ 33
Shen et al. [2] Colon 13 After NA 9 >3.9
Younan et al. [29] MP, PMP, ovarian 1 0.5 Before 11.3 8.2 10.8

No., number; HIPEC, heated intraperitoneal chemotherapy; F/A, fistula/anastomoses; PMP, pseudomyxoma peritonei; PM, peritoneal mesothelioma; NA,
information not available.
a
Median.
b
Mean.

203 procedures of CRS þ HIPEC undertaken for peritoneal surface
malignancies of various origin. A total of 194 anastomoses were
performed with a mean of 0.96 anastomoses per patient (range: 0–4).
In contrast to the other groups only one patient (0.5%) had a diverting
colostomy and overall 22 patients (10.8%) had bowel complications [29].
There remains therefore considerable variation between surgeons
regarding the use/need for stomas. The objective of the expert panel
was to explore this area more thoroughly.
MATERIALS AND METHODS
In order to achieve a consensus among experts, the Delphi
methodology was employed [18]. Conflicting points were identified
and related multiple choice questions along with a scientific review
document on the topic were circulated among a panel of experts who had
a special interest in peritoneal surface oncology. Two rounds of web-
based voting were carried out the second conducted after disclosing the
results of the first round. Consensus was defined as the agreement of
51% of the voters [13,14]. A detailed description of the methodology
used for this consensus development is available elsewhere in this issue.
Presentation of the results and conference discussion occurred at the
Fifth International Workshop on Peritoneal Surface Malignancy held in
Milan, Italy, December 4–6, 2006.
RESULTS
The contents of the related scientific review document are outlined
in the Introduction of this paper. The conflicting points circulated
among the experts with their respective results of the first
and second round voting were as follows:
1. Peritonectomy
In case of limited disease dissemination to parietal peritoneum
in which one of the following situations could a partial parietal
peritonectomy restricted to the macroscopically involved regions be
indicated? (more than one alternative allowed).

Disease Result voting first round (%) Result voting second round (%)

Pseudomyxoma peritonei 45.16 65.63

Cystoadenocarcinoma G1 of the appendix 74.19 81.25
Cystoadenocarcinoma G2, G3 of the appendix 67.74 78.13
Adenocarcinoma of the appendix 83.87 90.63
Carcinoid tumor of the appendix 83.87 87.50
Mucinous G1, G2, G3 colorectal cancer 70.97 78.13
Intestinal colorectal cancer 87.10 90.63
Diffuse gastric cancer 64.52 75.00
Intestinal gastric cancer 70.97 87.50
Serous ovarian cancer 80.65 96.88
Mucinous ovarian cancer 61.29 75.00
Diffuse malignant mesothelioma 29.03 46.88
There is no circumstance in the above-mentioned diseases in which a surgically 0.00 0.00
sparing approach could be considered. A complete parietal peritonectomy is
indicated in all these situations even in the presence of a localized disease,
irrespective of the primary tumor histology

Journal of Surgical Oncology

 Consensus on Cytoreductive Surgery 235
2. Mesenteric disease but the second vote achieved consensus (65%). Interestingly
despite the knowledge that for mesothelioma the disease origin is
In the presence of numerous small metastatic nodules (<2.5 mm) in the peritoneum no consensus was achieved. This may reflect the
the mesentery, without infiltration, after the completion of cytoreduc- experience of the experts in observing that the limitation for achieving
tion in other areas which approach is best? complete cytoreduction is more related to the presence of disease on
the small bowel than the peritoneum.
Result All experts considered electroevaporization of metastatic disease
Result voting voting second (<2.5 mm) to be recommended even where HIPEC could be effective.
Alternative first round (%) round (%) Overall deferring anastomoses to follow HIPEC administration
gained consensus (53%). Not surprisingly the indication for protective
Cytoreduction with electroevaporization 90.32 100.00
ostomies proved difficult and reflected the variation in practice already
Sparing policy leaving these residues to be 9.68 0.00
treated by the intraperitoneal reported. The experts did not agree on the need for a stoma following
chemotherapy rectal resection preferring to opt for surgical discretion.
This has been the first attempt to gain consensus and attempt
to align techniques according to disease type and to standardize
3. Timing of anastomoses approaches where possible. Many areas remain for debate when
considering application of surgical techniques as part of CRS. There
In the closed abdomen technique for administration of hyperthermic remains a need to define the place and indication for second
intraperitoneal chemotherapy which is the optimal timing for intestinal cytoreduction for disease relapse and explore a place for rectosigmoid
anastomosis after CRS? preservation and nerve sparing peritonectomy in different peritoneal
surface malignancies.

Result voting
Alternative first round (%)
Before the perfusion 35.48
After the perfusion 48.39
The constructive procedure could be 16.13
performed at any time after the
cytoreduction, without a significant
impact on the morbidity and/or mortality
4. Ostomies
Indications of protective proximal ostomies after CRS are not
uniform, with no consensus in the literature. When is a protective
ostomy indicated?
Result voting voting second
Alternative first round (%) round (%)
Whenever a rectal resection is performed 22.58
In cases of low anterior resections in which the 32.26
preservation of the rectum is not possible
In case of ileo-rectal anastomoses 29.03
The policy for protective stoma could be 61.29
flexible and the procedure done at the
surgeon’s discretion; the performance of
unprotected colorectal anastomoses does
not influence the morbidity and mortality
significantly
DISCUSSION AND COMMENTS
Using the Delphi methodology consensus was achieved in all areas
explored and for each alternative option presented except for
peritonectomy in mesothelioma. In all areas second round voting
achieved greater consensus.
With regard to peritonectomy, the greatest consensus was achieved
for serous ovarian, appendiceal and intestinal colorectal adeno-
carcinoma. For PMP the first round demonstrated variation in opinion
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 Journal of Surgical Oncology 2008;98:237–241

Postoperative Residual Disease Evaluation in the Locoregional Treatment of

Peritoneal Surface Malignancy

SANTIAGO GONZÁLEZ-MORENO, MD, PhD,1* SHIGEKI KUSAMURA, MD, PhD,

2

DARIO BARATTI, MD,2 AND MARCELLO DERACO, MD2

1
Department of Surgical Oncology, Peritoneal Surface Oncology Program, Centro Oncológico MD Anderson International España, Madrid, Spain
2
Surgical Department, Peritoneal Surface Malignancy Program, IRCCS Istituto Nazionale dei Tumori Milano, Italy

Background: The maximum size of the residual lesions left behind after cytoreductive surgery for peritoneal surface malignancy has consistently
been shown to be the main prognostic factor in this setting. However, a uniform assessment method and categorization for this paramount
prognostic indicator is lacking.
Methods: In order to achieve a consensus among experts, the Delphi methodology was employed. Conflicting points were identified and related
multiple choice questions were circulated among a panel of experts on peritoneal surface oncology. Two rounds of web-based voting were carried
out.
Results: The completeness of cytoreduction (CC) Score described by Sugarbaker was considered the current best classification for residual
disease size. The experienced surgeon’s naked-eye estimation was considered the ideal method to assess residual disease size. There was
agreement that the definition of CC-0 or R0 cytoreduction needs further specification. A redefinition of ‘‘completeness of cytoreduction’’
according to disease process was favored by the experts but not favored for the type of intraperitoneal chemotherapy employed.
Conclusions: Following the experts’ consensus, it is recommended that the CC score be used to categorize residual disease after cytoreductive
surgery for peritoneal surface malignancy. Pending issues for further consensus development in this area have been identified.
J. Surg. Oncol. 2008;98:237–241. ß 2008 Wiley-Liss, Inc.

KEY WORDS: peritoneal carcinomatosis; cytoreductive surgery; prognosis; residual disease

INTRODUCTION of high precision, such as microscope, which is usually not available in

The maximum size of residual disease remaining after surgical
cytoreduction has been shown to predict prognosis in patients with
cancerous peritoneal dissemination treated with cytoreductive surgery
and perioperative intraperitoneal chemotherapy.
Based on this residual lesion size, cytoreductive procedures have
been categorized as complete or incomplete. Results of several
studies [1–3] have shown a direct relation between the completeness of
cytoreductive surgery and survival for peritoneal dissemination from
all primary cancer locations (ovary, stomach, colon, appendix),
including the peritoneum itself. However, although this finding is
very consistent across groups and studies, there is a wide variation in
the methodology employed by different authors to assess residual
disease size and subsequently completeness of cytoreduction. The
different residual disease classifications currently employed are shown
in Figure 1.
Sugarbaker and colleagues found that prognosis can be estimated by
completeness of cytoreduction. For colon cancer there is a 40% chance
of survival at 5 years in those who undergo complete cytoreduction
versus 0% survival for the incomplete cytoreduction category [1,2].
Numerous other groups have confirmed that complete cytoreduction is
a requirement for long-term survival after treatment of peritoneal
carcinomatosis from appendiceal, colorectal and gastric cancer and
peritoneal mesothelioma [4–12].
There are several questions and inconsistencies that could be raised
to the currently available residual disease classification systems. One
of them is the precision of the limits between optimal and suboptimal
residual tumor size. According to CC score proposed by Sugarbaker
the cut-off value is 2.5 mm and represents the maximum intratumoral
penetration ability of cisplatin when administered intraperitoneally
[13,14]. Obviously the value was obtained in well-controlled ex-
perimental conditions, with the employment of measuring instruments
the operating room. The justification behind the cut-off value of 5 mm
adopted by other groups [2] does not seem to be consistent with
this rationale. Even when the limits defining the optimal residual
disease size should be based on the intratumoral penetration ability of
intraperitoneal cisplatin, the cut-off of 2.1–2.5 mm does not hold
true for other chemotherapies, frequently used for intraperitoneal
hyperthermic perfusion. Drugs such as doxorubicin, carboplatin and
oxaliplatin have much lower intratumoral penetration capacity.
The reproducibility of the methods used for postoperative residual
disease measurement is also of concern, as it has been demonstrated
that intraoperative estimation of tumor size shows a significant
interobserver variability. Prefontaine et al. used a simulated patient
model to evaluate surgeon accuracy in estimating tumor size [15].
They found that the range of estimates was very wide. More surgeons
underestimated rather than overestimated tumor diameters. He
estimated, given these results, that 25% and 20% of suboptimal
and optimal patients, respectively, were erroneously categorized.
Although such study was conducted with gynecologic oncologists, it is
intuitively expectable that at least the same level of inaccuracy and/or
lack of reproducibility could occur among peritoneal surface oncology
experts in the intraoperative assessment of residual tumor, unless it is
done by sterile rule or calliper at surgery.
The author has no financial interest related to the contents of this article to
disclose.
*Correspondence to: Dr. Santiago González-Moreno, MD, PhD, Calle
Gómez Hemans 2, 28033 Madrid Spain. Fax:þ34-91-768-0681.
E-mail: sgonzalez@mdanderson.es
Received 19 March 2008; Accepted 27 March 2008
DOI 10.1002/jso.21072
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.

238 González-Moreno et al.
Fig. 1. Residual disease size classifications currently found in the peritoneal surface oncology literature.
Furthermore, the definition of a CC-0 or R0 cytoreduction might
need additional specifications. Both conceptually and in the clinical,
operating room setting, a 12-hr cytoreduction down to ‘‘no visible
tumor nodules’’ might not equal a CC-0 or R0 resection if we start with
a large volume, widespread peritoneal disease (i.e. Peritoneal Cancer
Index (PCI) above 31 out of 39). In these cases, a very carefully
directed inspection might likely reveal tiny remaining nodules, and at
the very least microscopic tumor could be expected to remain. Some
surgeons consider this situation a CC-1 cytoreduction, despite the
inability by most witnesses in the operating room to see any remaining
tumor nodule, whereas other surgeons will not hesitate to label it as a
CC-0 resection.
Finally, although no formal statement in the literature is available, it
is thought that the definition of complete versus incomplete
cytoreduction may vary with the histological type of the malignancy.
For example, mucinous tumors are well penetrated by intraperitoneal
chemotherapy solutions. With minimally invasive mucinous tumors
such as pseudomyxoma peritonei, complete cytoreduction may occur
in the combined treatment plan with tumor nodules up to a full
centimetre in size. Likewise, Sebbag and cols [16]. found that patients
affected by peritoneal mesothelioma undergoing a CC-2 cytoreduction
with perioperative intraperitoneal chemotherapy could be grouped
along with the CC-0 and CC-1 categories, also benefiting from a long-
term survival. This finding holds true in the recently updated series
from the same institution [17]. In contrast, hard fibrotic non-mucinous
colon cancer is poorly penetrated by chemotherapy solutions. Only
cytoreduction down to no visible evidence of disease would be
expected to result in long-term survival with a sclerotic malignant
process.
Also, some cancers may be remarkably more responsive to
chemotherapy than others. This is likely the case of a majority of
ovarian cancers. Their complete response to systemic chemotherapy
is also frequently seen with intraperitoneal chemotherapy solutions or
a bidirectional (intraperitoneal combined with intravenous chemo-
therapy) approach. All these situations show that ‘‘completeness
of cytoreduction’’ is a dynamic concept and that the definition of
Journal of Surgical Oncology
‘‘complete cytoreduction’’ might need to be reconsidered according to
the clinical situation and disease process.
For all the above reasons, the need for a consensus and further
reflection on residual disease evaluation are warranted.
MATERIALS AND METHODS
In order to achieve a consensus among experts, the Delphi
methodology was employed [18]. Conflicting points were identified
and related multiple choice questions along with a scientific review
document on the topic were circulated among a panel of experts on
peritoneal surface oncology. Two rounds of web-based voting,
the second one after disclosing the results of the first round, were
carried out. A detailed description of the methodology used for this
consensus development is available elsewhere in this issue. Presenta-
tion and discussion of the results were done at the Fifth International
Workshop on Peritoneal Surface Malignancy held in Milan, Italy,
December 4–6, 2006.
The contents of the related scientific review document are outlined
in the Introduction section. The accompanying related questions
circulated among the experts were the following:
(1) Which one is the current best method to assess the residual disease
after cytoreductive surgery in patients affected by peritoneal
surface malignancies?
(a) AJCC/UICC R classification [19] with Dutch modification (R0
and R1: no macroscopic; R2a  2.5 mm and R2b > 2.5 mm)
[20];
(b) AJCC/UICC R classification [19] with French modification
(R0 and R1: no macroscopic; R2: macroscopic disease) [21];
(c) AJCC/UICC R classification [19] with American modification
(R0: no gross disease with negative microscopic margins; R1:
no gross disease with positive microscopic margins; R2a:
<5 mm, R2b: tumors of 6–20 mm and R2c: tumors of
>20 mm) [2];
(d) Completeness of Cytoreduction Score [22].
 Residual Disease After Cytoreductive Surgery 239
(2) What should be the ideal method to assess residual disease size RESULTS
after cytoreductive surgery?
(a) The experienced surgeon’s naked-eye estimation; Results of the web-based voting can be found in Table I.
(b) Direct measurement by a sterile rule or calliper;
(c) The average of the naked-eye estimation of all members of the Best Classification for Residual Disease
operating team.
(3) Consider the case of a young patient affected by pseudomyxoma Sugarbakeŕs Completeness of Cytoreduction Score (so-called ‘‘CC
peritonei undergoing cytoreductive surgery. Initial PCI is 35, score’’) was overwhelmingly considered in the second voting round
operating time including hyperthermic intraoperative chemother- the best classification by 93.75% of the experts. In the first voting this
apy (HIPEC) is 11 hr, and there are no apparent visible disease option was also the most voted obtaining 74.19% of the votes. All
nodules at the end of a very laborious cytoreductive procedure. advocates of the AJCC/UICC classification with French or American
What is your completeness of cytoreduction scoring? modification, and some of the Dutch modification in the first round
(a) CC-0; gave their support to the CC score in the second round.
(b) CC-1;
(c) other. Ideal Method to Assess Residual Disease
(4) Consider the same case. What is your R scoring?
(a) R0; Experts considered that subjective assessment of the residual
(b) R1; disease size was acceptable and preferable over a more objective
(c) other. method like direct measurement by a ruler. In the first voting, the
(5) Would you favor a further specification in the definition of a CC-0 naked-eye estimation of an experienced surgeon and the average of
or R0 cytoreduction? the estimations done by all members of the operating team obtained
(a) yes; similar results, but in the second round the naked-eye estimation by
(b) no. the experienced surgeon gained a significantly better support with
(6) Would you favor a redefinition of the completeness of cytoreduc- 65.63% of the votes compared to the other two options.
tion according to the disease process?
(a) yes; Clinical Case
(b) no.
(7) Would you favor a redefinition of the completeness of cytoreduc- In the above-described case, final voting results labeled the
tion according to the type of intraperitoneal cytotoxic agent(s) cytoreduction as CC-0 and R1. Regarding the CC-score, there were
employed? no significant changes in voting between the first and second rounds.
(a) yes; However, for the R classification, an initial tie between the R0 and R1
(b) no. subsequently gave way to a very significant majority (75%) supporting

TABLE I. Results of the web-based voting of the panel of experts

Votes (%) Votes (% second

Question Possible answers first round round

Question 1
Best residual disease classification system AJCC/UICC (Dutch) 9.68 6.25
AJCC/UICC (French) 12.9 0
AJCC/UICC (American) 3.23 0
CC Score 74.19 93.75
Question 2
Ideal method to assess residual disease size Expert surgeon’s naked eye 38.71 65.63
Ruler or calliper 25.84 18.75
Average naked-eye estimation 35.48 15.63
Question 3
Clinical case, CC score CC-0 70.97 75
CC-1 25.81 25
Other 3.23 0
Question 4
Clinical case, R score R0 48.39 25
R1 48.39 75
Other 3.23 0
QUESTION 5
Need for redefinition of CC-0 or R0 Yes 58.06 75
No 41.94 25
QUESTION 6
Need for redefinition of CC according to disease Yes 54.84 78.13
No 45.16 21.88
Question 7
Need for redefinition of CC according to Yes 29.03 21.88
chemotherapy
No 70.97 78.13

CC, completeness of cytoreduction.

Journal of Surgical Oncology

240 González-Moreno et al.
the R1 option. This was the result of initial R0 proponents changing
their vote to R1 in the second round.
Need for Further Specification of
CC-0 or R0 Definition
The second voting round consolidated and increased the support for
such a redefinition, already seen in the first round.
Need for Redefinition of Completeness of
Cytoreduction According to the Disease Process
Such a redefinition was clearly favored (78.13% vs. 21.88%), and
differences between voting rounds were very similar to the ones
observed in the previous question.
Need for Redefinition of Completeness of Cytoreduction
According to Chemotherapy Agent(s) Employed
A clear majority of experts (78.13%) rejected such a possibility,
with similar results in the first and second voting rounds.
DISCUSSION
The radical treatment of peritoneal surface malignancies consists of
an inseparable combination of cytoreductive surgery and perioperative
intraperitoneal chemotherapy. Neither component of this therapy could
achieve the same result alone, and need each other for optimal results.
Therefore, residual disease size left behind after a maximum
cytoreductive effort should ideally be small enough so that the limited
penetration of intraperitoneal chemotherapy could result in complete
cancer eradication. This criterion is the basis of the definition of a
complete cytoreduction, the main goal to achieve in this therapy, and
should be honored in any attempt or proposal to establish disease size
cut-off values that make up different prognostic groups.
Given the crucial importance of the measurement of residual tumor
nodules, and being well aware of the high interobserver variability in
this topic, as demonstrated by Prefontaine and colleagues [15], experts
still agreed on not using an objective measurement instrument for this
purpose, but rather rely on their own naked-eye estimation.
All residual disease classifications considered, although hetero-
geneous in definition criteria, have demonstrated their ability to place
Fig. 2. A possible proposal for a redefinition of completeness of cytoreduction according to disease process. Such redefinition was favored by
the panel of experts who participated in the consensus. For each disease, the vertical line to the right of its name sets the division between complete
and incomplete cytoreduction.
Journal of Surgical Oncology
apart groups of patients with different prognosis. However, for the
great majority of experts that participated in this consensus, the CC
score proposed by Sugarbaker was considered the best residual
disease classification. Several reasons could justify this election. The
cut-off value of 2.5 mm is well established in the literature and
corresponds to the maximum intratumoral penetration of intraperito-
neal cisplatin. Although other drugs vary in their penetration capacity,
none of them reach the 5 mm employed in other classifications as
the limit between the first two prognostic groups. Following this
rationale, heterogeneity in drug intratumoral penetration capacity
could determine different residual disease size cut-off values according
to the drugs employed, but this was not considered a need by the
participating experts.
Secondly, the CC score was specifically designed for this purpose:
delineation of prognostic groups following cytoreductive surgery and
perioperative intraperitoneal chemotherapy for peritoneal surface
malignant diseases. However, the R classification (AJCC/UICC) was
created to assess residual disease in a different context, i.e. surgical
resection of a tumor mass, not of diffuse peritoneal involvement.
Actually, the original AJCC/UICC definition does not consider
different residual disease size values within the R2 (macroscopic
disease) category, a factor which we know has a key impact on
survival. For this reason different groups (except for the Lyon group)
created their own subdivisions within the R2 category (Table I), adding
further confusion to this issue.
In the third place, the AJCC/UICC R classification includes an
‘‘R1’’ category, defined as microscopic residual disease. However,
because of the nature of the procedure and of the underlying neoplastic
disease, microscopic residual disease is expected to be present after
virtually all cases of cytoreductive surgery, providing the rationale
for the employment of regional chemotherapy. Following this line of
reasoning, the group from Lyon advocates using a joint R0/R1 category
within the R classification. Furthermore, microscopic assessment
of resection margins in the numerous peritonectomy and visceral
resection specimens rendered by these procedures would be an impos-
sible endeavour for a pathologist. For these reasons, a microscopic
residual disease category would not need to be included in a residual
disease classification after cytoreductive surgery for peritoneal surface
malignancy, just as it occurs in the CC score. Putting it in different
words, all CC-0 cytoreductions would implicitly be CC-0/R1
procedures, and CC-0/R0 scoring would be achieved after en-bloc
resection of a primary tumor, but rarely after a cytoreductive procedure
for peritoneal carcinomatosis. This was reflected in the experts’

answers to the proposed clinical case (questions 3 and 4), where an
extensive cytoreduction down to no visible tumor nodules (the most
complete we could consider) was categorized as CC-0 but R1, and
subsequently a majority agreed on the need to further specify the
definition of a CC-0 or R0 cytoreduction (question 5), although
this was not formulated. It is possible that the definition of a true CC-0/
R0 cytoreduction should incorporate a statement alluding to the
predictable absence of microscopic disease (or margins) and be
reserved for situations with no visible disease in cases with a very low
initial Peritoneal Cancer Index, similar to the situation encountered
after an en-bloc resection of a primary tumor.
As outlined in the related document circulated among our experts
and included in the above introduction, the different biological
behaviour and chemosensitivity patterns of the different neoplasms
grouped as ‘‘peritoneal surface malignancies’’ could eventually result
in considering different residual disease classifications for each
disease (Fig. 2). Intuitively this is a reasonable, plausible statement
and, although no scientific confirmation is available, a majority of our
experts actually favored such a redefinition. The only published
evidence for this comes from the peritoneal mesothelioma series
results published by the Washington Cancer Institute group, whereby
cases with residual disease nodules up to 2.5 cm in size (equivalent to a
CC-2 cytoreduction) were included in the more favorable survival
group along with CC-0 and CC-1 cases (thereby somehow considered
complete cytoreductions), in contrast with the pseudomyxoma or
colorectal carcinomatosis experience by the same group where CC-2
cases are grouped with CC-3 cases in the incomplete cytoreduction
category. This has not been confirmed by other groups. However, it is
possible that in the future new, more active drugs will become available
and that their use might help modulate the cytoreductive effort
necessary for an optimal combined treatment result, raising the need to
consider a change in terminology from ‘‘complete’’ cytoreduction to
‘‘optimal’’ or ‘‘adequate’’ cytoreduction.
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1. Elias D, Blot F, El Otmany A, et al.: Curative treatment of
peritoneal carcinomatosis arising from colorectal cancer by
complete resection and intraperitoneal chemotherapy. Cancer
2001;92:71–76.
2. Shen P, Levine EA, Hall J, et al.: Factors predicting survival after
intraperitoneal hyperthermic chemotherapy with mitomycin C
after cytoreductive surgery for patients with peritoneal carcino-
matosis. Arch Surg 2003;138:26–33.
3. Witkamp AJ, de Bree E, Kaag MM, et al.: Extensive
cytoreductive surgery followed by intra-operative hyperthermic
intraperitoneal chemotherapy with mitomycin-C in patients with
peritoneal carcinomatosis of colorectal origin. Eur J Cancer 2001;
37:979–984.
4. Glehen O, Kwiatkowski F, Sugarbaker PH, et al.: Cytoreductive
surgery combined with perioperative intraperitoneal chemo-
therapy for the management of peritoneal carcinomatosis from
colorectal cancer: A multi-institutional study. J Clin Oncol 2004;
22:3284–3292.
5. Glehen O, Mithieux F, Osinsky D, et al.: Surgery combined with
peritonectomy procedures and intraperitoneal chemohyperther-
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mia in abdominal cancers with peritoneal carcinomatosis: A
phase II study. J Clin Oncol 2003;21:799–806.
6. Sugarbaker PH, Jablonski KA: Prognostic features of 51 color-
ectal and 130 appendiceal cancer patients with peritoneal
carcinomatosis treated by cytoreductive surgery and intraperito-
neal chemotherapy. Ann Surg 1995;221:124–132.
7. Elias D, Blot F, El Otmany A, et al.: Curative treatment of
peritoneal carcinomatosis arising from colorectal cancer by
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2001;92:71–76.
8. Witkamp AJ, de Bree E, Kaag MM, et al.: Extensive
cytoreductive surgery followed by intra-operative hyperthermic
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11. Yonemura Y, Fujimura T, Nishimura G, et al.: Effects of intra-
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12. Deraco M, Nonaka D, Baratti D, et al.: Prognostic analysis of
clinicopathologic factors in 49 patients with diffuse malignant
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intraperitoneal hyperthermic perfusion. Ann Surg Oncol 2006;13:
229–237.
13. Los G, Verdegaal EM, Mutsaers PH, et al.: Penetration of
carboplatin and cisplatin into rat peritoneal tumor nodules after
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15. Prefontaine M, Gelfand AT, Donovan JT, et al.: Reproducibility of
tumor measurements in ovarian cancer: A study of interobserver
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16. Sebbag G, Yan H, Shmookler BM, et al.: Results of treatment of
33 patients with peritoneal mesothelioma. Br J Surg 2000;87:
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17. Yan TD, Brun EA, Cerruto CA, et al.: Prognostic indicators for
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22. Jacquet P, Sugarbaker PH: Clinical research methodologies in
diagnosis and staging of patients with peritoneal carcinomatosis.
Cancer Treat Res 1996;82:359–374.
 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
1,2
AND GILLY FRANCOIS NOEL, MD, PhD,
1
Department of Oncologic surgery, Centre Hospitalo-Universitaire Lyon Sud, Pierre Bénite Cedex, France
2
EA 3738, UCBL, Faculté de médicine Lyon Sud, Oullins Cedex, France
3
Fondazione IRCCS Istituto Nazionale dei Tumori Milano, Milan, Italy
4
Department of Anesthesiology, CHLS—HCL, Pierre Bénite 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 Modalities of Perfusion

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
currently used into specialized centers. Although the use of HIPEC has
gained wider acceptance, the specifics of its administration lack
uniformity. Debate on the best technique for HIPEC is still open. In this
review, after the report of consensus on nomenclature, the methodo-
logy, benefits, and risks associated with each technique are discussed.
Standardized Nomenclature
Multiple names and its acronyms have been used into scientific
literature to refer to the intraoperative administration of hyperthermic
intraperitoneal chemotherapy, often causing confusion. The Dutch
group [1] proposed in 2004 during the 4th Workshop on Peritoneal
Surface Malignancies held in Madrid, the use of the term ‘‘HIPEC.’’
The Workshop participants were already in favor of its acronym [2].
The results of the web based voting confirmed this consensus and
‘‘HIPEC’’ was choosed by 61.29% and 78.1% of experts during the
first and the second round of the vote, respectively. So this acronym
should be used to refer to the hyperthermic intraperitoneal chemo-
therapy into scientific literature and communication.
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.
But it also has inconvenient: because the chemotherapeutic
agents persist in the peritoneum cavity, there is a greater opportunity
for significant systemic absorption and adverse effects. This can be
partially overcome by the use of drugs that have a high first-pass effect
after portal absorption such as 5-fluorouracil (5-FU) which is the most
common drug used with this technique [4]. Some other toxicity
related to catheter complications (infections, bowel obstruction) has
been reported. EPIC was found to significantly increase the rate of
postoperative complications in the large multicentric retrospective
The authors have no financial interest related to the contents of this article to
disclose.
*Correspondence to: Dr. Olivier Glehen, MD, PhD, Department of surgery,
CHLS, 69495 Pierre Bénite Cedex, France. Fax: 00(33)478 863 343.
E-mail: olivier.glehen@chu-lyon.fr
Received 17 March 2008; Accepted 21 March 2008
DOI 10.1002/jso.21061
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.


study including 504 patients with colorectal carcinomatosis
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
perfusion. Precooling can be obtained by using cooling hat, legs or
blankets. But for most of teams, it was not found to be necessary and
precooling is simply accomplished by limited use of body warming
during the cytoreduction, which is often a long procedure [12]. During
the procedure, temperature probes must be placed at different sites of
circuit and intraperitoneal cavity: heat generator, inflow and outflow
drains, bladder, liver, mesentery [13]. It is agreed that the desirable
intra-abdominal temperatures range to maintain during HIPEC is
41.5–438C, needing inflow temperatures at 46–488C [2]. The duration
of the procedure varies according to investigators and drugs used from
30–120 min. An increased drug concentration in the instillate with a
shorter bathing duration would probably give similar pharmacokinetic
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
Journal of Surgical Oncology
HIPEC: Modalities of Perfusion 243
Fig. 1. The coliseum apparatus. [Color figure can be viewed in the
online issue, available at www.interscience.wiley.com.]
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
leads to heat dissipation at the surface of the instillate, making it
more difficult to achieve hyperthermia with high temperatures. It also
increases exposure of operative personnel to chemotherapy. Because
the surgeon is required to manually manipulate the viscera, increased
potential exists for contact exposure. Moreover, despite the use of
the smoke evacuator, heated chemotherapy can aerosolize, creating
inhalational exposure. Stuart et al. [16] evaluated the safety of
operating room personnel during the coliseum technique. All
assessments (urine members, air sampled, and sterile gloves examina-
tion) were found to be in compliance with established safety standards.
Since this study, no trial reported on increased risk of chemotherapy
exposure. However, guidelines concerning safety considerations for
operative room personnel are needed and have well established by
Gonzalez-Bayon et al. [17]: selection and education of operative room
personnel, restriction of personnel inside the operative room, used of
rigid containers, protective barrier garments, disposable, impervious
gown, high power filtration mask, smoke evacuator, avoided spills.
Mortality and morbidity rates may be compared following
HIPEC using different techniques, but side effects from HIPEC appear
to be principally related to the magnitude of the surgery in the largest
trials of literature (Table I) [18–23]. Moreover, because of differences
in term of patient selection, chemotherapy agents used, level of
TABLE I. Mortality and Morbidity Following Cytoreductive Surgery
Combined With HIPEC Using Closed or Open Abdomen Techniques
Authors Technique Nb Mortality (%) Morbidity (%)
Sugarbaker et al. [22] Opened 356 2 19
Verwaal et al. [23] Opened 102 8 65
Elias et al. [18] Opened 64 9 55
Shen et al. [21] Closed 109 8 36
Kusamura et al. [20] Closed 209 1 12
Glehen et al. [19] Closed 216 3 24
244 Glehen et al.
Fig. 2. HIPEC device using a closed abdomen procedure. [Color figure can be viewed in the online issue, available at www.interscience.
wiley.com.]
hyperthermia, and goal of treatment (curative or palliative intent)
comparisons of postoperative results as well as survival results between
the different procedures are difficult.
Closed abdomen technique. The intraoperative closed technique is
perhaps the most widely used method of HIPEC. The closure of
the abdominal wall may be temporary or definitive. Anastomoses are
performed before or after perfusion. No increased risk of anastomotic
fistula or recurrence have been reported for teams which are performing
their anastomoses before [19,20]. This abdominal wall may be manually
agitated during the perfusion in an attempt to promote uniform heat
distribution. Figure 2 illustrated the technique used in Lyon.
The major advantage of the closed technique is the ability to rapidly
achieve and maintain hyperthermia, because there is minimal heat
loss from the closed abdomen. The technique has been refined
with modeling studies to optimize thermal homogeneity [24,25]. In
addition, there is minimal contact or aerosolized exposure of the
operating room staff to the chemotherapy. Moreover, intraperitoneal
Fig. 3. Peritoneal cavity expander. [Color figure can be viewed in the
online issue, available at www.interscience.wiley.com.]
Journal of Surgical Oncology
chemotherapy with positive pressure has been reported to enhance the
penetration of drugs into tissue. It was reported in vivo by Jacquet et al.
[26] for the intraperitoneal administration of doxorubicin at pressure of
20–30 mm Hg. Recently, Esquis et al. [27] reported that intraperitoneal
administration of cisplatin with increased intra-abdominal pressure
(40 mm Hg) improved the tumor accumulation and the antitumor effect
of the drug in rats bearing advanced peritoneal carcinomatosis.
The main disadvantage of the closed technique is the lack of
uniform distribution of the heated intraperitoneal chemotherapy. With
the instillation of methylene blue during the procedure, uneven
distribution was reported [14,15]. Inadequate circulation of heated
intraperitoneal perfusate leads to pooling and accumulation of heat and
chemotherapy in dependant parts of the abdomen. This may result in
increased systemic absorption and result in foci of hyperthermic injury
that could contribute to postoperative ileus, bowel perforation, and
fistula. However, the two largest clinical trials evaluating the closed
abdominal technique on more than 200 patients, the mortality and
Fig. 4. The abdominal cavity expander. [Color figure can be viewed
in the online issue, available at www.interscience.wiley.com.]
 HIPEC: Modalities of Perfusion 245
TABLE II. Techniques of Intraperitoneal Chemotherapy Administration

Technique Advantages Disadvantages

Early postoperative chemotherapy Multiple cycles of chemotherapy Increased toxicity

Uneven distribution of chemotherapy
Port malfunctions
No hyperthermia
Closed intraoperative Minimizes exposure of OR staff to chemotherapy Uneven heat distribution
Easier to achieve high perfusion temperatures Lack of uniform drug distribution
Increased drug penetration and tissue uptakes with high
intraabdominal pressure
Open intraoperative More uniform heat distribution Increased risk of OR staff exposure to chemotherapy
‘‘Coliseum technique’’ More uniform drug distribution Heat dissipation
Peritoneal cavity expander Uniform distribution of chemotherapy Increased risk of OR staff exposure to chemotherapy
More complex apparatus
Semi-closed (semi-opened) intraoperative More uniform heat distribution More complex apparatus
More uniform drug distribution Not popular
Minimizes exposure of OR staff to chemotherapy

TABLE III. Expert Votes Regarding the Best Technique of HIPEC (Milan, December 2006): Results of 1st and
2nd Round

HIPEC technique 1st round 2nd round

Open abdominal technique 25.8% 25%

Peritoneal cavity expander 3.2% 0%
Closed abdominal technique 9.7% 6.25%
Semi-opened technique 0% 3.25%
There is no sufficient evidence in literature confirming the superiority of one technique over 61.3% 62.5%
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

morbidity rates were 1 to 3% and 12 to 24%, respectively (Table I)
[19,20]. Authors did not report any complications that may be caused
by the problem of inadequate circulation.
Peritoneal cavity expander. An alternative method to increase the
distribution of heated chemotherapy involves the use of a peritoneal
cavity expander (PCE), first reported by Fujimura et al. [28] The PCE
is an acrylic cylinder containing inflow and outflow catheters that
are secured over the wound. When filled with heated perfusate, the
PCE can accommodate the small intestine, allowing the small intestine
to float freely and be manually manipulated in the perfusate (Fig. 3). It
was particularly developed by Japanese authors for the treatment or the
prevention of gastric carcinomatosis [29–31].
By temporarily increasing the volume of the peritoneal cavity, a
more uniform distribution is theoretically achieved compared with the
closed technique.
The main disadvantage of the PCE technique is the risk of exposure
to operating room personnel as discussed for the coliseum tech-
nique. Moreover, it is a complex apparatus that need experience to be
manipulated and it does not allow treatment of parietal wound.
Semi-opened (or semi-closed) abdominal techniques. It may be
interesting to combine advantages of the closed and the open
technique. Rat et al. [32] reported the use of an abdominal cavity
expander (Fig. 4). The skin edges are water tightly stapled with a soft
‘‘abdominal cavity expander,’’ supported by a Thompson self-retaining
retractor positioned over the abdomen. So, the level of the liquid can be
widely raised above the level of the skin edges. The anterior wall
peritoneum, the wall edges are constantly exposed to the liquid. Large
amplitude movements become possible: introduction into the abdomen
of two forearms, even two arms, does not induce loss of any liquid.
Paul Sugarbaker also reported the use of an instrument to provide
containment of intraperitoneal chemotherapy, that may allow to limit
heat loss and staff exposure to chemotherapy [33].
A summary of the advantages and disadvantages of the above
techniques are depicted in Table II.
CONSENSUS VOTE ON MODALITIES
OF PERFUSION
Experts were asked to vote on the best technique of HIPEC. The
results of two rounds of vote are reported in Table III. The majority
thought that there is no sufficient evidence in literature to establish
the superiority of one technique over the others. The only way to
demonstrate it would be to conduct a prospective randomized study.
Actually, each specialized team have to improve and adapt their
technique (open or closed) to allow acceptable mortality and morbidity
rates, low risk of staff exposure to chemotherapy and improved
survival outcomes.
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130–138.

Journal of Surgical Oncology

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 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, MD1
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

At the Fifth International Workshop on Peritoneal Surface Malignancy, in Milan, the consensus on technical aspects of cytoreductive surgery
(CRS) for peritoneal surface malignancy was obtained through the Delphi process. Conflicting points concerning drugs, carrier solution and
optimal temperature for hyperthermic intraperitoneal chemotherapy (HIPEC) were discussed.
J. Surg. Oncol. 2008;98:247–252. ß 2008 Wiley-Liss, Inc.

KEY WORDS: peritoneal carcinomatosis; hyperthermic intraperitoneal chemotherapy; consensus

INTRODUCTION
On December 4–6, 2006, the National Cancer Institute of Milan
organized a consensus statement on the management of peritoneal
surface malignancy (PSM). This conference brought together experts
in the field of local–regional therapy in an effort to discuss current
approaches to this PSM.
Eligible Drugs for Hyperthermic
Intraperitoneal Chemotherapy
Several drugs are available for intraperitoneal use, as outlined in
Table I. Theoretically, only cell cycle phase non-specific agents are
indicated for this single-shot cancer treatment. In other words cell
cycle phase specific agents should be not suitable for HIPEC.
The drug (or combination of drugs) should be allocated by the
experts in one of the following phase of scientific investigation
pathway:
. phase I or dose finding;
. phase II for evaluation of tumor response;
. phase III for evaluation of efficacy in terms of survival;
. routine clinical use.
However, attention should be paid to some important aspects. The
maximum tolerated dose determined for one drug by a study on early
postoperative intraperitoneal chemotherapy (EPIC) should not neces-
sary be applicable to hyperthermic intraperitoneal chemotherapy
(HIPEC). The same succeeds between the modalities of HIPEC: the
maximum tolerated dose of one drug defined a phase I study using the
Coliseum technique should not be adopted by those who works with
the closed abdomen technique.
Carrier Solution
The choice of a carrier solution in which the chemotherapy is
administered plays an important role in the clearance of drugs from
peritoneal cavity to plasma.
However, it is necessary to underline that the chemical aspect of the
carrier is not the only factor that impact on pharmacokinetics and
penetration of the agents inside the tumor deposit. Other factors such as
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-
action between heat and chemotherapies, method of control, besides
the risk of side-effects. Potential development of thermo-tolerance due
to the activation of heat shock proteins during short exposure time
(30 min or less) should also be taken in consideration [8].
Regarding the type of drugs this does not constitute a problem as all
of those usually used for HIPEC are chemically stable at temperature
as high as 508C.
Synergism between various cytotoxic drugs and hyperthermia starts
at a temperature of 398C but is stronger at higher temperatures;
according to in vitro studies on culture cells at temperature of 458C
cytotoxicity of the chemotherapies is far more intense than at 41 or
428C; thus intuitively it is reasonable to use the highest level of
hyperthermia restricted only by the clinical tolerance.
The author has no financial interest related to the contents of this article to
disclose.
{
Chief.
*Correspondence to: Elias Dominique, MD, PhD, Département de chirurgie
générale oncologique, Institut Gustave-Roussy, 39 rue Camille-Desmoulins,
Villejuif Cedex, France. Fax: (33) 01 42 11 5256. E-mail: elias@igr.fr
Received 20 March 2008; Accepted 21 March 2008
DOI 10.1002/jso.21051
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.

 TABLE I. Chemotherapy Agents Used for Intraperitoneal Chemotherapy

Normothermic intraperitoneal
HIPEC chemotherapy
248
Dose-escalation Dose-escalation
Molecular Heat Depth of study as single study as single
Drug weight AUC ratio synergy penetration agent MTD agent MTD Comments
2
Doxorubicin 580.0 230 Yes 4–6 cell No — Yes [12] 15 mg/m Sugarbaker et al. conducted a dose escalation study with early
layers postoperative intraperitoneal doxorubicin using
pharmacokinetic monitoring [12]
Melphalan 305.2 93 Marked NA No — Yes [13] 70 mg/m2 Hyperthermia affects the pharmacokinetics of intraperitoneal

Journal of Surgical Oncology

Melphalan by decreasing the AUC of peritoneal fluid Melphalan
Kusamura et al.

without increasing the plasma AUC in rat models [14]

Under investigation with hyperthermia in a clinical trial in patients
with small-volume residual carcinomatosis postcytoreduction at
a dose of 70 mg/m2 [15]
Mitomycin C 334.3 23.5 Yes 2,000 m Yes [16] 35 mg/m2 No — Used by most of the centers that participated in the Fourth
International Workshop on PSM for the treatment of
carcinomatosis of appendiceal or colonic origin [17]
According to Zoetmulder et al. the maximal tolerated dose, when
used as a single agent is 35 mg/m2 for HIPEC [18]
Cisplatin 300.1 7.8 Yes 1–3 mm Yes [19] 300 mg/m2 Yes It was demonstrated in animal models that hyperthermic perfusion
with 15 mg/ml (in 200 ml) cisplatin gave equivalent plasma drug
levels to a maximum tolerated dose (MTD] ip bolus injection
of 4 mg/kg (36 micrograms/ml in 20 ml) [20]
Gemcitabine 299.5 500 At 48 h NA No — No — The cytotoxicity of the drug is synergized by heat if the
hyperthermia is used at 48 h after intravenous drug
administration in a rat model [21]
A dose escalation study was conducted for the combination
cisplatin þ gemcitabine in normothermic condition. The MTD
was cisplatin (75 mg/m2) on day 1 and gemcitabine at 500 mg/m2
on days 1 and 8 on a 21-day schedule for four courses [22]
Mitoxantrone 517.41 115–255 Yes 5–6 cellular No — Yes [23] 28 mg/m2 Hyperthermic perfusion seems to lower mitoxantrone levels in the
layers peritoneal fluid without greatly influencing plasma levels
In phase I/II studies, Link et al. determined that a single
intraperitoneal instillation of 28 mg/m2 is well tolerated. The
study was conducted for the evaluation of the treatment with
a palliative intent in normothermic condition [24]
The only phase I study on mitoxantrone in HIPEC evaluated the
pharmacokinetics properties of the drug [25]
Oxaliplatin 397.3 16 Yes 1–2 mm Yes 460 mg/m2 No — According to a dose escalation Phase II study conducted by Elias
et al. oxaliplatin should be administered by a very short pulse of
high-dose (460 mg/m2) using a short dwell time (30 min) [26]
Etoposide 588.58 65 Yes NA No — Yes [27] 700 mg/m2 Experiences with Etoposide for HIPEC succeeded in combination
with other drugs in the treatment of gastric cancer [28,29]
Irinotecan 677.19 N/A No NA No — No — Elias et al. conducted a phase I study on pharmacokinetics of the
combination oxaliplatin and irinotecan, after intravenous
leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2) [26]
Paclitaxel 853.9 1,000 No >80 cell No — Yes [30] 120–180 mg Up to date of the present consensus meeting there is no report in
layers total dose literature documenting the employment of paclitaxel for HIPEC
Docetaxel 861.9 552 No NA No — Yes [31] 156 mg/m2 Tested for HIPEC phase I study in gynecologic cancer patients [32]
5-Fluorouracil 130.08 250 Minimal 0.2 mm No — Yes [33] 650 mg/m2  Reported experiences of the 5-fluorouracil in combination with
5 days hyperthermia are limited to experimental studies [34,35]. The
drug has been employed mostly in early perioperative
intraperitoneal chemotherapy
Carboplatin 371.25 10 Yes 0.5 mm Yes [36] 800 mg/m2 Yes [37,38] 500 mg/m2 Steller et al. concluded that the maximum tolerated dose of
carboplatin for HIPEC with closed abdomen technique
is 800 mg/m2 [36]
 Consensus in Local-Regional Treatment 249

Although not formally defined by a phase I dose escalation trial this recommended dose is popular

HIPEC: heated intraperitoneal chemotherapy; normothermic intraperitoneal chemotherapy; MTD: maximum tolerated dose; NA: not available. CDDP: cisplatin; TNF: tumor necrosis factor; Dx: doxorubicin; MMC:
The limiting factor for the employment of temperature as high as
Used by almost unanimously for advanced ovarian cancer according to the progress report of
The combination has been tested in phase II studies using HIPEC to treat a variety of tumors

The hospital mortality rate was 2.5%; grade 3-4 hematological toxicity rate was 58% [26]
458C is the tolerance of the small bowel. The only one study addressing

and irinotecan, after intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2).
Elias et al. conducted a phase I study on pharmacokinetics of the combination oxaliplatin
the thermo-tolerance was performed in animal model (rat). It was
peritoneal mesothelioma [40,41], peritoneal sarcomatosis [42], ovarian cancer [43]

concluded that 448C during 30 min was the maximal well-tolerated

temperature [9].
However, two points remain unresolved: (1) it is not known whether
Strongly advocated by Elias D. at 4th International Workshop on PSM [17]

the conclusions drawn by experimental studies with animal models

This dose schedule was reported as a single experience by Park et al. [19]

This dose schedule was reported as a single experience by Ryu et al. [46]
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
Observation

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
among the local–regional therapists [44,45]

needs to use cooling systems to decrease the body’s temperature.

4th International Workshop on PSM [17]

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.
(20 mg/m2 iv) and 5-fluorouracil (400 mg/m2 iv)
CDDP (250 mg/m ) and TNF alpha (0.1 mg) [19]

NB: using 360 mg/m2 for the two agents gives less
hematological toxicity (¼ recomanded dosage)
CDDP (25 mg/m2/L of perfusate) and MMC

The Different Parameters Impacting on

Oxaliplatin (460 mg/m2 ip) þ leucovorin

Carboplatin (350 mg/m2) þ interferon-a

CDDP (43 mg/L of perfusate) and Dx

Oxaliplatin (460 mg/m2) þ irinotecan

Pharmacokinetics and Efficacy of HIPEC

Recommended dose

(15.25 mg/L of perfusate) [39]

At last, eight parameters can be modified during HIPEC: type of

(3.3 mg/m2/L of perfusate)

drugs, concentration of drugs, combination of them, carrier solution,

(5,000,000 IU/m2) [46]

volume of the perfusate, level of the temperature, the duration, and the
technique (open or close cavity). The possible different combinations
(400 mg/m2) [26]
2

of them are unlimited. Moreover, when one parameter changes, a

pharmacokinetics study must be performed.
mitomycin C; INF: interferon; PSM: peritoneal surface malignancy.

MATERIALS AND METHODS

In order to achieve a consensus among experts, the Delphi
methodology was employed. Conflicting points were identified and
Tested in dose-escalation

related multiple choice questions along with a scientific review

study for HIPEC

document on the topic were circulated among a panel of experts on

peritoneal surface oncology. Two rounds of web-based voting,
Yes
Yes

Yes

Yes
No

No

the second one after disclosing the results of the first round, were
carried out. Consensus was defined as the agreement of 51% of the
voters [10,11]. A detailed description of the methodology used for this
consensus development is available elsewhere in this issue. Presenta-
tion and discussion of the results were done at the Fifth International
Workshop on Peritoneal Surface Malignancy held in Milan, Italy,
Oxaliplatin ip þ leucovorin

December 4–6, 2006.

Carboplatin þ INF alpha
TABLE I. (Continued )

Oxaliplatin þ Irinotecan
iv þ 5-fluorouracil iv
CDDP þ TNF alpha

RESULTS
CDDP þ MMC
Combinations

CDDP þ Dx

The contents of the related scientific review document are outlined in

Introduction Section. The accompanying conflicting points circulated
among the experts with their respective results of the second voting
round were the following:

Journal of Surgical Oncology

250 Kusamura et al.

Fig. 1. Scientific pathway for drug development.

Drugs DISCUSSION AND COMMENTS

Several drug schedules have been used in the last two decades for
HIPEC in the treatment of peritoneal surface malignancies. Usually the
scientific pathway expected to be followed before the introduction of
a antiblastic drug (alone or in combination) in the routine clinical
practice is outlined in Figure 1.
However, this pathway has not been strictly respected in the local–
regional therapy scenario. As an example, some drugs have been tested
in phase II studies without having been adequately tested in phase I
trials. Fortuitously such situations could have resulted in procedures
with acceptable morbidity, which accords with the conceptual goal of
local–regional therapy of minimal systemic antiblastic side-effects.
However, the disadvantage of such a skipping policy is that the drug
(alone of combination) could be adopted by local–regional therapist
with a ill-defined suboptimal dose, which does not exploit the whole
antiblastic potential of the chemotherapy(ies). Thus, taking into
account the state of the art relative to each of the following drug (or
combination) for HIPEC, we would like to ask you in which phase it
should be allocated to be adequately studied (the results of the voting
are outlined in Table II).
The panel of experts reached a consensus in only 2 out of 19 points
submitted to voting with respect to the allocation of the drugs in the
different phases of scientific investigational pathway. About seventy
percent of the voters agreed that Cisplatin and Mitomycin-C could be
employed in the routine clinical practice of local–regional therapy as
single agents.
Although no consensus was established in the following points (as
the minimum cut-off level of 51% was not reached) the voters
preferences could be summarized as follows: (1) drugs not eligible for
HIPEC: paclitaxel and 5-fluoruracil; (2) drugs elected for experimental
studies: gemcitabine, mitoxantrone, etoposide, docetaxel, cispla-
tin þ TNF alpha and carboplatin þ INF alpha; (3) drugs elected for
phase I studies: melphalan, irinotecan, carboplatin, oxalipla-
tin þ irinotecan; (4) drugs elected for phase II studies: none; (5) drugs
elected for phase III studies: oxaliplatin, oxaliplatin ip þ leucovorin
iv þ 5-fluorouracil iv; (6) drugs elected for routine clinical use:
doxorubicin, cisplatin and mitomycin-C.
TABLE II. Types of Carrier Solution for Hyperthermic Intraperitoneal
Chemotherapy

Type of carrier Characteristic

Carrier Solutions
Isotonic salt solutions Rapidly absorbed due to low molecular weight [47]
The choice of carrier solution in which the antineoplastic drug is and dextrose solutions
administered can play an important role in the clearance of drugs from Inability to maintain a prolonged high intraperitoneal
peritoneal cavity to plasma. In the circumstance of a high molecular fluid volume
weight drugs with delayed systemic metabolism or excretion, which Hypotonic solutions According to experimental evidences, hypotonic
one of the following alternatives may present more advantages, solution was promising in vitro as it increases the
according to experimental data? Cisplatin accumulation in tumor cells and
enhances its cytotoxicity [48–50]
On the other hand, the administration of heated
(a) isotonic salt solutions and dextrose solutions: 53.13%; intraoperative oxaliplatin in increasing hypotonic
(b) hypotonic solutions: 0%; solutions resulted in a high incidence of
(c) hypertonic solutions: 0%; unexplained postoperative peritoneal bleeding
(d) isotonic high molecular weight solutions: 6.25%; and no pharmacokinetics advantage [51]
(e) the use of carrier solutions of varying tonicity requires further Hypertonic solutions Allows a prolonged high intraperitoneal volume [52]
investigation: 40.63%. Slows down the clearance of intraperitoneal fluid
Main disadvantage is dilution of intraperitoneal drug
due to fluid shift inward to the peritoneal
cavity [53]
Temperature Isotonic high molecular Solutions such as icodextrin allows a prolonged high
weight solutions intraperitoneal volume [54], a reduced drug
The optimal range of temperature (8C) levels during the HIPEC is: clearance from the peritoneal cavity
However, the reduced drug clearance from the
(a) 40–41; 0%; peritoneal cavity does not necessary imply an
(b) 41–43; 62.50%; increased cancerours surfaces exposure to the
(c) 41.5–42.5; 21.88%; drug. Up to date there is no proof that icodextrin
(d) 42; 0%; releases the agents and that the agents penetrates
(e) 42–42.5; 0%; inside the tumor and bathed tissues
Indication for HIPEC based on this elements is
(f) 42–43; 15.63%;
questionable
(g) 42–45; 0%.

Journal of Surgical Oncology

 Consensus in Local-Regional Treatment 251
TABLE III. Results of Voting Regarding the Allocation of Chemotherapies in the Scientific Pathway for Drug Development (only the Results of the Second
Round Are Outlined)

(a) Not eligible (b) Experimental (f) Routine

Drug/Combination for HIPEC phase (c) Phase I (d) Phase II (e) Phase III clinical use

Doxorubicin 12.50% 6.25% 9.38% 12.50% 12.50% 46.88%

Melphalan 25.00% 21.88% 37.50% 6.25% 0% 9.38%
Mitomycin-C 12.50% 3.13% 0% 3.13% 9.38% 71.88%
Cisplatin 6.25% 6.25% 0% 6.25% 12.50% 68.75%
Gemcitabine 18.75% 37.50% 31.25% 6.25% 3.13% 3.13%
Mitoxantrone 28.13% 34.38% 15.63% 12.50% 3.13% 6.25%
Oxaliplatin 9.38% 15.63% 9.38% 18.75% 31.25% 15.63%
Etoposide 28.13% 34.38% 12.50% 9.38% 6.25% 9.38%
Irinotecan 18.75% 21.88% 31.25% 15.63% 9.38% 3.13%
Paclitaxel 31.25% 21.88% 21.88% 9.38% 3.13% 12.50%
Docetaxel 18.75% 34.38% 31.25% 3.13% 6.25% 6.25%
5-Fuorouracil 37.50% 15.63% 12.50% 0% 0% 34.38%
Carboplatin 15.63% 15.63% 21.88% 15.63% 15.63% 15.63%
CDDP þ TNF alpha 15.63% 37.50% 25.00% 12.50% 6.25% 3.13%
CDDP þ Dx 9.38% 12.50% 18.75% 6.25% 21.88% 31.25%
CDDP þ MMC 9.38% 15.63% 12.50% 6.25% 21.88% 34.38%
Oxaliplatin ip þ leucovorin 3.13% 15.63% 15.63% 25.00% 28.13% 12.50%
iv þ 5-fluorouracil iv
Oxaliplatin þ irinotecan 9.38% 12.50% 37.50% 12.50% 18.75% 9.38%
Carboplatin þ INF alpha 18.75% 43.75% 28.13% 6.25% 3.13% 0%

The figures highlighted in bold represent the preferred option by the experts after the voting.

The drugs to be used in local–regional therapy was the most
complex topic approached in the present methodological consensus
statement. In fact, the panel of experts achieved the lowest rate of
agreement in allocating the chemotherapies (as single agent or in
combination) in different phases of scientific pathway. Most of them
voted an option without taking into account the state of the art related
to this issue, that was outlined in Table II. This material was available
to the panel, during the first and second rounds.
Other aspects that should have been carefully considered is that
conclusions drawn with respect to pharmacokinetics or MTD of a
determinate chemotherapy should not be applied in all technical and
modalities variations of local regional therapy. What is true for the
open abdomen technique of HIPEC is not necessarily applicable for the
closed technique. This topic of drugs should be a priority for discussion
in the upcoming 6th International Workshop on Peritoneal Surface
Malignancy as little has been cleared with the present debate.
Isotonic salt solutions and dextrose solutions were elected the
advisable type of perfusate for HIPEC. Only 41% of the experts were
of the opinion that further studies should be carried out on this matter.
The optimal range of temperature was 41–438C. This decision is
close to that of previous Consensus meeting held in Madrid in 2004.
At that occasion the experts elected 41.5–42.58C as the optimal
range [17].
CONCLUSION
A partial consensus was obtained on these different points of
techniques of HIPEC. Eight different parameters impact on the
pharmacokinetics and the efficacy, defining infinite combinations,
which cannot be studied one by one. A strategic choice of the most
promising combinations to be tested will be determinant for the future.
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 Journal of Surgical Oncology 2008;98:253–257

Morbidity, Toxicity, and Mortality Classification Systems in the

Local Regional Treatment of Peritoneal Surface Malignancy

RAMI YOUNAN, MD,1 SHIGEKI KUSAMURA, MD, PhD,2 DARIO BARATTI, MD,2
ALEXIS-SIMON CLOUTIER, MD,1 AND MARCELLO DERACO, MD2*
1
Department of Surgery, Surgical Oncology Unit, University of Montreal Health Center (CHUM), Montreal, Canada
2
Department of Surgery, Peritoneal Surface Malignancy Unit, Istituto dei tumori, Milano, Italy

To reach a consensus for reporting complications related to cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy
(HIPEC). Reporting the adverse events related to CRS þ HIPEC is not standardized yet. Post-operative complications can be divided in two
categories: the effects of surgical manipulation per se and the toxic effects of the heated intraoperative chemotherapy. Additive and/or synergistic
effects also exist. Different centers have published their experience with regard to the complications associated with the procedure. Various
classification systems have been used which makes a temptative comparison of the different techniques and results almost impossible. An effort
was made here to review the existing major classification systems: The Bozzetti classification, the Clavien classification (and two proposed
modifications from Feldman et al. and Elias et al.) and the Common terminology criteria for adverse events (CTCAE) version 3.0 of the National
Institute of Health (NIH) criteria. A related document was sent to an international panel of experts. The CTCAE was adopted by the panel of
experts as the unique classification system to be used for reporting complications related to CRS þ HIPEC.
J. Surg. Oncol. 2008;98:253–257. ß 2008 Wiley-Liss, Inc.

KEY WORDS: peritoneal surface malignancy; HIPEC; cytoreductive surgery; morbidity; toxicity; intraperitoneal
chemotherapy

INTRODUCTION
Surgical literature lacks a uniform classification system for surgical
complications. No standard classification system has been agreed on
by the surgical community. This makes the comparison of negative
outcomes of a specific procedure difficult to analyze. Mostly
misreporting and to a lesser extent underreporting of complications
is a frequent happening in the day to day care of patients.
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal che-
motherapy (HIPEC) is not an exception to the rule. In spite of this,
appreciable effort has been developed by investigators performing
CRS þ HIPEC to report morbidity, toxicity, and mortality related to the
procedure and push further the concept of morbidity reporting.
However, non-standardized classification systems exist for morbidity
and mortality which further complicates this task. A definite effort
should be undertaken to better report complications across the surgical
literature and specifically regarding peritoneal surface malignancy
treatment. The aim of the last consensus meeting in Milan was to find a
consensus for morbidity reporting to: (a) better compare techniques
and results between centers; (b) set standards in the surgical literature;
and (c) demonstrate leadership in the field. Postoperative complica-
tions after CRS þ HIPEC are related to surgical manipulation, the
intraperitoneal chemotherapy component or a combination of both
(overlap). Most authors classify surgical morbidities separately from
the toxicity related to the chemotherapy perfusion. Before the Milan
Conference, North American and European series were the largest
reporting on complications. Multiple classification systems were used.
No conclusion could be drawn from these reports, no comparison could
be made and no consensus was obvious. In this report, we discuss the
major classification systems of morbidity and toxicity related to
CRS þ HIPEC, review the main series from various institutions
reporting these complications and elaborate a consensus with regard
to reporting complications associated with CRS þ HIPEC.
DISCUSSION
Death and complication rates remain the most comprehensive
measures used to assess short-term outcomes of a specific procedure.
Surgical complications can be in many cases the prime reason for
modifying patient management and ultimately getting wide acceptance
for a specific procedure throughout the medical community. However,
these two outcome measures remain hard to assess and define
throughout the surgical literature because of the lack of standardization
and underreporting. Most probably underreporting of complications
is the consequence of the absence of a clear system to classify
complications. Martin et al. [1] analyzed reports from various centers
describing complications related to three major surgical procedures:
pancreatectomy, esophagectomy, and hepatectomy. They also develop-
ed 10 criteria used to assess the quality of reporting complications
in published series. Interestingly their criteria included the use of a
severity grading system for major and minor complications. When
reviewing the 119 studies they analyzed, only 24 graded the severity of
the complications; furthermore, none of these used a numeric grading
system as recommended by the authors. Accurate assessment of the
morbidity related to CRS þ HIPEC is of major concern. The issue is
relatively complex for CRS þ HIPEC because the emergence of
postoperative complications related to surgical manipulation can be
None to disclose by any of the authors.
*Correspondence to: Marcello Deraco, MD, Fondazione IRCCS Istituto
Nazionale dei Tumori Milano, Via Venezian 1, 20133 Milano, Italy.
Fax: þ39-02-23902404. E-mail: marcello.deraco@istitutotumori.mi.it
Received 19 March 2008; Accepted 21 March 2008
DOI 10.1002/jso.21057
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.

254 Younan et al.
TABLE I. Classification of Complications According to Clavien et al. [3]
Grade I Events carrying minor risks, that is, complication if left untreated resolves spontaneously or at most requires a simple bedside procedure. Analgesics,
antipyretics, antiemetics, oral antibiotics and antidiarrheals are permitted
Grade II Potentially life-threatening; require some form of intervention. Grade IIa require other drugs than above, parenteral nutrition or transfusions. Grade IIb
require invasive procedures (radiological or endoscopic) or reoperation
Grade III Events with residual or lasting disability including organ resection
Grade IV Death

confounded with toxic side effects of the intraperitoneal chemotherapy
(IES). For example, the emergence of postoperative anemia depending
on the timing of its onset could be attributed to bleeding or to bone
marrow suppression or both. Another evidence favoring the existence
of an overlap between side effects related to surgery and to
intraperitoneal chemotherapies was given by a recent study conducted
by Kusamura et al. [2] They found that a dose of Cisplatin > 240 mg
used for HIPEC, using the closed abdomen technique, is an
independent risk factor for the emergence of major surgical morbidity
related to CRS þ HIPEC. Despite these considerations, most authors
propose to report and classify the surgical morbidities separately from
the toxicity related to the chemotherapy component, adopting two
separate classifications. We define here morbidity as any adverse
event related to surgical manipulation during the procedure. Toxicity
is defined as any adverse event that can be clearly related to the
chemotherapy component. Mortality is finally an adverse event
resulting in death. Some investigators have employed for morbidity
the modified Clavien system [3,4] while others have adopted more
simple criteria derived from their local institutional experience like the
Bozzetti classification [2,5,6]. And others have used the National
Institute of Health (NIH) common terminology criteria to report on
both morbidity and toxicity [7–9]. This heterogeneity in the adopted
systems hampers the comparison of treatment-related complication
rates among the various studies. Clavien et al. [3], in 1992, proposed a
classification system for complications in surgery. It included a four-
grade severity scale (Table I). Their proposed system’s relevance was
tested and validated on 650 cases of elective cholecystectomy. The
system was later slightly modified by Feldman et al. [10] to exclude the
prolongation of hospital stay as a criterion to increase the grade of the
complication (Table II). The latter was then used and modified by
investigators reporting on complications related to CRS þ HIPEC.
Elias et al. [4] reported on surgical complications using their
modification scheme (Table III). They found a 2.5% mortality rate
(one patient). The morbidity rate (grade 3–5 complications only) was
69% for major events. Only 12 patients or 30.5% did not present any
postoperative complication. Other investigators have used the Bozzetti
system for surgical complications [5]. It was developed at the Italian
National Cancer Institute in Milan to report on their local institutional
experience. It is a very simple four-grade scale to report complications
(Table IV). Kusamura et al. [2] reported their morbidity results using
this system. They analyzed 209 patients with various peritoneal surface
malignancies and found a 30-day mortality rate of 0.9%. Their
major (grade 3 or 4) morbidity rate was 12% overall. The Bozzetti and
modified Clavien classifications are not intended to account for
toxicities related to the use of chemotherapy during CRS þ HIPEC.
The investigators from Milan used the World Health Organization
(WHO) toxicity scale for that purpose. It is a relatively simple four-
grade scale that includes twelve categories for toxicity: Hematological,
gastrointestinal, pulmonary, allergic, cutaneous, infection, cardiovas-
cular, neurotoxicity, fever with drug, hair and renal. Pre-determined
cut-offs are determined within each category to grade the adverse
event. Ten (4.8%) patients presented Grade 3/4 toxicity in their series.
The investigators from Institut Gustave-Roussy [4] used the joint
National Cancer Institute(NCI)/National Institute of Health(NIH)
Common Terminology Criteria for Adverse Events (CTCAE) version
3.0 [7] to report the toxicity related to the procedure. This classification
system was initially designed as a clinical trials research tool. It is
widely used by investigators to accurately record medication toxicity
in randomized control trials. It is a very complete and extensive guide
regrouping 310 types of complications within 28 categories based on
the anatomy and/or pathophysiology of the complication (Table V).
Examples of that include separate definitions for fistula, anastomotic
leak and perforation. All the categories are very well defined and
detailed within the 70-pages booklet produced by the NCI/NIH.
Complications are graded within a 5-scale system well detailed in the
booklet with predetermined definitions (Table VI). One of the main
advantages of the CTCAE version 3.0 is that it can be used to
determine both toxicity and surgical morbidity. Two more representa-
tive series on CRS þ HIPEC have used exclusively the CTCAE
classification system for both toxicity and surgical morbidity. Smeenk
et al. [8] from the National Cancer Institute of Holland have reported
on 103 procedures performed for pseudomyxoma peritonei. They
found a treatment-related mortality of 11% and an overall complica-
tions rate of 54% for grade 3–5 events. This included both toxicity
and surgical morbidity. Surgical morbidity occurred after 38% of the
procedures. Their conclusion was that ‘‘. . .differences in the method
of grading toxicity make it difficult to compare these reports. . .’’
Finally Glehen et al. [9] from Lyon published their results after
216 procedures performed for various peritoneal surface malignancies.
They found a 3.2% mortality rate and a combined grade III/IV toxicity
and morbidity rate of 24.5%. The authors used the previous version of
the CTCAE to report their results.

TABLE II. Feldman et al. [10] Classification of Complications

Grade I Minor complications that resolve spontaneously if left untreated or require a simple bedside procedure. Analgesics, antipyretics, antiemetics, oral
antibiotics and antidiarrheals are permitted. Examples include superficial surgical site infection, urinary retention, lower urinary tract infection, ileus
requiring nasogastric tube
Grade II Potentially life-threatening; require intervention that carry some risks. Grade IIa require other drugs, parenteral nutrition or transfusions. Examples
include pneumonia, arrhythmia or acute pancreatitis. Grade IIb require invasive procedures (radiological or endoscopic) or reoperation. Examples
include CT-guided abcess drainage
Grade III Events with residual or lasting disability or organ loss. Examples include cerebrovascular events with residual disability and iatrogenic splenectomy.
All complications in this classification are categorized as cardiac, respiratory, gastrointestinal, urinary, local, or ‘‘other’’
Grade IV Death

Journal of Surgical Oncology

 Classification of Locoregional Treatment 255
TABLE III. Elias et al. [4] Classification of Surgical Complications Related to CRS þ HIPEC
Grade 0 No complications
Grade 1 Complications requiring either no intervention or minor interventions such as oral antibiotics, bowel rest, or basic monitoring
Grade 2 Complications requiring moderate interventions such intravenous medication (e.g., antibiotics or antiarrythmics), total parenteral nutrition, prolonged
tube feeding, or chest tube insertion
Grade 3 Complications are those requiring hospital readmission, surgical intervention, or radiologic intervention
Grade 4 Complications are those producing chronic disability, organ resection, or enteric diversion
Grade 5 Complications result in death

A numeric grading system seems the most appropriate to report
complications related to CRS þ HIPEC based on the recommendation
from Martin et al. [1] and after reviewing the major published series.
As discussed above, many classification systems have been used when
reporting complications. That makes a temptative comparison of the
above reports impossible to make and renders the rates of complica-
tions almost meaningless. In that sense, the high rate of complications
reported by Smeenk et al. can be explained by the fact that the CTCAE
version 3.0 is a system that accounts for a myriad of parameters and is
then expected to produce such a high complications rate. On the other
hand, the other classifications are more simplistic and less extensive
and would expectedly produce less complications as a final outcome.
Agreeing on a single classification system for complications is in that
sense of up most importance. A quick evaluation of the various
classification systems (Table VII) allows us to raise the following
considerations:
TABLE IV. Bozzetti et al. [5] Classification of Surgical Complications
Grade I No complications
Grade II Minor complications: Wound infection, Urinary tract infection,
pancreatitis, ileus, deep vein thrombosis
Grade III Major complications (requiring re-operation or Intensive care
admission or interventional radiology treatment)
Grade IV In-hospital or intensive care unit mortality
(1) They are different in terms of the total number of classes: they can
be of 4 grades or 5 grades.
(2) There is no correspondence between the grades: For example grade
2 in Feldman classification means a potentially life-threatening
complication usually requiring some form of intervention while in
the Bozzetti classification grade 2 means a mild complication.
(3) One interesting thing in common between the various classifica-
tions is that the grades can be grouped into two main subdivisions:
Minor complications and Major complications.
In order to achieve the consensus among experts, the Delphi
methodology was employed. [11] A conflicting point was identified
and related multiple choice questions along with a scientific review
document on the topic were circulated among the panel of experts on
peritoneal surface oncology. Two rounds of web-based voting, the
second one after disclosing the results of the first round, were carried
out. Consensus was defined as the agreement of 51% of the voters.
[11,12] A detailed description of the methodology used for this
consensus development is available elsewhere in this issue. Presenta-
tion and discussion of the results were done at 5th International
Workshop on Peritoneal Surface Malignancy held in Milan, Italy, 4–6,
December 2006. The question presented to the experts was the follow:
For the assessment of morbidity, toxicity and mortality, which
classification system is the most appropriate for a patient undergoing a
local-regional therapy?
Three answers were possible and included:

1. Bozzetti et al. criteria for surgical complications and WHO criteria

TABLE V. Categories Included in the CTCAE Version 3.0 [7] for toxicity?
2. Feldman (Clavien or Elias) et al. criteria for surgical complications
Allergy/immunology Infection
and WHO criteria for toxicity?
Auditory/ear Lymphatics
Blood/bone marrow Metabolic/laboratory 3. NCI CTC version 3.0 criteria for both surgical complications and
Cardiac arrhythmia Musculoskeletal/soft tissue toxicity?
Cardiac general Neurology
Coagulation Ocular/visual
Constitutional symptoms Pain The first round of results were as follows: the Bozzetti/WHO
Death Pulmonary/upper respiratory combination 25.81%, the Feldman/WHO combination 12.90% which
Dermatology/skin Renal/genitourinary left the NCI CTC version 3.0 with 61.29% of the vote. The results of
Endocrine Secondary malignancy the second round of voting were even more definitive giving the NCI
Gastrointestinal Sexual/reproductive function CTCAE version 3.0 an approval of 87.5% of the expert members. This
Growth and development Surgery/intraoperative injury classification system was adopted as the consensus system to report all
Hemorrhage/bleeding Syndromes future complications related to CRS þ HIPEC.
Hepatobiliary/pancreas Vascular

CONCLUSION
TABLE VI. Morbidity and Toxicity Grading According to CTCAE Version
A numeric grading system seems to be the most appropriate way to
3.0 [7]
report the complications related to CRS þ HIPEC. It is well known that
Grade 1 Mild adverse event the CTCAE version 3.0 five-level grading system is used for
Grade 2 Moderate adverse event chemotherapy and radiation therapy associated toxicities. The same
Grade 3 Severe adverse event
scale could possibly be used for cytoreductive surgery in an effort to
Grade 4 Life-threatening or disabling adverse event
Grade 5 Death
standardize across those three interdisciplinary oncologic specialties.
Grade 5 would certainly represent death and grade 0 no complications

Journal of Surgical Oncology

 256
Younan et al.

Journal of Surgical Oncology

TABLE VII. Summary of the Various Morbidity and Toxicity Classifications

Clavien et al. system [3]

Common terminology criteria for

Bozzetti et al. criteria [5] Feldman et al. modification [10] Elias et al. modification [4] adverse events version 3.0 [7]

Grade I No complications Grade 0 No complications Grade 0 No adverse event or Minor

within normal limits complications
Grade II Minor Grade 1 Complications are minor and are likely Grade 1 Complications requiring either no Grade 1 Mild Adverse Event
complications to resolve spontaneously or with intervention or minor interventions such
antipyretics, analgesics, antidiarrheals as oral antibiotics, bowel rest, or basic
or oral antibiotics monitoring
Grade 2 Complications are potentially Grade 2 Complications requiring moderate Grade 2 Moderate adverse event
life-threatening and interventions such intravenous
usually require some form of medication (e.g., antibiotics or
intervention. Subsets of this include 2a, antiarrythmics), total parenteral
requiring medications other than above nutrition, prolonged tube feeding,
or total parenteral nutrition for treatment or chest tube insertion
2b implies the need for reoperation or an
invasive procedure
Grade III Major Grade 3 Complications have lasting disability Grade 3 Complications are those requiring Grade 3 Severe and undesirable Major
complications or require an organ resection hospital read mission, surgical adverse event complications
(requiring intervention, or radiologic intervention
re-operation or
ICU admission
or interventional
radiology)
Grade IV In-hospital or Grade 4 Death Grade 4 Complications are those producing Grade 4 Life-threatening or
intensive care chronic dis ability, organ resection, disabling adverse event
unit mortality or enteric diversion
Grade 5 Complications result in death Grade 5 Death related to adverse event

resulting from the treatment. The CTCAE version 3.0 was indeed
adopted by an international panel of experts as the definitive
classification system for complications resulting from CRS þ HIPEC.
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358:1487–1492.
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6. Younan R, Kusamura S, Baratti D, et al.: Bowel complications
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8. Smeenk RM, Verwaal VJ, Zoetmulder FA: Toxicity and mortality
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9. Glehen O, Osinsky D, Cotte E, et al.: Intraperitoneal chemo-
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 Journal of Surgical Oncology 2008;98:258–262

The Fifth International Workshop on Peritoneal Surface Malignancy (Milan, Italy,

December 4–6, 2006): Methodology of Disease-Specific Consensus

DARIO BARATTI, MD, SHIGEKI KUSAMURA, MD, PhD, AND MARCELLO DERACO, MD*
Department of Surgery, National Cancer Institute, Milan, Italy

Peritoneal surface malignancies (PSM) have been traditionally regarded as uniformly terminal conditions. The combination of cyto-reductive
surgery and perioperative intraperitoneal chemotherapy has changed PSM management from palliation to possible cure. Due to the inherent
differences in biological and clinical behavior, the optimal adaptation of comprehensive treatment to each PSM is still a matter of debate. A
session of ‘‘The Fifth International Workshop on Peritoneal Surface Malignancy’’ (Milan, Italy, December 4–6, 2006) was committed to reach a
consensus pertaining to conceptual and technical aspects of the loco-regional treatment of each PSM. The consensus developing process was
based on principles of the Delphi method. A total of 103 international experts from 17 countries were included in six Working Groups (WG) for
each of the following PSM: peritoneal mesothelioma, abdominal sarcomatosis, carcinomatosis of gastric, colo-rectal, appendiceal, and ovarian
origin. Evidence reports were written by the respective WG. The main conflicting points (CP) regarding preoperative evaluation, patient
eligibility, combined treatment methodology, postoperative follow-up and future investigational perspectives were summarized as a list of
multiple-choice questions. Overall, 160 CP were identified. A consensus
51% of voters favoring one option was reached in 143/160 CP (89.4%).
The general treatment guidelines and future investigational perspectives were defined.
J. Surg. Oncol. 2008;98:258–262. ß 2008 Wiley-Liss, Inc.

KEY WORDS: consensus; peritoneal surface malignancies; cytoreductive surgery; hyperthermic intraperitoneal
chemotherapy; HIPEC

INTRODUCTION
The Fifth International Workshop on Peritoneal Surface
Malignancy took place in Milan (Italy) on December 4, 5 and 6,
2006. The meeting was entitled ‘‘Integrating Cytoreductive Surgery
and Hyperthermic Intra-peritoneal Chemotherapy into the Manage-
ment of Peritoneal Malignancies: a Consensus Meeting.’’
Since the first International Workshops was held in London in
1998, a meeting of international centres and health care professionals
currently involved or interested in the management of peritoneal
surface malignancy (PSM) took place every 2 years [1]. International
collaboration has played a prominent role in the progress of peritoneal
surface oncology. The Peritoneal Surface Oncology Group Interna-
tional (PSOGI) includes primarily surgical oncologists, but also
pathologists, gynaecologists, medical oncologists, radiologists, anaes-
thesiologists, biologists, nutrition specialists, as well as nurses and
perfusionists from all over the world. PSOGI was founded in order to
facilitate the collaboration among groups from different countries,
bring together a broad expertise, generate new scientific hypothesis,
accumulate theoretical and practical resources and build an interna-
tional network for the design of future prospective controlled studies.
The workshop was organized into three main sessions. The
Methodological Consensus Session was committed to reach a consensus
pertaining to conceptual and technical aspects of the local-regional
treatment of PSM. The objectives of the Specific Disease Consensus
Session were to define the state of the art of the operative methodology,
the general treatment guidelines and the future investigational per-
spectives for the following PSM:
(1) peritoneal mesothelioma;
(2) peritoneal dissemination from mucinous appendiceal neoplasms
(pseudomyxoma peritonei);
(3) carcinomatosis from colorectal cancer;
(4) carcinomatosis from gastric cancer;
(5) carcinomatosis from ovarian cancer;
(6) abdominal sarcomatosis.
In the third session, a discussion has been conducted regarding the
disciplines indirectly involved in the local-regional therapy, such as
cellular and molecular biology, anaesthesiology, clinical nutrition
and quality of life, nursing, to define the state of the art and future
prospects.
The consensus developing process was based on the principles of
the Delphi method, supported by summarized evidence reports. The
Delphi method has been used widely in health research and in clinical
practice developing as a mean to assess the extent of agreement
(consensus measurement) and to resolve disagreement (consensus
development). The method involves the participation of experts who
are invited to provide opinions on a specific topic, based on their
knowledge and experience, and the use of anonymous questionnaires
where the main headings and statements are draft for circulation and
ranking to all participants. The process occurs in consecutive rounds,
allowing the participants to know the distribution of the group’s
response and to change their opinions [2,3].
This article summarizes and discusses the most relevant methodo-
logical issues of the Specific Disease Consensus Session, along with
the results pertaining to the organization of the consensus attain-
ment process. Selected topics regarding each PSM discussed during
the Workshop are covered in detail by the articles contained in
this monography and authored by the speakers who presented each of
them.
The authors have no financial interest related to the contents of this article to
disclose.
*Correspondence to: Dr. Marcello Deraco, MD, Istituto Nazionale Tumori
Milano, Via Venezian,1 20133 Milano, Italy. Fax: þ39-02-23902404.
E-mail: marcello.deraco@istitutotumori.mi.it
Received 19 March 2008; Accepted 21 March 2008
DOI 10.1002/jso.21056
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.


DEVELOPING THE
DISEASE-SPECIFIC CONSENSUS
The disease-specific consensus attainment process has been
conducted during the whole year of 2006. It was organized into a
few consecutive steps, which took place partly during the months
before the meeting and partly during the Workshop itself. The whole
process was coordinated by the Workshop President, the Workshop
Director (MD) and the International Scientific Committee (ISC), which
included previous Workshop Directors and internationally renown
experts on local-regional therapy from the main centres. The Scientific
Secretariat (SS) and the Italian Organizing and Scientific Committee
(IOSC) provided scientific and organizational support.
Working Groups
The first step of the consensus development process was the
composition of six Working Groups (WG). The WG are multi-
disciplinary international teams which received the responsibility to
conduct the discussion about the role of loco-regional therapy in the
clinical management of each single PSM. Two coordinators for each
WG, as well as the other members, were elected by the SS and the ISC
based on their expertise in the management of PSM and additional
parameters, such as the institutional role in the country of origin and
the scientific publications regarding the disease being considered.
To guarantee a multidisciplinary feature and to enlarge the base of
the consensus, not only surgical oncologists directly involved in the
local-regional treatment of PSM, but also medical oncologists,
pathologists and other specialists were included in the WG. Analo-
gously, also physicians not necessarily favorable to the local-regional
comprehensive treatment were involved to strengthen the external
validity of the consensus. The Working Group Coordinators had the right
to modify the list of the members of their WG according to their personal
criteria.
The composition of the six disease specific Working Groups is
detailed in Table I, along with the represented peritoneal malignancy
treatment centres and countries of origin. Overall, 12 WG coordinators
and 91 members from 69 centres of 17 different nations were involved to
express their opinion through the web-based vote. They were 58 surgical
oncologists, 16 gynaecologic oncologists, 20 medical oncologists,
5 pathologists, and 3 other health care professionals.
Consensus Elaboration
On August 11, 2006 the beginning of the activity of the six Working
Groups was announced. The goal of this phase was the elaboration of a
consensus document regarding the specific disease of interest and the
TABLE I. Working Groups Composition
WG
Working groups coordinators
Abdominal sarcomatosis 2 15
Colo-rectal cancer carcinomatosis 2 21
Gastric cancer carcinomatosis 2 17
Ovarian cancer carcinomatosis 2 26
Peritoneal mesothelioma 2 19
Pseudomyxoma peritonei 2 15
12
WG, working group.
a
Some members were involved in more than 1 WG.
b
More members were affiliated to the same center.
Journal of Surgical Oncology
Consensus on Peritoneal Malignancies 259
identification of the main conflicting points, along with the possible
alternatives supported by the current scientific literature.
The consensus document elaboration guidelines included the
following topics:
. Preoperative evaluation: to define a brief clinical pathway guiding
the physician to choose the best instruments (imaging studies,
laboratory tests, invasive procedures) for the diagnosis and the
staging of the disease entity being considered.
. Eligibility: to identify the circumstances of the natural history of
each single disease that could be amenable to be treated by cyto-
reductive surgery (CRS) and peri-operative intra-peritoneal che-
motherapy (PIC), as well as the selection criteria of patients most
likely to benefit from a combined modality treatment approach. The
identification of quantitative prognostic indicators and risk factors
for major morbidity was also addressed.
. State of the art of the treatment methodology: to delineate the
technical variations of the procedure of CRS and PIC that could best
fit in the treatment of each single disease, based on the results of the
Methodological Consensus. A special attention was paid on the
possible role of adjuvant and neo-adjuvant systemic treatments.
. Definition of the scientific evidence: the degree of the scientific
evidence of the indication and methodology of the combined
modality treatment approach of PSM, according to a five level
ranking, as shown in Table II [3].
. Follow-up: to identify the most rational postoperative surveillance
schedule and the diagnostic tools most suitable to assess therapeutic
response or disease progression after comprehensive local-regional
treatment.
. Future perspectives: to define both basic and clinical potential
investigational lines, with a special focus on drafting prospective
randomized controlled trials.
All the consensus documents were available on the Workshop web
site (http://www.peritonealworkshop2006.com) for consultation.
The main conflicting points were organized according to the same
topics addressed in the consensus documents (preoperative evaluation,
patient eligibility, combined treatment methodology, postoperative
follow-up, and future investigational perspectives) and were summarized
as a list of multiple choice questions. The respective possible solutions
were given to be examined and selected by WG members. In Table III
the conflicting points are displayed by specific topics and disease
process. A total of 160 conflicting points were identified.
Web-Based Voting
Once the consensus documents and the conflicting points were
available on the web, the members of each WG were involved to
WG Represented Represented
members centres countries
12 5
17 10
16 7
22 11
15 5
14 8
91a 69b 16a
260 Baratti et al.
TABLE II. Evidence Based Methodology: Type of Basis
‘‘TYPE C basis’’ (General consensus)
There is a widespread consolidated consensus. Randomized trials have not been carried out or have been inadequate, but the issue is settled without major
controversy: currently, no (further) experimental evidence is felt to be needed.
‘‘TYPE 1 evidence’’ (Randomized trial(s) available, strong evidence)
Consistent results have been provided by more than one randomized trials, and/or a reliable meta-analysis was performed. In some instances, one randomized trial
can be considered sufficient to support this type of evidence.
Further confirmatory trials do not seem necessary.
‘‘TYPE 2 evidence’’ (Randomized trial(s) available, weak evidence)
One or more randomized trials have been completed, but the evidence they provide is not considered definitive (their results are not consistent, and/or they are
methodologically unsatisfactory, etc.). Some controlled evidence has therefore been provided, but confirmatory trials would be desirable.
‘‘TYPE 3 evidence’’ (External controlled comparisons available)
Evidence is available from non-randomized studies, with external controls allowing comparisons. Some uncontrolled evidence has therefore been provided, but
trials would be desirable.
‘‘TYPE R basis’’(Rational inference)
Little or no direct evidence from clinical studies is available. Yet clinical conclusions can be rationally inferred from available data and knowledge (e.g., by
rationally combining pieces of information from published studies and observations; for a rare neoplasm, or presentation, through analogy with a related, more
common tumor, or presentation; etc.). The inference can be more or less strong, and trials may, or may not, be desirable (although sometimes unfeasible).

express their opinion through a web-based voting system. They were
asked to browse the sequence of options and choose the one they found
more appropriate to every specific conflicting point. The literature
references were accessible online during the voting procedure, as well
as the consensus document pertaining to every single PSM. The
definition of consensus was at least 51% of voters favoring one option.
The WG coordinators were informed on the results of the web-based
voting.
Workshop Discussion and Voting
In Table IV the results of the consensus attainment process are
summarized. A consensus of at least 51% of voters favoring one of the
proposed options was reached in 143/160 conflicting points (89.4%). In
detail, consensus was obtained in 96.1% of the conflicting points
pertaining to pseudomyxoma peritonei and abdominal sarcomatosis.
Concerning the specific topics, the best agreement was observed for
follow-up. By contrast, the higher rate of disagreement was recorded
for ovarian cancer carcinomatosis and preoperative evaluation.
The Workshop President were responsible for the final approval of
the Specific Disease Consensus.

The final phases of the consensus attainment process took place

during the Workshop. A distinct plenary session was dedicated to
every single peritoneal malignancy. The state of the art and the basic
and clinical research perspectives pertaining to each PSM were
summarized by the coordinators of the respective WG. During
each Disease Consensus plenary session, the preliminary results of
the expert web-based vote were presented and discussed by all the
Workshop participants.
According to the Delphi method, a second round of voting was
accomplished during the Workshop. All the participants expressed
their opinion through a digital voting system on the same conflicting
points voted during the preliminary phase.
Consensus Approval
The results of the digital vote was immediately available for
evaluation and further discussion during each session. The Interna-
tional Scientific Committee had the responsibility to synthesize the
discussion about state of the art and the future investigational
perspectives of the local-regional treatment for each peritoneal
malignancy and to analyze and validate the results of voting.
DISCUSSION
During the last decades, better knowledge of the natural history,
innovative surgical techniques and the advances in loco-regional
chemotherapy have resulted in a new treatment strategy for peritoneal
surface malignancies. Improved understanding of the predictable
patterns of intra-abdominal disease redistribution, the observation that
mobile surfaces of small bowel and its mesentery may lastingly remain
free of tumor and the notion that PSM may be confined within the
peritoneal cavity during most of their clinical course have made an
intensive loco-regional treatment approach attractive [4]. Periton-
ectomy procedures to remove all the visible peritoneal tumor
dissemination have been greatly popularized by Sugarbaker [5] and
standardized methods to deliver intra-operative hyperthermic intra-
peritoneal chemotherapy have been developed to prevent the progres-
sion of microscopic residual disease [6].
The strong treatment rationale and striking clinical results have led
to the establishment of many highly qualified PSM management
centers in the USA, Australia, Asia, and nearly all countries in Europe.
The most common peritoneal surface malignancies which have
been treated are carcinomatosis of colorectal, gastric, ovarian and

TABLE III. Conflicting Points by Specific Topics and Peritoneal Surface Malignancy

Preoperative Patient State of the art of Future

Working groups evaluation eligibility the methodology Follow-up perspectives Total

Abdominal sarcomatosis 4 6 10 4 2 26
Colo-rectal cancer carcinomatosis 3 7 9 4 3 26
Gastric cancer carcinomatosis 3 11 10 4 4 32
Ovarian cancer carcinomatosis 2 9 11 2 2 26
Peritoneal mesothelioma 2 7 9 4 2 24
Pseudomyxoma peritonei 4 5 12 4 1 26

18 45 61 22 14 160

Journal of Surgical Oncology


TABLE IV. Results of the Disease Specific Consensus Attainment Process
Preoperative
Working groups evaluation Patient eligibility
Abdominal sarcomatosis 4/4 5/6
Colo-rectal cancer carcinomatosis 2/3 6/7
Gastric cancer carcinomatosis 2/3 10/11
Ovarian cancer carcinomatosis 2/2 6/9
Peritoneal mesothelioma 2/2 6/7
Pseudomyxoma peritonei 3/4 5/5
15/18 (83.3%) 38/45 (84.4%)
appendiceal origin, peritoneal mesothelioma and peritoneal sarcoma-
tosis. These disease processes represent different epidemiological,
biological, and clinical conditions. The optimal adaptation of CRS
and PIC to each PSM is still a matter of clinical investigations. This
prompted us to address the main conceptual and methodological issues
separately for each disease entity.
Colorectal cancer ranks third in incidence in both men and women
in the USA and western Europe as well (http://seer.cancer.gov/) [7].
Isolated peritoneal carcinomatosis is encountered in 7–10% of patients
at primary surgery and in 4–19% of those who recur after curative
surgery [8]. Ovarian cancer ranks seventh in women in USA and up to
75% of patients are diagnosed with an advanced stage disease (http://
seer.cancer.gov/). Gastric cancer accounts for 9.9% of all new cancer
diagnoses in the USA and it is the second leading cause of cancer-
related mortality worldwide [9]. It has been estimated that 15–50% of
patients have a peritoneal dissemination at surgical exploration,
especially when there is serosal involvement by the tumor [10].
Conversely, pseudomyxoma peritonei and peritoneal mesothelioma are
extremely uncommon tumor with an annual incidence of approxi-
mately 1/1,000,000 and 2.2/1,000,000 [11,12]. Sarcomas represent 1%
of all newly diagnosed cancer and abdominal sarcomas account for
10–15% of all-type sarcoma (http://seer.cancer.gov/).
Every PSM is a clinicopathologic entity with a unique natural
history. Before the era of cytoreduction and PIC, such conditions were
generally treated by palliative/debulking surgery and systemic
chemotherapy. In historical series, median survival was 5–6 months
for colorectal cancer carcinomatosis [13], 9–12 months for peritoneal
mesothelioma [12,14], 1.5–3.1 months for gastric cancer carcinoma-
tosis [15], 35–38 months for advanced ovarian cancer [16]. The
majority of pseudomyxoma peritonei are minimally aggressive and
they rarely cause lymphatic or hematogenous metastases. However,
previous reports demonstrated that serial debulking surgery with
various adjuvant therapies can only achieve a long-term survival of
20–30% [11,17].
Results of comprehensive treatment approach vary by indication.
Pseudomyxoma peritonei is the ‘‘classic’’ indication. In prospective
case-series treated by cytoreductive surgery and PIC, 5-year survival
rates varied from 52% to 96% and median survival from 51 to
156 months [17]. To date, there is an unquestionable consensus that
this combined treatment can be considered standard of care for all
cases of mucinous appendiceal neoplasms with peritoneal dissemina-
tion amenable to potentially complete surgical cytoreduction [11,18].
Especially in recent years, as the comprehensive approach
pioneered by Sugarbaker has expanded, the treatment results of
peritoneal mesothelioma have dramatically improved. The combina-
tion of CRS and PIC has reportedly resulted in a median survival of
34–92 months [14].
Multiple trials suggest that outcomes after CRS and PIC are better
for colorectal than for gastric cancer [8,15]. In patients with colon
cancer carcinomatosis, a phase III trial have confirmed the superiority
of such treatment approach over standard palliative therapies for
cancer [19]. Treatment of ovarian cancer peritoneal dissemination
Journal of Surgical Oncology
Consensus on Peritoneal Malignancies 261
State of the art of
the methodology Follow-up Future perspectives Total
10/10 4/4 2/2 25/26 (96.1%)
9/9 4/4 3/3 24/26 (92.3%)
10/10 4/4 4/4 30/32 (93.7%)
8/10 1/2 1/2 18/26 (69.2%)
7/9 4/4 2/2 21/24 (87.5%)
12/12 3/3 1/1 25/26 (96.1%)
58/61 (95.1%) 21/22 (95.4%) 13/14 (92.8%) 143/160 (89.4%)
through the use of intra-peritoneal chemotherapy was declared the
standard of practice by the National Cancer Institute, Bethesda, USA
after a recent phase III study [20].
Peritoneal involvement as an isolated site of tumor progression most
commonly results from GISTs or retroperitoneal sarcomas. At the
moment, medical therapy is the standard of care for these patients and
the combination of surgery and PIC should be considered investi-
gational [21]. A clear distinction can be made between GIST and other
adult soft-tissue sarcomas, because the natural history of GIST has
been deeply affected by the medical therapy [22]. The major benefit
gained from Imatinib, the availability of further second-line targeted
agents and the lack of formal proofs of efficacy of surgery for residual
disease, makes it difficult, at the moment, to define the role of
combined loco-regional therapies in advanced GIST patients, even
when the disease is confined to the peritoneum.
The results of CRS and PIC should be compared cautiously to
traditional therapies since, with only few exceptions, these treatment
strategies have not been directly compared [19,20]. More randomized
controlled studies may be difficult to undertake with exceedingly
uncommon tumors such as pseudomyxoma peritonei, sarcoma and
peritoneal mesothelioma. Furthermore, phase III trials would compare
a potentially curative treatment with merely palliative procedures and
patients would presumably be not prone to accept randomization.
Particularly with a slow progressing condition such as pseudomyxoma
peritonei, a long-term follow-up of at least 10–20 years is required to
demonstrate a statistical difference. However, the fact that randomized
trials are difficult to perform does not imply that more information
from multi-institutional international phase III trial would not be
desirable.
In an attempt to overcome such difficulties, we planned a Specific
Disease Consensus Session to define the state of the art of the operative
methodology, the general treatment guidelines and the future investi-
gational perspectives for each single PSM. Consensus making is an
alternative method of dealing with conflicting scientific evidence.
Considerable experience in using Delphi consensus technique exists,
since it has been widely used in health research, especially within the
fields of technology assessment, education training or nursing and
clinical practice developing [23].
Consensus methods consider a wider range of scientific studies
than conventional statistical reviews and allow a greater role for the
qualitative assessment of evidence [2,3]. They try to overcome
the disadvantages normally found with decision making in groups
or committees, which are commonly dominated by individuals or
coalitions representing specific interests. Delphi method enables a
large group of experts to be contacted inexpensively by mail or by
internet with a self administered questionnaire, with few or no
geographical limitations. Rounds in which the participants meet to
discuss the process and resolve uncertainty or any ambiguities in the
wording of the questionnaire may be included.
For studies concerned with defining criteria for clinical interven-
tion, the most appropriate experts will be clinicians practising in the
field under discussion. However, the inclusion of other clinicians, not
262 Baratti et al.
necessarily favorable to the debated topic may be appropriate to
provide an alternative clinical view, particularly when the study is
expected to have an impact beyond a particular specialist field.
In conclusion, the disease-specific consensus process brought
together internationally renowned experts in the field of peritoneal
neoplasms, team members of existing PSM treatment centers and
physicians planning to start new programs. Controversial issues
regarding the state of the art of the operative methodology, the general
treatment guidelines and the future investigational perspectives
were summarized and discussed through a multiple choice question
digital system. A high rate of agreement was reached by the
participants.
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 Journal of Surgical Oncology 2008;98:263–267

Consensus Statement on the Loco Regional Treatment of Colorectal

Cancer With Peritoneal Dissemination

JESUS ESQUIVEL, MD, FACS,1* DOMINIQUE ELIAS, MD,2 DARIO BARATTI, MD,3
SHIGEKI KUSAMURA, MD, PhD,3 AND MARCELLO DERACO, MD3
1
St. Agnes Hospital, Baltimore, Maryland,
2
Département de chirurgie générale oncologique, Institut Gustave-Roussy, Villejuif, France
3
Department of Surgery, National Cancer Institute of Milan, Italy

Medical management with combinations of cytotoxic chemotherapy, and/or biological agents, has resulted in an unprecedented median survival
>20 months in patients with Stage IV colorectal cancer. The management of disease limited to the peritoneal cavity has been controversial and at
the present time, there is no published data that outlines the impact of these new therapeutic regimens when given to patients with colorectal
cancer with metastatic disease confined to the peritoneum. Over the last 5 years, an increasing number of international treatment centers
have published their prospective results using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in the management
of peritoneal surface malignancies of colorectal origin and have shown that good long-term results can be achieved with a complete cytoreduction
and HIPEC. However, most of the surgical data comes from Phase II studies from single institutions and there is a wide range on inclusion/
exclusion criteria, drugs, temperatures and methods of delivering the heated chemotherapy. This manuscript will analyze and discuss the results of
a group of health care providers trying to achieve a consensus statement in the management of this group of patients.
J. Surg. Oncol. 2008;98:263–267. ß 2008 Wiley-Liss, Inc.

KEY WORDS: peritoneal carcinomatosis; intraperitoneal chemotherapy; cytoreductive surgery

INTRODUCTION techniques that include Peritonectomy Procedures, standardized

Surgical resection remains the hallmark therapy for primary colon
cancer. It allows the patients to become clinically disease free, provides
proper staging, and determines who should receive adjuvant systemic
chemotherapy. Treatment options for patients with unresectable
metastatic disease have improved significantly in the past few years.
A review of the published data in the treatment of patients with Stage
IV colorectal cancer, outlining the surgical and medical therapeutic
options demonstrates that medical management, with combinations of
cytotoxic chemotherapy, and/or biological agents, has resulted in an
unprecedented Median Survival >20 months [1]. Peritoneal involve-
ment in colorectal cancer occurs in approximately 30% of patients.
Approximately 8% of patients are diagnosed with synchronous
peritoneal dissemination at the time of primary colorectal surgery
and 25% of patients have recurrence confined to the peritoneal cavity
[2]. The management of disease limited to the peritoneal cavity has
been controversial. However, at the present time, there is no published
data that outlines the impact of these new therapeutic regimens when
given to patients with colorectal cancer with metastatic disease
confined to the peritoneum. Therefore, systemic treatment alone is an
unproven therapeutic strategy for this particular group of Stage IV
patients with limited peritoneal dissemination from a primary or
recurrent colon cancer.
The present paper will focus on the available scientific evidence of
the role of cytoreductive surgery and hyperthermic intraperitoneal
chemotherapy (HIPEC) in the management of peritoneal surface
malignancies of colorectal origin and will include the results of the
voting on conflicting points by 22 experts in the disease specific
workshop group in colorectal cancer.
In the 1990s, Sugarbaker and colleagues proposed cytoreductive
surgery and perioperative intraperitoneal chemotherapy as a definitive
treatment for peritoneal dissemination from appendiceal neoplasms
and diffuse malignant peritoneal mesothelioma [3–5]. Better surgical
methods to deliver intraoperative HIPEC and better patient selection
criteria, along with the strong treatment rationale and superior
results when compared to historical controls, have lead to the
establishment of numerous treatment centers in the United States
and Europe. Over the last 5 years, an increasing number of
international treatment centers have published their prospective results
using cytoreductive surgery and HIPEC in the management of
peritoneal surface malignancies of colorectal origin [6–10]. In 2003,
the Dutch group conducted a randomized controlled trial comparing
systemic chemotherapy with cytoreductive surgery combined with
HIPEC and this trial clearly demonstrated the superiority in survival of
the combined treatment group [11]. In 2004, a multi-institutional
registry study from 28 international treatment centers showed that the
median survival was 19 months and 3-year survival was 39% after
cytoreductive surgery and HIPEC for 506 patients with colorectal
peritoneal carcinomatosis [12].
An analysis of evidence indicates prolongation of survival and
potential for cure in patients with low volume metastatic adeno-
carcinoma of colonic origin limited to the peritoneal cavity using
cytoreductive surgery and HIPEC. However, as pointed out by Yan et al.
in a recent systematic review of the quality of evidence in 14 rigorously
The authors have no financial interest related to the contents of this article to
disclose.
*Correspondence to: Jesus Esquivel, MD, FACS, Surgical Oncology, St.
Agnes Hospital, 900 Caton Avenue, Baltimore, MD 21229. Fax: 410-951-
4007. E-mail: jesusesquivel@yahoo.com
Received 19 March 2008; Accepted 21 March 2008
DOI 10.1002/jso.21053
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.

264 Esquivel et al.
selected series, there were 2 randomized controlled trials, 1 randomized
comparative study, and 11 observational studies without control groups,
including one multi-institutional study [13]. In addition, the indications
for, the technique of HIPEC, the drugs used and the degree of heat, vary
among physicians using these methods of treatment.
A recent international conference on this subject was convened
and a consensus statement on the appropriate use of cytoreductive
surgery and HIPEC was developed and adopted by the Peritoneal
Surface Malignancy Group (PSMG) in an attempt to standardize the
indications and techniques for this treatment, Figure 1. We agreed that
the main strategy would be to use the peritonectomy procedures
necessary to achieve a complete cytoreduction. After all resections
were done then the hyperthermic chemotherapeutic perfusion would be
carried out. We agreed that most of us use Mitomycin C with some not
significant variations regarding dosage, temperatures and methods of
delivery. We also recognize that there is some exciting and provocative
data with the use of intraperitoneal Oxaliplatin and with the systemic
use of biological agents [14].
Fig. 1. Clinical pathway for the management of peritoneal surface malignancies of colonic origin.
Journal of Surgical Oncology
Reviewing the published data helps us learn about the outcome of
patients with colorectal cancer with peritoneal dissemination treated
with cytoreductive surgery and HIPEC. There is no question that
2-year survival rates are around 60% and 5-year survival rates approach
40% in many series when a complete cytoreduction can be achieved.
However, review of the data also teaches us about the biology of the
tumor as we all continue to have incomplete cytoreductions with an
expected median survival of about 6 months. At the present time, we
lack a universally accepted and easily reproducible prospective staging/
scoring system that addresses the quantity and location of the peritoneal
dissemination and its impact on achieving a complete cytoreduction. We
also do not have a universal agreement on inclusion/exclusion criteria.
Some centers would consider patients with a few liver metastases
candidates for this procedure while other centers would consider this
situation an absolute contraindication.
In the absence of a large prospective randomized trial that addresses
all the above-mentioned issues, it is going to be difficult to demonstrate
the true impact of cytoreductive surgery and HIPEC on the natural

biologic behavior of colorectal cancer with peritoneal dissemination,
especially in the era of newer systemic therapy, keeping cytoreductive
surgery and HIPEC still as an unproven and frequently questioned
therapeutic treatment modality.
PRE-OPERATIVE EVALUATION
Proper patient selection remains a crucially important aspect in
the treatment of patients with peritoneal dissemination from colo-
rectal cancer. As previously mentioned, long-term survival can only
be achieved with cytoreductive surgery and HIPEC when a complete
cytoreduction is accomplished. Review of the data in multiple
series shows that those patients that have an incomplete removal of
their peritoneal dissemination have a median survival of about
6 months and therefore these patients do not benefit from a surgical
procedure [11,12]. In addition, they represent a financial burden to the
institution.
Once a patient has been diagnosed with colorectal cancer with
peritoneal involvement, the work-up usually includes a complete
colonoscopy as well as a CT scan of the chest, abdomen and pelvis
with maximum oral and intravenous contrast to evaluate the extent of
peritoneal dissemination. A PET scan can be considered if there is any
question of extra-abdominal disease. Review of two published series
trying to address the diagnostic accuracy of the CT scan as an imaging
modality can be summarized by stating that the detection of peritoneal
carcinomatosis by CT scan is only moderately useful and that it
has severe limitations in detecting small peritoneal implants, especially
in the small intestine. In addition, CT scan was considered of
limited value in selecting colorectal patients with peritoneal carcino-
matosis who will not benefit from cytoreductive surgery with HIPEC
[15,16].
ROLE OF ABDOMINAL LAPAROSCOPY IN
THE PRE-TREATMENT EVALUATION OF
PERITONEAL CARCINOMATOSIS
Garofalo et al. reported on 97 cases of peritoneal carcinomatosis
submitted to video laparoscopy to stage the disease. They achieved full
laparoscopic Peritoneal Cancer Index assessment in 96/97 cases, while
only 2/96 cases were under staged. There was a good correlation
between the open successive surgery data and the laparoscopic
Peritoneal Cancer Index. There was no mortality and no neoplastic
colonization at the trocar port site. Patients with massive involvement
of their small bowel or mesentery by staging laparoscopy should be
considered not amenable for peritonectomy. They considered laparo-
scopy a useful tool in peritoneal surface malignancies. It allows direct
visualization even of small cancer nodules and provides a reliable
assessment of the feasibility of peritonectomy [17].
A group of French investigators also evaluated the role of
explorative laparoscopy to evaluate candidates for complete resection
of peritoneal carcinomatosis combined with HIPEC. Eleven patients
planned to undergo a cytoreductive surgery þ HIPEC underwent an
explorative laparoscopy. Laparoscopic evaluation was successful in all
11 patients. The median operating time was 38 min (range 23–75 min).
The laparoscopic examinations were well tolerated in all cases. For
3 patients, the peritoneal carcinomatosis was as judge as unresectable.
A complete resection of the peritoneal carcinomatosis combined
with HIPEC was performed in seven out of the eight patients with
peritoneal carcinomatosis considered resectable at laparoscopy. One
patient was diagnosed with more extensive disease than that as
assessed by the evaluative laparoscopy [18]. Of note, in 20% of the
patients taken directly for a laparotomy, a complete cytoreduction
was not possible. The conclusion was that laparoscopic scoring of
Journal of Surgical Oncology
Colorectal Cancer With Carcinomatosis 265
peritoneal carcinomatosis is accurate to assess the complete re-
sectability of peritoneal carcinomatosis in patients for which there
is inadequate or contradictory information concerning disease
extent.
VARIABLES ASSOCIATED WITH INCREASED
CHANCES OF HAVING A COMPLETE
CYTOREDUCTION
The following represent clinical and/or radiographic variables that
are usually associated with an increase chance of achieving a complete
removal of all tumors during cytoreductive surgery.
ECOG Performance status 2 or less
No evidence of extra-abdominal disease
Up to 3 small, resectable parenchymal hepatic metastases
No evidence of biliary obstruction
No evidence of ureteral obstruction
No evidence of intestinal obstruction at more than one site
Small bowel involvement: No evidence of gross disease in the
mesentery with several segmental sites of partial obstruction.
Small volume disease in the gastro-hepatic ligament.
These data represent characteristics that most peritoneal surface
malignancy centers agreed upon but it has not been submitted to a
prospective analysis. With the establishment of this consensus and the
participation of most of the international groups, we hope we can
validate these clinical and/or radiographic variables.
ELIGIBILITY CRITERIA
Establishing clear eligibility criteria for any given treatment
plan seems obvious in order to maximize benefits and minimize
unnecessary treatments. The indications for cytoreductive surgery
and HIPEC in the treatment of peritoneal surface malignancies
of colorectal origin have not been clearly defined and at the
present time range from being indicated because the patient is in
good physical condition to withstand this particular treatment to the
patients that have failed every other possible treatment and are looking
for a last chance.
Up to date, there are no published indications for the role of
cyotreductive surgery and HIPEC in the treatment of peritoneal surface
malignancies of colorectal origin. The medical oncology community,
labels these patients as Stage IV disease and extrapolate data from the
efficacy of modern combinations of cytotoxic and biological agents as
their rationale to treat patients with colon cancer metastatic to the
peritoneum. Unfortunately, they fail to realize that the vast majority of
the patients on the trials that generated these data, were patients with
metastatic extra-abdominal disease and the second largest group were
patients with liver metastases.
On the other hand, an analysis of the published data by the surgical
oncology community shows that the indications are very vague and
none specific like, having a good performance status and few
comorbidities in order to survive the operation. We have tried to
identify those patients in whom this particular treatment option is not
indicated, like in patients with extra-abdominal disease, or patients
with multiple sites of intestinal obstruction or patients with too much
disease. Sugarbaker et al. evaluated the prognostic value of the
Peritoneal Cancer Index (PCI) in patients with colorectal cancer
undergoing cytoreductive surgery plus HIPEC. A PCI < 10 was
associated with a 5-year survival rate of 50% while it was 0% if the
PCI > 20 (P-value < 0.0001). Based on these data, they concluded that
cytoreductive surgery plus HIPEC were contraindicated in patients
266 Esquivel et al.
with a PCI > 20 [19]. Verwaal et al. using their seven regions system Do you think there should be a PCI determination on CT scan?
found not only that the survival benefit was low in patients with more Yes 50%
than five regions involved but also that the morbidity was increased in Not sure 33%
No 16%
these patients [20].
Should a Peritoneal Cancer Index > 20 be an absolute exclusion
There are a few points on this subject that deserve attention.
criteria for CRS þ HIPEC?
The story of surgical treatment of colorectal liver metastases is Yes 33%
being rewritten with a different title. It would be impossible to think No 66%
that a medical oncologist would recommend systemic therapy for a Should Liver Metastases be an absolute exclusion criteria for
patient with a single liver metastasis 18 months after resection of the CRS þ HIPEC?
primary tumor as well as it would be impossible to think that a Yes 0%
surgical oncologist would favor surgical treatment in a patient with a No 66%
primary tumor and more than 20 liver metastases. In this particular Cannot answer 33%
Should ALL asymptomatic patients with CRC with PC receive
setting of metastatic disease, the indications appear to be well
systemic chemotherapy prior to CRS þ HIPEC?
described.
Yes 41.7%
When it comes to metastatic disease to the peritoneum, we face the No 58.3%
problem that not only we do not have a universally agreed upon scoring
system to follow the patients from time zero, but that it is very difficult
to measure with the current image modalities the amount and location
of the disease. Most of the patients that we treat, at least in the United T 4 N 0 M 1 (limited peritoneal dissemination)
States, have failed every possible combination of cytotoxic and
biological agents and come to us with a debilitated body and a depleted Best systemic therapy followed by surgery only to relieve symptoms 0%
bone marrow. However, we most address that these patients represent Best systemic therapy  3months followed by CRS þ HIPEC and BST 8.3%
the numerator and we do not know the denominator, making it very CRS þ HIPEC upfront followed by best systemic therapy 91.6%
difficult to have meaningful conclusions on the effect of systemic
therapy in patients with colorectal cancer metastatic to the peritoneum.
In addition, it is also difficult to measure the benefit of the procedure. T 4 N 2 (8/12) M1 (limited peritoneal dissemination)
We all have seen patients with intractable ascites that require weekly
paracentesis and that after cytoreductive surgery and HIPEC, live only Best systemic therapy followed by surgery only to relieve symptoms 0%
6 months but never needed to be tapped again. Palliative cytoreduction Best systemic therapy  3 months followed by CRS þ HIPEC and BST 50%
with HIPEC, plays a tremendous role in improving quality of life in CRS þ HIPEC upfront followed by best systemic therapy 50%
these patients.
In summary, we know that most of the patients with an incomplete
tumor removal will not benefit from cytoreductive surgery and HIPEC Asymptomatic patient with large omental cake, ascites, minimal
and face a median survival of 6 months. We also know that long-term small bowel involvement.
survival can only be achieved with a complete removal of the
peritoneal disease. Best systemic therapy followed by surgery only to relieve symptoms 0%
Best systemic therapy  3 months followed by CRS þ HIPEC and BST 33%
CRS þ HIPEC upfront followed by best systemic therapy 66%

RESULTS OF WEB-BASED VOTING ON

CONFLICTING POINTS Future Investigations
Pre-Operative Work-Up
Do you think it is necessary to perform a large Phase III trial in order to make
In addition to the basic work-up that includes a good history and
CRS þ HIPEC standard of care?
physical, blood work and a colonoscopy, 100% of the experts Yes 75%
agreed that the preferred imaging modality is a CT scan of the No 25%
abdomen and pelvis with maximum oral and intravenous contrast.
Regarding a CT scan of the chest, the vast majority, 83%, thought
that it was necessary to obtain such a study. Fifty-eight percent Of the following trials, which one would you recommend?
thought that a CT/PET scan should be performed in all patients. MRI
scans of the abdomen and pelvis, Ultrasound, Laparoscopy with
CRS and then HIPEC vs. no HIPEC both followed by best systemic 81.82%
biopsy, PET scan and upper endoscopy, were considered necessary by
therapy
less than 50% of the experts. More than 66% of the experts agreed that Best systemic therapy vs. CRS þ HIPEC 36.36%
it is necessary to obtain a CEA and a CA 19-9 level pre-operatively. All Best systemic therapy vs. CRS þ HIPEC vs. CRS with no HIPEC 18.18%
other tumor markers were recommended by less than 50% of the with the last two arms followed by best systemic therapy
experts.

Would you favor the following Phase II trial over a Phase III trial?
Eligibility
Best systemic therapy for 3 months followed by CRS þ HIPEC if a complete
Seven questions were asked regarding some of the conflicting
cytoreduction is achieved and then BST for 3 more months
indications and/or situations that would make a patient with colorectal Yes 33%
cancer and peritoneal dissemination a candidate for cytoreductive No 66%
surgery and HIPEC.

Journal of Surgical Oncology


DISCUSSION OF RESULTS
Understanding that the very vast majority of the experts in this
voting were surgical oncologists, we can make an analysis of where
we are in characterizing the role of a combination of surgery and
intraperitoneal chemotherapy in the management of patients with
colorectal cancer and peritoneal dissemination. There was universal
agreement regarding the imaging modality of choice in the pre-
operative evaluation of a patient considered a surgical candidate. Fifty
percent even though that there should be an attempt at trying to
quantify the amount of carcinomatosis by determining the PCI in the
CT scan. Even though the published data shows that the extent of
carcinomatosis is a prognostic indicator of outcome, and that patients
with incomplete cytoreductions in general do not benefit from surgery,
two thirds of the experts would not consider a PCI > 20 or the presence
of liver metastatses an absolute contraindication to cytoreductive
surgery and HIPEC.
Regarding the role of systemic therapy, it appears that the majority
of the experts believe that the role of systemic therapy should be in the
‘‘adjuvant’’ setting in patients with peritoneal dissemination and
negative nodes and even in patients with a large number of positive
nodes, only half recommended a 3 month course of neoadjuvant
therapy.
Seventy-five percent of the experts are in agreement that we need a
large scale Phase III trial in order to make cytoreductive surgery and
HIPEC standard of care. However, after a critical analysis and review
of the published data, we can conclude that we have surgical outcome
data that it is mostly from Phase II experience of single institutions and
that there is no data when it comes to evaluating the role of the newer
combinations of cytotoxic chemotherapy and biological agents in the
management of patients with colorectal cancer with limited peritoneal
dissemination. Therefore, it is not surprising that the majority of the
experts believe that the real question to be asked in such a trial is what
is the role of HIPEC after a complete cytoreduction as most of us
believe that the primary treatment modality and the only one that can
lead to a good long-term result is achieving a complete cytoreduction.
Only 36% thought that the right question would be to compare the role
of the newer systemic therapy versus surgery and HIPEC.
We have presented the available data and the strategy on how to
obtain the data that is necessary to make cytoreductive surgery and
HIPEC the standard of care in patients with colorectal cancer with
peritoneal dissemination. However, the reality is that patients with
colorectal cancer and peritoneal dissemination, even in the absence
of hematogenous dissemination, are still labeled as Stage IV, and
therefore the vast majority of our medical oncology colleagues will
agree that the best treatment modality is the combination of cytotoxic
chemotherapy and biological agents because of the dramatic improve-
ment in outcome using this regimens in patients with Stage IV
colorectal cancer as a result of hematogenous and/or lymphatic
dissemination. Therefore, all of the above can be summarized in saying
that we as surgeons know that there is a definitive role for cytoreductive
surgery and HIPEC in the management of patients with colorectal
cancer and peritoneal dissemination, we have the data to prove it. Our
medical oncology colleagues have very impressive data from large
Phase III trials in patients with Stage IV colorectal cancer. Only with a
continued interaction between both groups, will we be able to find the
best treatment modality for that subset of patients who are Stage IV as a
consequence of peritoneal dissemination.
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 Journal of Surgical Oncology 2008;98:268–272

Consensus Statement on Peritoneal Mesothelioma

MARCELLO DERACO, MD1* DAVID BARTLETT, MD,2 SHIGEKI KUSAMURA, MD, PhD,1 AND DARIO BARATTI, MD,1
1
Department of Surgery, National Cancer Institute, Milan, Italy
2
Department of Surgery, Division of Surgical Oncology, UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania

Diffuse malignant peritoneal mesothelioma (DMPM) has been traditionally regarded as a rapidly lethal disease. Recently, several independent
prospective trials have reported improved survival with an intensive loco-regional treatment strategy including cytoreductive surgery (CRS) along
with peri-operative intra-peritoneal chemotherapy (PIC). However, most of the surgical data comes from mono-institutional phase I or II studies
and there is a broad range of variability regarding inclusion criteria, cytoreductive surgical procedures, drugs, temperatures and methods of
delivering the heated chemotherapy (open vs. closed abdomen). This manuscript critically analyze and discuss the results of a group of health care
providers trying to achieve a consensus statement in the management of this group of patients. The main conflicting points regarding preoperative
evaluation, patient eligibility, combined treatment methodology, postoperative follow-up and future investigational perspectives were
summarized as a list of multiple-choice questions. A questionnaire was placed on the website of the ‘‘5th International Workshop on Peritoneal
Surface Malignancies’’ and the group members voted via internet. The results were presented for further debate during a dedicated session of the
Workshop. The general treatment guidelines and future investigational perspectives were defined.
J. Surg. Oncol. 2008;98:268–272. ß 2008 Wiley-Liss, Inc.

KEY WORDS: consensus; peritoneal mesothelioma; cytoreductive surgery; hyperthermic intra-peritoneal chemotherapy;
HIPEC

INTRODUCTION
Malignant mesothelioma is an uncommon tumor arising from the
serosal layer of pleura, peritoneum, pericardium, and tunica vaginalis
testis [1]. The incidence of the disease has been rising worldwide since
1970 and is not expected to peak for another 10–20 years, due to the
widespread exposure to asbestos during the last decades [2].
In the United States, where the incidence peak has likely already
been reached, about 2,500 new cases of DPM are registered each year
[3]. Diffuse malignant peritoneal mesothelioma (DMPM) accounts for
10–20% of all forms of malignant mesothelioma [3].
In the past, DMPM has been regarded as rapidly lethal disease.
Clinical results of conventional treatments, such as palliative
surgery, systemic or intra-peritoneal chemotherapy, have been far
from satisfactory in terms of both cure or palliation. Recently,
several independent phase I/II prospective trials have reported
improved survival with an intensive loco-regional treatment
strategy including cytoreductive surgery (CRS) along with peri-
operative intra-peritoneal chemotherapy (PIC) in the form of
hyperthermic intra-peritoneal chemotherapy (HIPEC) þ/ early
post-operative intra-peritoneal chemotherapy (EPIC).
There are objective difficulties in planning a phase III clinical trial
in this setting, since DMPM is a rare disease and a randomized study
would compare a potentially curative treatment with a palliative one.
Nevertheless, an extensive literature search of the available retro-
spective historical series has shown that the median survival after
palliative surgery and systemic and/or intra-peritoneal chemotherapy is
about 1 year, ranging from 9 to 15 months [4–11]. Conversely, the
median survival after aggressive surgery combined with HIPEC has
approached 5 years and seems to improve with subsequent reports
[4,12–19].
Taken together the aforementioned data suggest that treatment
of PMP by means of CRS and PIC is supported by ‘‘Type 3 evidence,’’
as scientific evidence is available from non-randomized studies, with
external controls allowing comparisons [20].
The present paper focuses on the results of a group of health care
providers trying to achieve a consensus statement in the management
of peritoneal mesothelioma.
PREOPERATIVE EVALUATION
Early diagnosis of DMPM is traditionally challenging [21,22]. Due
to its rarity and unspecific presentation, the disease is commonly
diagnosed at advanced stage or confused with ovarian cancer or other
peritoneal disseminations, often resulting in disease mistreatment. The
goal of a rationale diagnostic pathway is to start an adequate and timely
treatment, thus optimizing the clinical results. Since DMPM has a
great propensity to implant at needle tracts, laparoscopic port sites
or surgical incisions, preventing disease dissemination as a con-
sequence of inappropriate invasive procedures is an additional primary
objective [15].
CT-scan is the imaging test of choice for DMPM. The findings
associated to the disease have been recently reviewed. Diffuse disease
distribution throughout the peritoneal cavity with large tumor volume
in the mid-abdomen and in the pelvis may increase the level of clinical
suspicion. Additional findings that could be of help in the differential
diagnosis from other gastrointestinal or gynaecologic malignancies are
the lack of a primary site and the absence of lymph node or distant
metastases [23]. The role of other imaging studies, such as magnetic
resonance or positron emission tomography is presently unclear.
The authors have no financial interest related to the contents of this article to
disclose.
*Correspondence to: Dr. Marcello Deraco, MD, Fondazione IRCCS,
Istituto Nazionale Tumori Milano, Via Venezian 1, 20133 Milano, Italy.
Fax: þ39-02-23902404. E-mail: marcello.deraco@istitutotumori.mi.it
Received 19 March 2008; Accepted 21 March 2008
DOI 10.1002/jso.21055
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.


Laboratory tests are not useful in the diagnosis of DMPM since only
unspecific alterations may be occasionally observed [1,2]. In a recent
study CA125 was preoperatively elevated in the majority of patients
with DMPM, while CEA and CA19.9 were normal in all of them.
These data indicate that CA125 elevation is not a valid criterion to
exclude DMPM from diagnosis, although the tumor is less common
than ovarian cancer [24].
In patients with suspected DMPM or peritoneal dissemination of
unknown origin, laparoscopy rather than surgical exploration is a
recommended minimally invasive tool to obtain tumor tissue samples.
Allowing direct inspection of peritoneal surfaces, laparoscopy may
also facilitate disease staging and the selection of surgical candidates.
If DMPM is incidentally discovered during abdominal surgery carried
out for other causes, the surgeon should perform only multiple tumor
biopsies, in an effort to preserve as much as possible the integrity of the
peritoneal barrier and to not hinder a future multimodality approach.
Pathological confirmation is always required for definitive diag-
nosis [22]. In spite of the quality of modern immunocytochemical and
ultra-structural methods, cytological analyses of ascitic fluid are often
inconclusive [15,21,22]. The pathological differentiation from benign
mesothelial proliferations or from other peritoneal malignancies may
be difficult and requires appropriate immunohistochemical studies.
DMPM is characterized by positive staining for calretinin, epithelial
membrane antigen (EMA), Wilms tumor 1 antigen (WT1), cytokeratin
5/6, human mesothelial cell 1 (HBME-1), mesothelin and negative
staining for CEA, B72.3, MOC-31, TTF-1 and Ber-EP4. In most cases
positive calretinin and EMA with negative CEA is highly suggestive of
DPM [25]. Electron microscopy may be of help. Confirmation of the
diagnosis in highly qualified referral centers is recommended [1,2].
The definition of the histological sub-variant is prognostically and
therapeutically relevant. Diffuse malignant mesothelioma is the most
common primary peritoneal tumor. Localized forms usually show a
benign clinical behavior. According to the WHO classification, DMPM
can be broadly divided as displayed in Table I [26,27].
During the workshop, 100% of the voters stated that CT-scan of the
abdomen and pelvis has the greatest relevance in the preoperative
work-up. CT-scan of the chest was voted by 83.3% of the experts,
clinical examination by 58.3%, ultrasound by 54.5% and laparoscopy
by 50%. No significant consensus was reached about the role of
colonscopy, EGDS and PET-scan. Concerning laboratory tests,
consensus was achieved for complete blood count (75%), coagulation
studies (67.6%) and comprehensive metabolic panel with liver function
tests (75%). Apparently, there was no agreement on the role of
urinalysis pulmonary function tests and tumor serum markers.
TABLE I. Pathological Classification of Diffuse Malignant Peritoneal
Mesothelioma (DMPM)
% of
Tumor type DMPM
Epithelial 75%
Malignant DMPM Tubulo-papillary
Nonglandular (solid) 13%
Sarcomatous 6%
Biphasic (mixed) 6%
Undifferentiated
Desmoplastic
Lympho-histiocitoid
Small cells
Deciduoid
Border-line/low malignant DMPM Well-differentiated papillary Rare
Multicystic
Journal of Surgical Oncology
Consensus on Peritoneal Mesothelioma 269
PATIENT ELIGIBILITY TO CYTOREDUCTIVE
SURGERY AND PIC
The combination cytoreductive surgery and PIC is expensive in
terms of financial resources, operative time and major morbidity [28].
Therefore, patient selection is important to maximize the clinical
outcome and to exclude patients who will not benefit from a potentially
life threatening procedure. Candidates have to be medically fit in order
to undergo safely to CRS with HIPEC. Furthermore, performance
status has a prognostic relevance, since Eastern Cooperative Oncology
Group (ECOG) score of 0 has been demonstrated to be independently
related to better progression-free survival in patients with DMPM [18].
Hepatic or extra-abdominal metastases, as well as peritoneal disease
not amenable of macroscopically complete cytoreduction are exclusion
criteria for CRS and HIPEC. Unnecessary laparotomy can be avoided
by accurate radiological evaluation. Preoperative CT-scan can reliably
assess size and distribution of tumor deposits within the abdominal
cavity. This is useful for the physicians not only to plan the surgical
cytoreductive procedures but also to identify patients to be excluded
from comprehensive treatment. Tumor mass >5 cm in the epigastric
region and loss of normal architecture of the small bowel and its
mesentery (segmental obstruction and nodular thickening) are related
to failure in adequately removing all the macroscopic tumor. In a
composite analysis, none of the patients with both these radiological
features had an adequate cytoreduction. Patients lacking these two
preoperative CT-scan findings had a 94% probability of adequate
cytoreduction [29].
Biological aggressiveness is one of the most relevant prognostic
determinant for either pleural or peritoneal mesothelioma [1,2].
Patients affected by border-line malignant potential variants (well-
differentiated papillary and multicystic) are generally good candidates
for CRS and HIPEC. By contrast, biphasic and sarcomatoid histology
is associate to poor prognosis [2]. Epithelial variants with intermediate
prognosis represents the great majority of DMPM. In this setting,
additional selection factors would be needed to identify patients
who will benefit from the procedure and to design an individualized
multimodality treatment plan.
To date, only few centers have clinically investigated the potential
prognostic factors for patients with DMPM treated by cytoreductive
surgery and PIC, as summarized in Table II along with the statistical
methods used. There is a substantial agreement among the different
groups about the variables related to reduced overall survival: male sex,
incomplete surgical cytoreduction and aggressive tumor histology.
Tumor invasion of deep tissues, no history of prior surgical debulking,
non-incidental diagnosis and high mitotic count can also be considered
markers of aggressive biological behavior. Finally, Cerruto have re-
cently demonstrated by multivariate analysis that the size of the nucleus
of the DPM cells is independently associated with survival [30].
Correlation to progression-free survival was analyzed in only two
studies. No prior debulking, deep tissue invasion, ECOG performance
status >0 and mitotic count >5/50 HPF were recognized by
multivariate analysis as independent predictor of adverse prognosis
[14,18].
During the workshop, 81.7% of the experts agreed that histological
subtype has the maximal relevance in patient selection. In a scale from
1 to 5, 41.7% and 58.3% of the voters stated that mitotic count and
nuclear grade or size has a relevance of 5 and 4, respectively.
Concerning the radiological assessment, 63.6% and 58.3% of the
experts agreed on the unfavorable prognostic value of tumor mass in
the epigastric region and small bowel segmental obstruction. Patient
performance status was recognized as a useful selection criteria by the
50% of voters.
Available literature data suggest that systemic chemotherapy (CT)
may be integrated with the combined loco-regional treatment strategy
for DMPM. Cisplatin has shown the better activity rates as a
270 Baratti et al.
TABLE II. Prognostic Factors for Peritoneal Mesothelioma After Cytoreductive Surgery and Hyperthermic
Intraperitoneal Chemotherapy (HIPEC)
Principal investigator (Ref.) Feldman [14] Deraco [18] Yan-Sugarbaker [19]

Year 2003 2006 2006

Statistical analysis Multivariate Multivariate Multivariate
N. of patients 49 49 62

Age > 60 yrs X

Previous debulking X
Deep tissue invasion X
Nuclear Size X(3)
Completeness of cytoreduction X(1) X(2)
Mitotic count > 5/50 HPF X
(1)
residual disease >1 cm vs 1 cm; (2)residual disease >2.5 mm vs 2.5 mm; (3)Nuclear size I (10–20 mm) vs II (21–
30 mm) vs III (31–40 mm) vs IV (>40 mm).

single agent and particularly in combination with gemcitabine [31]. A
phase III clinical trial testing a new antifolates drug (pemetrexed) in
combination with cisplatin versus cisplatin alone showed increased
response rate and overall survival. Such combination is currently
considered by many oncologists the regimen of choice for pleural
mesothelioma [32]. There are little information on the effectiveness
of this combination for DPMP. The preliminary results of a non-
randomized trial started in June 2002 account for an overall objective
response rate of 26% among 73 patients with DMPM [33]. On these
bases, patients at high risk for postoperative failure may be potential
candidate for adjuvant systemic CT. Furthermore, patients not suitable
for immediate cytoreduction and HIPEC may theoretically benefit of
induction systemic CT to reduce disease extent and undergo a second
comprehensive surgical evaluation.
Different hypotheses of integrated treatment were debated during
the workshop for each clinical setting. Adequate surgical cytoreduction
and HIPEC was the favored treatment for low malignant potential
mesothelioma (multicystic and papillary well-differentiated), being
voted by 66.7% of experts. Concerning epithelial DMPM, 33.3% of
the participants voted for cytoreduction with HIPEC and adjuvant/
neo-adjuvant systemic CT, 41.7% for cytoreduction with HIPEC and
EPIC and only 25% for cytoreduction with HIPEC. CRS with HIPEC
and adjuvant/neo-adjuvant systemic CT was the treatment of choice for
biphasic and sarcomatoid DMPM according to 83.3% of voters.
The best treatment options for patients not amenable to adequate
cytoreduction were discussed. The following hypothesis were favored
by the experts: debulking surgery for multicystic and papillary well-
differentiated mesothelioma (83.3%); primary systemic CT followed
by re-evaluation for surgical cytoreduction with HIPEC in selected
cases with significant therapeutic response for epithelial peritoneal
mesothelioma (66.7%) and biphasic/sarcomatoid mesothelioma
(50%). Since no reliable staging system for DMPM is currently
available, we propose a rationale operative prognostic classification for
patients candidate to comprehensive loco-regional treatment. Based on
TABLE III. Proposal for Preoperative Prognostic Classification for Diffuse
Peritoneal Mesothelioma
Peritoneal disease suitable for
Stage complete cytoreduction Prognostic factors
I Yes No unfavorable prognostic factor
IIA Yes 1 unfavorable prognostic factors
IIB Yes 2/3 unfavorable prognostic factors
III No Any
IV Presence of extra-abdominal
and/or hepatic metastases
the aforementioned clinical data, the classification involves the
following parameters: (1) presence of extra-abdominal and/or hepatic
metastases; (2) disease potentially suitable for complete surgical
cytoreduction at preoperative imaging studies; (3) prognostic factors
(histology, nuclear grade, mitotic count). Prospective studies would
be needed to validate such classification (see Table III). The developing
of a new staging system was favored by 75% of the experts and 66.7%
of them would agree on the opportunity of planning prospective trials
to validate new staging systems.
STATE OF THE ART OF THE METHODOLOGY
Accurate exploration of the abdominal cavity and lyses of
adherences are needed to assess peritoneal disease extent. The surgical
cytoreduction is aimed at removing all the macroscopic tumor by
means of formal diaphragmatic, parietal and pelvic peritonectomies,
complete greater and lesser omentectomy. Small volume tumor
implants on bowel serosa and mesentery can be electro-fulgurated.
Conversely, the opportunity to perform multivisceral resections in case
of massive involvement should be carefully evaluated in light of the
deriving functional consequences and the individual prognosis.
The definition of adequate cytoreduction as residual tumor nodules
2.5 mm (cc-1 or R2a, according to the two main scoring systems) was
favored by 75% of voters, while 58.3% of the experts agreed on the
opportunity to perform complete parietal peritonectomy even in case of
disease involvement confined to a limited area, due to the possibility of
microscopic disease spread.
Technique of HIPEC (open vs. closed), type and dose of antiblastic
drugs, duration of treatment and degree of hyperthermia vary from
one series to other, as summarized in Table IV. Cisplatin has a
favorable pharmacological profile for intra-peritoneal administration
and is likely the most active drug against either pleural or peritoneal
mesothelioma [31]. Theoretically, Mitomycin-C has some advantage
for intra-peritoneal administration, since pharmacokinetic studies have
demonstrated a better area under the curve ratio of peritoneal fluid to
plasma [34]. Doxorubicin has shown a great activity in primary tissue
cultures obtained from surgical specimens of DPM (unpublished data).
A major technical variation is represented by EPIC but the contribution
of such therapeutic tool in addition to CRS and HIPEC is presently
unknown. A comprehensive treatment plan including induction intra-
peritoneal CT, second-look surgery, HEPIC and total abdomen
radiation have been tested in a phase I/II trial [16].
According to the voting results, a combination rather than a
single drug schedule (75% vs. 25%) was preferred by the experts; the
combination of cisplatin plus doxorubicin, with the 88.9% of votes,
was defined as the regimen of choice. Finally, a temperature of 428C
was considered the standard for HIPEC.

Journal of Surgical Oncology


TABLE IV. Technical Features of Cytoreductive Surgery and HIPEC
Residual HIPEC
Center Pts (no.) disease status technique
Wake Forest Un. 12 60% <2.5cm Closed
NCI Bethesda, MD 49 88% <1cm Open
Milan, Italy 49 82% <2.5mm Closed
Lyon, France 15 66% <2.5mm Closed
Washington, DC 62 69%<2.5cm Open
Columbia Univ.-Presbiterian 27 NS Open
Hospital
EPIC, early postoperative intra-peritoneal chemotherapy; 5-FU, 5-fluoruracil; IP, intra-peritoneal.
FOLLOW-UP
Clinical follow-up after CRS and HIPEC can be carried out on out-
patient base. CT-scan was voted as the best imaging study by 75% of
experts and should be regularly performed along with clinical
examination and serum CA125 determination. A recent study suggests
the utility of circulating CA125 to assess postoperative disease
progression in patients with elevated baseline levels [24]. In
asymptomatic patients, follow-up visits may be performed every
3–4 months during the first 2 years and every 6 months afterward. If
asymptomatic recurrences occur, treatment by means of early surgery
or chemotherapy was considered adequate by 83.3% and 75% of the
experts, respectively.
FUTURE PERSPECTIVES
Advances in diagnosis of DPM may come form new imaging
or laboratory tests. Positron emission tomography combined with CT-
scan is a new imaging technique which may be able to preserve
the high resolution of CT-scan and to provide at the same time
more functional information then CT-scan. This technique has been
suggested to reliably detect extra-abdominal disease and to accurately
assess response to chemotherapy in patients with mesothelioma [2].
Serum mesothelin-related proteins are a soluble form of mesothelin
which is elevated in 84% of patients with pleural mesothelioma and in
only 2% with other pulmonary diseases [35]. Serum osteopontin levels
were shown to be significantly higher in patients with pleural
mesothelioma than in those with asbestos exposure [36]. No data are
presently available about the clinical utility of these antigens in DPM
management.
Microarray techniques can assess simultaneously the expression of
thousands of gene in a single tumor sample. Mesothelioma and normal
pleural samples have been compared in a recent analysis providing
information about gene expression differences between the paired
normal and neoplastic tissues [37]. A microarray study yielded a 99%
accuracy in the difficult pathological distinction between pleural
malignant mesothelioma and lung carcinoma. Such result was obtained
by measuring the expression levels of three pair of genes encoding for
calretinin and TTF-1, which are widely used for the immunohisto-
chemical characterization of mesothelioma [38]. Microarrays are now
being used to systematically investigate the molecular changes that
may predict the individual response to specific drugs and correlate to
clinical outcome [2].
Due to the limited activity of traditional drugs, new therapeutic
agents are presently matter of both clinical and experimental
investigations. The platelet-derived growth factor (P-DGF) and the
Journal of Surgical Oncology
Consensus on Peritoneal Mesothelioma 271
HIPEC
HIPEC agents duration Temperature (8C)
Mitomycin-C 120 min 42.5
Cisplatin 90 min 41
EPIC (5-FU, paclitaxel)
Cisplatin þ doxorubicin 90 min 42.5
Cisplatin 90 min 42
Mitomycin-C
Cisplatin þ doxorubicin 90 min 42
EPIC (paclitaxel)
1st stage: debulking þ IP cisplatin and 60 min 40
doxorubicin þ IP gamma-interferon (4 courses)
2nd stage: 2nd look surgery þ HIPEC (cisplatin,
mitomycin-C) þ whole abdominal radiation
epidermal growth factor (EGF) signaling pathway have been
demonstrated to be active in malignant mesothelioma. Imatinib and
gefitinib, respectively, block these pathway. However, early studies
with these compounds have not yielded convincing results in the
treatment of mesothelioma [39]. Data from extensive studies in
mouse models have showed that mesothelioma is apparently sensitive
to immunotherapy. These findings have been supported by studies in
human beings with interferon-alpha, interleukin-2 and macrophage
stimulating factors, although standard use in clinical practice is not yet
warranted [40]. Recent studies in animals suggest the potential efficacy
of the combination of immunotherapy with apoptotic-inducing agents,
such as gemcitabine [41].
Two separate gene therapy approaches to mesothelioma have been
tested, involving respectively ‘‘suicide gene’’ and immunomodulatory
gene therapy. Encouraging response in small groups of men has been
observed [42]. Preliminary results indicate that the presence of
multiple telomere maintenance mechanisms and the over-expression
of survivin, an inhibitors of apoptosis protein, could be involved,
respectively, in the dysregulation of the apoptotic pathways and in the
immortalization of mesothelioma cells (unpublished data). This could
open new opportunities for the design of novel therapeutic strategies.
Other novel agents are involved in clinical trials: bevacizumab,
thalidomide and PTK/ZK 787 are new antiangiogenetic drugs targeting
in part the vascular endothelial growth factor (VGEF) pathway;
histone deacetylase and proteosome inhibitors are other drugs blocking
specific mesothelioma pathway [1,2].
The experts were asked to express their opinion on potential fields
of future investigational studies. The following topics were favored by
the voters: biological and pathological prognostic factors (100%),
biological target for gene therapy (100%), gene expression profile by
RNA microarray (100%), evaluation of asbestos concentration in the
specimens (70%).
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 Journal of Surgical Oncology 2008;98:273–276

Locoregional Treatment of Peritoneal Carcinomatosis From Gastric Cancer

F. BOZZETTI, MD,1 W. YU, MD, FACS,2* DARIO BARATTI, MD,3

SHIGEKI KUSAMURA, MD, PhD,3 AND MARCELLO DERACO, MD3
1
Department of Surgery, Hospital of Prato, 59100 Prato, Italy
2
Department of Surgery, Kyungpook National University, Daegu, South Korea
3
Department of Surgery, National Cancer Institute of Milan, Italy

The authors reviewed the natural history and the main features of the peritoneal carcinomatosis from gastric cancer briefly and analyzed the
pertinent literature concerning the locoregional modalities for prevention and for treatment. Results of the web based voting by experts were also
summarized. As regards the peritoneal perfusion with cytotoxic drugs with or without hyperthermia for preventing peritoneal carcinomatosis in
high risk patients, there are some randomized clinical trials and one meta-analysis supporting a benefit of the procedure. However, disparity in
methodology (drugs, dosage, duration of the treatment, addition of hyperthermia, etc.) precludes the adoption of a shared protocol to be used in the
clinical practice in high risk patients. Once the peritoneal carcinomatosis is established, the approach reported in literature is the peritonectomy
associated with hyperthermic perfusion. However, data supporting benefits are scanty, and limited to few centers with a specific experience in this
field. With regard to the main questions addressed to the experts’ panel and concerning the indications for treatment and methodology, there was a
general consistency among the experts and agreement with the findings of the literature. The need for a large multicenter trial to confirm the
benefit and risk of intraperitoneal chemotherapy was recognized by both the experts and the authors.
J. Surg. Oncol. 2008;98:273–276. ß 2008 Wiley-Liss, Inc.

KEY WORDS: peritoneal carcinomatosis; gastric neoplasm; intraperitoneal chemotherapy; peritonectomy

INTRODUCTION Staging laparoscopy has become an accepted part of the pretreat-

Peritoneal carcinomatosis (PC) from gastric cancer is a frequent
event even in the early phase of the disease. It has been estimated that a
percentage of patients ranging from 15% to 50% or more have a
peritoneal disease at the surgical exploration, especially when there is
serosal involvement by the tumor [1,2]. The main risk factors for PC
are the serosal involvement by the tumor [3–5], the lymph nodes
involvement [6], the infiltrative growth [7], the big size [8], the gross
appearance [9] and the scirrhous type reaction [5]. These rates can
dramatically increase if exfoliated neoplastic cells or their markers are
actively searched in the peritoneal lavage cytology as well as if one
considers autopsy findings.
PC, once established, is associated with a poor survival with median
values ranging from 1–1.6 months [10,11] to 3.1 and 9 months [1,12]
and no survival at 5 years [13,14]. Peritoneal dissemination is the most
common reason for failure after intensive chemotherapy [15] and
systemic chemotherapy is largely ineffective against peritoneal
carcinomatosis.
DIAGNOSIS AND STAGING
The preoperative diagnosis and staging of peritoneal disease is
limited by the insensitivity of traditional imaging modalities such as
computed tomography (CT), ultrasonography (US), and magnetic
resonance imaging (MRI). Although there is increased accuracy in
the assessment of extragastric disease with modern multiphase,
multidetector spiral CT imaging, sensitivity of CT for detection of
extragastric disease declines with the size of metastases. Current CT
techniques cannot consistently identify low-volume macroscopic
metastases that are 5 mm or less in size. However, CT scans are
sensitive for the detection of omental metastases or indirect evidence of
tumor such as the presence of ascites, mesenteric thickening, or
matting of loops of bowel.
Lee et al. [16] reported that EUS was more sensitive than combined
US and CT scan examinations in diagnosing ascites.
ment evaluation of patients who are thought to have advanced gastric
cancer. Laparoscopy allows for direct inspection of the peritoneal and
visceral surfaces for detection of CT-occult small-volume metastases.
Staging laparoscopy also allows for assessment of peritoneal cytology
and intraperitoneal evaluation with adjunctive diagnostic techniques
such as laparoscopic ultrasound (LUS). The accuracy of laparoscopy
for peritoneal metastasis is reported to be 92% [17,18]. Two
major unresolved issues remain regarding the timing and extent of
laparoscopy. Laparoscopy can be performed as a separate staging
procedure before definitive treatment planning or immediately before
planned laparotomy. LUS and extended laparoscopy are techniques
that may increase the diagnostic yield of laparoscopy. LUS involves
examination of the stomach, perigastric region, and peritoneal cavity
using a laparoscopic ultrasound probe, whereas extended laparoscopy
involves a more detailed laparoscopic examination of the perigastric
region that includes laparoscopic examination of the lesser sac and
retrogastric space.
The majority of patients with peritoneal carcinomatosis are
diagnosed and assessed at laparotomy. Among several systems for
assessing the distribution of peritoneal surface disease, peritoneal
cancer index (PCI) is commonly used. This is a clinical summary of
both lesion size and distribution of peritoneal surface malignancy [19].
The lesion size (LS) is used to assess the size of nodules. In order to
assess the distribution of peritoneal surface disease, the abdomino-
pelvic regions are utilized. For each of these 13 regions, an LS score is
The authors have no financial interest related to the contents of this article to
disclose.
*Correspondence to: W. Yu, MD, FACS, Department of Surgery,
Kyungpook National University, 50 Samduk-dong, Daegu 700-721, South
Korea. Fax: 82-53-421-0510. E-mail: wyu@mail.knu.ac.kr
Received 19 March 2008; Accepted 21 March 2008
DOI 10.1002/jso.21052
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.

274 Bozzetti et al.
determined. The summation of the LS in each of the 13 regions is the
PCI for that patient. It is basically a recording of what the surgeon
visualizes as he explores the abdomen. PCI can be easily applied to the
nodular type of peritoneal seeding from gastric cancer. However, it is
difficult to assess the diameter of peritoneal surface disease in diffuse
infiltrating type of dissemination.
CLINICAL PATHWAY
Patients who are found to have occult metastatic disease at
laparoscopy or laparotomy are considered incurable and only palliative
procedures are recommended for these patients [20].
In patients with peritoneal carcinomatosis from colon cancer, the
prognosis of patients with low PCI scores is significantly better than
that of patients with high PCI scores [21]. The value of the PCI as a
selection tool in this patient population is obvious, however, PCI as a
selection tool in gastric cancer has not been evaluated.
The peritonectomy is indicated for the patients with peritoneal
dissemination which is considered to be able to macroscopically
completely resected. Patients with a limited number of metastatic
nodules distributed in the peritoneal cavity, and those without evidence
of the involvement of the liver or distant lymph nodes are eligible for
peritonectomy [22]. Peritonectomy is contraindicated for patients with
many big nodules distributed on the mesentery of small bowel. In other
words, PCI should be converted to 0 by cytoreduction, that means
completeness of cytoreduction score 0 (no visible peritoneal
carcinomatosis remains after cytoreduction).
Invisible dissemination already spreads everywhere in the perito-
neal cavity, even if the complete resection of peritoneal dissemination
is achieved by aggressive surgical cytoreduction. A major role for
intraperitoneal chemotherapy is the prevention of subsequent perito-
neal carcinomatosis. Intraperitoneal chemotherapy is an important
treatment option for patients with T3 or T4 lesions as well as for
patients who are undergoing peritonectomy. Locoregional treatment
consists in peritoneal perfusion (with or without hyperthermia) as a
single procedure or following cytoreductive surgery. The two
procedures are not comparable since the first has usually been used
in the earliest stages and sometimes as an adjuvant treatment,
the second one has been exclusively used in advanced stages.
The treatment strategy composed of peritonectomy, intraoperative
and early postoperative intraperitoneal chemotherapy is expected to be
a powerful therapy for patients with peritoneal dissemination from
gastric cancer.
INTRAPERITONEAL CHEMOTHERAPY (IPEC)
A meta-analysis of 11 randomized clinical trials (1980–2003)
involving 1,161 patients receiving IPEC (usually without hyperthermia
and mainly with mitomycin C, but also cisplatinum or fluorouracil)
after curative resection for locally advanced gastric cancer showed a
benefit in the overall survival (pooled odds ratio 0.51, 95% CI 0.40–
0.60) [24]. We reanalyzed the Xu’s study [24] to find out which drug
combination proved to be the most active, but we found none of the
various drug combinations (mitomycin C-carbon particles, mitomycin
C and cisplatinum, fluorouracil, mitomycin C and fluorouracil) proved
to be consistently active. Similarly there was no consistent effect with
the use of IPEC or hyperthermic IPEC (HIPEC).
More recently two phase II studies were published [25,26], but the
only new report of a randomized clinical trial is from Yu [27] They
reported on 248 patients randomized to early postoperative intraper-
itoneal chemotherapy with mitomycin C and 5-fluorouracil for 5 days
versus control. There was a benefit in the 5- and 10-year survival in the
treated arm which was mainly confined to stage III. A multivariate
analysis confirmed that IPEC was a statistically significant prognostic
factor for survival and rate of postoperative complications and length
Journal of Surgical Oncology
of hospital stay, but not mortality, were significantly higher in the
treated group.
PERITONECTOMY (P) AND
HYPERTHERMIC INTRAPERITONEAL
CHEMOTHERAPY (HIPEC)
The experience with P-HIPEC is limited in number of studies
and number of patients undergoing the procedure. To our knowledge
there are three institutional studies on P-HIPEC in patients with
gastric cancer, one retrospective (42 patients) [23], one prospective
(49 patients) [28] and one comparative non-randomized (34 patients)
[29]. The median survival ranged from 8 months [28] to 10–11 months
[23,28] and the 5-year survival ranged from 6% [23,29] to 16%
according to Glehen et al. [28] Surgical mortality was acceptable,
namely 2–7.1% [23,28,29]. Interestingly, a multivariate analysis
showed that completeness of cytoreduction (and hence initial stages
of peritoneal dissemination versus advanced stages) and absence of
ascites were favorable prognostic factors for survival. More precisely,
in patients with CC-0 or CC-1 median survival was 21.3 months and
5-year survival was 29.4% [28], and Yonemura et al. [23] reported
quite similar figures: a complete cytoreduction was associated with a
median survival of 19.2 months and a 5-year survival of 27%. It is
noteworthy, however, that a complete cytoreduction was possible in
only 44–51% of patients operated on by Yonemura et al. [23] and
Glehen et al. [28] The most important prognostic factors for survival
are absence of ascites, completeness of cytoreduction, a low complete-
ness of cytoreduction score and a low peritoneal dissemination class.
EXPERTS’ CONSENSUS
A number of questions were addressed to 19 experts from 7 different
countries regarding IPEC (with or without hyperthermia), P-HIPEC
and some methodological issues.
Questions Regarded the Eligibility for IPEC
All the experts agreed that adjuvant IPEC should be recommended
in patients after curative gastrectomy if there was a positive cytology
and the 83% of them advised the procedure to be done for T3–T4
tumors. Moreover 4/5 of them accepted that T classification could
be defined on the basis of the simple intraoperative gross appearance
without the help of frozen sections or sophisticated instrumentation.
Should PC be discovered during laparotomy and gastric tumor
be adequately resectable patients might be eligible for IPEC if
PCI is less than 10 (92% consensus) and size of the single lesions
is 0.2 cm or less (92% consensus). The vast majority of the experts
(92%) supported the concept that IPEC should be associated with
hyperthermia, should be associated with postoperative adjuvant
systemic chemotherapy (77%), and should be delivered as a single
cycle (77%). Only 54% advised to prolong IPEC also in the
postoperative period.
Two questions explored the opinion of the experts about multicenter
randomized clinical trials on IPEC: 77% of them would be available to
take part in the trials of IPEC versus no-IPEC in CC-0 patients or in
patients at high risk for PC. A lesser percentage (62%) was available to
take part in a trial of IPEC versus other therapies in patients with PC
discovered during laparotomy.
Questions Regarding P þ HIPEC
The experts recommended the procedure in primary tumors and in
recurrent tumors in the following conditions: only in CC-0/CC-1
resections (100% in primary tumors, 75% in recurrent tumors); only in

absence of distant metastasis (83% in primary tumors, 73% in recurrent
tumors); only in absence of ascites (33% in primary tumors, 19% in
recurrent tumors); in stages PCI < 10 or 15, 38% or 71%.
The majority of the experts (92%) favored the association of
P þ HIPEC with systemic therapy. Again, 92% considered necessary a
large phase III trial to make P þ HIPEC the standard therapy in PC
from gastric cancer, and 77% would accept to take part in the trial
which compares P þ HIPEC with other therapies.
Miscellaneous Questions
Three quarters—two thirds of the experts advised not to attempt any
peritonectomy if a radical resection is not attainable and 89% suggest
limiting peritonectomy to the affected area only. Furthermore, 77% of
them were in favor of using multiple drugs for HIPEC, and in the order,
mitomycin C (85%), cisplatinum (77%), fluorouracil (46%) and
doxorubicin (31%).
DISCUSSION
It appears that there was, in general, a good agreement between data
of the literature and opinion of the experts and a good internal
consistency within the experts’ consensus.
Certainly IPEC or HIPEC as adjuvant treatment is a procedure more
validated than P-HIPEC, and there are randomized clinical trials and
also a meta-analysis supporting its efficacy. However, these trials are
often underpowered, their quality is suboptimal and studies from
eastern countries were more successful than those from Europe. All
these factors contribute to a limited spread of the procedure and to a
general agreement of the experts who recognize the need to plan a large
multicenter randomized clinical trial which definitely might prove the
efficiency of an adjuvant intraperitoneal chemotherapy versus the
standard systemic chemotherapy.
Although the majority of experts claim that the addition of
hyperthermia improves the efficacy of the IPEC, centers where
hyperthermia is readily available and feasible when a high-risk
patient is intraoperatively identified are relatively few. Probably the
larger number of patients who could undergo the simplest IPEC
would compensate for a lesser impact of this procedure and would
account for a higher number of patients who finally benefit from the
treatment.
Since there is a continuous progress in the field of chemotherapy a
reasonable approach for a multicenter randomized clinical trial would
be a two-arm study with following scheme: for patients at high risk for
PC (T3–T4), undergone a R0 gastrectomy, randomization to adjuvant
IPEC versus no-IPEC, regardless to any systemic therapy which could
be administered to both the groups. Previous experience has shown that
a 3-year follow up could be enough to demonstrate a potential benefit
in survival.
In contrast, P-HIPEC remains an approach less mature and to be
reserved for centers which are familiar with the procedure to maintain
an acceptable operative risk and select the patient population who
presumably can have the best benefit-to-risk option.
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 Journal of Surgical Oncology 2008;98:277–282

Consensus Statement on the Loco-Regional Treatment of Appendiceal Mucinous

Neoplasms with Peritoneal Dissemination (Pseudomyxoma Peritonei)

BRENDAN MORAN, MD,1 DARIO BARATTI, MD,2 TRISTAN D. YAN, BSc(Med), MBBS, PhD,
3

SHIGEKI KUSAMURA, MD, PhD,2 AND MARCELLO DERACO, MD2*

1
Colorectal Research Unit, North Hampshire Hospital, Basingstoke, Hampshire, UK
2
Department of Surgery, National Cancer Institute of Milan, Italy
3
University of New South Wales, Department of Surgery, St. George Hospital, Sydney, Australia

Pseudomyxoma peritonei (PMP) is a rare condition mostly originating from low malignant potential mucinous tumours of the appendix. Although
this disease process is minimally invasive and rarely causes haematogenous or lymphatic metastases, expectation of long-term survival are limited
with no prospect of cure. Recently, the combined approach of cytoreductive surgery (CRS) and perioperative loco-regional chemotherapy (PLC)
has been proposed as the standard of treatment for the disease. The present paper summarizes the available literature data and the main features of
the comprehensive loco-regional treatment of PMP. The controversial issues concerning the indications and technical methodology in PMP
management were discussed through a web-based voting system by internationally known experts. Results were presented for further evaluation
during a dedicated session of ‘‘The Fifth International Workshop on Peritoneal Surface Malignancy (Milan, Italy, December 4–6, 2006)’’. The
experts agreed that multiple prospective trials support a benefit of the procedure in terms of improved survival, as compared with historical
controls. Concerning the main controversial methodological questions, there was an high grade of consistency among the experts and agreement
with the findings of the literature.
J. Surg. Oncol. 2008;98:277–282. ß 2008 Wiley-Liss, Inc.

KEY WORDS: pseudomyxoma peritonei; appendiceal tumours; cytoreductive surgery; hyperthermic intraperitoneal
chemotherapy; HIPEC

Pseudomyxoma peritonei (PMP) is a rare condition characterized
by copious mucinous ascites and peritoneal mucinous implants [1–2].
The earliest description of the condition was by Rokitansky in 1842 in
a patient with a benign mucocele of the appendix [3].
Traditionally patients with PMP have been treated with repeated
interval debulking procedures for relief of symptoms, but with limited
expectation of long-term survival and no prospect of cure [1–2].
However, accurate historical controls of uniformly treated patients are
scarce, partly due to the rarity of the disease. In 1994, Gough reported a
10-year survival of 32% in 56 PMP patients who underwent serial
debulking procedures and selectively treated with intra-peritoneal
radiotherapy or chemotherapy between 1957 and 1983 [4]. In 2005,
Miner reported a 10-year survival of 21% in 97 PMP patients treated
with serial debulking, systemic chemotherapy and/or delayed inter-
mittent intra-peritoneal 5-fluorouracil over a 22-year period [5].
Misdraji reported on 107 patients with a median survival of about
7.5 years, and a 20-year survival of 25% after serial debulking and
intra-peritoneal chemotherapy. The number of patients in this group
who received aggressive locoregional treatment is unknown [6].
Although a subset of patients may remain asymptomatic for
many years, the disease almost always recurs and patients often re-
present with gastrointestinal obstructive symptoms. Over time each
repeated debulking procedure becomes more ineffective and sometimes
more dangerous due to the risk of bowel injury [1]. In addition, in some
patients the disease may not remain indolent throughout its clinical
course. Yan and colleagues showed that some patients underwent
transitions from a less aggressive to a more aggressive histopathologic
type over time and with repeated surgical interventions [7].
The structured approach of cytoreductive surgery (CRS) and
perioperative loco-regional chemotherapy (PLC) regimens has shown
in multiple studies improved survival, as compared with historical
controls [8–18]. Sugarbaker published a large series of 385 patients in
1999 [8]. Of these, 205 received hyperthermic intra-peritoneal
chemotherapy (HIPEC). He showed survival advantages in those
who had complete versus incomplete cytoreduction (80% vs. 20%) and
in those with low-grade versus high-grade tumours (80% vs. 28%) but
did not comment on whether the introduction of HIPEC made any
difference to survival. Most recent updates by Sugarbaker demon-
strated a median survival of 156 months and 5- and 10-year survival of
72% and 55% in 501 patients [11]. Taken together these data suggest
that treatment of PMP by means of CRS and PLC is supported by a
‘‘type 3 evidence’’, coming from non-randomised studies with external
controls allowing comparisons [19].
The present paper addresses the available scientific evidence and
the results of a group of health-care providers trying to achieve a
consensus statement in the management of PMP by means of CRS and
PLC regimens, including intra-operative HIPEC and/or early post-
operative intra-peritoneal chemotherapy (EPIC) within 7 days from
surgery.
Disclosures: The authors have no financial interest related to the contents of
this article to disclose.
*Correspondence to: Dr. Marcello Deraco, MD, Istituto Nazionale Tumori
Milano, Via Venezian, 1 20133 Milano, Italy. Fax: þ39-02-23902404.
E-mail: marcello.deraco@istitutotumori.mi.it
Received 19 March 2008; Accepted 21 March 2008
DOI 10.1002/jso.21054
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.

278 Moran et al.
TERMINOLOGY AND
PATHOLOGICAL CLASSIFICATION
There has been considerable confusion in the literature about the
site of origin and pathological classification of PMP [1,6]. High-grade
colonic mucinous neoplasms, adenocarcinomas of the appendix
and mucinous adenocarcinomas originating from any other intra-
abdominal organ can simulate the clinical, radiological and patho-
logical features of PMP. Additionally, there appears to be a histological
spectrum of disease from low to high-grade [1]. Recent pathological,
molecular genetic and immunohistochemical evidence supports the
theory that the majority of classical PMP originate from ruptured low-
grade appendiceal tumours [20–22]. Undoubtedly a small proportion
of cases arise from other organs and it is possible that an ovarian
primary mucinous tumour may be the commonest in this diverse group
arising from the stomach, colon, pancreas, gallbladder, urachus and
other intra-abdominal organs [23–26].
These difficulties in pathological classification of the clinical entity
of PMP have led to ongoing confusion as to the outcomes following
intervention. Thus, many series include all cases of PMP, of whatever
origin, and include patients with mucinous adenocarcinoma of the
appendix whereas others have reported only on classical pseudo-
myxoma from appendiceal cystadenomas. Ronnett, in a retrospective
review of a series of patients undergoing complete cytoreduction
reported a pathological system commonly quoted in the literature
[20]. They classified low-grade tumours as disseminated peritoneal
adenomucinosis (DPAM) and high-grade tumours as peritoneal
mucinous carcinomatosis (PMCA), with an intermediate group (IG).
Survival was significantly higher in DPAM group as compared with the
IG and PMCA, with actuarial 5-year survivals of 84%, 37.6% and
6.7%, respectively. They were unable to show a statistically significant
difference between the IG and PMCA groups and in subsequent
articles have grouped these together [27].
In a recent study by Misdraji, a different histopathologic classifica-
tion of appendiceal neoplasm was proposed [6]. They classified the
appendiceal mucinous tumours into low-grade appendiceal mucinous
neoplasms (LAMN) and high-grade mucinous adenocarcinomas
(MACA). The former diagnosis corresponds to mucinous cysto-
adenoma and the latter to mucinous cysto-adenocarcinoma in the
conventional classification system [28]. However, in this study, follow-
up data were available only in 66 of 107 patients and patients underwent
a variety of treatments by different surgeons over a 50-year period. More
recently, based on the clinically malignant behaviour of all PMP
varieties, Bradley has proposed that mucinous carcinoma peritonei,
either low-grade or high-grade, is best applied to all cases of PMP [29].
PREOPERATIVE EVALUATION
The clinical presentation of PMP has been poorly defined due to
few reports with large patient populations. The recent publication
by Esquivel and Sugarbaker is the most enlightening [30]. In a series of
410 patients with appendiceal tumours, 27% presented with suspected
appendicitis, 23% with increasing abdominal distension and 14%
with a new onset hernia. In women, a diagnosis of PMP was most
commonly made while being evaluated for ovarian mass (39%).
Nevertheless, the majority of patients are diagnosed at a laparotomy
performed for either suspected appendicitis, peritonitis or gynaeco-
logical cancer.
More recently, the diagnosis of PMP is suspected in an increasing
number of patients at imaging studies, particularly based on radio-
logical features at CT-scan [31,32]. Appropriate radiologic techniques
and a combination of oral, rectal and venous contrast are needed. On
CT-scan PMP appears of low attenuation but areas of high attenuation,
due to solid elements within the mucinous material or compressed
mesentery, can be seen [32]. The circulation of peritoneal fluid in the
Journal of Surgical Oncology
abdominal cavity is dictated by gravity, pressure changes associated
with respiration and physical boundaries of the peritoneal reflections.
The mucin-producing cells in PMP are poorly adherent and freely
circulate with peritoneal fluid. This process has been termed as
redistribution phenomenon [33]. Accordingly, the predictable pattern
of accumulation of mucinous ascites instead of the individual deposits
can suggest the diagnosis of early-stage PMP. When the peritoneal
cavity is completely, or almost completely filled with PMP, CT-scan
findings become less specific. In most cases, the striking feature is the
relative sparing of the small bowel and its mesentery and their
compartimentalization in the central abdomen by a large omental cake
and massive mucinous ascites.
The role of magnetic resonance imaging (MRI) in this clinical
setting is presently under investigation. According to a preliminary
report, the use of MRI seems promising in disease staging and patient
selection for cytoreductive surgery [34]. PET is of very limited value
for low-grade mucinous lesions, such as pseudomyxoma [35]. CT-scan
or US-guided biopsy may be useful, although the relatively acellular
material is often difficult to diagnose with certainty.
Most patients are referred from other surgical or gynaecological
units and have usually had variable degrees of surgery prior to formal
attempts at complete cytoreduction. Extensive previous attempts to
reduce tumour load were shown by one large study to have a negative
impact on survival [8]. It advisable, therefore, that the referring
teams perform the minimal amount of surgery required to establish a
histological diagnosis prior to referral to a specialist centre.
In total 78% of the panel agreed that PMP should always be
considered a cancer and therefore malignant. However, even when
the pathology was stated as ‘‘Malignant PMP syndrome-mucinous
Appendix Carcinoma and Mucinous Carcinoma from any origin’’
surprisingly 11% of the panel still considered this not to be a cancer.
Regarding pathological classification, no consensus was reached
with 44% favouring Ronnetts three-category classification. A further
44% voted for a two-category system of Low-Grade Adenocarcinoma
and High-Grade Adenocarcinoma. The novel recent terminology of
Mucinous Carcinomatosis Pertitonei (MCP) low-grade and MCP high-
grade, which is in reality new terminology similar to the two grade
system, was favoured by 12%.
These discrepancies in terminology and pathological classification
are important and really require universal agreement due to the
difficulties in comparing series, credibility in justifying major
surgical intervention, utilization of chemotherapy and difficulty in
establishing treatment programmes for what even experts consider a
‘‘benign disease’’. Based on the terminology of uncontrolled growth
of abnormal cells it is the authors opinion that PMP is at best a
‘‘borderline malignancy’’ with optimal treatment being that of a
cancer entailing complete macroscopic tumour removal combined with
intraperitoneal chemotherapy. An interesting comment to one of us at
the consensus meeting was ‘‘Based on this statement on PMP do you
equally consider endometriosis a malignancy?’’.
There was general agreement concerning pre-operative work-up
with 100% considering abdominal and pelvic CT-scan very important,
66% considering clinical examination very important with very
little role for PET-scan, CT-PET, MRI or US. The panel felt that
colonoscopy and laparoscopy and biopsy might help on occasion but
were not essential. Important laboratory work-up was considered to be
basic metabolic panel urea, creatinine and electrolytes, CEA, complete
blood count and coagulation studies by 75% of the panel with
little importance attached to pulmonary function, urinalysis or CA125
measurement.
ELIGIBILITY FOR SURGICAL TREATMENT
Careful selection for this expensive, time consuming and high-risk
surgery is essential. However, the potential surgical morbidity, along

with the spectrum of disease aggressiveness, makes preoperative
selection of patients for CRS and PLC critical. Current selection
criteria predominantly revolves around clinical assessment and CT-
scan imaging [32].
Patients affected by peritoneal carcinomatosis with performance
score ¼ 2/3 according to the Eastern Cooperative Oncology Group
(ECOG) have shown significantly poorer overall survival, compared to
those with ECOG score ¼ 1 [35].
In an effort to correlate the role of previous surgery in the
establishment of peritoneal implants, Sugarbaker introduced the
Prior Surgical Score (PSS). In patients with a PSS ¼ 0, diagnosis of
peritoneal carcinomatosis was obtained through biopsy or laparoscopy
only. PSS ¼ 1 indicates only a previous exploratory laparotomy.
PSS ¼ 2 indicates exploratory laparotomy with some resections.
Usually this was a greater omentectomy and/or right colectomy.
PSS ¼ 3 indicates patients had an attempt at a complete cytoreduction.
Patients with PSS ¼ 0–2 had a significantly improved survival
compared with those with a PSS ¼ 3 [8].
The current best method to assess operability is contrast-enhanced
CT-scan. Radiological features predicting the likelihood to adequate
remove all the peritoneal tumour deposits have been described by
Jacquet and validated by Sulkin [31,32]. In the study by Jacquet two
radiologic findings predicted complete versus suboptimal cytoreduc-
tion: the segmental obstruction of the small bowel and tumour masses
>5 cm on small bowel and its mesentery exclusive of distal ileum. A
statistical approach using a tree-structured diagram showed that
patients with both these features on preoperative CT-scan, had an
88% probability of incomplete resection. Patients without these two
findings had a 92% probability of complete resection [31].
Allowing direct inspection of peritoneal surfaces, laparoscopy may
also facilitate disease staging and the selection of surgical candidates.
The role of laparoscopy for PMP has never been specifically addressed.
The experiences with patients affected by carcinomatosis from
colorectal cancer has led to the conclusion that laparoscopy is accurate
to score peritoneal involvement and to assess the complete resectability
of carcinomatosis in patients for which there is inadequate or
contradictory information [36].
Finally, in recent years the prognostic value of markers has been
extensively addressed. In the paper by Baratti and colleagues: normal
preoperative CA125 correlated to adequate CRS, but only at univariate
analysis; in the same study, increased baseline CA19.9 was an
independent predictor of worse progression-free survival at multi-
variate analysis [37]. In 63 patients, van Ruth found only weak
statistical association between baseline CA19.9 and disease-free
interval, but elevated CA19.9 after the procedure or rising during
follow-up was related to disease recurrence [38]. Survival correlated to
preoperative CEA and CA19.9 among 532 patients studied by
Carmignani. Both markers, measured at the time of disease recurrence,
correlated to survival after a second cytoreduction [39]. In a recent
TABLE I. Technical Modalities of Perioperative Intra-Peritoneal Chemotherapy for Pseudomyxoma Peritonei Combined with Cytoreductive Surgery
Principal investigator Center Year
McGregor [9] Vancouver 2002
Elias [10] Paris 2003
Sugarbaker [11] Washington DC 2004
Piso [12] Regensburg 2005
Glehen [13] Lyon 2005
Loggie [14] Winston-Salem 2006
Moran [15] Basingstoke 2006
Zoetmulder [16] Amsterdam 2007
Morris [17] Sydney 2006
Deraco [18] Milan 2007
HIPEC: hyperthermic intra-peritoneal chemotherapy; EPIC: early postoperative intra-peritoneal chemotherapy; MMC: Mitomycin-C; 5-FU: 5-fluoruracil; OX:
oxaplatin; FA: folinic acid.
Journal of Surgical Oncology
Consensus on Pseudomyxoma Peritonei 279
paper, recurrence-free interval was statistically reduced for patients
with increased CEA, but also for patients with at least one positive
marker (among CEA, CA125 and CA19.9) [40].
CT imaging and CT-scan with tumour marker measurements were
chosen by 71% and 83% as key eligibility criteria with only 50%
support for laparoscopy or other investigations. With regards to disease
extension 100% felt that all asymptomatic patients with PMP
with resectable peritoneal dissemination should have CRS and PLC,
as should patients with minimal small bowel involvement and node
negative primary (100%). There was 100% agreement that peritoneal
carcinomatosis index (PCI) >20 was not an absolute exclusion
criterion in PMP, with a low grade tumour (87%), young age (63%),
absence of mesenteric invasion (88%) or liver metastases (75%) were
important factors to consider in conjunction with PCI.
STATE OF THE ART OF THE METHODOLOGY
The aim of surgery in PMP is complete cytoreduction as described
by Sugarbaker [2]. This involves up to six different peritonectomy
procedures in combination with visceral resections as required, to
remove all visible tumour, or if this was not possible, to leave tumour
deposits less than 2.5 mm (2.5 mm being the maximum direct
penetration of locally applied chemotherapy). In brief, peritonectomy
includes a greater omentectomy and splenectomy, left upper quadrant
peritonectomy, right upper quadrant peritonectomy, lesser omen-
tectomy and cholecystectomy, appendicectomy or right/total colec-
tomy, partial or total gastrectomy, and pelvic peritonectomy with
anterior resection of the recto-sigmoid colon. Females require
hysterectomy and bilateral salpingo-oophorectomy.
No study has reported on the effect of hyperthermic compared to
normothermic intra-peritoneal chemotherapy in patients in whom a
complete cytoreduction was performed. The chemotherapy agents
utilized, the dosage, the temperature or duration of intra-peritoneal
chemotherapy have not been subject to randomised trials but have been
chosen on knowledge of the agents’ intra-peritoneal pharmacokinetics.
The commonly used intra-operative agents are mitomycin, cisplatin,
5-fluorouracil or a combination of these and are usually administered
for 30-120 min [41]. For EPIC, 5-fluorouracil, cyclophosphamide and
mitomycin C are most frequently used for up to 6 days (see Table I).
To date, all the English language articles regarding PMP treated by
CRS combined with locoregional chemotherapy are observational
studies without control groups performed by tertiary referral centers.
Most are serial publications reporting accumulating numbers of
patients or increased follow-up. There are no randomized trials or
comparative studies. Six studies included 100 patients [8,11,14–
16,18] and the remaining series <100 patients. Five studies exclusively
reported PMP originating from appendiceal mucinous neoplasms
[8,11,14,15,17] and the remaining PMP originating mainly from
appendiceal mucinous neoplasms, representing 86–97% of their
Perioperative intra-peritoneal chemotherapy
EPIC (MMCþ5-FU)
HIPEC (MMC or OX or MMCþCisplatin) þ/ EPIC (5FU or 5FUþ FA)
HIPEC (MMC)þ EPIC (5-FU)
HIPEC (MMC or Cisplatin)
HIPEC (MMCþCisplatin)
HIPEC (MMC)
HIPEC (MMC)þ EPIC (5-FU)
HIPEC (MMC)
HIPEC (MMC)þ EPIC(5-FU)
HIPEC (MMCþcisplatin)
280 Moran et al.
TABLE II. Effectiveness of Cytoreductive Surgery and Perioperative Intra-Peritoneal Chemotherapy for Pseudomyxoma Peritonei

Overall survival (%) Disease status (%)

Principal investigator Pts (no.) Median survival (months) 1 year 2 years 3 years 5 years 10 years NED AWD DFD

McGregor [9] 11 NA — — 60 — — — — —
Elias [10] 36 NA — — — 66 — 23 3 4
Sugarbaker [11] 501 156 — — — 72 55 47 15 32
Piso [12] 28 51 — — — — — — —— —
Glehen [13] 27 NA 100 88 78 52 — — — —
Loggie [14] 110 64 80 — 59 53 — — — —
Moran [15] 123 NA — 57* 758 — — — —
Zoetmulder [16] 103 NA 90 83 71 60 — 61 5 19
Morris [17] 50 NA 89 76 69 69 — — — —
Deraco [18] 104 NA — — — 72 — 68 15 18

NED: no evidence of disease; AWD: alive with disease; DFD: died from disease; NA: not reached; 8: 83 patients undergoing complete cytoreduction; *: in 34 patients
undergoing major palliative resections.

sample population. The rate of complete cytoreduction is 40–91%.
This supports the benefits of centralising this aggressive surgical
treatment at institutions with an interest in PMP. Effectiveness of CRS
and PLC on survival and recurrence is demonstrated in Table II.
A number of recent reports in the literature have addressed the
morbidity and mortality in patients with PMP treated by CRS and PLC
(see Table III). The overall morbidity rate varied from 33 to 56%,
hematological toxicity from 4 to 9%, blood loss from 2100 to
8000 cm3, mean operation duration from 6.0 to 12.6 hr. Re-operation
rates for postoperative adverse events were 11–21%, as reported in two
studies. Overall mortality rates ranged from 0 to 18%. The median and
mean hospital stay ranged from 16 to 21 days and 26 to 29 days,
respectively (see Table III).
One aspect that has not been fully addressed is a strategy for the
many patients whose tumours were preoperatively considered unlikely
to be completely removable, either due to tumour extent and
distribution, or as a result of serious co-morbidity or age. There is
increasing evidence that many of these may benefit from a major
palliative resection with reasonable intermediate-term survival of 43%
at 2 years and 15% at 5 years and improved quality of life [42]. In these
situations an approach involving extended right hemicolectomy,
greater omentectomy and splenectomy with an ileocolic anastomosis
may be advisable [43]. Glehen recommended combination of
comprehensive surgical debulking with HIPEC except for patients
with signet ring histology or lymph node involvement in his experience
of 174 patients with incomplete cytoreduction [42].
There remains confusion as to the definition of complete
cytoreduction with 100% stating this should be CC0 but 100% also
agreeing it should include CC1. Maximal palliative surgery for patients
not amenable to complete cytoreduction was endorsed by 78% of
the panel, but 89% felt not for all cases, and 67% agreement
for appendiceal tumours. In limited disease, 65% felt a limited
peritonectomy was not appropriate, though 63% felt a complete
parietal peritonectomy was not necessary for patients with a limited
affected area. In patients with palliative or inoperable disease, 56% felt
PLC should not be used compared to 44% in favour suggesting that this
aspect might be amenable to a randomized trial. There was ambiguity
concerning the optimum drug and relative temperature though 428C
was considered optimal for irinotecan and gemcitabine by 100% and
for mitomycin and doxorubicin by 63% and 67%, respectively. The
optimal single agent was felt to be mitomycin-C by 100% but 66% felt
that combination therapy was optimal. If combination therapy was
used 83% favoured cisplatin and mitomycin-C.
A common dilemma is the aspect of systemic chemotherapy in
PMP. There was unanimous consensus that systemic chemotherapy
should not be used whilst awaiting surgery and HIPEC, but should be
given in non-resectable cases and those with high tumour grade. High
tumour markers were considered an indication to consider systemic
chemotherapy by 71%.
There was 100% agreement that the preferred imaging modality for
follow-up was CT-scan with no role for MRI, PET or CT PET. Tumour
markers, CT imaging and clinical examination at intervals of
0–12 months were favoured by 89% with 11% suggesting an
interval of 12–24 months. For asymptomatic recurrence, 66%
felt should have early surgery and 33% voted for no surgery and
systemic chemotherapy. There was 100% support for a clinical trial of
cytoreductive surgery and HIPEC followed by best systemic
chemotherapy in patients with high-grade disease if a complete

TABLE III. Morbidity and Mortality of Cytoreductive Surgery and Perioperative Intra-Peritoneal Chemotherapy for Pseudomyxoma Peritonei

Principal Hematol. Hospital

investigator Pts (no.) Morbidity (%) toxicity (%) Blood loss (ml) Operation duration (hr) Reoperation (%) Mortality (%) stay (days)

McGregor [9] 11 56 — — — — 18 —
Elias [10] 36 44 19 1200 10.08 14 248
Piso [12] 28 36 — 2100 6.0* 21 7 29*
Glehen [13] 27 44 — — — — 0 168
Loggie [14] 110 38 4 — 10.5* — — —
Moran [15] 123 — — — 108 — 5 228
Sugarbaker [46] 356 40 5 — — 11 2 218
Zoetmulder [47] 103 54 — 8000 9.0 — 3 218
Morris [17] 50 48 — — 10.0* — 4 26*
Deraco [18] 104 19 4 — — — 1 —

* mean; 8 median.

Journal of Surgical Oncology


cytoreduction was achieved. There was a 50/50 split concerning
systemic chemotherapy after complete cytoreduction in patients with
high tumour markers suggesting an area that could be considered for a
randomized trial.
CONCLUSION
Recent evidence suggests that optimal surgical resection (complete
cytoreduction if possible) combined with HIPEC is the most
fundamentally based strategy for PMP. A combined approach makes
both common and scientific sense, in that surgery attempts to remove
all macroscopic disease whilst HIPEC addresses residual microscopic
disease. This treatment strategy is a complex procedure, associated
with significant morbidity and mortality with a substantial institutional
and individual ‘‘learning curve’’ phenomenon [44,45].
The clinical results for cytoreduction and HIPEC in PMP show
good survival for those patients with low-grade histology amenable to
complete cytoreduction. Poorly defined and often confusing terms in
the literature have resulted in most series being a heterogeneous
population. This has limited the quality of the evidence with a lack of
randomised controlled trials [41]. This deficiency is not unique to PMP
surgery as few, if any, major surgical techniques are amenable to
randomisation. Recent publications in the last 15 years with increasing
numbers of medium to large case-series in the literature reflect an
improved awareness and understanding of the disease. This trend
should continue with the development of centralised treatment centres
throughout the world such that the quality of care and information
available for patients with PMP should ultimately improve.
An emerging network of specialized centres may facilitate multi-
centre studies on aspects of chemotherapy type, duration and
temperature to help allay the criticisms of many surgical, and in
particular, medical oncologists on the lack of hard scientific evidence
in PMP management.
Meanwhile good evidence is rapidly accumulating and surgical
nihilism is no longer acceptable in this inexorably progressive,
universally fatal, but eminently treatable disease.
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 Journal of Surgical Oncology 2008;98:283–290

Hyperthermic Intraperitoneal Chemotherapy With and

Without Cytoreductive Surgery for Epithelial Ovarian Cancer

C. WILLIAM HELM, MB.BChir,1* ROBERT E. BRISTOW, MD,2 SHIGEKI KUSAMURA, MD, PhD,
3

DARIO BARATTI, MD,3 AND MARCELLO DERACO, MD3

1
Division of Gynecologic Oncology, James Graham Brown Cancer Center, University of Louisville, Kentucky
2
The Kelly Gynecologic Oncology Service, Department of Gynecology and Obstetrics, The Johns Hopkins Medical Institutions,
Baltimore, Maryland
3
Department of Surgery, National Cancer Institute of Milan, Milan, Italy

Women with epithelial ovarian cancer (EOC) usually present with advanced disease and overall only just over half survive 5 years. Even following
a complete response to front-line treatment two-thirds will recur, with a resultant dismal prognosis. We review and discuss the role of surgery and
hyperthermic intraperitoneal chemotherapy (HIPEC) in EOC and present the results of the ovary consensus panel (OCP) convened for the 5th
International Workshop on Peritoneal Surface Malignancy.
J. Surg. Oncol. 2008;98:283–290. ß 2008 Wiley-Liss, Inc.

KEY WORDS: hyperthermic intraperitoneal chemotherapy (HIPEC); cytoreductive surgery; epithelial ovarian cancer;
hyperthermia; loco-regional therapy; intraperitoneal chemotherapy

INTRODUCTION AND BACKGROUND RATIONALE FOR HYPERTHERMIA WITH

Worldwide there are approximately 204,000 new cases and
125,000 deaths per annum from epithelial ovarian cancer (EOC) [1].
The disease most often presents in advanced stage by which time cure
is difficult. This review addresses the role that hyperthermic
intraperitoneal chemotherapy (HIPEC) with or without cytoreductive
surgery (CRS) might play in improving the treatment of EOC and
reports the results of the ovary consensus panel (OCP) convened for
the 5th International Workshop on Peritoneal Surface Malignancy.
The OCP responded to a series of clinical questions set by the co-
chairmen (REB and CWH) with answers rated from 1 to 5 (strongly
disagree to strongly agree). Opinions reported here are the percentage
of the OCP answering 4 or 5 to the question. Levels of evidence are
classified by that described by the Center for Evidence-Based
Medicine, Oxford [2] and ‘State-of-the-Art Oncology in Europe’
(START) [3].
RATIONALE FOR REGIONAL
(INTRAPERITONEAL) CHEMOTHERAPY
IN OVARIAN CANCER
HIPEC and CRS include the following modalities: hyperthermia,
intraperitoneal chemotherapy and CRS. Dedrick proposed that the
intraperitoneal delivery of certain chemotherapeutic agents could lead
to a significant increase in peritoneal cavity drug exposure compared to
that in the systemic vascular compartment [4]. For drugs most active in
EOC the ratio of their intraperitoneal to plasma concentrations varies
from 18 to 20
for carboplatin and cisplatin to 120 to >1,000
for the
taxanes, docetaxel and paclitaxel (see Table I) [5]. EOC should be a
good target for intraperitoneal treatment because it is relatively chemo-
sensitive and it remains confined within the peritoneal cavity for much
of its natural history.
INTRAPERITONEAL CHEMOTHERAPY
Hyperthermia alone is tumoricidal [6] and it increases the
cytotoxicity of many chemotherapeutic agents in both human cell
culture and animal models [7–11]. Much of the work in this area has
been performed on cisplatin with investigations of the cellular effects
of the combination demonstrating increased DNA cross-linking and
increased DNA adduct formation [9,12] and deeper penetration into
peritoneal tumor implants when delivered intraperitoneally with
hyperthermia [12]. However, the precise underlying molecular
mechanisms of these effects are still unknown.
The possible synergy between hyperthermia and chemotherapy
treatment combined with the possibility of delivering these two
modalities directly into the peritoneal cavity has sparked clinical trials
in many cancers including, gastric [13], mesothelioma [14], appendi-
ceal [15], endometrial [16] and colorectal [17]. A phase III randomized
study of HIPEC following CRS surgery compared with traditional
intravenous chemotherapy and palliative care in patients with
peritoneal spread of colo-rectal carcinoma showed a statistically
significant prolongation of life in the experimental arm [17].
The authors have no financial interest related to the contents of this article to
disclose.
*Correspondence to: Dr. C. William Helm, MB.BChir, Associate Professor,
Division of Gynecologic Oncology, James Graham Brown Cancer Center,
University of Louisville, 529 South Jackson Street, Louisville, KY 40207.
Fax 502-561-7205. E-mail: cwhelm@uoflobgyn.com
Received 15 April 2008; Accepted 15 April 2008
DOI 10.1002/jso.21083
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.

284 Helm et al.
TABLE I. Peritoneal to Plasma Ratios for Peak Concentration and AUC
Peritoneal to plasma ratio
Drug Peak
Cisplatin 20
Paclitaxel >1,000 >1,000
Gemcitabinea
Doxorubicin 474
Melphalan 93
5-Fluoruracilb 298
Oxaliplatin 25
Carboplatin 18
Docetaxel 120
Mitomycin 71
Mitoxantrone 57
Interferon-a 100
Etoposide
Adapted from [5].
a groin node disease are not considered contraindications to CRS, they
Cytotoxic activity augmented if given before hyperthermia.
b
Activity not augmented by hyperthermia.
The standard initial treatment of EOC following an attempt
at maximal cytoreductive surgery involves combination normothermic
platinum/taxane regimens previously given intravenously only and
now often including combined intravenous/intraperitoneal [18]. For
the treatment of recurrent EOC a wide range of agents have shown
activity in addition to platinums and taxanes including topotecan,
etoposide, liposomal doxorubicin, doxorubicin, epirubicin, gemcita-
bine, hexamethylmelamine, navelbine, ifosfamide, irinotecan, 5-
fluorouracil (5FU), melphalan and mitoxantrone with response rates
between 20% and 77% in platinum-sensitive disease and up to 28% in
platinum-resistant disease [19]. Until newer agents come on-line any of
these agents with proven activity could conceivably be used for HIPEC
provided that they fit with the Dedrick theory, have activity enhanced
by heat and have acceptable side-effects.
RATIONALE FOR CYTOREDUCTIVE SURGERY
The role of cytoreductive surgery (CRS) in the front-line treatment
of EOC was initially demonstrated in a study reporting an inverse
relationship between the largest diameter of disease remaining after
CRS and survival [20]. Multiple subsequent retrospective reports
have confirmed this finding [21–23]. The role of surgery in this dual
modality approach was supported in a meta-analysis of 6885 patients
undergoing CRS during the platinum era where on an institutional
basis for each 10% increase in the percentage of patients undergoing
maximal CRS there was a 5.5% increase in median survival
duration [24].
The reason CRS is thought to be effective when combined
with chemotherapy is that it removes bulky disease containing poorly
oxygenated, non-proliferating cells which are either resistant or
potentially resistant to chemotherapy and leaves small volume tumors
with a higher proportion of cells in the proliferative phase making them
more susceptible to chemotherapy.
Even though ‘optimal’ residual disease at completion of initial CRS
for EOC was accepted as being any nodule <2 cm in dimension [25], it
is now established that the most favorable prognosis is in patients
with no macroscopic residual disease at all [26]. Currently, there is no
universally accepted working definition of optimal cytoreduction
among gynecologic oncologists. A survey of members of the Society
of Gynecologic Oncologists reported that the majority believed
optimal CRS was a residual maximal lesion size of 1 cm [26]. Based
on in vitro and in vivo evidence that diffusion of intraperitoneally
delivered chemotherapy agents into peritoneal tumors is to a maximum
Journal of Surgical Oncology
of 2.5–5 mm even with hyperthermia [27–29], the largest residual
lesion size prior to HIPEC should be no more than 5 mm and optimally
less. Some drugs such as doxorubicin, carboplatin and oxaliplatin have
AUC
much lower intratumoral penetration capacity. Some 90% of the OCP
felt that the objective should be a residual lesion size of 2.5 mm or less
12 prior to HIPEC.
There appears to be a clear theoretical rationale for the utilization of
500 CRS with HIPEC in ovarian cancer but who should be considered for
230 this and at what time-points in the natural history of the disease?
65
367
16
PRE-OPERATIVE EVALUATION
18 AND ELIGIBILITY
552
23 In order to undergo CRS and/or HIPEC, eligible patients must be
115 sufficiently healthy to withstand the surgery and chemotherapy and
their disease should be resectable to <5mm residual and confined to
65 the peritoneal cavity. Since in the front-line setting, malignant pleural
effusions in the absence of bulk disease in the chest and resectable
could be considered within the criteria of eligibility for HIPEC pending
further investigation. In fact, metastatic disease to groin nodes does
not upstage the disease from IIIC in the front-line setting [30]. The
OCP were equally split on this issue. Those that said they would give
HIPEC would do so for sub-renal retroperitoneal nodes 89%, liver
parenchymal disease 78%, groin nodes 67%, and positive pleural
effusion 56%.
Pre-operative assessment to identify patients whose disease is not
likely to be optimally resectable would enable such patients to avoid
the morbidity of unnecessary surgery. Although several studies have
investigated the accuracy of computed tomography (CT) scans in
determining the resectability of EOC [31–35] the factors associated
with prediction of suboptimal surgery vary between studies and centers
probably reflecting the surgical philosophy at individual institutions
[36]. Magnetic resonance imaging (MRI) is equally as accurate in the
staging of EOC as CT [35,37]. 18F-FDG PET may add accuracy
in evaluating peritoneal carcinomatosis [38]. The level of surgical
expertise is of major importance with regard to the operability of EOC
and this will ultimately determine the chance of optimal CRS [39].
Although the serum CA125 level has been correlated with the
achievement of optimal CRS, it is not accurate enough to be used
alone [40–42]. The OCP consensus on investigations to determine the
extent of disease is given in Figure 1.
Fig. 1. Optimum investigations to define extent of disease—% of
respondents answering 4 or 5. CT, computed tomography; C/A/P,
chest, abdomen, and pelvis; PET, positron emission tomography; CXR,
chest X-ray; MRI, magnetic resonance imaging.

Fig. 2. Pre-operative criteria to defer attempt at cytoreductive
surgery until after neoadjuvant therapy—% responding 4 or 5.
The OCP agreed broadly that involvement of the porta hepatis,
liver parenchyma, mesenteric root, high small bowel obstruction
(SBO), and extra-abdominal metastasis identified pre-operatively were
of concern to preclude a successful resection. These are not absolute
contraindications to successful CRS and every case should be
individualized (Fig. 2). The OCP were concerned that the following
medical morbidity indicators would preclude CRS and HIPEC: heart
failure 94%, pulmonary compromise 94%, previous pulmonary
embolus 63%, previous deep venous thrombosis without pulmonary
embolus 26%, body mass index (BMI) >35 48%, BMI 30–34 26%.
TIME-POINTS FOR POSSIBLE USE
OF CRS AND HIPEC
There are five time-points in the natural history of EOC at which
discussion of treatment with HIPEC and research can usefully be
directed: front-line, interval debulking following initial neo-adjuvant
chemotherapy, consolidation following complete response to front-line
therapy and at the time of recurrence, including front-line failure with
disease still present at the end of initial treatment.
Front-line
Standard front-line therapy for ovarian carcinoma evolved to
be CRS followed by intravenously administered chemotherapy with a
platinum and taxane combination, usually carboplatin/paclitaxel.
Although response rates of EOC to front-line chemotherapy are high,
20–30% of tumors are inherently platinum-resistant [43] and 60–70%
of all patients with ovarian carcinoma will recur [44–47] with the
overall 5-year survival still being only around 50%.
Clinical research interest in regional treatment for ovarian
carcinoma has existed for many years but in January 2006 interest
rose when a Gynecologic Oncology Group study (GOG-172)
randomizing 415 patients to either standard intravenous chemotherapy
only, or experimental intravenous/intraperitoneal chemotherapy fol-
lowing optimal CRS for ovarian cancer, showed a significant increase
in median progression-free and overall survival in the experimental
arm from 18 to 23 months and 49 to 66 months, respectively.[18]
GOG-172 was the third of three, large randomized studies [18,28,48]
reporting a benefit for intraperitoneal chemotherapy. A Cochrane
Systematic Review of all randomized trials of intraperitoneal chemo-
Journal of Surgical Oncology
HIPEC With and Without CRS in Ovarian Cancer 285
therapy in ovarian cancer involving 1819 patients also revealed an
overall benefit of intraperitoneal chemotherapy [49].
HIPEC performed at the time of initial surgery would have the
following advantages over standard intraperitoneal chemotherapy:
(1) intraperitoneal adhesions have been divided allowing the HIPEC
solution to reach all surfaces of the peritoneal cavity, (2) residual tumor
is at the smallest possible volume, optimally leaving only microscopic
and free floating cells to be treated and (3) treatment would be
delivered many days prior to the usual time when postoperative
chemotherapy is given.
The first report of the use of HIPEC at the time of front-line CRS
was from the United States National Cancer Institute when a Phase 1
study was performed to examine the feasibility, toxicity and
pharmacokinetics of carboplatin given to six patients, five of whom
had small-volume residual disease following optimal CRS [50]. There
are reports of only around 50 patients treated in this fashion [51–
56,91]. These numbers are currently too small to assess any meaningful
effect. See Table II for a list of studies reporting HIPEC in ovarian
cancer in English.
The precedent for treatment at the time of front-line surgery has
been set and further study is needed. Such studies would ideally be
randomized phase III design but this would require several hundred
patients and require collaboration between many centers. The natural
history time-points that the OCP considered HIPEC to be relevant
were interval debulking and recurrent platinum-sensitive disease 79%,
consolidation 63%, front-line failure 58%, front-line 53%, and for
platinum-resistant recurrent disease 42%.
Interval Debulking
Although the standard of care for patients presenting with ovarian
cancer is initial maximal CRS, this is not always possible due to
factors such as medical unfitness for major surgery, cardiac disease,
pulmonary compromise, recent pulmonary embolus, poor nutritional
status, and other co-morbidities. In this circumstance, neoadjuvant
chemotherapy for two to three cycles may allow time for performance
status to be improved whilst reducing the extent of disease and
increasing tumor resectability. This may lead to less intraoperative
blood loss, shorter operative times, less intensive care unit admissions,
and shorter length of hospital stay [69,70]. Another indication for
neoadjuvant chemotherapy may be the absence of a surgical specialist
to perform the necessary CRS in the local setting.
Individual case series on outcome for neoadjuvant chemotherapy
followed by interval debulking involve relatively small numbers and
heterogeneous groups of patients and surgeons [70] but outcomes are
overall not as good as those achieved with front-line maximal CRS
followed by chemotherapy [71,72].
A useful time to investigate the incorporation of HIPEC would be in
those situations where interval debulking surgery is performed. In
addition to the theoretical reasons stated for using front-line, there
would be the advantage of lead-time to arrange for the HIPEC
perfusion team and equipment to be available at this surgery. Its use
may add progression-free or survival benefit to these patients whose
overall outcome is inferior to those treated with initial maximal CRS
followed by chemotherapy. Several series have included patients
treated with HIPEC at the time of interval debulking but the numbers
are too small for meaningful analysis and conclusions[50,54,62,64,66];
the level of evidence is 4 [2] and R [3].
Ryu [64] reported on 57 women who underwent HIPEC at the time
of either interval debulking or second-look surgery following front-line
therapy but it is not known how many were treated in each group.
Others have reported small numbers. [50,54,62,66] HIPEC at
the time of interval debulking would be a fruitful area for research.
Currently, there is a randomized phase III trial under coordination by
the Netherlands Cancer Center, Amsterdam randomizing patients to
286 Helm et al.
TABLE II. Studies of HIPEC for EOC
Time Temperature
Author Year Reference Type Situation n Agent Dose (min) (8C)

Loggie 1994 [57] Pilot Advanced 1 Mitomycin 30 mg 120 39–40.5

Steller 1999 [50] Pilot Front-line 6 Carboplatin 800–1,200 mg/m2 90 41–43
van der Vange 2000 [58] Pilot Recurrent/persistent 5 Cisplatin 50/75 mg/m2 90 40
Cavalieri 2000 [59] Retrospective Recurrent/persistent 20 Cisplatin 25 mg/m2/L 90 41.5–42.5
Deraco 2001 [60] Phase II Recurrent/persistent 27 Cisplatin 25 mg/m2/L 60 42.5
Panteix 2002 [61] pK Recurrent 16 Cisplatin 60/80/100 mg 90 41–43
de Bree 2003 [62] Prospective Recurrent/persistent 19 Docetaxel 75 mg/m2 120 41–43
Zanon 2004 [63] Phase II Recurrent/persistent 30 Cisplatin 100/150 mg/m2 60 41.5–42.5
Look 2004 [52] Retrospective Front-line, recurrent/persistent 12a Cisplatin mitomycin b
60 41.5–42.5
Piso 2004 [53] Retrospective Primary/recurrent 19 Cisplatin or mitoxantrone 75 mg/m2 90 41.5
15 mg/m2
Ryu 2004 [64] Retrospective Interval 57 Carboplatin interferon-a 350 mg/m2 90 43–44
debulking/second-look 5
106 IU/m2
Gori 2005 [65] Retrospective Second-look 32 Cisplatin 100 mg/m2 60 41–43
Reichman 2005 [66] Retrospective Recurrent/interval debulking 13 Cisplatin 50 mg/m2 90 40
Yoshida 2005 [54] Retrospective Front-line/interval 10 Cisplatin mitomycin 100 mg 20 mg 50 41–44.5
debulking/second-look etoposide 100 mg
Raspagliesi 2006 [67] Retrospective Recurrent/persistent 40c Cisplatin/MMC or 25/3.3 mg/m2/L b
42.5
cisplatin/ doxorubicin 43/15.25 mg L
Rufian 2006 [55] Retrospective Front-line/recurrent 33 Paclitaxel 60 mg/m2 60 41–43
Helm 2007 [68] Retrospective Recurrent/persistent 18 Cisplatin or mitomycin 100 mg/m2 40 mg 90 42–43
Lentz 2007 [91] Phase I Front-line/second-look 17 Carboplatin 400–1200 mg/m2 90 39–43
Cotte 2007 [56] Prospective Front-line, recurrent/persistent 81 Cisplatin 20 mg/m2/L 90 44–46 inflow
Max. 80 mg

Excludes case report [51].

a
Some patients received EPIC.
b
Not stated.
c
Some previously reported in [60].

receive HIPEC or no HIPEC at the time of interval debulking (W. van
Driel, personal communication).
The Consensus Group’s opinion with regard to the pre-operative
criteria to defer an attempt at cytoreductive surgery until after
neoadjuvant chemotherapy is detailed in Figure 2. There was broad
agreement that involvement of the porta hepatis, liver parenchyma,
mesenteric root, high small bowel obstruction, and extra-abdominal
metastasis identified pre-operatively were of concern to preclude a
successful resection. These are not absolute contraindications to
successful CRS and every case should be individualized.
Consolidation
Despite the high initial response rates to front-line CRS and
chemotherapy in EOC in most patients the disease will recur. In GOG-
172, 65% of those in the experimental IP/IV arm (which had the best
outcome) developed recurrent disease [18]. Almost two decades ago it
was reported that stage III/IV patients with a complete pathologic
response confirmed at second-look surgery experienced recurrence
rates of 28% at 2 years, 56% at 5 years, and 60% at 10 years [73]. One
way of improving outcomes in EOC is to consider methods of
consolidating front-line therapy in those patients with no clinical
evidence of disease.
There is no established method of consolidation following front-
line therapy for EOC. A randomized study, investigating additional
intravenous paclitaxel was stopped early when interim analysis showed
a significantly improved disease-free survival in patients randomized to
the 12-month arm (in comparison to the 3-month arm) and the trial
was discontinued early making full analysis difficult [74]. Investigators
have looked at the use of chemotherapy agents intraperitoneally
for consolidation. In 2003, the European Research Group (EORTC)
reported a randomized study of consolidation with four cycles of
intraperitoneal cisplatin versus no further treatment following com-
plete response to front-line therapy. The study was closed due to poor
recruitment but over 150 patients were entered and randomized. The
recurrence rates were 49% in the experimental arm and 55% in the
control arm. [75] Memorial Hospital, New York reported a long-term
review of patients treated with intraperitoneal chemotherapy agents
including cisplatin and paclitaxel [76]. In a group of 89 patients with
complete pathologic response following front-line therapy treated for
consolidation, the median survival was 8.7 years. In a phase II study
from the same institution using IP cisplatin and etoposide, 36 patients
were compared with 46 historical controls and recurrence occurred in
39% versus 54%, respectively [77,78].
There is some non-randomized evidence that disease found
at second-look surgery following front-line therapy may be helped
by CRS if it can be reduced to microscopic or small volume [79–82].
CRS alone has no role in this situation and chemotherapy would
always be required for best outcome. Secondary CRS for persistent
disease following a previous attempt at maximal CRS has been
investigated and shown not to significantly extend survival [83].
Patients with platinum-resistant disease do extremely poorly with both
CRS and chemotherapy. There have been no randomized studies
investigating the role of HIPEC as consolidation therapy at second-
look laparotomy in EOC but some promising work has been reported in
this setting, although the level of evidence is 4 [2] and 3 [3]. Ryu
et al.[64] reported on 57 women who underwent front-line cytor-
eductive surgery followed by intravenous chemotherapy and were then
treated with a second surgery with HIPEC who were compared with
a historical control group of 60 patients who underwent initial cyto-
reductive surgery followed by intravenous chemotherapy only. HIPEC
was given in the form of carboplatin 350 mg/m2 and interferon-alpha at
a temperature of 43–448C. The disease-free survival and overall
survival were significantly better in the experimental arm but the study
included patients with germ cell tumors and it is not stated how many
received treatment at the time of interval debulking or as consolidation.
Gori [65] reported on 51 patients with ovarian carcinoma who
underwent primary surgery with optimal cytoreduction to <2 cm
followed by chemotherapy with intravenous cisplatin and cyclopho-
sphamide. Of this group, 32 patients then underwent second-look
laparotomy with HIPEC cisplatin and 19 who refused second-look
laparotomy formed the control group. There was a trend to improved
outcome in the HIPEC group with median survival of 64.4 months
versus 46.4 months in the control arm (P ¼ 0.29). In a Phase I study,

Journal of Surgical Oncology


Lentz [91] performed HIPEC at the time of second-look laparotomy in
14 patients to determine the maximum tolerated dose of carboplatin.
The perhaps inappropriately named, ‘second-look laparotomy’, is a
relatively safe and accepted procedure for patients on clinical trials for
ovarian carcinoma. As a marker of its safety, there were no deaths
reported in seven major series including 682 operations [84]. In this
era, it is not a procedure that is performed to merely assess the presence
or absence of disease. Surgery is the only setting in which disease
status can be accurately assessed due to the lack of accuracy of clinical
investigations to detect small volume disease. It is also the optimum
way of delivering intraperitoneal chemotherapy in the total absence of
adhesions. The use of the laparoscope to assess the extent of disease
and deliver HIPEC [85] could facilitate the incorporation of HIPEC
research protocols in this setting.
A randomized phase III study of HIPEC for consolidation would
require several hundred patients but would be the best way to
investigate it. Meanwhile, Phase I and II studies could investigate the
tolerability and results of various drugs following front-line IV and
front-line IV/IP chemotherapy. Of the OCP, 63% felt that HIPEC
should be considered at second-look laparotomy after complete
response to cisplatin/taxane therapy even if the patients had up to six
courses of intraperitoneal cisplatin and taxane. A Phase I trial is
underway at the University of Louisville to investigate whether
patients can tolerate HIPEC following standard front-line therapy with
surgery followed by combined intravenous/intraperitoneal chemo-
therapy. The OCP was equally split as to whether the consolidation
should be single agent or double agent.
HIPEC With and Without CRS in Ovarian Cancer 287
Where reported, progression-free survival was 10, 23.9, and 31 months
[55,67,68]. Cotte [56] reported on 81 patients (65 with recurrent
disease) with overall disease-free survival of 19.2 months and survival
of 28.4 months; 47 patients had three or more surgeries and it is not
clear how many received more than one HIPEC treatment.
The peri-operative mortality rate for CRS and HIPEC was 3.7%
(8/236 cases) [50,53–55,58,60,62–65,67,68] compared with 1.4%
(0–3.4%) out of 631 patients undergoing CRS for recurrent EOC [88].
Neither the risks nor risk/benefit ratio associated with HIPEC þ CRS
versus CRS alone have been clearly defined. However, patients
historically selected for secondary CRS are likely patients with better
disease characteristics and performance status than many who
underwent CRS þ HIPEC as shown in Table II.
Where postoperative morbidity information for CRS þ HIPEC in
recurrent/persistent EOC is detailed in Table III [50,53–55,58,60,62–
65,67,68] grade 3 or 4 hematologic toxicity was 4.7% (11/236) and
raised creatinine, mainly associated with the use of cisplatin, was
3.4% (8/236). The rate of anastomotic leaks was 1.7% (4/236) and
gastrointestinal perforations 2.5% (6/236). The incidence of anasto-
motic leaks appears low but it is difficult to be sure of the exact
percentage since the performance of diverting stomas is not always
mentioned. The occurrence of ‘spontaneous’ intestinal perforations
following HIPEC is of concern and may be related to the effect of
heat and chemotherapy agents on bowel serosa traumatized even
mildly during enterolysis. Sepsis is of concern when peri-operative
TABLE III. Complications Associated With CRS and Delivery of HIPEC
(n ¼ 236) Patientsa

Recurrence n

Most patients with EOC will initially respond to front-line therapy Hematologic
and then recur. The mainstay of treatment for recurrent EOC has been DIC 1
chemotherapy and a wide range of active agents which are listed in the Leucopenia grade three 6
‘‘Introduction’’ section [19]. Thrombocytopenia 4
Metabolic
Recurrence is most often not curable but duration of survival
Hypoalbuminemia 8
depends greatly on the time interval from initial treatment to the Raised liver enzymes 4
recurrence [86,87]. Patients with platinum-resistant tumors have Renal toxicity 8
response rates of up to 28% with an overall median survival of Renal failure 6
6–12 months and platinum-sensitive patients have response rates of up Unknown grade 2
to 77% with median survival of 12–40 months [19,88]. Pulmonary and neck
For patients with disease confined to the peritoneal cavity, Embolus 3
secondary CRS may have a role in extending survival with or without Pleural effusions 9
post-operative normothermic chemotherapy [88,89]. Patients with no Pneumonia 4
Central vein thrombosis 2
gross residual after CRS for recurrent disease have survival of
Surgical
44–60 months [88] with the best survival associated with a disease- Anastomotic leaks 4
free interval of more than 12 months, platinum-sensitive tumors, Intestinal perforation 5
absence of ascites, the number of recurrence sites, and the extent of Gastric perforation 1
residual disease [89,90]. Bowel obstruction 7
Since CRS with post-operative normothermic chemotherapy has Paralytic ileus 1
shown promise, the incorporation of HIPEC with CRS in the context of Intra-abdominal bleeding 5
recurrent disease should be investigated. All studies to date (Table II) Hematuria 2
have been non-randomized and are difficult to meaningfully compare Sepsis 10
Peritonitis 2
and assess due to their heterogeneity. Although the defined levels of
Wound infection 11
evidence are 4 [2] and 3 [3] it is possible to obtain some useful Wound seroma 1
information from this work. Abscess 3
The first paper to report the use of HIPEC in recurrent ovarian Dehiscence 2
cancer was that of van der Vange and colleagues in 2000. Studies with Total 1
the most clearly definable results for recurrent/persistent disease Deep 1
report median overall survivals of 28.1, 31, 41.4, and 57 months, Hernia 2
[55,63,67,68], overall 2-year survival 55% [60] and 60% [63], 3-year a
Excluding Grades 1 and 2 complications.
survival 37.5%, [61] 51%, [55] and 55% [66] and overall 5-year Other complications have included hematoma from the inferior epigastric
survival 15% [67]. Rufian reported 2- and 5-year survival of 75% for vessels, abdominal pain 4, temporary cutaneous fistula after removal of
patients with recurrent disease 55 years of age [55]. Panteix reported gastrostomy tube, and a femoral nerve neuropathy due to retraction at surgery,
an overall 7-year survival rate of 12.5% [61] and De Bree [62] reported complications of ileostomy, pancreatitis and neurological complication. Table
25% (3 of 12) of patients surviving a mean of 74 (72–79) months. incorporates data from [50,53–55,58,60,62–65,67,68].

Journal of Surgical Oncology

288 Helm et al.
chemotherapy is given and septic complications were reported in
26 (11%) patients with wound infection in 11 (4.7%), peritonitis in
2 (0.8%) and abscess in 3 (1%). Overall, the rates of severe morbidities
reported are not much higher than that of 11% (67/631) reported for
CRS alone [88].
Prognostic Factors
Reported prognostic factors for survival in recurrent/persistent
disease include the interval from diagnosis to HIPEC [60,68], the
peritoneal cancer index (PCI) [60,63,66], the extent of residual disease
prior to HIPEC [55,60,63,66–68], patient age [55,60], WHO
performance status [67], and the presence of lymph node metastases
[55].
Much more research is still required to improve outcomes in
recurrent/persistent EOC. Randomized studies in this setting are
extremely difficult to accomplish. A recent study of the Italian Society
of Integrated Loco Regional Therapy (SITILO), which randomized
patients with persistent EOC following front-line therapy to CRS and
HIPEC versus chemotherapy, only closed due to lack of accrual and
suboptimal outcomes. Patients in this setting have a very poor survival
with standard therapy and further work is needed. The challenge will
be to compare CRS with and without HIPEC in patients with
recurrence with favorable prognostic factors.
CONCLUSION
HIPEC delivered at the time of surgery for ovarian cancer has
definite potential. The growing literature documents its relative
tolerability and supports the continuation of further research in EOC
where outcomes remain so poor with current therapy.
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 Journal of Surgical Oncology 2008;98:291–294

The Consensus Statement on the Locoregional Treatment

of Abdominal Sarcomatosis

CARLO RICCARDO ROSSI, MD,1 PAOLO CASALI, MD,2 SHIGEKI KUSAMURA, MD, PhD,
3

DARIO BARATTI, MD,3 AND MARCELLO DERACO, MD3*

1
Sarcoma and Melanoma Unit, Clinica Chirurgica II, University of Padova Italy
2
Department of Medical Oncology, National Cancer Institute of Milan, Italy
3
Department of Surgery, National Cancer Institute of Milan, Italy

Abdominal sarcomatosis (AS) is a rare condition characterized by soft tissue sarcoma spreading throughout the abdomen, in the absence of extra-
abdominal dissemination. Retroperitoneal sarcomas, pelvic sarcomas, particularly uterine leiomyosarcoma, and gastrointestinal stromal tumors
(GISTs) most frequently give rise to AS. Systemic chemotherapy is the standard of care for AS from non-GIST sarcomas, but with an essentially
palliative aim and major limitations. Innovative targeted therapies has deeply affected the natural history of GIST, at least in prolonging
significantly survival in responsive patients. In this context, the notion that abdominal spread in the lack of extra-peritoneal lesions may typically
occur in a number of patients, along with the dismal prognosis generally carried by AS, has prompted a few centers to perform cytoreductive
surgery and perioperative intraperitoneal chemotherapy. To date, the rarity of these presentations makes it difficult to evaluate the clinical results
and the role of combined local-regional treatment is still a matter of debate. This article presents the results of a group of experts from around the
World trying to achieve a consensus statement in AS comprehensive management. A questionnaire was placed on the website of the 5th
International Workshop on Peritoneal Surface Malignancy and the experts voted via internet.
J. Surg. Oncol. 2008;98:291–294. ß 2008 Wiley-Liss, Inc.

KEY WORDS: consensus; local regional therapy; abdominal sarcomatosis

INTRODUCTION therapies by definition. At the moment, chemotherapy of adult soft

Abdominal sarcomatosis (AS) may be defined as the spread of a soft
tissue sarcoma throughout the abdomen, in the absence of any extra-
abdominal dissemination, or at least other sites of disease of major
clinical concern. This gives rise to presentations in which the
abdominal spread of disease is the dominating clinical factor, thus
the main therapeutic challenge [1]. The perspective may be palliative
or curative, the former situation being more frequent than latter.
Retroperitoneal soft tissue sarcomas are the most frequent sarcomas
to give rise to disseminated abdominal disease [2]. Indeed, the local
regional risk of a retroperitoneal sarcoma may well be in the 70% range
in the long term. Liposarcomas are especially at risk, given their
inherent anatomic characteristics (average tumor size, multinodularity
or even multifocality, etc.) and their tendency to remain confined to
the abdomen in many cases throughout their natural history. Even
pelvic tumors may result in peritoneal sarcomatosis, such as a uterine
leiomyosarcoma relapsing with scattered tumor masses throughout the
abdomen. Gastrointestinal stromal tumors (GISTs) essentially meta-
stasize to two sites, peritoneum and the liver, the former in the lack of
the latter in a number of patients. Other rare mesenchymal entities may
metastasize throughout the abdomen, such as the desmoplastic small
round cell abdominal tumor of young adults or adolescents, typically
spreading with multiple tumor nodules over the peritoneal surface. All
these tumors are rare. Their abdominal spread in the lack of lesions
outside is even less frequent, though it may typically occur, indeed, in a
number of patients. Finally, the prognosis of AS is generally dismal,
although liposarcomas may run a slow course, and GIST are now
amenable to effective medical therapies which at least prolong
significantly survival.
Medical Therapies
Disseminated disease spreading throughout the abdomen
makes the patient metastatic, and thus a candidate for medical
tissue sarcomas is based on anthracyclines and Ifosfamide, given either
alone or in combination (Type 1 evidence). The response rate is in
the 20–40% range, and median survival is in the 1-year range.
Gemcitabine plus/minus Docetaxel may exert a palliative effect
especially in leiomyosarcoma (Type 3 evidence). The new marine
agent Trabectedin (ET-743) is active in liposarcoma and leiomyosar-
coma, that is, the two main retroperitoneal mesenchymal entities, with
an exceedingly high activity in myxoid liposarcoma, which however is
rare in the retroperitoneum (but an abdominal widespread extent of
disease, even in the lack of lesions elsewhere, may occur following a
primary tumor in a limb; Type 3 evidence). Imatinib is exceedingly
effective in GIST, with a progression-free interval and an overall
survival, respectively, in the 2-year and 5-year range if the disease is
metastatic. Surgery of residual disease is often carried out following
optimal response of GIST to Imatinib, though, possibly, peritoneal
lesions may benefit less than liver metastases from such an approach,
which in any case remains investigational (Type R basis evidence).
Medical therapy is active, but generally of limited prognostic meaning,
in desmoplastic small round cell abdominal tumor. Therefore,
medical therapies have some activity against peritoneal sarcomatosis,
but always with an essentially palliative aim, major limitations,
and variability across tumor entities. A huge distinction can be made
between GIST and other adult soft tissue sarcomas, because the natural
The authors have no financial interest related to the contents of this article to
disclose.
*Correspondence to: Marcello Deraco, MD, Istituto Nazionale Tumori
Milano, Via Venezian 1, 20133 Milano, Italy. Fax: þ39-02-23902404.
E-mail: marcello.deraco@istitutotumori.mi.it
Received 25 March 2008; Accepted 27 March 2008
DOI 10.1002/jso.21067
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.

292 Rossi et al.
history of GIST has been deeply affected by the medical therapy, while
this is still not the case for other sarcomas. Integrated approaches are
often resorted to, often using surgery in the case of tumor response
to medical therapies, and/or medical therapy in the case surgery is
unfeasible. Surgery is obviously the treatment mainstay in most cases
with a localized disease stage, but the surgeon is well aware of the
risk of sarcomatosis, which may be inherent to the natural history
of disease, and also a consequence of complications occurring
during surgery (tumor rupture, etc.). Therefore, the value of adjuvant
procedures has been long explored. Unfortunately, as of today, no
adjuvant medical therapy has been proved of value in these diseases
[3]. Prospective trials on adjuvant Imatinib are ongoing in inter-
mediate-high risk GIST patients [4,5]. On the other hand, patients with
adult soft tissue sarcomas are often offered adjuvant chemotherapy in
several institutions across the world when the disease is high-risk, as is
the case by definition in most cases of high-grade retroperitoneal, or
pelvic, sarcomas. However, we lack any formal proof of efficacy
thereof. Local regional drug delivery systems can yield high
intraperitoneal concentrations of chemotherapeutic agents, while
keeping low their systemic levels. As the intraperitoneal route cannot
guarantee an adequate drug penetration into tumor deposits larger than
1–3 mm, cytoreductive surgery is the main prerequisite for any
intraperitoneal chemotherapy. In addition, by entrapping cancer cells
and preventing them from being reached by chemotherapeutic agents
[6], early postoperative adhesions may limit the effect of intraper-
itoneal therapies when given postoperatively. This has led to place
these therapies immediately after surgery (early postoperative
intraperitoneal chemotherapy: EPIC). Furthermore, the notion that
some antineoplastic drugs act synergistically with others, as well as
with heat, led some authors to propose hyperthermic intraperitoneal
chemotherapy (HIPEC) for the treatment of locally advanced
intraabdominal malignancies [7,8]. So far, aggressive cytoreductive
surgery combined with EPIC or HIPEC has been mainly considered for
peritoneal carcinomatosis from gastrointestinal cancers, with encoura-
ging results [9,10]. Based on the same rationale, studies have been
performed also in patients with PS.
Intraperitoneal Chemotherapy
The first published study investigating this therapeutic approach in
patients with PS is attributed to Berthet et al. [11]. These authors
combined complete gross resection through a peritonectomy procedure
with early peritoneal chemotherapy with or without hyperthermia.
Only 16 out of 43 underwent HIPEC. Overall, the 43 patients achieved
a median survival of 20 months. Only the completeness of cyto-
reductive surgery had a significant impact on survival. Eilber et al. [12]
used a similar aggressive surgical approach for recurrent abdominal
sarcoma, including first recurrence with/without sarcomatosis, but
intraperitoneal chemotherapy was delayed (1–2 weeks after complete
surgery) with the risk of postoperative adhesions preventing complete
bathing of the peritoneal cavity. The 35 patients having intraperitoneal
disease alone showed a median survival of 24 months. The median
survival of patients treated in these two studies does not differ from that
reported by Bilimoria, who treated 51 patients with sarcomatosis or
GISTs at the MD Anderson Cancer Centre by means of surgery and
conventional chemo/radiotherapy, thus obtaining a median survival of
around 22 months [1]. Bonvalot et al. [13] recently published a
randomized trial on 19 patients with peritoneal sarcomatosis treated
with surgery alone, versus 19 who underwent surgery followed by
intraperitoneal chemotherapy with doxorubicin and cisplatin for
5 days. After a median follow-up of 60 months, the local relapse-
free, metastatic relapse-free and overall survival were similar in the
two groups. So far, the most relevant experience reported with surgery
combined with HIPEC is from the Italian Society for Locoregional
Journal of Surgical Oncology
Treatments in Oncology (SITILO) [14]. In a study, 60 patients affected
by advanced (multifocal primary or locally recurrent) intraabdominal
visceral or retroperitoneal soft tissue sarcomas underwent optimal
cytoreductive surgery (tumor remnants diameter <3 mm) followed by
HIPEC with doxorubicin and cisplatin. The postoperative complication
rate was 23%, locoregional toxicity 15%, and overall morbidity 33%.
The median time to local disease progression and the median
overall survival were 22 and 34 months, respectively. A multivariate
analysis showed a significant advantage for patients who had
undergone complete versus near-complete cytoreduction. Moreover,
the importance of inherent tumor aggressiveness was underscored by
the different prognosis of high versus low grade malignancies.
Although in this group of patients an improved median overall survival
was observed in comparison to other case series (34 vs. 20–29 months),
these results should be interpreted by considering: (1) heterogeneity of
histological types across the case series; (2) different inclusion criteria;
(3) different treatments (HIPEC end EPIC). One possible explanation
for these poor results in PS might lie in the natural history of sarcomas,
which tend to spread across anatomical structures as nerves and
vessels, which in the abdomen are retroperitoneal, and are therefore not
accessible to peritoneal bathing. It may be concluded that, at present,
there is no sufficient evidence supporting the treatment of patients with
peritoneal sarcomatosis with HIPEC or EPIC, even if the former may
be slightly more effective (Type 3 evidence). This treatment modality
is highly demanding both for patients and health resources, and thus
should be all the more considered investigational for patients with
multiple peritoneum implants (true peritoneal sarcomatosis).
Perspectives
The rarity of these presentations makes it difficult to undertake
formal clinical trials. However, only the joined efforts of several
institutions might achieve the goal. At the moment, medical therapy is
the standard of care for these patients. The histological entity dictates
which medical treatment to select, and/or clinical studies may be open
in the various presentations. Following optimal tumor response,
surgery is often resorted to in sarcomas, and may well be used also
in these patients. Its combination with HIPEC should be considered
investigational in retroperitoneal and/or pelvic sarcomas. The major
benefit gained from Imatinib, and the availability of further second-line
molecularly targeted agents, in the lack of any formal proof of efficacy
of surgery for residual disease, makes it difficult, at the moment, to
foresee that HIPEC may make any difference in advanced GIST
patients, even when the disease is confined to the peritoneum.
A prospective study on the combination of aggressive cytoreductive
surgery with HIPEC might be foreseen in principle, if a collaborative
effort can be put in place. Eligible for such a trial could be
patients with: (1) histologically proven multifocal peritoneal implants
of non-GIST adult soft tissue sarcoma; (2) tumor remnants <3 mm
following cytoreductive surgery; (3) absence of distant metastasis on
CT/MR imaging. Patients’ selection should be based on an accurate
preoperative work-up encompassing thoraco-abdominal CT scan.
Intraoperative staging should include a peritoneal cancer index.
Cytoreductive surgery should be performed according to the criteria
by Sugarbaker [15]. HIPEC should be based on Doxorubucin and
Cisplatin, according to the results of a previously reported Phase I
study [16,17]. In the event such a clinical trial provides interesting
results, further investigations with randomized confirmatory studies
and/or on new pharmacological regimens could be pursued.
Results of Web Based Voting on Conflicting Points
This section reports and comments on the results of the peritoneal
sarcomatosis consensus group, which was composed of 13 physicians
from around the World. A questionnaire was placed on the website of
 Consensus in Local Regional Treatment 293
the 5th International Workshop on Peritoneal Surface Malignancy Eligibility
and the group members voted via internet. Questions generally asked
for a ranking of answers on a 1–5 scale where 1 was considered Six questions were asked regarding some of the conflicting
NOT important and 5 MOST important. For the purposes of clarity indications and/or situations that would make a patient with peritoneal
in presentation of the results of the consensus, the answers 4 and 5 sarcomatosis a candidate for cytoreductive surgery and HIPEC.
have been added together as were answers 1 and 2 and the results
are expressed as percentages of the total respondents. The percentages (1) With regard to the non-GIST sarcomas, may we foresee a role for HIPEC in
were rounded up and down to the nearest whole number. the era of molecularly targeted therapies?
In some cases meaningful data could not be obtained from the YES 67%
questionnaire and this data is not reported here. NO 33%
(2) With regard to the GIST model, may we foresee a role for HIPEC in the era
of molecularly targeted therapies?
Preoperative Work-Up YES 50%
NO 50%
What investigations are optimal to define extent of disease?
(3) With regard to the GIST model, may we foresee a role for HIPEC in patient
(Tables I–III). non-responsive to targeted therapies?
YES 67%
NO 33%
(4) Referring to retroperitoneal sarcomas, pelvic sarcomas, GIST, is there any
clinical presentation in which abdominal sarcomatosis could be treated
today with HIPEC outside a clinical study? In other words, as of today,
TABLE I. Optimal Investigations to Define Extent of Disease: 1 (Not should we consider HIPEC:
Important) to 5 (Most Important) Investigational only 58%
Suitable for individual clinical use in selected patients 42%
% of respondents (5) As of today’s knowledge, which is the selective contribution of cytoreductive
surgery, antiblastic perfusion and hyperthermia to the potential efficacy of
Exam 1–2 3 4–5 HIPEC, if any, in abdominal sarcomatosis?
Only for palliation 33%
Clinical examination 0 10 90 For locoregional control 67%
CT chest 0 8 92 For improvement on survival 0%
CT abdomen/pelvis 0 0 100 (6) With regard to non-GIST sarcomas, which role for HIPEC may we foresee
MRI abdomen/pelvis 42 16 42 within combined approaches incorporating pre/postoperative chemotherapy?
PET/CT 25 50 25 At the time of primary tumor treatment 9%
Laparoscopy with biopsy 25 42 33 At the time of recurrence 73%
Ultrasound 42 50 8 Both 18%
Colonoscopy 33 42 25
OGDS 45 55 0

State of the Art of the Methodology

The following questions were presented to the voters concerning the
TABLE II. Recommended Laboratory Work-Up Prior to Surgery: 1 (Not technical aspects of the local-regional therapy.
Important) to 5 (Most Important) Sixty-two percent of the voters defined complete cytoreduction as
% of respondents
the presence of a residual disease <2.5 mm (CC-1).
Three quarters of the voters were of the opinion that there would be
Exam 1–2 3 4–5 a role of maximal palliative cytoreduction in cases not amenable to
radical surgery.
Basic metabolic panel urea, creatinine, electrolytes 9 9 82 Regarding the advisable extent of radicality the majority of the
Comprehensive metabolic panel above plus liver function 0 0 100 panel (92%) voted that a limited peritonectomy to affected area would
Complete blood count 0 0 100 be sufficient, rather than performing a complete peritoneal resection
Coagulation studies 8 0 92 even in the absence of macroscopic disease.
Urinalysis 25 17 58
Seventy-three percent of the panel was of the opinion that HIPEC
Pulmonary function testing 17 41 42
CA125 50 33 17
would not be performed in inoperable cases.
CEA 75 17 8 Hundred percent of the panel voted that the combination of
CA 19-9 58 17 25 chemotherapies would be better than single agent to use in HIPEC. The
CA 15.3 56 17 17 preferred combination was cisplatin þ doxorubicin.

Follow-Up
Ninety-one percent of the panel voted CT scan as the preferred
imaging modality for the follow-up.
In case of asymptomatic recurrence three quarters of the voters favored
TABLE III. Do You Think That There Should be an Effort to Document a
the surgical approach and 92% favored the systemic chemotherapy.
Peritoneal Cancer Index on the Pre-Operative CT Scan? (Just One
Alternative Allowed)
Definitely 25% FUTURE INVESTIGATIONS
Not sure or does not matter 67%
Ninety-two percent of the panel was of the opinion that a
No, it is too cumbersome 8%
prospective multicentric randomized trial testing the efficacy of

Journal of Surgical Oncology

294 Rossi et al.
CRS þ HIPEC in the treatment of peritoneal sarcomatosis would be of
concern. The same rate of voters agreed that the patients should be
randomized to CRS þ HIPEC versus CRS alone.
DISCUSSION OF RESULTS
The great majority of the experts, accounting for more than 90% of
voters, agreed that physical examination and CT-scan of the chest
abdomen and pelvis are of the utmost importance to define the extent of
peritoneal involvement by sarcomatous tumor. Furthermore, there was a
general agreement that additional diagnostic tools, such as MRI
imaging, PET-scan, laparoscopy and endoscopy play a limited role in
the preoperative work-up of potential candidates to local-regional
treatment. However, it is surprising that only 25% stated that there
should be an effort to document a Peritoneal Cancer Index on the pre-
operative CT scan, while for 67% of voters such an issue is not relevant.
Concerning the local-regional treatment of abdominal sarcoma, the
most controversial issue is presently represented by the availability of
innovative targeted therapies which has shown favorable effectiveness
at least in prolonging significantly survival for patients affected by
GIST [18]. This, along with the lack of formal proof of the efficacy of
the combined modality approach in this clinical setting, led the
majority of the experts to conclude that today HIPEC should be
considered a merely investigational option to be performed in case of
recurrent disease presentation with the aim to achieve better local
control, but with no impact of long term survival. Accordingly, when
the role of surgical cytoreduction and HIPEC in the management of the
different sub-types of sarcoma was discussed, no agreement was
reached on the use of the intraperitoneal perioperative chemotherapy in
patients affected by GIST responsive to the molecular therapy. By
contrast, two-third of voters favored the hypothesis of a combined
treatment approach to treat non-GIST sarcomas or GIST not responsive
to the molecular therapy.
The rarity of abdominal sarcomas and the controversies surrounding
their local-regional aggressive management have resulted in a limited
number of patients treated by a multimodality approach being
reported in the literature [12–14,19–24]. Consequently, many technical
aspects of the comprehensive procedure still have to be optimized.
Nevertheless, according to the base principles of peritoneal surface
tumor management, the expert panel emphasized that maximal
cytoreductive surgical efforts should be paid to reduce the volume of
residual disease as much as possible, or at least to diameter less than
2.5 mm. Analogously, due to the well-known limited tumor penetration
of locally applied chemotherapy, they agreed that HIPEC would
not be performed in patients not amenable to significant surgical
cytoreduction.
In conclusion, treatment of peritoneal recurrence following surgical
resection of intraabdominal sarcomas presents a significant challenge
to clinicians. Although the rarity of this disease presentation makes it
difficult to undertake formal clinical trials a prospective multicentric
randomized trial testing the efficacy of CRS þ HIPEC in the treatment
of peritoneal sarcomatosis was considered advisable by the majority
of the expert panel and it would ideally compare the combination of
cytoreductive surgery and HIPEC with cytoreductive surgery alone.
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 Journal of Surgical Oncology 2008;98:295–299

Treatment Failure Following Complete Cytoreductive Surgery and

Perioperative Intraperitoneal Chemotherapy for Peritoneal Dissemination
From Colorectal or Appendiceal Mucinous Neoplasms

1 2
LANA BIJELIC, MD, TRISTAN D. YAN, BSc(Med), MBBS, PhD, AND PAUL H. SUGARBAKER, MD1*
1
Peritoneal Surface Malignancy Program, Washington Cancer Institute, Washington Hospital Center, Washington, District of Columbia
2
University of New South Wales, Department of Surgery, St. George Hospital, Sydney, Australia

Background: Peritonectomy combined with perioperative intraperitoneal chemotherapy is a successful treatment option for patients with
peritoneal dissemination of appendiceal and colorectal malignancy. Despite its efficacy, recurrences remain a common problem.
Methods: Patients with peritoneal dissemination from appendiceal or colorectal malignancy who underwent complete cytoreduction and
perioperative intraperitoneal chemotherapy were included in this study. Data regarding recurrent disease found on abdominal exploration and/or
diagnostic studies was extracted from a prospective database and analyzed.
Results: Seventy patients with colorectal cancer carcinomatosis and 402 with appendiceal neoplasm were analyzed. Forty-nine of 70 and 111 of
402 patients developed documented recurrences. The median survival of 49 patients with colorectal cancer was 33 months while the median
survival for patients with appendiceal neoplasms was not reached. The most common type of recurrent disease was a localized intra-abdominal
recurrence for both appendiceal and colon cancer patients. Patients who underwent second surgery for recurrent disease had an improved survival.
Conclusion: Additional treatments should be strongly considered in patients who fail an initial cytoreduction combined with perioperative
intraperitoneal chemotherapy. This resulted in 5-year survival in 17% of colorectal patients and 70% of the appendiceal mucinous neoplasm
patients.
J. Surg. Oncol. 2008;98:295–299. ß 2008 Wiley-Liss, Inc.

KEY WORDS: cytoreductive surgery; intraperitoneal chemotherapy; appendiceal neoplasms; pseudomyxoma peritonei;
colorectal cancer; recurrence; survival

INTRODUCTION Eligibility Criteria

The management of peritoneal carcinomatosis has progressed over
the last two decades. The long-term survival of patients with
disseminated mucinous appendiceal neoplasms has led the way to
defining this success [1]. Another rare disease, peritoneal mesothe-
lioma, now shows long-term survival in a group of patients who in the
past all rapidly died of disease progression within the abdomen and
pelvis [2]. Currently, cytoreductive surgery (CRS) and perioperative
intraperitoneal chemotherapy (PIC) is being explored as a treatment
option for colorectal cancer [3,4].
However, even with these improvements in the management of
gastrointestinal malignancies, most patients who are currently treated go
on to progress on peritoneal surfaces. In all of these peritoneal surface
malignancies treatment failure is most commonly seen on the peritoneal
surface and at the site of the surgeons’ best efforts. This present study is
designed to clarify the sites of treatment failure for appendiceal and
colorectal carcinomatosis. It is an attempt to improve and if possible
eliminate peritoneal surface progression of disease in these two groups
of patients. It is hoped that an improved understanding of treatment
failure following CRS and PIC will allow new and more beneficial
management strategies to be initiated. Our satisfaction with these
treatments should not occur until the peritoneal surface component of
appendiceal and colorectal cancers have been eliminated.
METHODS
Between June 1981 and July 2006, CRS combined with
perioperative intraperitoneal chemotherapy was used to treat patients
with peritoneal carcinomatosis, by the same surgeon (P.H.S.) at the
Washington Cancer Institute, Washington, DC.
Patient characteristics, pathologic features and treatment-related
data were obtained from a prospective database. The inclusion criteria
of this study consisted of patients who had a diagnosis of appendiceal
mucinous neoplasm or colorectal cancer with peritoneal dissemination
and underwent a complete cytoreduction. All sites and volumes
of residual disease following the CRS were prospectively recorded
using the Completeness of Cytoreduction Score (CCR Score). A
complete cytoreduction was defined as CCR-0 or CCR-1 (residual
tumor < 2.5 mm). These eligibility requirements were designed to
assess patterns of treatment failure and progression-free survival after
optimal combined treatment. In this failure analysis, all analyzed
patients had documented recurrent disease.
Preoperative Management
All patients underwent extensive preoperative investigations which
included physical examination, abdominal, pelvic and chest computed
tomography (CT) scans to assess the extent of the disease involved.
CT scans were performed following the administration of oral and
intravenous contrast media. Extent of prior surgery was determined
*Correspondence to: Dr. Paul H. Sugarbaker, MD, 106 Irving Street, NW,
Suite 3900N, Washington, DC 20010; Fax: 202-877-8602.
E-mail: paul.sugarbaker@medstar.net
Received 3 April 2008; Accepted 15 April 2008
DOI 10.1002/jso.21084
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.

296 Bijelic et al.
according the number of abdominopelvic regions dissected during
previous surgery.
Cytoreductive Surgery
The volume and extent of the tumor deposits were prospectively
recorded using the Peritoneal Cancer Index (PCI), as described
previously. All patients underwent CRS by the same surgical team with
intent to remove all visible intraperitoneal tumor deposits. Periton-
ectomy procedures included total anterior parietal peritonectomy,
omentectomy
splenectomy, right and left subphrenic peritonectomy,
pelvic peritonectomy, and lesser omentectomy with stripping of the
omental bursa
cholecystectomy [5]. These resections were used at
the anatomic sites where there was visible evidence of disease.
Perioperative Intraperitoneal Chemotherapy
For colorectal cancer patients mitomycin C was administered as a
normothermic solution on postoperative day 1 in the first 36 patients
and as a hyperthermic solution intraoperatively in the subsequent
34 patients treated after 1997. The 5-fluorouracil was administered on
postoperative days 2–6 in the first 36 patients and on days 1–5 in the
subsequent 34 patients. Patients with appendiceal neoplasms treated
between January 1994 and July 2006 with CRS and hyperthermic
intraperitoneal chemotherapy (HIPEC) followed by early postopera-
tive intraperitoneal chemotherapy (EPIC) were included. The coliseum
technique was used for administration of HIPEC with mitomycin
C (10 mg/m2 for females and 12.5 mg/m2 for males) at approximately
428C in 2 L of 1.5% dextrose peritoneal dialysis solution for 90 min.
During postoperative days 1–5, 5-fluorouracil (650 mg/m2) was
administered into the peritoneal cavity in 1 L of 1.5% dextrose
peritoneal dialysis solution. By the principle of intention-to-treat, all
patients were to receive EPIC with 5-fluorouracil. However, patients
with postoperative bleeding, hemodynamic instability, prior extensive
chemotherapy treatment or other complications experienced early in
the postoperative period were exempt from EPIC. For appendiceal
and colorectal cancer patients, further systemic chemotherapy was
administered as clinically indicated.
Patients having repeat CRS for recurrence did not receive HIPEC or
EPIC, if gross residual disease remained after a best surgical effort at
complete cytoreduction.
Follow-Up and Study Methods
All patients were followed prospectively until the last time of
contact or death. The follow-up review included clinical examination,
measurement of relevant tumor markers (every 3 months performed by
the treating medical oncologist) and assessment of abdominopelvic
CT scans every 6 months or when recurrence was suspected
clinically. Other diagnostic modalities or procedures were used based
on the patients’ symptoms. Colorectal cancer patients were offered
elective second-look surgery approximately 6 months following
cytoreduction unless they declined surgery or had obvious progressive
disease. Patients undergoing ostomy closure underwent full abdominal
exploration (second-look surgery) at the time of the ostomy closure.
Patients with a rise in tumor markers and no obvious metastatic disease
underwent abdominal exploration.
For colon cancer patients, recurrences found within 3 months of
the initial recurrence, either by imaging studies or by abdominal
exploration were included in the analysis. For patients with
appendiceal neoplasms, the sites of treatment failure were determined
from those patients who underwent repeat CRS and PIC and recorded
prospectively in the 13 abdominopelvic regions during repeat
laparotomy: central abdomen/parietal peritoneum of anterior abdo-
minal wall, perihepatic region, epigastric/lesser sac region, perisplenic
Journal of Surgical Oncology
region, left pericolic gutter region, left inguinal region, pelvic region,
right inguinal region, right pericolic gutter region, proximal portion
of jejunum, distal portion of jejunum, proximal portion of ileum
and distal portion of ileum. Treatment failure in the abdominal wall
incisions and/or other systemic sites found on imaging was also
recorded prospectively and included in the analysis if they occurred
within 3 months of the initial site.
The statistical analyses of clinicopathologic and treatment-related
parameters used progression-free and overall survival as the endpoints.
All survival analyses were performed using Kaplan–Meier method and
compared using the log-rank test. Statistical analyses were performed
by the intent-to-treat principle, using SPSS for Windows (Version 14.5;
SPSS GmbH, Munich, Germany). A significant difference was
assumed for P < 0.05.
RESULTS
Failure Analysis of Progressive Colorectal Cancer
Between June 1981 and November 2004, 70 patients with
carcinomatosis from colorectal cancer underwent a complete cytor-
eduction. One patient suffered postoperative death and was eliminated
from further data analysis. The mean and median follow-up of this
group of 70 patients was 40.8 and 29.5 months, respectively. Forty-nine
patients developed documented recurrences during follow-up while
an additional six patients had inadequate documentation of their
recurrences. Four of these six patients have died of disease, one is alive
with disease as of last follow-up in January 2005 and one was lost to
follow-up. These six patients were excluded from further data analysis
making 49 patients with documented recurrence eligible for further
study. The median time to progression defined as the time from
definitive cytoreduction to time of first documentation of recurrent
disease was 9 months. The median survival for this group of patients
was 30 months and the 5-year survival was 17%. The time to
progression and the survival curves for patients with documented
recurrences is shown in Figure 1.
There were 12 patients who recurred within 6 months and 37 who
recurred after 6 months. Those who developed recurrence within
6 months of cytoreduction had a significantly shorter overall survival
(17 months) than patients who developed recurrence more then
6 months after cytoreduction (36 months, P ¼ 0.001) (Fig. 2).
Twenty-six of the 49 patients (53%) had at least one reoperation after
the initial cytoreduction. Eighteen of the 26 patients had a complete
Fig. 1. Time to progression and overall survival for 49 patients
who failed complete cytoreduction and perioperative intraperitoneal
chemotherapy as treatment for colorectal peritoneal carcinomatosis.

Fig. 2. Overall survival of 49 patients with documented recurrence
according to the time to first evidence of recurrence (P ¼ 0.001). All
patients failed complete cytoreduction and perioperative intraperitoneal
chemotherapy as treatment for colorectal peritoneal carcinomatosis.
second cytoreduction (no visible tumor or tumor nodules <2.5 mm in
diameter). The median survival of patients who had a second operation
was significantly longer then that of patients who did not have a second
operation (39 months vs. 20 months, P ¼ 0.0003) (Fig. 3).
The anatomic sites of recurrence, character of recurrence and their
associated survival are shown in Table I. Eighteen patients had
localized intra-abdominal recurrence (including retroperitoneum and
pelvis) with or without abdominal wall recurrence. The recurrence was
categorized as localized if three or less non-contiguous abdomino-
pelvic regions were involved by discrete tumor masses. Ten patients
had diffuse peritoneal disease and ten had isolated distant metastases.
Eleven patients had both distant metastases and another form of
recurrence (diffuse or localized peritoneal disease).
Failure Analysis of Progressive Appendiceal Cancer
Four hundred and two patients had complete cytoreduction (CCR-0
or CCR-1) after initial CRS and PIC at the Washington Cancer
Fig. 3. Overall survival in 49 patients with documented recurrences
according to second surgery (P ¼ 0.0003). All patients failed complete
cytoreduction and perioperative intraperitoneal chemotherapy as
treatment for colorectal peritoneal carcinomatosis.
Journal of Surgical Oncology
Failures After Carcinomatosis Treatment 297
TABLE I. Anatomic Location and Character of Disease Recurrence,
Number of Patients and Median Survival for 49 Patients Who Failed
Complete Cytoreduction and Perioperative Intraperitoneal Chemotherapy
as Treatment for Colorectal Peritoneal Carcinomatosis
Median
Character of Number of survival
Location of disease recurrence disease recurrence patients (months)
Localized intra-abdominal with Localized 18 37
or without abdominal wall
Intra-abdominal and pelvic Diffuse 11 29
Isolated distant metastases Systemic 10 13
Distant metastases and other site Systemic þ other 10 30
Institute. One hundred and eleven patients (26%) after the initial
complete cytoreduction were found to have subsequent disease
progression. Of these 111 patients, 98 patients underwent second
CRS and PIC. Seventy-six patients had complete second cytoreduction
(CCR-0/CCR-1) and 22 patients had incomplete second cytoreduction
(CCR-2/CCR-3).
Figure 4 demonstrates overall survival and actual progression-free
survival of these 111 patients. It shows that median survival was not
reached and 5-year overall survival was 74%. This was associated with
a median actual progression-free survival of 15 months. Analysis of
prognostic factors for survival in these 11 patients showed that
progression-free interval of 2 years was not associated with an
improved survival (vs. <2 years, P ¼ 0.836) (Fig. 5). However, in
patients who underwent a repeat CRS and PIC (n ¼ 96), the survival
results was significantly improved when compared to those who were
not selected for repeat surgery P < 0.001) (Fig. 6).
Table II demonstrates the distribution of treatment-failure sites and
their associated median survival. Fifty-seven patients had diffuse intra-
abdominal disease progression. Forty-one patients had focal intra-
abdominal disease progression. Twenty-four patients had systemic
progression, including 11 patients had progression only at a systemic
site and 13 patients had progression both at systemic and intra-
abdominal sites. Two patients had abdominal wall recurrence only.
Fig. 4. Time to progression and overall survival for 111 patients who
failed complete cytoreduction and perioperative intraperitoneal
chemotherapy as treatment for appendiceal neoplasms with peritoneal
dissemination.
298 Bijelic et al.
Fig. 5. Overall survival of 111 patients with documented recurrence
according to the time to first evidence of recurrence (P ¼ 0.863). All
patients failed complete cytoreduction and perioperative intraperito-
neal chemotherapy as treatment for appendiceal neoplasms with
peritoneal dissemination.
DISCUSSION
The evidence that supports a combined treatment of peritoneal
carcinomatosis aimed at long-term survival has grown significantly in
the last two decades. A number of referral centers have been developed
in the USA, Europe and Australia that have reported on phase II data
regarding the use of cytoreductive surgery and perioperative
intraperitoneal chemotherapy for peritoneal carcinomatosis from
appendiceal neoplasms as well as colorectal cancer [2,6]. The Fourth
International Workshop on Peritoneal Surface Malignancy that was
held in Spain in December 2004 determined as one of the key
consensus points that ‘‘cytoreductive surgery combined with perio-
perative intraperitoneal chemotherapy is considered the current
standard of care for all cases of mucinous appendiceal neoplasms
with peritoneal dissemination, in an otherwise fit patient in the absence
of distant metastases’’ [7]. The only available level I evidence on
the treatment of colorectal carcinomatosis examined the role of
cytoreductive surgery combined with intraperitoneal chemotherapy.
This study showed a median survival of 22.3 months for the group of
Fig. 6. Overall survival in 111 patients with documented recurrences
according to second surgery (P < 0.001). All patients failed complete
cytoreduction and perioperative intraperitoneal chemotherapy as
treatment for appendiceal neoplasms with peritoneal dissemination.
Journal of Surgical Oncology
patients treated with cytoreductive surgery and heated intraoperative
intraperitoneal chemotherapy followed by systemic chemotherapy
compared to 12.6 months for the group treated with systemic
chemotherapy without combined treatment [4]. However, it has to be
realized that the clinical evidence on treatment failure after the
combined treatment is still limited, especially regarding peritoneal
dissemination from appendiceal neoplasms where a long-term follow-
up is needed to achieve mature results due to the biology of the disease.
Some, even though limited data on the timing and distribution of
recurrences following cytoreductive surgery and perioperative intra-
peritoneal chemotherapy for colorectal cancer is available. Glehen
et al. reported an overall incidence of recurrence of 73.3% in a multi-
institutional retrospective study of 506 patients [3]. In this study, there
were 377 patients who underwent CCR-0 or CCR-1 and had a
recurrence rate of 64.2% with 41.9% having peritoneal recurrence.
Verwaal et al. published their results of 106 patients treated
with cytoreductive surgery, heated intraoperative intraperitoneal
chemotherapy followed by systemic chemotherapy showing that
recurrences developed in 69/106 patients (65%) [8]. The
median time to development of recurrences differed according to the
completeness of cytoreduction: patients with a macroscopically
complete cytoreduction had a median time to recurrence of 13.7 months
while patients with a cytoreduction to <2.5 mm had a median time of
10.8 months. The majority of patients recurred in the abdomen but
more precise anatomic characterization of intra-abdominal recurrences
was not given.
The present study demonstrated that after initial complete CRS and
PIC for appendiceal neoplasm, the overall 5- and 10-year progression-
free survival rates were 70% and 67%, respectively. One hundred and
eleven patients (28%) developed progressive disease and disease
progression was the only independent risk factor associated with a
reduced overall survival. In the colorectal cancer group, 70% of
patients developed disease recurrence with a median progression-free
survival of 9 months. These strikingly different results emphasize the
differences in cancer biology and aggressiveness between appendiceal
and colorectal tumors but also indicate that further efforts to optimize
the results of combined treatment for both of these diseases need to be
undertaken.
The pattern of recurrence after an initial optimal treatment of
peritoneal carcinomatosis (that includes complete cytoreduction and
perioperative intraperitoneal chemotherapy) may be suggestive of the
underlying cause of failure and thus indicate the direction for possible
changes in management. It is possible that a localized form of
recurrence within the abdomen is a result of ‘‘surgical failure’’ to
completely eradicate disease even though patients had complete
adhesiolysis before the administration of intraperitoneal chemo-
therapy. Tumor cells entrapped in scar tissue are less likely to be
eradicated with intraperitoneal chemotherapy than free cancer cells.
Another potential cause for surgical failure is the disease burden on the
small bowel during initial cytoreduction as electroevaporative surgery
cannot be used in the same manner as in other anatomic locations in the
abdomen, which may result in higher failure rates at these sites. Indeed,
an interesting observation on patterns of treatment failure is the
progression of disease on the small bowel surface at reoperation in the
appendiceal group. On the other hand, a diffuse intra-abdominal
recurrence probably suggests a failure of intraperitoneal chemotherapy
to eradicate tumor cells remaining after initial cytoreduction. This is an
important type of failure since it is associated with worse outcomes
both in the colorectal and the appendiceal group of patients.
This study clearly shows that additional efforts to reduce the
incidence of intra-abdominal recurrences after cytoreductive surgery
and HIPEC need to occur. Our suggestion is that improved local-
regional methods to maintain a disease-free peritoneal surface after
complete cytoreduction are needed. This should include efforts to
improve HIPEC by determining optimal agents, maximal doses and

TABLE II. Anatomic Location and Character of Disease Recurrence, Number of Patients and Median Survival
for 111 Patients Who Failed Complete Cytoreduction and Perioperative Intraperitoneal Chemotherapy as
Treatment for Appendiceal Neoplasms With Peritoneal Dissemination
Character of
Location of disease recurrence disease recurrence
Abdominal wall only Localized
Focal intra-abdominal Localized
Diffuse intra-abdominal Diffuse
Systemic only Systemic
Systemic and others Systemic þ other
optimal levels of hyperthermia to be used. Also, considering the very
high propensity for recurrence, especially in high-grade cancers,
additional intraperitoneal treatments administered as early post-
operative intraperitoneal chemotherapy are likely to be beneficial.
Cell cycle-specific agents such as paclitaxel and 5-fluorouracil should
be chosen for this purpose. The concept of biphasic treatment, utilizing
the synergy between different chemotherapeutic agents as well as
between heat and some systemic agents should be employed in the
operating room when the cancerous nodules in the peritoneum have
been heated [9]. The intraoperative bidirectional chemotherapy is a
definite direction for optimization of HIPEC. Multiple controlled trials
in ovarian cancer showed clear benefits for long-term bidirectional
chemotherapy [10,11,12]. The same principle may need to be applied
in carcinomatosis of appendiceal and colorectal origin in order to
maintain control of disease on peritoneal surfaces.
This study also showed that a second attempt at cytoreduction in
patients with recurrence is of benefit. This is especially true for
appendiceal neoplasms where prolonged survivals were achieved
with second cytoreduction. Considering the risk of recurrence, perhaps
all patients with high-grade cancers such as colorectal cancer should be
scheduled for second-look surgery to help accurately select patients
who may benefit from additional surgery. Certainly, strict protocols for
follow-up that include surgery for evidence of recurrent disease need to
be part of the management plan of this group of patients.
ACKNOWLEDGMENTS
Lana Bijelic and Tristan D. Yan are surgical oncology research
fellows, supported by the Foundation for Applied Research in
Gastrointestinal Oncology. The authors thank David Chang for his
assistance in statistical analysis.
REFERENCES
1. Sugarbaker PH: New standard of care for appendiceal epithelial
neoplasms and pseudomyxoma peritonei syndrome? Lancet
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2. Yan TD, Welch L, Black D, et al.: A systematic review on the
efficacy of cytoreductive surgery combined with perioperative
Journal of Surgical Oncology
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2 NR
57 NR
41 NR
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13 74
intraperitoneal chemotherapy for diffuse malignant peritoneal
mesothelioma. Ann Oncol 2007;18:827–834.
3. Glehen O, Kwiatkowski F, Sugarbaker PH, et al.: Cytoreductive
surgery with perioperative intraperitoneal chemotherapy for
the management of peritoneal carcinomatosis from colorectal
cancer: a multi-institutional study. J Clin Oncol 2004;22:3284–
3292.
4. Verwaal VJ, van Ruth S, de Bree E, et al.: Randomized trial of
cytoreduction and hyperthermic intraperitoneal chemotherapy
versus systemic chemotherapy and palliative surgery in patients
with peritoneal carcinomatosis of colorectal origin. J Clin Oncol
2003;21:3737–3743.
5. Sugarbaker PH: Peritonectomy procedures. Ann Surg 1995;221:
29–42.
6. Yan TD, Black D, Savady R, et al.: A systematic review on the
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7. Gonzalez-Moreno S: Peritoneal surface oncology: A progress
report. Eur J Sur Oncol 2006;32:593–596.
8. Verwaal VJ, Boot H, Aleman BMP, et al.: Recurrences after
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9. Elias D, Sideris L, Pocard M, et al.: Efficacy of intraperitoneal
chemohyperthermia with oxaliplatin in colorectal peritoneal
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10. Armstrong DK, Bundy B, Wenzel L, et al.: Intraperitoneal
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11. Markman M, Bundy B, Alberts D, et al.: Phase III trial of
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 Journal of Surgical Oncology 2008;98:300–305

Quality of Life and Nutritional Assessment in Peritoneal Surface

Malignancy (PSM): Recommendations for Care

RICHARD MCQUELLON, PhD,1* CECILIA GAVAZZI, MD,2 POMPILIU PISO, MD, PhD,
3

DAVID SWAIN, BSc (Hons), PGDip RD,4 AND EDWARD LEVINE, MD5
1
Department of Internal Medicine, Section of Hematology and Oncology, Wake Forest University School of Medicine,
Winston-Salem, North Carolina
2
Clinical Nutrition Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
3
Department of Surgery University of Regensburg, Regensburg, Germany
4
Department of Nutrition and Dietetics, Basingstoke and North Hampshire NHS Foundation Trust, England, UK
5
Surgical Oncology Service, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Quality of life (QOL) and nutritional status of patients treated for peritoneal surface malignancy are important areas for ongoing assessment.
A working group of clinicians including a dietitian, physicians, and quality of life researchers was formed as part of the Fifth International
Workshop on Peritoneal Surface Malignancy. The purpose of the group was to form a consensus statement on both quality of life and nutritional
assessment in PSM. The relevant literature from the quality of life and nutritional assessment in peritoneal surface malignancy was reviewed and
integrated to form a consensus statement. Baseline and ongoing assessment of both quality of life and nutritional status of patients undergoing
cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) is recommended.
J. Surg. Oncol. 2008;98:300–305. ß 2008 Wiley-Liss, Inc.

KEY WORDS: quality of life; nutrition; peritoneal surface malignancy

INTRODUCTION
Cytoreductive surgery (CS) plus hyperthermic intraperitoneal
chemotherapy (HIPEC) has been associated with high rates of
morbidity and mortality. However, a recent report of a randomized
trial by Verwaal and colleagues and more extensive systematic
evaluation of this procedure have suggested that mortality and
morbidity can be reduced with improved selection criteria [1–3].
Nevertheless, most patients undergoing this treatment will experience,
at the very least, short periods of physical discomfort and impairment
to their overall quality of life and nutritional status [4–6].
The purpose of this article is to establish guidelines for assessing
and maintaining patient overall quality of life and nutritional status
before and after this extensive surgical and chemotherapeutic
procedure. It should be noted that nutritional status has a direct
effect on the patients overall quality of life. In fact most quality of life
instruments include questions about appetite since both disease and
treatment affect eating and nutritional status. This article is written in
two parts: Part I, quality of life issues and Part II, nutritional status.
We recognize that this is an artificial distinction and that the two
areas are closely related. Integration of these important areas of patient
functioning remains to be accomplished.
PART I: HEALTH RELATED QUALITY
OF LIFE FOR PATIENTS WITH PERITONEAL
SURFACE MALIGNANCY (PSM)
Surgical, radiological, and chemotherapeutic treatments of cancer
have a potential to do great harm and impair the patient’s quality of
life both in the short- and long-term. However, they also provide the
possibility for cure in some instances and prolonged life with quality in
others. For patients with PSM, life is precious since almost everyone
enters treatment with a poor prognosis and limited lifespan. In this
setting, it is very important to help patients maintain a life of quality for
as long as possible. It is not good enough to extend life if this is at the
expense of quality living. Prior to the systematic evaluation of PSM
patients with QOL instruments, there was only anecdotal and clinical
data to evaluate patient outcome following CS plus HIPEC. Clinical
trials [4–8] now provide data on which to base judgments about QOL
following this procedure. There is much work to do, particularly
since there has been no randomized clinical trial on the procedure with
a companion quality of life component.
Health Related Quality of Life—Definition
Health related quality of life (HRQL) refers to how a person’s
health affects their ability to carry out normal social and physical
activities. There is a general consensus among researchers that the
quality of life concept is measurable, multi-dimensional, and
subjective or meaningful to the individual patient [9]. Prior to the
development of psychometrically sound QOL instruments, perfor-
mance status or toxicity ratings were thought to represent QOL. While
these are dimensions of quality of life, and while performance status
may serve as a crude proxy, there is no substitute for a standardized
QOL questionnaire properly administered.
The QOL construct is measurable in that its dimensions can be
assessed reliably over time and have been shown to be valid with
reference to other validated instruments. There are at least four areas,
sometime referred to as domains, that can be measured in quality of
*Correspondence to: Richard McQuellon, PhD, Comprehensive Cancer
Center of Wake Forest University/Baptist Medical Center, Medical Center
Blvd., Winston-Salem, NC 27157-1082. Fax: 336-716-5687.
E-mail: rmcquell@wfubmc.edu
Received 21 March 2008; Accepted 21 March 2008
DOI 10.1002/jso.21050
Published online in Wiley InterScience
(www.interscience.wiley.com).

ß 2008 Wiley-Liss, Inc.


life assessment (Fig. 1) [10]. These include physical well-being
(symptoms and side effects such as pain, nausea, etc.), social/family
well-being (sociability and intimacy, including feeling close to friends,
satisfaction with family communication, etc.), functional well-being
(role performance and activities of daily living such as work, sleep etc.)
emotional well-being (sadness, nervousness, etc.). There are other
important factors in a patient’s life that may modify how they
experience their overall QOL. These include spirituality, financial and
support resources, psychological resilience, sexuality, and family
functioning.
At one time, subjectivity was thought to be a detriment in the
assessment of the patient’s status. However, asking the patient to assess
the quality of their life has proven to be a valuable source of data for
clinicians in making treatment related recommendations as well as
providing ongoing care. In fact, patient ratings have been shown to be
very useful relative to clinician ratings which may overestimate or
underestimate the patient’s functioning and overall quality of life.
Additionally, this subjective assessment of the patient’s QOL provides
for a measure of meaningfulness.
Why is it important to measure quality of life in the PSM
context? Most patients with peritoneal surface malignancies will die of
their disease. Nevertheless, CS plus HIPEC allows for extended life far
beyond what might be predicted with no treatment [11–13]. However,
extended survival is often at the expense of short-term health since
morbidity rates of up to 40% have been reported in this population.
There are common surgical complications which may result in lengthy
hospitalizations, far beyond the predicted course with no complica-
tions. Even without complications, patients will likely face a
significant period of convalescence after the procedure. Nevertheless,
depending on how symptomatic the patient is at presentation, they may
show improvements in QOL within several weeks of treatment. We
have reported that patients without major symptoms report a drop in
QOL scores not long after surgery plus HIPEC while those with
significant symptoms such as ascites show improvement in QOL at
post-surgery [5].
What methods and instruments have been used to measure quality of
life in this context? While the methodology for assessing QOL in the
PSM context is simple, it is not easy. Patients presenting with PSM
Fig. 1. Quality of life domains and modifiers [10].
Journal of Surgical Oncology
Quality of Life and Nutrition in PSM 301
at the initial consultation are often symptomatic and anxious. For
successful QOL assessment, it is necessary to have a nurse or a
research assistant introduce the questionnaires to the patient and
explain the rationale for conducting the assessment. Often this is done
at the time of the outpatient consultation with the surgeon or at
some time prior to surgery. At the initial assessment, it is very
important for the research assistant to check all the data to make sure
the patient has answered each question. These data are not recoverable
at a later time point. Subsequent assessments can either be conducted at
follow-up outpatient appointments or by mail. Often patients travel a
significant distance for their treatment and will need to complete
follow-up questionnaires at home and mail them back to the treatment
center. To ensure the completion of the follow-up questionnaires, it
may be necessary to repeatedly send questionnaires out to patients and/
or phone them to answer any questions they may have.
Oftentimes, patients are confronted with recurrent disease, signi-
ficant debilitating symptoms, and/or may be hospitalized at the time
that they received the questionnaires. Also, they may assume that if a
great deal of time has passed since the questionnaires arrived, that there
is no longer any use to complete them. Thus, it is helpful to talk with
them to encourage continued participation.
Systematic assessment of patient rated outcomes including health
related quality of life in the PSM context is new. At this time, to our
knowledge, there are few published reports of the health related
quality of life of patients following cytoreductive surgery plus HIPEC
[4–8,10]. The general methodology is simple with a pre-surgery
assessment followed by post-surgery assessments at various time
points ranging from 2 to 4 weeks (at the first follow-up appointment
after surgery) to up to 2 years. Several studies have reported on long-
term survivors from 2 to 8 years post-HIPEC [4,11].
QOL instruments can be thought of as generic, disease specific, or
symptom specific. Depending on the purpose of the assessment, one or
more of these instruments could be used to inform both clinicians and
patients.
Instruments that have been reported in the literature in this context
are the Functional Assessment of Cancer Therapy-C (FACT-C), the
Short Form-36 (SF-36) of the medical outcome study, the European
Organization for Research on Treatment-Cancer (EORT-C) instru-
302 McQuellon et al.
ment. Additionally, the Eastern Cooperative Oncology Group
Performance Status measure has been reported in the literature. Both
the FACT and EORTC are specific to cancer while the SF-36 has been
used in the general population and can be used for comparison
purposes.
What do Quality of Life Scores mean? Statistical and clinical
significance are not the same thing. While P values are important,
especially in randomized trials which compare two different groups,
the P-value in and of itself does not indicate whether a particular result
has clinical significance. A P-value simply indicates whether or not the
results of the study are more or less likely to be found by chance.
In clinical trials using very large samples, there will be considerable
statistical power to detect very small and perhaps meaningless
differences between two different treatments. In the PSM setting,
large sample sizes with QOL data at 1 year post-CS plus HIPEC are
non-existent. Thus, statistically significant differences over time on a
QOL questionnaire with smaller samples are likely to indicate clinical
significance as well.
There has been much progress in implementing QOL measurements
in oncology clinical practice and trials. The literature suggests that
both patients and clinicians appreciate knowing more about the
patients’ QOL in this context [9]. Nevertheless, once a specific QOL
score has been observed, what does it mean? At present there is no
indication of the appropriate clinical pathway for patients with a
particular QOL score. In other words, the use of QOL scores for
determining individual rehabilitation programs outside of clinical trials
is rare if not non-existent in clinical practice.
Relatively small gains in HRQL can have significant value for
individual patients. Comparable declines may be less meaningful,
since patients may minimize personal negative evaluations about their
condition. This has important implications for the interpretation of the
meaningfulness of change scores on QOL questionnaires. Factors such
as adaptation to disease, response shift, dispositional optimism and the
need for signs of clinical improvement may be contributing to the
results and should be investigated in future studies [9].
The minimally important difference (MID) has been defined as the
smallest change in a patient related outcome measure that is perceived
by patients as beneficial or that will result in the change in treatment.
There are a number of anchor based and distribution based methods
that have been used to determine MID for QOL measures. The anchor
based methods require an external patient base or clinical criteria for
comparison to determine what changes in QOL scores are meaningful.
The distribution based methods reflect one of several statistical indices
of change. The method for determining the MID is still evolving [9].
This is particularly true in the PSM context where patients are choosing
major surgery with the high likelihood of significant morbidity. They
are choosing short-term (1–3 months) reduction in quality of life for
long-term gain in the form of additional life span. Clinical experience
suggests that for the patients with minimal morbidity, this is a
reasonable option. However, for those with significant morbidity and
presumed deficits in quality of life, it remains an open question as to
whether or not the decision to seek this intensive treatment was in fact
the ‘‘right’’ decision for the patient.
What time periods need to be studied? More patient-rated QOL data
in the 1- to 3-week time period following surgery are needed as well as
the time period over the first year where data on recurrent disease and
accompanying QOL are sparse. There is very little information on
patients who do not have a reasonably successful course following CS
plus HIPEC. In one study, survivors reported having no regrets
following the CS plus HIPEC procedure [6]. Nevertheless, clinical
experience suggests that for a substantial minority of patients, post-
surgery recovery is very difficult and fraught with numerous
complications, severely compromising short-term QOL.
How can quality of life scores be used? To date, the pre-surgery QOL
assessments have only been used to establish a baseline score for
Journal of Surgical Oncology
patient reference. However, there has been no systematic evaluation of
how these scores might affect patient decision-making regarding the
acceptance or rejection of cytoreductive surgery. Also the baseline
evaluation has not been used to predict morbidity and mortality.
The utility of assessment after surgery could be in helping the patient
who has reduced QOL scores to get additional support resources as
necessary such as physical therapy, nutritional counseling and/or
psychosocial care. While clinical assessment by the surgeon or other
medical team members is crucial, systematic patient-related outcomes
using a QOL instrument will provide additional data upon which to
make rehabilitation treatment decisions.
What is the tradeoff between short-term (1–3 months) and longer-
term (4–12 months) quality of life in the PSM setting? Patients who
opt for this aggressive treatment are likely to have, at minimum,
significant pain and disability immediately post-surgery and for up to
7–10 days. Their functional status will be severely limited and
they may be bedridden for a significant amount of time should
complications develop. Nevertheless, when faced with certain
progressive disease and death, many patients will opt for short-term
loss of function and impairment in quality of life with the hopes of
having longer-term survival and restoration of life’s quality. To date,
we have not systematically assessed patient quality of life in the period
immediately following surgery (1–10 days). It is simply assumed that
this is a time of misery for most patients. In general, patients can be
counseled to expect a return to baseline levels of QOL (if they
are nearly symptom free when CS plus HIPEC is performed) in the
3–6 months post-surgery time period. However, that the return to pre-
surgery functioning may occur as late as between 6 and 12 months [2].
Analytic Strategies for Handling QOL Data
A serious challenge to understanding QOL results in PSM trials is
the fact that many patients are either too sick to complete
questionnaires at follow-up time points or deceased. For example,
one study reported 64 patients completing QOL questionnaires at
baseline with only 31 completing questionnaires at the 12-month
follow-up due to the fact that 24 patients had died [5]. Because of this
rate of mortality, it is necessary to use analytic techniques that account
for data that are missing, not at random, to avoid a biased estimate of
the QOL in the study population. (See Fairclough et al. [14] for an
excellent discussion of this analytic problem.) Similar results with
regard to drop-outs have been reported by Alexander et al., [6] who
began with a total of 73 patients at baseline and reported 45 patients at
the 9-month follow-up and Schmidt et al. [4] with 67 patients assessed
at baseline and 20 patients being assessed ranging 1–8 years following
treatment.
Using HIPEC Quality of Life Data in Clinical Practice
The current literature suggests that a sub sample of patients may
return to near baseline levels of functioning on quality of outcome
measures at between 6 and 12 months, with some reporting
improvement to baseline as early as 3 months. It is important to
underscore this is likely the best of outcomes since attrition rates from
baseline to 6 months are substantial and range from 50% to 60%. Thus,
the sickest patients may not be represented in these data. In other
words, the data may be overly optimistic. Nevertheless, it is useful for
patients to see this information. Figure 2 illustrates how such data can
be utilized in patient counseling prior to and after cytoreductive
surgery plus HIPEC. The graph illustrates physical functioning, role
functioning and general health as reported by patients in the study
conducted by McQuellon, et al. [13]. Also, normative sample scores of
patients age 45–54 are reported for comparison. This is necessarily an
imprecise comparison. The ideal comparison would be a patient of
similar age without cancer who was identified by each of the study

subjects in the HIPEC sample. Nevertheless, this gives us some general
framework for comparison and suggests that even though patients do
relatively well and return to greater than baseline levels of physical
function and role functioning following HIPEC, these scores are still
considerably lower than the comparison sample. Further, their reported
general health is significantly lower than a sample of the general
population. On the one hand, the ‘‘glass is half full,’’ and patients return
to baseline functioning as early as 3–6 months. On the other hand,
the ‘‘glass is half empty,’’ in that, at least on physical measures, this
group of patients scores lower than the normative sample comparison
group.
Recommendations for QOL Assessment in PSM
(1) All patients being evaluated for CS plus HIPEC for PSM should
have their QOL and performance status evaluated. This can be
utilized to help evaluate the risk of the proposed procedure.
(2) Evaluation of quality of life after surgery should be systematically
evaluated by treating centers.
(3) Standardized instruments such as the FACT or EORTC should
be used as core instruments. Additional general quality of life
measurers, that is, the SF-36 or symptom specific questionnaires
(the Brief Pain Inventory), can be used at the clinicians discretion
based on patient’s symptoms.
(4) Clinical trials assessing the efficacy of CS plus HIPEC should
incorporate a quality of life patient-rated outcome instrument. This
is particularly important in any randomized trials since the impact
of treatment in two different trials can be assessed. This is crucial if
there are significant survival benefits for one treatment over the
other and can answer the question as to whether or not survival
benefit is at the expense of the patient’s quality of life.
(5) Future studies should focus on answering the following questions:
(a) What is the minimally important difference in quality of life
measures in this context? This is a developing field of inquiry
where much work is needed. What exactly do these differences
on specific instruments mean to patients?
(b) Can preoperative quality of life data contribute to clinical
parameters in predicting survival?
Fig. 2. Selected SF-36 Scales at four time points.
Journal of Surgical Oncology
Quality of Life and Nutrition in PSM 303
PART II: NUTRITIONAL CARE OF PATIENTS
WITH PSM AND CANDIDATES
FOR CS PLUS HIPEC
It is well documented that malnutrition is associated with
depression of humoral and cellular immune function, alterations in
the inflammatory response and delay or failure of the wound healing
process. As a result, increased complication rates, length of stay,
cost, and mortality occur in surgical patients [15]. Moreover there is a
strong relationship between nutritional status and various clinical
outcomes, including quality of life, survival and the ability to tolerate
treatment [16,17].
We know of no published nutritional data on patients selected for
CS plus HIPEC for PSM. Nutritional assessment and adequate
nutritional treatment should be considered in these patients in the
perioperative period and nutritional follow-up should be planned for at
least 1 year after surgical procedures [18,19].
Prevalence of Malnutrition in Patients
Affected by PSM
Few data are available on the prevalence of malnutrition in patients
affected by PSM. Nutritional status varies considerably based on the
different underlying diseases associated with PSM. For example,
pseudomyxoma peritonei (PMP) is rarely associated with malnutrition.
Patients affected by PMP and admitted to Instituto Nazionale Dei
Tumori (INT) for surgery, reported a history of involuntary weight loss
and reduced food intake in less than 3% of cases. No data are available
for peritoneal mesothelioma. In contrast, peritoneal carcinomatosis in
ovarian, colon and gastric cancer is usually a situation of a long lasting
and advanced disease; when it is diffuse, it creates difficulties in
regular oral alimentation and it is generally associated with a high
prevalence of malnutrition.
Among patients affected by different types of gynaecologic cancer,
malnutrition has been reported significantly higher in women with
ovarian cancer, with a prevalence of 67% [20,21]. The percentage of
patients affected by colon cancer malnutrition has been reported
to range from 34% to 54% [16,22]. The highest prevalence of
304 McQuellon et al.
malnutrition has been always reported in patients affected by gastric
cancer, ranging from 62% to 83% [16].
Standard Methods for Nutritional Status Assessment
Standard nutritional screening is needed for all candidates for major
elective surgery and especially patients affected by PSM. More in-
depth nutritional assessment should be considered in malnourished
patients only. A variety of nutritional indices have been found to be
valuable in predicting outcome when used alone, but there is no
consensus on the best method for preoperative nutritional risk
assessment in patients undergoing major surgery [23]. The European
Society for Clinical Nutrition and Metabolism has stated that recent
weight loss, body mass index and reduced dietary intake are considered
the more important indicators for nutritional screening in the hospital
setting, by Laviano and Meguid [22].
Malnutrition should be considered in the presence of weight loss
greater than 5% within 3 months, body-mass index below 18.5 Kg/m2,
and/or food intake below 50% of normal requirement. A more in-
depth nutritional assessment can be performed using biochemical
and functional measures. Biochemical nutritional indicators include:
serum levels of total protein, albumin, prealbumine, transferrin,
cholinesterase, and lymphocytes. Serum albumin <30 g/L, with no
evidence of hepatic or renal dysfunction should be considered an
indicator of potential morbidity [24]. A functional measure that could
assess nutritional status indirectly is evaluated muscle strength by hand
grip dynamometer.
Perioperative Nutrition Interventions
Although no data are available on nutrition support in patients with
PSM and undergoing CS and HIPEC, perioperative artificial nutrition
should be planned considering the extent of abdominal surgery and
the important postoperative catabolic state, following international
guidelines for surgical patients [25–26]. All malnourished patients
should be supported in pre- and post-operative phases. In the
preoperative phase, oral nutritional supplements should be given if
the gut is functioning; total parenteral nutrition (TPN) should be
administrated only in presence of mechanical bowel obstruction.
Postoperative artificial nutrition should start as soon as possible, when
general conditions are stable. In line with international guidelines early
enteral nutrition (EN) should be planned; however, the lack of
knowledge on the small bowel physiology after HIPEC indicates that
EN nutrition should be started with caution and initially to overlap
with TPN.
Nutrition Interventions After Discharge
Metabolic and mechanical effects of surgery can have a negative
impact on nutritional status and quality of life for a long time after
discharge [27]. All patients with gastrectomy, colectomy and ileal
resection have a progressive weight loss for several months after
surgery. Weight loss can be so severe in patients with multiple
resections that home parenteral nutrition should be considered. More
systematic study of the post-discharge time period is necessary.
Recommendations for Nutritional Management
(1) Systematic study of the nutritional status of PSM surgery
candidates is needed before during and after CS plus HIPEC.
(2) Nutritional screening should be performed in all patients affected
by PSM and candidates to major elective surgery, while a more in-
depth nutritional assessment should be considered in malnourished
patients only.
Journal of Surgical Oncology
(3) Prospective randomized studies are needed to define the best
timing and route perioperative nutrition.
(4) Nutritional counselling should be given to patients before
discharge and ambulatory follow-up should be planned with
a time schedule correlated to number and type of resections.
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