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Cancer Therapy Vol 3, page 299
Cancer Therapy Vol 3, 299-320, 2005
Management of peritoneal carcinomatosis from
colon cancer, gastric cancer and appendix
malignancy
Review Article
Paulo Goldstein1, Rodrigo Gomes da Silva2, Jacobo Cabanas3, Paul H.
Sugarbaker4
1
Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo (Brasil)
Faculdade da Medicina da Minas Gerais Federal University, Belo Horizonte (Brasil)
3
Hospital Universitario Ramón y Cajal, Madrid (Spain)
4
Program in Peritoneal Surface Malignancy, Washington Cancer Institute, Washington DC (USA)
2
__________________________________________________________________________________
*Correspondence: Paul H. Sugarbaker, M.D., Washington Cancer Institute, 106 Irving Street, NW, Suite 3900, Washington, DC 20010,
USA; Phone: (202) 877-3908; Fax: (202) 877-8602; e-mail: [email protected]
Key words: Intraperitoneal chemotherapy, cytoreductive surgery, peritonectomy, appendiceal cancer, colon cancer, gastric cancer,
peritoneal surface malignancy
Abbreviations: Completeness of cytoreduction score, (CCS); cytoreduction score, (CC); diffuse peritoneal adenomucinosis, (DPAM);
early postoperative intraperitoneal chemotherapy, (EPIC); hyperthermia, (HIIC); long-term intraperitoneal chemotherapy, (LTIC);
peritoneal cancer index, (PCI); peritoneal mucinous adenocarcinomas, (PMCA); Prior surgical score, (PSS)
Received: 25 March 2005; Accepted: 18 April 2005; electronically published: May 2005
Summary
Peritoneal dissemination from gastrointestinal malignancies can occur either as a result of direct seeding during the
growth process of the primary tumor or after cell spillage caused by surgical manipulation. Until recently this
condition was treated only with palliative intent and resulted in a cancer death associated with a period of poor
quality of life. However, new concepts regarding the pathobiology of peritoneal seeding and new treatment options
supported a rationale for a major revision of management strategies. Peritonectomy procedures are now used to
remove macroscopic tumor nodules. Perioperative chemotherapy delivered by an intraperitoneal route allows high
local-regional exposure of peritoneal surface associated with minimal systemic toxicity. This combined treatment
has been used in the management of several gastrointestinal malignancies. Mucinous appendiceal tumors are the
paradigm of this new approach with 80% 5-year survival. Colon cancer has been successfully treated in
approximately 30% of patients and in selected patients with gastric cancer approximately 10% have reached 5-year
survival. In this review the natural history of peritoneal carcinomatosis is presented, the results of phase II and III
trials are evaluated and morbidity, mortality and quality of life with this definitive approach assessed.
A. Colorectal carcinomatosis
I. Introduction
Despite advances for early diagnosis of colorectal
cancer, peritoneal carcinomatosis persists as a major
problem. Peritoneal implants are present in 10% of
patients with colorectal cancer at the time of diagnosis and
are the second cause of death after liver metastasis
(Sugarbaker, 1990). In contrast to the other two main sites
of colorectal cancer metastasis, liver and lymph nodes,
peritoneal seeding is considered a condition uniformly
lethal with no perspective of cure. From a database of
3019 colorectal cancer patients, Jayne and colleagues
identified 349 patients with peritoneal carcinomatosis
(Jayne et al, 2002). The median survival of this group was
7 months. Unfortunately this recent data showed no
Peritoneal carcinomatosis represents a significant
adverse step in the natural history of any gastrointestinal
cancer using conventional management. It eliminates any
hope of cure and with disease progression leads to poor
quality of life. Patients who relapse through peritoneal
seeding will experience a succession of complications
secondary to the progressive carcinomatosis. Those
patients who present with peritoneal implants with the
primary cancer in place may suffer not only from
progressive carcinomatosis but also from the
complications of the primary tumor, most commonly
obstruction, bleeding and perforation.
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Goldstein et al: Management of peritoneal carcinomatosis
improvement in the survival of these patients if compared
with the first study of the natural history of peritoneal
carcinomatosis published 13 years before (Chu et al,
1989). Also, a European multicenter trial (EVOCAPE 1)
evaluated prospectively 118 patients with peritoneal
carcinomatosis arising from colorectal cancer. The mean
survival of those patients was 6.9 months (Sadeghi et al,
2000).
carcinomatosis patients. Recognition of the peritoneal
layer as the first defense barrier to tumor progression
allows one to assume that cure might be possible if tumor
nodules were eradicated from all peritoneal surfaces
(Sugarbaker, 1990). Also in 1984, Flessner and colleagues
showed in pharmacokinetics experiments that the
clearance of a drug from the peritoneal cavity is inversely
proportional to its molecular weight (Flessner et al, 1984).
This new pharmacologic concept, known as PeritonealPlasma Barrier, represents the basis of intraperitoneal use
of chemotherapeutic agents. In 1995, Sugarbaker
published new surgical strategies collectively referred to
as peritonectomy procedures (Sugarbaker, 1995). These
surgical techniques allow the resection of all parietal
peritoneum involved by peritoneal seeding. Visceral
peritoneum invaded by tumor may require organ resection.
When the concept of peritonectomy is combined with
new pharmacokinetics studies, strategies for the effective
management of peritoneal surface malignancies can be
formulated for a significant proportion of patients.
Accumulated experience shows that success against
carcinomatosis from gastrointestinal tumors depends on a
coordinated and dose intensive effort. That means
maximal
surgical
cytoreduction
plus
maximal
chemotherapy delivered directly into the abdominal and
pelvic cavity during the perioperative period. Unless both
strategies are used as a planned part of the surgical
intervention little success can be expected.
The most direct test of this new concept of the
peritoneum as the first line of defense against peritoneal
dissemination is pseudomyxoma peritonei arising from an
appendiceal adenoma. It represents a paradigm of this new
approach to peritoneal surface malignancies with
approximately 85% 5-year survival (Sugarbaker et al,
1999). No other treatments for this group of patients have
been shown to be curative. From the remarkable results
achieved in appendiceal mucinous tumors using this new
combined treatment a rationale for the treatment of
peritoneal carcinomatosis from colorectal cancer and
gastric cancer emerges. The treatment modalities are
further described, selection criteria discussed, results of
clinical studies presented and morbidity, mortality and
quality of life among treated patients evaluated.
B. Gastric carcinomatosis
In the United States 20 to 30% of patients with
gastric cancer being explored for potentially curative
resection will be found to have peritoneal seeding at the
time of surgical exploration (Sugarbaker, 2003 or 2004).
Current standard treatment is systemic chemotherapy
which may delay onset of symptoms but is not curative.
The median survival of these patients is 5 months with
virtually no long-term survivors (Sadeghi et al, 2000). Yoo
and colleagues reviewed 2328 patients with gastric cancer
who underwent curative resection with at least 5-years
follow-up (Yoo et al, 2000). Documented evidence of
relapse of the disease was found in 508 patients. Isolated
peritoneal recurrence was noted in 34% of patients who
relapsed. Hematogenous recurrence occurred in 26% and
local-regional persistence of the tumor was seen in 19%.
Two or more sites of recurrence were documented in the
remaining patients. Serosal invasion and lymph node
metastasis were risk factors of relapse in all patterns of
recurrence.
This high incidence of peritoneal carcinomatosis
following curative resections is shared by others, with an
average incidence between 20% and 50% (Gunderson and
Sosin, 1982; Koga et al, 1984; Wisbeck et al, 1986;
Landry et al, 1990). These data show that in an impressive
number of patients the recurrence is isolated within the
peritoneal cavity. It also suggests that if an effective
treatment could be targeted toward peritoneal
dissemination, at least a third of the patients with
advanced gastric cancer could experience a better
outcome.
Systemic chemotherapy for gastric patients
presenting with peritoneal seeding at the time of
abdominal exploration or as a manifestation of disease
recurrence after a curative surgery is uniformly
disappointing. Preusser and colleagues published a
response rate for advanced gastric cancer of 50%;
nevertheless patients with peritoneal dissemination
obtained the worst response (Preusser et al, 1989). Ajani
and colleagues, treated patients prior to gastrectomy
(Ajani et al, 1991). At exploration, peritoneal
carcinomatosis was the most common cause of failure of
intensive neoadjuvant chemotherapeutic treatment. Also,
radiation showed limited results in this situation and is
expected to cause significant morbidity when applied to
such a large field.
C. Rationale for
malignancy treatments
peritoneal
II. Peritonectomy procedures
Until recently any patient with peritoneal seeding
from a gastrointestinal primary had no surgical option with
intent to cure. This was based on the assumption that even
if the peritoneal nodules were the only anatomical sites of
advanced disease, they were untreatable by conventional
surgical techniques. However, the study of the
pathobiology of the peritoneal surface component of
cancer and also of the patterns of this dissemination
allowed the evolution of six surgical procedures for the
treatment of macroscopic disease spread on peritoneal
surfaces (Sugarbaker, 1995).
An important concept regarding tumor behavior
derives from the studies of Weiss. He showed that even
though a large number of malignant cells reached the liver
through the blood stream only a few adhere to the
endothelium and develop into true metastasis. This
surface
However, during the last two decades new concepts
have arisen with the intent to develop treatment options for
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Cancer Therapy Vol 3, page 301
phenomenon known as “metastatic inefficiency”
characterizes hematogenous dissemination of disease
(Weiss, 1986). In contrast, free cancer cells in the
peritoneal cavity implant and grow with great efficiency.
Schott and colleagues evaluated the prognostic
significance of isolated tumor cells detected in the bone
marrow and in the peritoneal lavage of 84 patients with
gastric cancer and in 109 patients with colorectal cancer
(Schott et al, 1998). Although cancer cells identified in the
bone marrow showed little prognostic significance, free
cancer cells in the peritoneal cavity were highly correlated
with limited long-term survival.
From observations collected from reoperative
surgical procedures, Sugarbaker, (1996) described four
patterns of intracoelomic cancer dissemination. In the
absence of peritoneal fluid aggressive tumors tend to
spread randomly to the peritoneum surrounding the
primary tumor. However, tumors that are mucus producing
or those that lead to ascitic fluid accumulation, present a
characteristic redistributed pattern. The tumor cells tend to
adhere at the peritoneal resorption sites in the greater
omentum and beneath the diaphragm. Also, gravity is a
determinant in tumor distribution since the peritoneal fluid
accumulates in the pelvis creating a fluid rich in tumor
contamination. Thus, these malignant cells have the
opportunity to implant and progress on pelvic peritoneal
surfaces.
The third pattern of intracoelomic cancer
dissemination was described by Carmignani and
colleagues (2003). They documented the influence that
peritoneal motion has on tumor distribution. Many
structures in the abdomen are stationary, whereas others
such as the jejunum and ileum are in continuous
peristalsis. When cancer cells are present within the
peritoneal space, especially when ascitic or mucoid fluid is
present, the malignant cells tend to deposit within nonmobile anatomic sites such as the rectosigmoid junction,
around the cecum and the appendix, over the liver and in
the subpyloric space. In contrast, the surfaces of the small
bowel and its mesentery may remain almost free of
disease. This is one of the observations that led to a
rationale for peritonectomy procedures and a curative
approach to peritoneal surface malignancies.
A fourth mechanism influencing tumor distribution
into the abdominopelvic cavity occurs as a result of
surgical manipulation and is called “tumor cell
entrapment.” The malignant cells present in the peritoneal
cavity at the time of the first surgery have a tendency to
implant on wounded surfaces such as the laparotomy scar,
along the bed of the resected primary tumor, or in suture
lines. These cells become entrapped by fibrin and are
stimulated by inflammatory growth factors released during
the healing process. The concept that tumor cell
entrapment and enhancement can result from surgical
procedures should profoundly affect the practice of cancer
surgery (Sugarbaker, 1990).
Considering that a significant proportion of patients
with carcinomatosis arising from gastrointestinal cancer
have a preponderance of spread on parietal peritoneum
and have limited disease over their small bowel surfaces,
Sugarbaker described the peritonectomy procedures with
the intent to reduce peritoneal surface dissemination to a
microscopic level (Sugarbaker, 1995). These procedures
are used for resection of peritoneum involved by cancer.
On the small bowel surface tumor nodules are
electroevaporated and normal peritoneum is spared in
order to preserve gastrointestinal function. These
techniques are summarized as follows:
•
Epigastric peritonectomy: includes any prior
midline scar in continuity with preperitoneal epigastric fat
pad, the xiphoid process and the round and falciform
ligaments of the liver.
•
Anterolateral peritonectomy: removes the
greater omentum with the anterior layer of the peritoneum
from the transverse mesocolon. If the spleen is involved it
is resected. The peritoneum of the right paracolic gutter
along with the appendix, the spleen and in some patients,
the peritoneum covering the left paracolic gutter must be
stripped.
•
Subphrenic peritonectomy: the peritoneum
underneath the right and left portions of the diaphragm is
removed along with the left triangular ligament of the
liver; this includes the peritoneum lining the retrohepatic
space. Glisson’s capsule is removed in part or completely
as required by cancer implants.
•
Omental bursa peritonectomy and lesser
omentectomy: begins with the cholecystectomy and is
followed by removal of the peritoneum of the porta
hepatis, anterior and posterior aspects of the
hepatoduodenal ligament, hepatogastric ligament and the
peritoneal floor of the omental bursa, including the
peritoneum overlying the pancreas.
•
Pelvic
peritonectomy:
removes
the
peritoneum from the rectovesical or rectouterine space
(pouch of Douglas) and usually the rectosigmoid colon
must be resected. In women, both ovaries and the uterus
are also removed.
•
Partial/total gastrectomy: if the subpyloric
space is involved an antrectomy may be enough to
eliminate the disease. However, especially in mucinous
tumors, the entire lesser curvature of the stomach may be
encased by tumor and only a total gastrectomy allows
complete removal of disease.
III. Intraperitoneal chemotherapy
A. Rationale
Cytoreductive surgery alone can treat gross and
macroscopic disease. However, it leaves behind
microscopic disease which will progress not only on the
peritoneal surfaces, but also within the scar tissues.
Residual disease will be stimulated by growth factors
released during the healing process (Sugarbaker, 1990).
This iatrogenic mechanism for tumor dissemination
(tumor cell entrapment and enhancement) is a major cause
for both systemic and intraperitoneal chemotherapy
failure.
Intraperitoneal chemotherapy was designed to treat
the entire abdominal and pelvic cavity using high drug
concentrations locally with reduced systemic toxicities. As
would be expected, the results of intraperitoneal
chemotherapy administered alone for the treatment of
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Goldstein et al: Management of peritoneal carcinomatosis
established peritoneal metastasis are disappointing. This
failure occurs as a result of the very limited penetration of
the drugs into tumor nodules. Experimental studies show
that only the outer layers of the cancer implants will
achieve cytotoxic concentrations of the chemotherapeutic
agent (Ozols et al, 1979; Los and McVie JG, 1990). The
most optimistic studies suggest a maximum of 3 mm depth
of penetration by the cytotoxic drugs (van de Vaart, 1998).
These data establish that intraperitoneal chemotherapy
should be used only after complete cytoreduction.
Another important limitation for the use of
intraperitoneal chemotherapy alone for the treatment of
peritoneal surface malignancies is the non-uniform
distribution of the drug inside the abdominal and pelvic
cavity. The tumor itself may cause extensive adhesions;
also, a significant number of these patients have had prior
surgical interventions leading to scar formation. Thus,
unless all adhesions are taken down one cannot expect a
uniform distribution to all peritoneal surfaces (Elias et al,
2000).
Preoperative intraperitoneal chemotherapy has been
used by Yonemura (Japan), for the treatment of gastric
cancer presenting with established peritoneal metastasis.
This group also utilizes HIIC and EPIC in the same
patients trying to improve the results in this poor prognosis
clinical entity (Yonemura et al, 2003).
The use of intraperitoneal chemotherapy just after the
cytoreduction, but before the construction of the
anastomosis; HIIC, is the most widely used method
(Glehen et al, 2004). In addition to the advantages of the
route of administration of the chemotherapeutic agent
(intraperitoneal) and the association of hyperthermia, all
adhesions are eliminated at this point in the surgery
allowing the distribution of the fluid to the whole
peritoneal cavity. Another major benefit of HIIC utilized
after maximal cancer resection with peritonectomy is
related to the reduction of tumor burden to a microscopic
level. The cytotoxic drugs can eliminate free cancer cells
before they implant deep in scar tissue and away from the
effects of both systemic and intraperitoneal chemotherapy.
There are four techniques by which to perform the HIIC:
closed, partially closed, open and by a peritoneal
expander. In the closed technique the intestinal
anastomoses, the fascia and skin of the abdominal wall are
closed prior to the HIIC. In the partially closed technique
the skin of the abdominal wall is closed with a running
suture. After the chemotherapy treatment the abdominal
skin is reopened and intestinal anastomoses performed.
However, these methods do not guarantee a uniform drug
and heat distribution as shown through radiological exams
and dye studies (Hughes et al, 1992; Elias et al, 2000). The
open technique or “Coliseum technique” (Figure 1) was
described by Sugarbaker and is performed by elevating the
skin edges of the midline abdominal incision on a selfretaining retractor (Sugarbaker, 1999). This method, in
spite of greater heat-loss and the theoretical problem of
environmental chemotherapy contamination, has the
advantage of allowing the surgeon to manipulate the fluid
inside the abdominal cavity in order to optimize heat and
drug distribution. Yonemura et al. also described an open
technique with the help of a peritoneal expander which, as
the coliseum method, permits the surgeon to distribute the
fluid (Yonemura, 2003). The peritoneal expander
technique is performed through the closure of the proximal
and distal portions of the abdominal incision, leaving a
central gap for a plastic cylinder. Through this opening the
surgeon’s hand can manipulate the abdominal contents.
The peritoneal expander is attached to a self-retaining
retractor. This method was designed to accelerate the
heating process inside the abdomen and diminish the heat
loss (De Simone et al, 2003).
Some groups use HIIC and also EPIC in the same
patient; only a few groups utilize EPIC alone as a
preferential route of drug administration (Glehen et al,
2004). HIIC plus EPIC may have some disadvantages
when compared with EPIC alone:
•
Hyperthermia is usually not used in EPIC;
•
Drug distribution depends on gravity;
•
This technique is more associated with a
greater incidence of wound healing complications.
B. Hyperthermia
Hyperthermia alone already has some cytotoxic
properties that can be summarized as follows: inhibition of
angiogenesis, induction of apoptosis, denaturation of
essential proteins, impaired DNA repair and induction of
heat-shock proteins which can be receptors for naturalkiller cells (Christophi et al, 1999; Dahl et al, 1999).
Perhaps more important, chemotherapy has been
shown to be potentiated by hyperthermia. The ideal
temperature for specific chemotherapy agents have not
been precisely determined, but it is between 41oC and
44oC. Above this temperature the heat will be cytotoxic to
non-cancerous cells and cause destruction of the
chemotherapy agents (Shimizu et al, 1991).
Hyperthermia decreases interstitial pressure of the
tumor nodules to a level expected for normal tissues. It
also increases cell membrane permeability allowing a
higher drug concentration inside tumor nodules (Storm,
1989; Leunig et al, 1992; Jacquet et al, 1998). Although
hyperthermic enhancement of penetration deep into the
cancer nodule has only been demonstrated for cisplatin
and doxorubicin, it should occur also with other cytotoxic
drugs (van der Vaart et al, 1998).
Another benefit of higher temperatures is heat
augmentation with selected drugs such as mitomycin C,
cisplatin and doxorubicin (Storm, 1989). Some
chemotherapy
agents
such
as
melphalan,
cyclophosphamide and ifosfamide are synergized by heat
to a great extent (Urano et al, 1999, 2002; Mohamed et al,
2003; Glehen et al, 2004).
C. Technique
The timing of drug delivery can be classified as
preoperative intraperitoneal chemotherapy; intraoperative
intraperitoneal chemotherapy, usually associated with
hyperthermia (HIIC); early postoperative intraperitoneal
chemotherapy (EPIC); and long-term intraperitoneal
chemotherapy (LTIC).
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Cancer Therapy Vol 3, page 303
Figure 1. The “Coliseum technique” for heated intraoperative intraperitoneal chemotherapy.
The
delayed
delivery
of
intraperitoneal
chemotherapy produces the worst results (Sautner et al,
1994). In addition to the disadvantages presented by the
closed technique, in this method the drugs are delivered
after adhesion formation. This not only prevents treatment
of the entire abdominal and pelvic cavity, but also allows
viable tumor cells to become imbedded inside the scar of
healing tissue. Trapped in scar tissue and under the
stimulus of growth factors released by inflammatory cells,
these cancer cells are in a sanctuary site and cannot be
reached by chemotherapeutic drugs (Sugarbaker, 1990;
Sugarbaker, 1996).
The duration of the peritoneal washing with
chemotherapy solution varies greatly. In the HIIC
techniques, this period varies between 60 to 90 minutes.
The volume and flow employed are also differences
encountered among the groups; 3 liters of fluid, with a
flow of 2L/minute can be considered an average (Glehen
et al, 2004).
In the EPIC technique the drug is administered as
fast as possible and remains within the peritoneal cavity
for 23 hours. An additional chemotherapy instillation
occurs the next day. The EPIC usually is performed during
the first five post-operative days. Changes in patient
position facilitate drug distribution.
with complete healing of the abdomen and scar tissue
accumulation after peritonectomy procedures (Sugarbaker
et al, 1990).
The peritoneal-plasma barrier has an important
practical utility since it maintains a high concentration of
the drug inside the peritoneal cavity with a lower plasma
concentration. This diminishes the systemic toxicities that
accompanies cancer chemotherapy treatment. From this
data the ideal drug to be used should have the following
characteristics: high molecular weight, fast systemic
clearance and water solubility. For use as HIIC
augmentation by hyperthermia and non-cell cycle specific
cytotoxicity is desired.
A large number of chemotherapeutic agents have
been used for the treatment of peritoneal surface
malignancies arising from gastrointestinal tumors.
Mitomycin C is the most frequently used agent. The
synergism between hyperthermia and mitomycin C has
been demonstrated in the laboratory. Clinically, it has been
found to be effective in the control of cancer lines with
low growth rates and high chemotherapy resistance such
as the mucinous appendiceal adenocarcinomas
(Sugarbaker et al, 1999).
Five-fluorouracil is an ideal agent to be used in
EPIC, but not in HIIC, since the 5-fluorouracil does not
show augmentation with hyperthermia and its cytotoxicity
is cell-cycle related (Storm, 1989).
Doxorubicin has proven to be an excellent drug to be
used in HIIC. In a rat model, when used at 43oC, this drug
showed a marked deep penetration without increasing
plasma concentrations (Jacquet et al, 1998). These positive
characteristics make this drug an appropriate choice in
many tumors. At high doses and repeated treatments,
peritoneal sclerosis is a limiting factor in dose escalation.
Synergism between cisplatin and hyperthermia has
been shown in several clinical trials. In animal models this
finding was considered to be a consequence of higher and
selective uptake of the drug by the cancer cells (Los et al,
1993). Thus, cisplatin clearly deserves special attention
from investigators for use in HIIC.
D. Drugs
The
pharmacokinetics
characteristics
of
intraperitoneal administration of chemotherapeutic agents
are of great importance in the choice of drugs. Selected
chemotherapy agents have a prolonged retention within
the peritoneal cavity. In 1978 Dedrick and colleagues
demonstrated that the peritoneal clearance of a drug is
inversely proportional to its molecular weight. Further
investigation confirmed that certain agents delivered into
the peritoneal cavity will maintain higher levels inside the
abdomen compared to the plasma levels. This finding is
known as the peritoneal-plasma barrier. This is an
inaccurate nomenclature; even after extensive stripping of
the peritoneal surfaces there are no large changes in the
clearance of the drugs. There is an increase in the barrier
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Goldstein et al: Management of peritoneal carcinomatosis
Oxaliplatin, used for several years in Europe, but
only recently approved in the United States, was the
subject of a pharmacokinetics study by Elias and
colleagues (Elias et al, 2002). Their report showed that this
agent achieved high tumor and intraperitoneal
concentrations without toxic plasma levels. Since this drug
has shown an impact in the systemic treatment of
advanced colorectal cancer, it must be explored in the
treatment of carcinomatosis secondary to colorectal
tumors.
appendiceal adenoma. These tumors may have extensive
intraperitoneal accumulation without local invasion,
lymphatic infiltration or hematogenous dissemination.
Thus, the use of peritonectomy procedures, even in bulky
tumors, can eradicate all macroscopic disease and when
combined with perioperative intraperitoneal chemotherapy
leads to long-term survival.
B. Prior surgery score
The occurrence of prior abdominal surgeries greatly
influences the likelihood of complete cytoreduction.
During surgery, cancer cells free in the peritoneal space
have a tendency to adhere to raw surfaces such as sites of
surgical dissection. These entrapped tumor cells may now
grow along retroperitoneal structures such as the ureters
and the vena cava. Abraided and surgically traumatized
small bowel surfaces also are favored sites for cancer cells
to implant. This deeper non-anatomical cancerous
dissemination caused by prior abdominal surgery
represents a major cause of incomplete cytoreduction and
thus of limited survival. The “Prior Surgical Score” (Table
1) was developed to quantitate the previous surgical
trauma and to estimate the likelihood of a complete
resection (Jacquet and Sugarbaker, 1996). This scoring
system has proved to have a good correlation with
prognosis in patients with mesothelioma (Sebbag et al,
2000) and pseudomyxoma peritonei (Sugarbaker and
Chang, 1999) treated by cytoreductive surgery and
intraperitoneal chemotherapy. Also, primary colon cancer
with carcinomatosis may have a better prognosis that
carcinomatosis with recurrent disease (Pestieau et al,
2000).
Recommendations
regarding
primary
gastrointestinal cancer operations need to change in order
to minimize the prior surgical score.
One must conclude that if unexpected carcinomatosis
is found, modification of the first surgical intervention is
required. For example, if mucinous carcinomatosis arising
from a ruptured appendiceal neoplasm is observed in a
patient thought to have appendicitis, a minimal dissection
should be undertaken. Beyond appendectomy, the surgeon
is advised to aspirate the free mucoid fluid and to perform
generous biopsies to plan a future definitive combined
treatment (Gonzalez and Sugarbaker, 2004). A right
colectomy should not be performed to avoid deep
entrapment of tumor cells in the groove between the psoas
muscle and vena cava. A more common situation is
patients presenting with obstructing colonic malignancies
with peritoneal seeding. If the patient has a good
performance status, the only procedures indicated are a
decompressing ostomy and biopsies.
IV. Quantitative prognostic indicators
When confronted in the operating room with
peritoneal seeding from gastrointestinal cancer, the
surgeon must make a decision regarding the possible risks
and benefits of a definitive treatment versus supportive
care. Although this combined treatment has proven to be
the only possibility of cure for patients presenting with
peritoneal carcinomatosis, one cannot forget the
morbidity, mortality and cost that accompany the
combined treatment. With the combined treatment strategy
a proportion of patients will be free of disease and a
second group will experience a better outcome with longer
survival. However, as in most gastrointestinal cancer
treatments, there will be a group of patients that will be
treated with minimal benefit. The disease will continue to
progress despite the treatment provided; sometimes these
patients will have a worse clinical course due to the
inappropriately excessive treatment. In an attempt to offer
a suitable treatment for individual patients quantitative
prognostic indicators have been developed.
The peritoneal surface malignancy literature supports
three pre-operative quantitative prognostic indicators:
tumor histopathology, radiological features and prior
surgical score. In the operating room after complete
exploration of the abdomen and pelvis, the surgeon has
another prognostic indicator that is an index to measure
the tumor burden within the peritoneal surfaces. This is
called the peritoneal cancer index (PCI). Unfortunately,
the most reliable prognostic indicator to date can be
assessed only after the surgical procedure. The
completeness of cytoreduction score indicates the amount
of tumor that could not be surgically resected.
A. Tumor histopathology
The biologic behavior of the peritoneal surface
malignancy is a major determinant of prognosis in these
patients. Pancreatic adenocarcinomas with peritoneal
seeding exemplify one clinical situation in which
combined treatment is of no known value due the
extremely aggressive behavior of this neoplasm. Gastric
cancer patients represent another major challenge to the
combined treatment since only those presenting small
volume of peritoneal surface disease seems to have an
improved life expectancy. Colon cancer patients are in an
intermediate position. Even though these patients have a
moderate amount of disease, if a complete cytoreduction is
achieved, improvement in life expectancy may be
observed. On the other hand there are the non-invasive
tumors such as pseudomyxoma peritonei arising from an
Table 1. Prior surgical score (PSS)
PSS-0 (none)
PSS-1 (minimal)
PSS-2 (moderate)
PSS-3 (heavy)
304
Biopsy only
Exploratory laparotomy, one region
dissected
Exploratory laparotomy, two to five
regions dissected
Extensive prior cytoreduction, more
than five regions dissected
Cancer Therapy Vol 3, page 305
Only the debilitated patient that will not be a candidate for
the combined approach should undergo definitive
resection.
complete cytoreduction. Masses along the terminal ileum
are common findings and can be resected with the cecum.
These poor prognosis findings suggest a more advanced
disease with an invasive component. Also, the nodules
associated with the small bowel surfaces reflect the failure
of the redistribution phenomenon, usually a result of
previous surgical trauma or from end-stage of the disease.
C. Radiological features
Pre-operative CT of chest, abdomen and pelvis are
performed in invasive tumors such as gastric and
colorectal cancer patients to exclude systemic disease.
Unfortunately, there is no reliable radiological
examination able to predict the intraperitoneal tumor
burden or its distribution in invasive tumors. This lack of
accuracy occurs as a result of the pattern of the cancerous
growth in the peritoneal cavity. In contrast with solid
organs such as the liver in which metastasis grow as
nodules, aggressive cancerous implants spread along the
contours of the peritoneal surfaces. This means that a
negative pre-operative CT may have little value in
quantitating carcinomatosis in invasive tumors (Jacquet et
al, 1993).
In contrast there are non-invasive malignancies for
which CT represents a reliable tool to predict the success
of a complete cytoreduction. In a retrospective analyses
Jacquet et al, (1995) compared patients with mucinous
tumors with complete and incomplete cytoreduction. The
authors identified two radiological findings that were
correlated with incomplete resection:
• Signs of segmental small bowel obstruction
• Tumor masses of 5 cm or greater diameter
associated with the jejunum or the upper ileum or their
mesentery.
The association of both findings in the same patient
indicated a likelihood of less than 5% to achieve a
D. Peritoneal cancer index
The extent of carcinomatosis has proven to be
directly related to the likelihood of a complete
cytoreduction and thus with survival. With the intent to
quantitate the extent of intraperitoneal disease Jacquet and
Sugarbaker described the PCI.
The PCI (Figure 2) is a score obtained in the
operating room with surgical exploration after the release
of adhesions (Jacquet and Sugarbaker, 1996). The
peritoneal space is divided into 13 abdominopelvic regions
as seen in Table 2. Then, the largest tumor nodule within
each anatomical location is measured. A value that goes
from 0 to 3 is given to each of the 13 regions according to
the size of the largest nodule found in the region. The
number of nodules in each area is not counted but only the
size of the largest nodule is registered. Then the PCI is
calculated by the sum of the 13 values recorded; the PCI
will range from 0 to 39 (13x3).
The PCI has two distinct roles. First, it provides an
objective parameter for the surgeon that can be used in the
decision-making process regarding the choice of the most
suitable treatment for an individual patient. Second, the
Figure 2. The “Peritoneal Cancer Index” for staging peritoneal malignancies.
305
Goldstein et al: Management of peritoneal carcinomatosis
Table 2. Description of the anatomic structures included in each of the 13 abdominopelvic regions used to calculate the
Peritoneal Cancer Index (PCI).
Regions
0 Central
1 Right upper
2 Epigastrium
3 Left upper
4 Left flank
5 Left lower
6 Pelvis
7 Right lower
8 Right flank
9 Upper jejunum
10 Lower jejunum
11 Upper ileum
12 Lower ileum
Anatomic structures
Midline abdominal incision – entire great omentum – transverse colon
Superior surface of the right lobe of the liver – undersurface of the right hemidiaphragm – right
retrohepatic space
Epigastric fat pad – left lobe of the liver – lesser omentum – falciform ligament
Undersurface of the left hemidiaphragm – spleen – tail of pancreas – anterior and posterior
surfaces of stomach
Descending colon – left abdominal gutter
Pelvic sidewall lateral to the sigmoid colon – sigmoid colon
Female internal genitalia with ovaries, tubes and uterus – bladder – Douglas pouch –
rectosigmoid colon
Right pelvic sidewall – cecum – appendix
Ascending colon – right abdominal gutter
Including both bowel and its mesentery
Including both bowel and its mesentery
Including both bowel and its mesentery
Including both bowel and its mesentery
PCI is a tool that facilitates standardization of patients
among researches at different institutions for better
communication and evaluation of the results obtained with
the combined treatment.
Despite the detailed information provided by the
PCI, two important caveats are necessary. There are some
patients with low PCI but with very guarded prognosis.
This usually occurs in aggressive tumors with spread
restricted to vital and unresectable anatomic sites such as
the porta hepatis, the ureters, or the small bowel.
A second caveat regarding PCI concerns patients
with non-invasive tumors that even in the presence of high
PCI score can achieve a complete cytoreduction.
Pseudomyxoma peritonei patients may have a large PCI
but should still have definitive treatment. This finding can
be explained in part due to the redistribution phenomenon
and small bowel sparing that occurs in non-invasive
mucus-producing tumors such as pseudomyxoma
peritonei.
With these exceptions in mind, the PCI has
prognostic implications in the survival in patients with
colorectal, gastric and non-mucinous appendiceal tumors
submitted to the combined treatment (Pestieau and
Sugarbaker, 2000; Yonemura et al, 2003; Mahteme and
Sugarbaker, 2004).
Other scores have been described such as the Gilly
peritoneal carcinomatosis staging (Gilly et al, 1994), the
carcinomatosis staging of the Japanese Research Society
for Gastric Cancer (Fujimoto et al, 1997) or the Dutch
simplified peritoneal carcinomatosis assessment (van der
Vange et al, 2000). These scoring systems may be simpler
but lack the precision when compared with the PCI.
As described by experimental studies and confirmed in
clinical trials, when there are large residual nodules
intraperitoneal chemotherapy is unable to eradicate
peritoneal surface disease. Some treatment centers suggest
that residual large nodules present within the peritoneal
cavity indicate that intraperitoneal chemotherapy should
be avoided (Katz and Barone, 2003).
However, minute nodules may be successfully
treated by intraperitoneal chemotherapy. This concept
raises the question of what would be a complete
cytoreduction. Sugarbaker described the completeness of
cytoreduction score (CCS) to measure the amount of
disease left behind (Sugarbaker and Jablonsky, 1995). The
important information for the CCS is not the number of
nodules remaining, but the size of the largest nodules. The
cutoff value used in this score to separate complete from
incomplete cytoreductions is dependent on the penetration
achieved by the chemotherapy into the cancer nodules.
Considering these concepts and the pharmacokinetics
studies Sugarbaker describes the CCS for mucinous
appendiceal malignancy as follows (Figure 3):
• CC-0: no visible tumor
• CC-1: no nodule larger than 0.25 cm
• CC-2: nodules between 0.25 cm and 2.5 cm
• CC-3: nodules larger than 2.5 cm or a layering of
cancer at any site.
Patients with no tumor greater than 0.25 cm (CC-0
and CC-1) after surgery are in the group considered as
complete cytoreduction since chemotherapy can penetrate
these small nodules. However, clinical trials have shown
that patients with CC-2 or CC-3 score have a uniformly
poor prognosis (Sugarbaker and Chang, 1999; Loggie et
al, 2000; Pestieau and Sugarbaker, 2000).
The CCS has proven to be the strongest quantitative
prognostic indicator in gastrointestinal cancer patients
with peritoneal seeding that were treated with the use of
this combined approach independent of the site of origin.
This result has been demonstrated by several
E. Completeness of cytoreduction score
(CCS)
A profound determinant of survival is the volume of
tumor remaining after cytoreductive surgery that will be
treated with perioperative intraperitoneal chemotherapy.
306
Cancer Therapy Vol 3, page 307
Figure 3. Completeness of cytoreduction score (CC score) after cytoreductive surgery.
groups involved in the management of peritoneal surface
malignancies in appendiceal, colorectal and gastric
malignancy (Loggie et al, 2000; Pestieau and Sugarbaker,
2000; Elias et al, 2001; Yonemura et al, 2003; Pilati et al,
2003; Glehen et al, 2004).
One must consider that the CCS should be
individualized according to the site of origin of the
primary cancer, considering that the penetration of the
chemotherapy inside of a tumor nodule is dependent on
the intrinsic interstitial pressure of each malignancy. Thus,
for more aggressive neoplasms such as gastric cancer that
produce hard peritoneal surface nodules, the cutoff value
may be 1 mm or less. More studies are needed to establish
precise CCS for the different gastrointestinal cancer sites.
regimens evolved during the 22 years of the study. Seven
patients treated early in this experience received only
EPIC, while thirteen patients received HIIC mitomycin C
at the end of the surgical procedure plus EPIC (5fluorouracil). Carcinoid syndrome was noted in only one
patient. Survival rates at 2 and 5 years were 39% and 25%
respectively. The PCI and CCS were significant
determinants of survival, but the extent of previous
surgery was not (Mahteme and Sugarbaker, 2004).
The epithelial tumors of the appendix can be divided
into mucus-producing neoplasms and intestinal
adenocarcinomas.
The
last
subtype
represents
approximately 10% of the appendiceal malignancies. Its
biologic behavior is similar to colorectal tumors and
carcinomatosis from this non-mucinous tumor should be
treated as a colonic adenocarcinoma.
The carcinomatosis arising from mucus-producing
appendiceal neoplasms are collectively grouped under the
term “Pseudomyxoma peritonei” due to the characteristic
mucoid ascites. However, these neoplasms do not have a
uniform prognosis. Ronnett and colleagues after their
study of 109 patients with pseudomyxoma peritonei
treated by cytoreductive surgery and intraperitoneal
chemotherapy developed a classification with clear
prognostic value. According to this classification a
minimally
invasive
and
histologically
bland
pseudomyxoma peritonei occurs in patients with mucoid
ascites as a result of ruptured appendiceal adenomas. This
type of peritoneal surface malignancy is referred to as
diffuse peritoneal adenomucinosis (DPAM). This group of
patients presents an excellent prognosis since it is a
disease that is restricted to the peritoneal cavity and thus if
combined treatment is successfully completed it will lead
to cure in 85% of patients. These authors showed, in
contrast, an aggressive behavior of the mucus-producing
adenocarcinomas referred to as peritoneal mucinous
adenocarcinomas (PMCA). There is also a third subtype
that is similar to DPAM but with isolated foci of PMCA,
the “hybrid type” (Ronnett et al, 1995).
Sugarbaker et al, (1999) reported on the treatment of
385 patients with appendiceal mucinous malignancies with
a mean follow-up of 37.6 months. A complete
cytoreduction (CC-0 and CC-1) was obtained in 250
patients. They showed approximately 80% 5-year survival,
while patients with CC-2 or CC-3 cytoreductions reached
V. Results of clinical trials
A. Appendiceal tumors
Appendiceal
malignancies
correspond
to
approximately 1% of all tumors arising from the large
bowel. Three distinct histopathologic tumors have been
described as primary neoplasms from the appendix:
carcinoid, adenocarcinoma and tumors with features from
both, designated adenocarcinoid tumors. Carcinoid tumors
account for approximately two-thirds of all appendiceal
malignancies, however carcinomatosis from this primary
site is exceptional with only one case reported in the
literature (Vasseur et al, 1996).
A small percentage of carcinoid tumors have mucus
producing epithelial cells associated. This uncommon
combined feature is known as adenocarcinoid and
represents less than 5% of all appendiceal tumors.
Adenocarcinoid tumors of the appendix spread frequently
to the peritoneum (Aizawa et al, 2003; Mahteme and
Sugarbaker, 2004). Carcinoid syndrome in these patients is
usually not seen. The limited survival observed in these
patients show that their prognosis is more dependent on
the progression of malignant epithelial cells than on the
carcinoid component. A recent study in the literature
regarding the use of this combined approach for the
treatment of patients with peritoneal carcinomatosis
arising from adenocarcinoid tumors was reported by
Mahteme and Sugarbaker. From 810 patients with
peritoneal malignancy of appendiceal origin treated by
cytoreductive surgery and intraperitoneal chemotherapy,
22 patients (2.7%) had adenocarcinoid. The treatment
307
Goldstein et al: Management of peritoneal carcinomatosis
only a 20% 5-year survival (Figure 4). As expected,
patients with DPAM did better than patients with PMCA
or the hybrid subtype. The prior surgical score also
showed to be an important statistically significant
prognostic indicator. These favorable results are shared by
other groups experienced in the use of the combined
treatment (Table 3).
Appendiceal malignancies with peritoneal seeding
are considered the paradigm for success of the combined
treatment. This good outcome occurs as a result of four
features that are unique for appendiceal tumors
(Sugarbaker and Chang, 1999). First, these tumors
demonstrate a wide spectrum of invasion, with the
majority exhibiting a noninvasive histology. Second, the
appendix has a tiny lumen that is obstructed early in the
development of these tumors leading to perforation and
release of epithelial cells into the peritoneal cavity early in
the natural history of the disease. Symptomatic
carcinomatosis will result in treatment prior to lymph node
or hematogenous metastasis. Third, the texture of
mucinous tumors is compatible with a deep penetration by
the chemotherapeutic agent. Fourth, since these neoplasms
are restricted to the peritoneal cavity, if the residual
microscopic disease is sensitive to the intraperitoneal
chemotherapy all the cancer may be eradicated and the
patient will survive long term.
Figure 4. Influence of complete cytoreduction (CC-0 or CC-1) in the prognosis of patients with pseudomyxoma peritonei from
appendiceal origin treated by peritonectomy procedures and perioperative intraperitoneal chemotherapy. Reproduced from Sugarbaker
and Chang, 1999 with kind permission from Annals Surgical Oncology.
Table 3. Literature review of cytoreductive surgery and perioperative intraperitoneal chemotherapy as a treatment for
mucinous appendiceal tumors with peritoneal dissemination
Author
Year
Institution
Sugarbaker
1999
Witkamp
Piso
Shen
2001
2001
2003
Deraco
Guner
2004
2004
Washington
DC
Amsterdam
Regensburg
WinstonSalem
Milan
Hanover
Loungnarath
2005
Lyon
No. of
Patients
385
Method
5 year
Morbidity
Mortality
MMC
3 year
survival
74%
63%
27%
2.7%
46
17
23
MMC
Cisplatin
MMC
81%
75%
61%
NA
NA
NA
39%
63%
NA
8%
11%
NA
33
28
Cisplatin/MMC
Cisplatin/MMC/
5FU
Cisplatin/MMC
NA
NA
96%
75%
33%
36%
3%
7%
80%
50%
44%
0%
27
308
Cancer Therapy Vol 3, page 309
Esquivel and Sugarbaker showed, (2001) that
patients with relapse of mucinous appendiceal
malignancies should be treated again by the combined
approach. If a complete cytoreduction is achieved at
reoperation then the chance of long-term survival will be
similar to the first intervention. Even a third or fourth
reoperation may have palliative benefit in selected patients
and prolong survival (Mohamed et al, 2003).
The pattern of recurrence after combined treatment
using cytoreductive surgery plus EPIC was described
(Zoetmulder and Sugarbaker, 1996). From 118
consecutive patients evaluated, only three exhibited
metastatic disease. Nine patients developed pleural
disease; however, in all of them the pleural cavity had
been entered by dissection of the hemidiaphragm in the
previous surgery. Two anatomic sites were the most
common places for recurrence: small bowel surface and
left sub-hepatic space along the lesser curvature of the
stomach. Also it was noted that in 52% of the patients that
recurred, disease was present within their abdominal scar.
Of great importance was to the finding that 60% of all
recurrences occurred within suture lines. These data
reinforced the need to perform the intraperitoneal
chemotherapy prior to the intestinal reconstruction and
prior to abdominal closure (Zoetmulder and Sugarbaker,
1996).
decade of time suggest these studies a reliable historical
control group.
Several phase II studies have demonstrated long-term
survival in peritoneal carcinomatosis secondary to
colorectal cancer when the combined treatment modality is
used (Table 4). In 2004, a retrospective multicenter study
reported the experience of 28 institutions used
cytoreductive surgery and perioperative intraperitoneal
chemotherapy (Glehen et al, 2004). The evaluation of 506
patients treated by the combined approach revealed an
overall median survival of 32.4 months when complete
cytoreduction was obtained. Despite differences in the
protocols of the participating centers, the median survival
achieved in this retrospective study was approximately 3
times higher than the historical controls. The majority of
the researchers combine cytoreductive surgery with
hyperthermic intraoperative intraperitoneal chemotherapy
alone. In this study two hundred seventy-one patients
underwent HIIC alone (53.5%), 123 underwent EPIC
alone (24.3%) and 112 (22.2%) were submitted to both
HIIC and EPIC treatments. The chemotherapeutic agents
used were not similar among the centers and neither were
the doses of the drugs employed. In addition, both open
technique and the closed system were used to perform the
intraperitoneal chemotherapy washing.
Even though a better outcome (never seen before in this
group of patients) has been demonstrated by phase II
studies, one could suggest that selection bias would be
responsible for these good results. Only through phase III
studies would this method be definitely validated as
standard of care for these patients. In 2003, Verwaal and
colleagues published the first prospective randomized trial
regarding the combined approach for patients with
carcinomatosis from colorectal cancer (Verwaal et al,
2003). In this study, 105 patients were randomly assigned
to receive systemic chemotherapy (control group) or
cytoreductive surgery plus HIIC followed by the same
systemic chemotherapy employed in the control group.
After a median follow-up of 21.6 months, the median
survival was 12.6 months in the control group and 22.3
months in the experimental group (p=0.032). The
mortality in the experimental group was 8%. This first
clinical trial established the beneficial effect that the
combined treatment might have in peritoneal
carcinomatosis arising from colorectal cancer as compared
to
the
standard
of
care.
B. Colorectal cancer
The natural history of peritoneal carcinomatosis
arising from colorectal tumors is well known and marked
by the lack of improvement with any treatment used. In
1989, Chu and colleagues evaluated 45 colorectal patients
with peritoneal carcinomatosis and found a median
survival of 6 months (Chu et al, 1989). The EVOCAPE-1
study reported a median survival of 6.9 months for these
patients (Sadeghi et al, 2000). More recently, Jayne et al,
(2002) from Singapore related a median survival of 7
months in patients with peritoneal carcinomatosis of
colorectal origin. In these three studies, the 5-year survival
was 0%. In general, the authors of phase II studies that
employ the combined aggressive approach for the
treatment of peritoneal seeding arising from colorectal
malignancies, use these historical controls to evaluate their
results. The similar median survival seen in these three
studies, ranging from 6 to 7 months, the uniform absence
of long-term survivors and consistent survival data over a
Table 4. Results of phase II trials that combined aggressive cytoreduction with perioperative intraperitoneal chemotherapy
for the treatment of patients with carcinomatosis of colorectal origin
Author
Mahteme
Glehen
Shen
Pilati
Glehen
Elias
Pestieau
Verwaal
Journal
Br J Cancer
Br J Surg
Ann Surg Oncol
Ann Surg Oncol
J Clin Oncol
Cancer
Dis Colon Rectum
Br J Surg
Year
2004
2004
2004
2003
2004
2001
2000
2004
309
Median survival
32
32.9
28
18
32.4
35.9
24
21.6
Goldstein et al: Management of peritoneal carcinomatosis
However, many oncologists desire to have a second
randomized trial. Unfortunately, previous experience has
shown that the randomization of patients into this kind of
study can be very difficult. In 1995, Elias designed a
prospective randomized trial involving patients with
colorectal
peritoneal
carcinomatosis.
Systemic
chemotherapy would be used in the control group to be
compared to maximal cytoreduction plus EPIC. He reports
that this trial was rapidly abandoned due to the great
dissatisfaction with inclusion criteria in six of the first
seven eligible patients; the patients were fully aware of the
futility of the control arm of the study. Then, the design of
the trial was modified. The control group would now
receive maximal cytoreductive surgery and systemic
chemotherapy while the experimental arm would be
treated by cytoreductive surgery and EPIC plus similar
systemic chemotherapy. However, during the 4 years of
study only 35 patients were enrolled in this phase III
randomized study in spite of the 90 patients that were
necessary. There were enough eligible patients, but most
of them refused to be randomized in the trial. They asked
to be enrolled in the phase I-II trials involving HIIC (Elias
and Pocard, 2003; Elias et al, 2004).
The experience of this French group reflects a
changing proactive behavior of patients who refuse to be
randomized in a control group with well-known
established poor prognosis. Future trials will probably be
designed to standardize the most effective features of the
combined approach instead of denying an effective
treatment for the control group.
However, one should not assume that this combined
treatment is suitable for all patients with peritoneal
carcinomatosis arising from colorectal cancer. As in all
surgical treatments for cancer it is important to exercise
proper patient selection. Several quantitative prognostic
indicators have been identified. For colorectal tumors
there are two prognostic indicators that have shown to be
reliable; the PCI and the CCS.
In patients with colorectal carcinomatosis, Pestieau
and Sugarbaker reported that a PCI of 10 or less was
associated with a five-year survival rate of 50%; a PCI
between 10 and 20 carried a 5-year survival of 15%; a PCI
greater than 20 resulted in no 5-year survivals (Pestieau
and Sugarbaker, 2000). Elias in 2001, also using
mitomycin C as the intraperitoneal chemotherapy agent,
reported an improved prognosis when the PCI was lower
than 16. Patients with PCI below 16 had a 3-year survival
rate of 60.3% versus 32.5% in patients with PCI above this
cutoff (Elias et al, 2001). More recently, the same French
group using intraperitoneal oxaliplatin combined with
systemic 5-fluorouracil and leucovorin used a PCI of 24 to
separate patients with good prognosis from those with
restricted long-term survival (Elias et al, 2002). These
studies demonstrate that the PCI be used to separate
patients who are likely to benefit from this aggressive
combined treatment from those patients who should be
treated with palliative intent. The numerical value for this
PCI cutoff must be determined for a particular treatment
regimen in a specific carcinomatosis disease state. In other
words the critical PCI for colorectal cancer, gastric cancer
and appendiceal cancer will all be different. Most likely,
the more aggressive the cancer and the more heavily
pretreated the patient, the lower the PCI that will be
associated with long-term survivors.
The second quantitative prognostic indicator of
predictive value in colorectal carcinomatosis in CCS. In
the multicentric analysis performed by Glehen, the
actuarial survival rate at 1-year, 3-years and 5-years for
patients classified as CC-0 or CC-1 were 87%, 47% and
31%, respectively (Glehen et al, 2004). Shen and
colleagues reported on 77 colorectal cancer patients
treated by the combined approach. The 5-year survival rate
for complete resection of all visible disease was 34% with
a median survival of 28 months (Shen et al, 2004). In
2000, Sugarbaker reported the results of 104 patients with
peritoneal seeding from colorectal cancer. The median
overall survival for patients with complete cytoreduction
was 24 months with a 30% 5-year survival, whereas
patients with incomplete cytoreduction had a median
survival of 12 months and 0% 5-year survival (Pestieau
and Sugarbaker, 2000).
Other prognostic factors to be recognized in
colorectal carcinomatosis patients were the use of
neoadjuvant chemotherapy, lymph node involvement,
presence of liver metastasis, poor histological
differentiation, presence of signet ring cell type and
location of the primary tumor in the rectum. The presence
of these clinical features has been associated with poor
prognosis (Gomez-Portilla et al, 1999; Marcus et al, 1999;
Elias et al, 2001; Carmignani et al, 2004; Glehen et al,
2004; Knorr et al, 2004).
Gomez-Portilla et al, (1999) evaluated 86 patients
with peritoneal carcinomatosis from colorectal origin with
a median follow-up of 36.2 months. These authors showed
that second-look operations were more likely to be
successful if patients had a complete cytoreduction at the
time of first surgery. They concluded that second-look
surgery should be considered a treatment option in patients
who could fulfill two criteria: First, they had a complete
initial cytoreduction and second, a new complete resection
was judged possible (Gomez-Portilla et al, 1999). Similar
findings were reported by Verwaal et al, (2004).
C. Gastric cancer
1. Background and rationale
Among gastrointestinal cancers discussed in this
paper, gastric cancer with peritoneal seeding deserves
special attention because of its aggressive behavior and
short median survival. In most gastric carcinomatosis
patients this new combined treatment should first of all be
considered a good palliation; in a small percentage of
patients hope for cure may be realistic.
A review of multiple journal articles over the last 20
years supports palliative resections, even total gastrectomy
if necessary, as the treatment of choice in selected patients
with stage IV gastric cancer (Table 5). Complete removal
of the primary cancer has a statistically significant
improvement not only in survival, but also a better quality
of life for these patients.
The rationale for palliative resection of the primary
gastric cancer is to eliminate the serious complications that
can result from the primary malignancy. These are most
310
Cancer Therapy Vol 3, page 311
Table 5. Journal articles since 1980 from English literature supporting palliative gastrectomy
Reference
Ekbom and Gleysteen a
Location
Milwaukee, WI
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Washington, DC
Meijer et al. a
Amsterdam, Netherlands
Boddie et al. b
Houston, TX
Bozzetti et al.
Milan, Italy
Hallissey et al.
Birmingham, UK
Butler et al. a
Haugstvedt et al b
Monson et al. a
Torrance, CA
Norway
Rochester, NY
Ouchi et al. a
Natori, Japan
Kikuchi et al.
Kanagawa, Japan
a
b
Treatment and no.
No resection, 20
Palliative gastrectomy, 147
No resection, 53
Palliative gastrectomy, 147
No resection, 25
Palliative gastrectomy, 26
No resection, 21
Palliative gastrectomy, 45
No resection, 185
Palliative gastrectomy, 61
No resection, 9,597
Palliative gastrectomy, 884
Palliative total gastrectomy, 27
No resection, 311
No resection, 226
Palliative gastrectomy, 53
No resection, 31
Palliative gastrectomy,64
No resection, 59
Palliative gastrectomy,63
Survival
0% (2 year minimum)
16% (2 year minimum)
P < 0.05
4.2 m (median)
9.6 m
3.6 m (median)
10.4 m
3.0 m
8.0 m
P < 0.001
15.0 m
4.0 m (median)
3.5 m (median)
19.0 m
6.0 m P < 0.01
12.0 m
5.5 m P < 0.0001
12.2 m
Marked symptom relief documented
Marked patients for symptoms and stage
commonly obstruction, perforation and bleeding. Another
rationale for the resection of the primary tumor is more
theoretical. By Skipper’s log-kill hypothesis, if a
significant proportion of the tumor burden is removed,
then both systemic and intraperitoneal chemotherapy are
expected to show a greater response (Skipper et al, 1952).
This may have a particular importance in gastric cancer
because it is a chemotherapy-resistant tumor.
In the absence of liver or systemic metastases, the
primary gastric tumor should not be considered
unresectable prior to laparotomy. As long as the primary
lesion and the organs it invades can be removed without
significant morbidity, an attempt should be made to resect
regardless of size. Leaving the gastric mass behind not
only allows obstruction, bleeding and perforation during
the chemotherapy treatment, but also diminishes the
likelihood of a meaningful response from the
chemotherapeutic drugs. Peritonectomy can be used to
further reduce and, in some patients, even eliminate all
visible carcinomatosis. In this situation, the response to
subsequent intraperitoneal and systemic chemotherapy
should be maximized.
Sugarbaker reported, (1995) the use of five different
peritonectomy procedures for carcinomatosis from gastric
cancer. The goal of these procedures is to reduce the
intraperitoneal burden of tumor to a microscopic level,
which can then be knowledgeably treated by both
intraperitoneal and systemic chemotherapy. The
peritonectomy procedures utilized for gastric cancer
patients have been described previously.
In discussing the peritonectomy procedures for
gastric cancer it needs to be emphasized that these
resections are performed selectively; rarely are all
procedures performed in a single patient. Peritoneum that
is involved by carcinomatosis is removed but normal
peritoneum is spared. Unfortunately, peritoneum on the
small bowel surface invaded by cancer nodules often
cannot be removed.
Yonemura et al, (1999) expanded the visceral
peritonectomy in gastric cancer with peritoneal
dissemination. Beyond a subtotal or total gastrectomy, the
peritonectomy may involve a total colectomy if it proves
to be necessary for removal of gastric cancer implants.
This combination of procedures allows the surgeon to
perform a total parietal peritonectomy and a very
extensive visceral peritonectomy which is limited most of
times by the risk of short bowel syndrome.
Intraperitoneal chemotherapy has as its objective the
eradication of the microscopic residual disease and tiny
tumor nodules that the surgeon cannot see or cannot
remove because of a diffuse involvement of small bowel
peritoneum. Conceptually, the peritoneal cavity may
qualify as a “pharmacologic sanctuary” because
intravenously injected drugs penetrate poorly at this site
(Dedrick et al, 1978). This limited access to peritoneal
implants may be one reason why patients with gastric
cancer presenting with peritoneal seeding respond so
poorly to systemic chemotherapy.
2.
Gastrectomy
chemotherapy
plus
intraperitoneal
In 1988 Fujimoto and colleagues from Chiba, Japan
presented their initial experience in patients with gastric
cancer and peritoneal seeding treated with gastrectomy
and intraperitoneal hyperthermic perfusion with
mitomycin C and misonidazole. All 15 of their patients
tolerated the procedure well. They maintained the
311
Goldstein et al: Management of peritoneal carcinomatosis
temperature inside of the peritoneal cavity at 43oC to
44.5oC (Fujimoto et al, 1988).
One year later the same authors reported on 59
patients that received gastrectomy combined with
intraperitoneal hyperthermic perfusion with mitomycin C
(Fujimoto et al, 1989). Compared with historical controls,
the patients of the protocol showed a statistically
significant improvement in survival (p=0.001). The results
were most impressive in patients who had demonstrated
peritoneal seeding. Median survival of the untreated group
was approximately 6 months. Median survival of the
patients treated with intraperitoneal chemohyperthermia
was approximately 18 months (p=0.001).
In 1990 Fujimura and colleagues from Kanazawa,
Japan reported on continuous hyperthermic peritoneal
perfusion for the treatment of peritoneal dissemination of
gastric cancer. Thirty-one patients with gastric cancer and
peritoneal dissemination received cisplatin and mitomycin
C. All but one of these patients had peritoneal
dissemination assessed as P3. The peritoneal fluid was
heated between 41 oC and 43 oC. A special peritoneal cavity
expander was used in an attempt to improve distribution of
chemotherapy and heat so that the surgeon could
manipulate the small bowel with his hand during the
chemotherapy treatments. Two of their patients survived
more than 2 years (6%).
Noh et al from Seoul, Korea reported on 23 patients
who had gastric resection plus intraoperative
intraperitoneal chemotherapy and early postoperative
intraperitoneal chemotherapy. These patients were
compared to 17 who had no resection and systemic
chemotherapy. Two patients died after resection. The
mean survival in the resection group was 7 months as
compared to 5 months in the non-resection group. These
authors suggested that cytoreductive surgery plus
intraoperative and early postoperative intraperitoneal
chemotherapy appears to be relatively safe and provides
an improved outcome (Noh et al, 1995).
Yu et al from Taegu, Korea reported on the treatment
of 64 patients with resectable stage IV gastric cancer (Yu
et al, 1998). Half of these patients had gastrectomy only
and half underwent gastrectomy plus early postoperative
intraperitoneal chemotherapy with mitomycin C and 5fluorouracil. The median survival was 4.9 versus 27.8
months (p=0.0098).
These reports demonstrate the benefit in gastric
cancer of treating patients with established peritoneal
implants
with
gastrectomy
plus
intraperitoneal
chemotherapy. However new data has supported the use of
peritonectomy procedures in selected patients at the time
of resection of the primary gastric cancer.
3.
Gastrectomy
procedures combined
chemotherapy
plus
with
with hyperthermic intraperitoneal chemotherapy for the
treatment of gastric cancer with peritoneal dissemination.
In 1991, these authors published results on 41 patients
with peritoneal dissemination of gastric cancer in the
absence of liver metastasis. The overall median survival
was 14.6 months with a 3-year survival in 4 patients
(9.8%). The procedure also had a favorable impact on the
relief of symptoms. In 7 of 9 patients who had ascites, the
ascites disappeared after continuous hyperthermic
peritoneal perfusion. These authors suggest that
continuous hyperthermic peritoneal perfusion with
mitomycin C and cisplatin is of benefit in the treatment of
gastric cancer patients with peritoneal dissemination
(Yonemura et al, 1991).
Yonemura and colleagues updated their experience in
1995. They reported on 43 patients who had
peritonectomy in addition to continuous hyperthermic
peritoneal perfusion with mitomycin C, cisplatin and
etoposide. Patients who had a complete cytoreduction had
a mean survival of 419 days, a 1-year survival of 61% and
a 5-year survival of 17%. Patients who had residual
disease had a mean survival of 205 days, a 1-year survival
of 30% and a 5-year survival of 2%. The survival of
patients with complete cytoreduction (n=28) as compared
to patients with residual disease (n=55) was significantly
different (p=0.034). Twenty-eight patients underwent a
second-look surgery. In 8 patients who had a complete
response recorded at the time of the second-look
operation, there was a 47% five-year survival. These
authors concluded that chemotherapy was most effective
in those patients who had a small tumor burden as a result
of cytoreductive surgery because this is the clinical
situation in which there is a maximal response to
chemotherapy. They suggested that cytoreductive surgery
and continuous hyperthermic peritoneal perfusion are an
effective treatment strategy for peritoneal dissemination of
gastric cancer (Yonemura et al, 1995). The findings of this
study also show that the results of treatment are greatly
affected by proper patient selection.
In 1995 these authors updated this information
reporting on the effects of this treatment in 83 patients
(Yonemura et al, 1995). The overall one-year survival was
43% and 5-year survival was 11%. Again, patients who
underwent a complete cytoreduction survived significantly
longer than those with residual disease and those with a
complete response to chemotherapy as observed at the
time of the second-look operation survived longer than
those with a partial response or no response.
Hirose et al, (1999) from Fukui, Japan, reported on
hyperthermic peritoneal perfusion to treat gastric cancer
with peritoneal metastasis in 17 patients. Patients given the
combined treatment had a significantly better survival than
20 control patients. There was an 11-month versus 6month median survival time and a one-year survival rate
of 44% versus 15% (p=0.00479). All 5 patients who had a
complete cytoreduction prior to continuous hyperthermic
peritoneal perfusion survived more than 14 months. A Cox
multivariate regression analysis showed that complete
resection of localized peritoneal metastasis was an
independent prognostic factor (p=0.0062). In these
patients, continuous hyperthermic peritoneal perfusion
peritonectomy
intraperitoneal
In theory and in practice, the more complete the
surgical eradication of gastric cancer prior to initiation of
chemotherapy, the greater the likelihood of cancer
eradication.
Yonemura and colleagues are the pioneers in the
combination of gastrectomy plus cytoreductive surgery
312
Cancer Therapy Vol 3, page 313
was not a statistically independent prognostic variable
(Hirose et al, 1999).
Yoo and colleagues reported the effectiveness of
early postoperative intraperitoneal chemotherapy on 91
patients with stage IV gastric cancer. Additional cycles of
intraperitoneal chemotherapy were administered on a
monthly basis for four cycles. The results were compared
with those from 140 historical controls who had surgery
only. The overall 3-year survival in the group treated with
chemotherapy was 17.5% and in the surgery alone group it
was 11.4% (Yoo et al, 1999).
advantage was not seen in three studies, but the trend with
small number of patients was for benefit with adjuvant
intraperitoneal chemotherapy. Moreover, peritoneal
recurrence was shown to be lower in two study groups
treated with perioperative intraperitoneal chemotherapy
(Hamazoe et al, p=0.0854; Fujimoto, p<0.0001). Taken
together, these reports strongly suggest improved overall
survival in the adjuvant-treatment group, which received
chemotherapy given intraoperatively or immediately
following surgery, as compared with patients who
underwent gastrectomy alone.
Of interest is a report by Sautner and colleagues who
randomized patients to receive or not receive
intraperitoneal cisplatin between postoperative days 10
and 28 after gastrectomy. No improvement in survival was
seen (Sautner et al, 1994). It has been suggested that both
the route (intraperitoneal vs systemic) and the timing
(perioperative vs delayed) of this surgically directed
chemotherapy were crucial factors in the benefits observed
in adjuvant gastric cancer trials (Sugarbaker et al, 1990).
The negative results of the Sautner study supports the
tumor cell entrapment hypothesis as an important factor of
failure in the treatment of peritoneal seeding. This study
was not included in Table 6 or in the meta-analysis since
it did not adhere to the principles required for the adequate
treatment of peritoneal surface malignancies.
Certain groups of randomized patients benefited more
from perioperative intraperitoneal chemotherapy than
other groups. A study by Ikeguchi and colleagues did not
show statistically significant benefits for all patients of the
trial. However, in 72 patients who had 1-9 positive nodes,
the survival rate was 44% in the control group and 66% in
patients treated by intraperitoneal chemotherapy (Ikeguchi
et al, 1995). In the study by Yu et al, (1998) patients with
N2-positive lymph nodes had 5-year survival rate of 15%
in the control group and 44% in patients treated by
intraperitoneal chemotherapy (p=0.03). Patients with
lymph nodes positive for gastric cancer may be at special
risk for local-regional cancer dissemination, which
perioperative intraperitoneal chemotherapy can eradicate.
Investigators must use some caution when interpreting the
results of these randomized studies of adjuvant
perioperative intraperitoneal chemotherapy. Because of
the difficulty of accurately staging patients prior to
treatment, some patients with resectable stage IV cancer
were included in the randomization. Therefore, true
adjuvant results are combined with the use of
intraperitoneal chemotherapy in patients with stage IV
cancer who were able to have a gastrectomy.
These eight prospective randomized trials for the adjuvant
treatment of gastric cancer may be suitable for metaanalysis. They involved only patients with a well-defined
clinical entity: resectable gastric cancer without visible
peritoneal seeding. They represent all randomized clinical
trials that have been presented to date, with no exclusions.
Also, the trials were sufficiently similar in terms of
treatment to make the calculation of average effects
medically meaningful. The average treatment effect has a
hazard ratio of 1.75. In other words, a patient with
resectable gastric cancer treated by gastrectomy plus
perioperative intraperitoneal chemotherapy was almost 2
4. Prevention of peritoneal carcinomatosis in
patients with gastric cancer treated with intent to
cure
Analyses of recurrence patterns after potentially
curative resections of primary gastric cancer have shown
that local and intra-abdominal sites of progressive disease
have an impact on survival. They are the only site of first
recurrence in approximately 50% of patients. Even at
death, the tumor often remains confined to the abdomen
(Gunderson and Sosin, 1982; Wisbeck et al, 1986; Landry
et al, 1990). The anatomic sites of treatment failure with
postoperative systemic adjuvant chemotherapy treatments
or neoadjuvant chemotherapy are essentially the same as
those observed after surgery alone (Bruckner and Stablein,
1983; Wils, Meyer and Wilke, 1994). After extended
lymphadenectomy, the peritoneal surfaces and the liver
remain the major sites of recurrence; the rate of localregional relapse is considerably lower when compared to
recurrence patterns with more limited surgery (Maruyama
et al, 1987; Kaibara et al, 1990; Korenaga et al, 1992).
From this analysis of the clinical data on surgical
treatment
failure,
perioperative
intraperitoneal
chemotherapy as an adjuvant to surgery may be
considered a rational therapeutic modality. There is a
strong theoretical basis for the use of perioperative
intraperitoneal chemotherapy as a planned part of primary
gastric cancer surgery. The tumor cell entrapment
hypothesis suggests that surgical manipulation of the
cancerous stomach, transection of lymphatic channels and
blood loss from the cancer specimen result in free
intraperitoneal cancer cells. These cells become fixed in
fibrin and tumor progression is enhanced by the woundhealing process. All available data indicate that gastric
cancer cells present in the peritoneal cavity are always
lethal (Boku et al, 1990; Fujimura et al, 1997; Bando et al,
1999; Kodera et al, 1999).
Eight studies were identified reviewing publications
over the last 20 years in the English language that reported
on the use of perioperative intraperitoneal chemotherapy
in patients who had potentially curative resection of their
primary gastric cancer. Perioperative chemotherapy was
used during the surgical procedures in seven studies and
immediately after surgery in one trial. All eight studies
were prospective and randomized.
Table 6 shows statistically significant data for a 3year survival rate (p=0.01) in one study (Fujimura et al,
1994) and a 5-year survival rate in the three other studies
(Hamazoe et al, p=0.02; Yu et al, p=0.0278; and Fujimoto
et al, p=0.0362). A statistically significant survival
313
Goldstein et al: Management of peritoneal carcinomatosis
Table 6. Eight reports of adjuvant treatment with perioperative intraperitoneal chemotherapy in gastric cancer having an R0 resection*.
Reference
Location
Koga et. al.
Yonago
No. of patients
study/
control
26/21
Hamazoe et al.
Yonago
42/40
Fujimura et al.
Kanazawa
22/18
Yonemura et
al.
Ikeguchi et al.
Kanazawa
79/81
Yonago
78/96
Yu et al.
Taegu
125/123
Fujimoto et al.
Chiba
71/70
Kim et al.
Seoul
52/51
Survival rates % study/
control
P
NS
Study/
control
morbidity %
3.1/7.1
Study/
control
mortality %
NA
2.5-year
83/67.3
5-year
61.3/52.5
3-year
68/23
3-year
55/38
5-year
51/46
5-year
54.1/38.1
5-year
69/55
5-year
34.6/31.4
0.02
4.8/7.50
0
0.01
36/NA
0
0.05
2
NS
3/2.5
3/2.5
1.2/2.08
1.2/2.08
28.8/20.3
6.4/1.6
2.81/2.85
0
NA
NA
0.02
78
0.03
62
NS
* Negative margins of excision and absence of disseminated disease.
NA, not available; NS, not significant
more times more likely to survive 5 years than a patient
treated by gastrectomy alone.
According to these survival data, cure after resection
of gastric cancer increased significantly in five of eight
trials and showed a trend toward improvement in the other
three when adjuvant perioperative intraperitoneal
chemotherapy was used. This is in sharp contrast with a
previously published meta-analysis of adjuvant systemic
chemotherapy randomized trials (Hermans et al, 1993).
The advantages of adjuvant intraperitoneal chemotherapy
were especially evident in patients with stage III gastric
cancer.
Regional chemotherapy used in such a manner can
not be expected to effectively eradicate disease left behind
in lymph nodes. It is likely that extended lymph node
dissection is necessary to obtain the beneficial effects of
perioperative intraperitoneal chemotherapy. This treatment
is designed to eradicate microscopic residual disease
present in peritoneal cavity after cancer resection. From a
conceptual perspective and from clinical trials data,
perioperative intraperitoneal chemotherapy alters the
pattern of dissemination after potentially curative gastric
cancer surgery, but is not a treatment for residual disease
in lymph nodes or systemic metastasis.
Selection of patients needs to involve not only
quantitative prognostic indicators of carcinomatosis but
also the performance status of the patient. Acceptable
nutritional status and renal, hepatic, pulmonary and
myocardial function must be present. The clinical
judgment and experience of the surgeon is subjective, but
extremely important. As might be expected the rates of
morbidity range from 10% to 54%. Mortality rates vary
from 1.5% in series with large number of patients to above
10% in small series. A long and steep learning curve exists
in this group of patients (Table 7).
Two large studies conducted in specialized centers
involved in the treatment of peritoneal carcinomatosis
reported their morbidity and mortality secondary to the
combined procedure. Stephens and colleagues, in 1999,
reviewed 200 consecutive patients with peritoneal
carcinomatosis from a variety of origins treated at the
Washington Cancer Institute. The authors reported a
combined grade III/IV morbidity rate of 27%.
Peripancreatitis, intestinal fistula, postoperative bleeding
and hematological toxicity were the most common serious
complications. The mortality rate was 1.5% (Stephens et
al, 1999). In another extensive study, Glehen and
colleagues studied 216 consecutive patients who
underwent cytoreductive surgery combined with closed
abdominal hyperthermic perfusion. The postoperative
morbidity and mortality were 24.5% and 3.2%,
respectively. Intestinal fistulas (6.5%) and hematological
toxicity (4.6%) were the principal causes of serious
complications (Glehen et al, 2003).
Both of these studies identify the extent of the
surgical procedure as the most important variable
associated with morbidity and mortality. Duration of
surgery, number of peritonectomy procedures and
VI. Morbidity and mortality
Intuitively, one would expect that the morbidity and
mortality would correlate with the magnitude of the
surgery. Considering that cytoreductive surgery is a
prolonged series of surgical dissections and extensive
reconstructions one should expect a high rate of
complications. Two other variables may contribute to
increase the incidence of complications: retarded wound
healing associated with perioperative intraperitoneal
chemotherapy and the hyperthermia.
314
Cancer Therapy Vol 3, page 315
Table 7. Morbidity and mortality after cytoreductive surgery and intraperitoneal perioperative chemotherapy
Author
Stephens
Beaujard
Elias
Witkamp
Butterworth
Verwaal
Glehen
Elias
Pilati
Glehen
Glehen
Guner
Zanon
Deraco
Glehen
Shen
Journal, year
Ann Surg Oncol,
1999
Cancer, 2000
Cancer, 2001
Br J Surg, 2001
Am J Surg, 2002
J Clin Oncol, 2003
J Clin Oncol, 2003
Gastroenteral Clin
Biol, 2003
Ann Surg Oncol,
2003
Ann Surg Oncol,
2003
J Clin Oncol, 2004
Int J Colorectal Dis,
2004
World J Surg, 2004
Ann Surg Oncol,
2004
Br J Surg, 2004
Ann Surg Oncol,
2004
N
200
Morbidity (%)
27
Mortality (%)
1.5
83
64
46
11
48
56
36
9.6
54.6
39.1
56
66
28.6
44
3.6
9.3
8.7
9
8
1.8
13.8
46
35
0
216
24.5
3.2
506
28
22.9
36
4
2/28
30
33
16.7
18
3.3
3
53
77
23
30
4
12
resections, number of sutures lines and carcinomatosis
stage were variables associated with major complications.
In another study, Elias and colleagues reported that the
rate of complication was directly correlated with the PCI.
In this series, the rate of reoperations was 28.8%. The
more extensive the disease as estimated by the PCI, the
higher was the rate of complications (Elias et al, 2001). In
the multicentric study of patients with peritoneal seeding
from colorectal cancer, Glehen showed association
between EPIC and major complications (Glehen et al,
2004).
Experimental studies showed that the 5-fluoruracil
diminished the strength of suture lines (Fumagalli et al,
1991; Graf et al, 1992; van der Kolk et al, 1999; Haciyanli
et al, 2001). Recently, Haciyanli and colleagues reported
that the administration of 5-fluoruracil for 5 days after the
surgery in rats results in higher rates of anastomotic
complications, reductions in anastomostic breaking
strength and hydroxyproline content when compared with
rats without infusion of intraperitoneal 5-FU (Haciyanli et
al, 2001). In another study, Fumagalli et al, (1991) studied
the role of mitomycin C on healing of intestinal
anastomosis in rats. After 7 days of surgery the animals
were killed. The rate of anastomotic fistula was 52.8% in
the intraperitoneal group, 20% in the intravenous-group
and none in the control group (Fumagalli et al, 1991).
These studies and the data of clinical trials support the
recommendation to avoid multiple anastomoses whenever
possible and avoid anastomoses altogether in high risk
groups.
In addition to anastomotic fistula, postoperative
perforation of traumatized small bowel is a condition to be
actively prevented. During the cytoreductive surgery the
small bowel may require extensive manipulation to divide
intestinal adhesions and multiple resections of cancer
implants on its serosal surface. The seromuscular layer of
the small bowel may be weakened by electrosurgical
dissection; the systemic effects of chemotherapy damage
the submucosa and mucosa layers of the small bowel.
These combined surgical and chemotherapy-induced
injuries may at least in part explain the high level of bowel
perforations described in the clinical studies.
In 1994 Fernandez-Trigo and Sugarbaker studied 33
gastrointestinal fistulas in patients who had extensive
gastrointestinal surgery and EPIC. There were 11 (35%)
anastomotic leaks and 22 (65%) sidewall bowel
perforations. The definitive diagnosis of a fistula was
made on average at day 14 postoperatively. The most
common site of fistula was the ileum or colorectal
anastomosis. The perforations occurred with more
frequency in the small bowel than in stomach or large
bowel. From the patients presented in this study 84%
required further surgical procedures for sepsis control
(Fernandez-Trigo and Sugarbaker, 1994). In another study,
Murio and Sugarbaker, (1993) identified prior bowel
obstruction and prior intraabdominal chemotherapy as
significant risk factors for fistula development after the
cytoreductive surgery.
The retrospective multicenter study reported that
intestinal fistula was the main complication among 509
patients treated by the combined approach with a rate of
8.3% (Glehen et al, 2004). Also, this complication was
present in seven of the twenty postoperative deaths
reported. Intestinal fistula rates varied from 1.3% to 22.2%
(Table 8).
315
Goldstein et al: Management of peritoneal carcinomatosis
Table 8. Incidence of intestinal fistula and hematological toxicity associated with cytoreductive surgery and intraperitoneal
intraoperative chemotherapy.
Complication
Author
Stephens, 1999
Beujard, 2000
Witkamp, 2001
Elias, 2001
Butterworth, 2002
Verwaal, 2003
Glehen, 2003
Pilati, 2003
Elias, 2003
Glehen, 2003
Guner, 2004
Zanon, 2004
Deraco, 2004
Ghehen, 2004
Shen, 2004
Intestinal fistula
n (%)
9/200 (4.5)
2/83 (2.4)
6/46 (13)
12/64 (18.7)
Hematologic toxicity
n (%)
8/200 (4.0)
3/83(3.6)
22/46 (47.8)
2/64 (3.1)
2/11 (18.1)
19%
2/56 (3.6)
4/46
7/36 (19.4)
10/216 (4.6)
2/28 (7.1)
1/30 (3.3)
7/
12/506 (2.4)
15/77 (19)
7/48 (15)
7/56 (12.5)
2/46
8/36 (22.2)
14/216 (6.5)
3/28 (10.7)
1/30 (3.3)
2/33 (6)
42/506 (8.3)
1/77 (1.3)
In the prospective protocol used by Verwaal and
colleagues the administration of a high dose of mitomycin
C (35 mg/m2) was required. This may explain in part the
15% incidence of intestinal fistula (Verwaal et al, 2003).
In another study with high rate of intestinal fistula
(22.2%), oxaliplatin was the drug used (Elias et al, 2002).
The high dosage or the type of intraperitoneal
chemotherapy may contribute to an unexpected high
incidence of anastomotic dehiscence and fistula.
The role of the type of irrigation technique (open
versus closed) on the rate of anastomotic fistulas is
controversial. The open technique has the theoretical
advantage to distribute the heated chemotherapy solution
more uniformly (Sarnaik et al, 2003). Stephens reported a
rate of 4.5% of intestinal complications with the open
“Coliseum Technique” (Stephens et al, 1999). However,
possible disadvantages of a non-uniform heated irrigation
on the anastomosis was not observed in the Glehen study
which showed similar rate of intestinal fistula (6.5%)
using the closed technique (Glehen et al, 2003).
The timing of development of intestinal fistulas in
patients who underwent intraperitoneal chemotherapy can
be later than usual in other operations on the
gastrointestinal tract. In the study of Glehen et al, (2003)
the mean time of occurrence of these fistulas was the
sixteenth postoperative day.
Another major concern regarding combined
treatment relates to the hematologic toxicity of
intraperitoneal chemotherapy. The rate of hematological
toxicity varies considerably between series. It depends on
the chemotherapy dosage used and the extent of stem cell
damage from prior systemic chemotherapy treatment
(Schnake et al, 1999). The higher the dosage, the higher
the rates of toxicity. Postoperative hematological toxicity
rates varied among these studies from 3.1% to 47.8%. It is
important to note that the toxicity due to chemotherapeutic
agents may occur early in the postoperative course. In the
study of Shen and colleagues, the two patients that died as
a consequence of bone marrow suppression developed this
Dosage/drug
10/12.5 mg/m2/MMC
10 mg/L/MMC
35mg/m2/MMC
10 mg/m2/MMC
Max 70 mg/MMC
Max 60 mg/MMC
26.2 mg (median)/MMC
460 mg/m2/oxaliplatin
Max 60 mg/MMC
12.5 mg/m2
Cisplatin
30-40 mg/m2/MMC
complication within 72 hours
chemotherapy (Shen et al, 2004).
after
intraperitoneal
VII. Quality of life
The quality of life after cytoreductive surgery plus
perioperative intraperitoneal chemotherapy has been
evaluated in only a few studies. Although this combined
approach may confer long term survival for a proportion
of patients suffering from peritoneal carcinomatosis
secondary to invasive cancers, in a large percentage of
patients it will be a palliative procedure. Especially in
patients treated with palliative intent the quality of life is
an important consideration.
McQuellon and colleagues reported on quality of life
data prospectively obtained from 64 consecutive patients
treated by the combined approach for peritoneal
carcinomatosis. Within 3 to 6 months after the surgery, the
quality of life, measured by questionnaires, returned to
baseline (McQuellon et al, 2001). From the same group of
patients, McQuellon focused on 17 patients who had
survived more than 3 years after the cytoreductive surgery
and hyperthermic intraperitoneal chemotherapy. Ten
patients (65.5%) described their health as excellent or very
good; 4 (25%) as good; and 2 (13%) as fair. In 94% of
cases, no limitations on moderate activity were reported.
When the authors analyzed the life satisfaction of the
patients since their treatment, 76% indicated that
everything was different, but better after the treatment
(McQuellon et al, 2003).
Schmidt and colleagues, (2005) assessed the quality
of life in 25 patients who were alive following treatment
by cytoreductive surgery and heated intraperitoneal
chemotherapy. The mean duration for these assessments
following surgery was 4 years. The global health status
score was 62.6% in the study group and 75.3% in the
general population. The differences were not significant
(p=0.07). However, there was a definite trend towards
reduced quality of life in treated patients. Symptoms of
nausea and diarrhea were significantly more frequent in
316
Cancer Therapy Vol 3, page 317
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Esquivel J and Sugarbaker PH (2001) Second-look surgery in
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Fernadez-Trigo V and Sugarbaker PH (1994) Diagnosis and
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Flessner MF, Dedrick RL and Schultz JS (1984) A distributable
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Fujimoto S, Shrestha RD, Kokubun M, Kobayashi K, Kiuchi S,
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