Evidence-based medicine in the treatment of ... - Alfredo Garofalo

Evidence-based medicine in the treatment of peritoneal
carcinomatosis: past, present and future
Aviram Nissan 1 , Alexander Stojadinovic 2 , Alfredo Garofalo 3 ,
Jesus Esquivel 4 , Pompiliu Piso 5
From:
1. Department of Surgery, Hadassah Hebrew University Medical Center Mount Scopus,
Jerusalem, Israel.
2. Department of Surgery, Division of Surgical Oncology, Walter Reed Army Medical
Center, and the United States Military Cancer Institute, Washington, D.C., USA.
3. Director, Department of Surgical Oncology, Digestive Branch, National Cancer
Institute “Regina Elena”, Rome, Italy.
4. Director, Peritoneal Surface Malignancy Program, Depratment of Surgery, St. Agnes
Hospital, Baltimore, Maryland, USA.
5. Leitender Oberarzt, Klinik und Poliklinik für Chirurgie der Universität Regensburg,
Regensburg, Germany.
Correspondence:
Aviram Nissan, M.D.
Department of Surgery
Hadassah-Hebrew University Medical Center Mount Scopus
P.O.B. 24035
Jerusalem, 91240 Israel.
Tel: 011-972-2-5844550
Fax: 011-972-2-5844028
e-mail: anissan@hadassah.org.il

Introduction
In order to discuss the rational for the treatment of peritoneal surface
malignancies it is imperative to define the problem, its magnitude, and understand its
underlying biology and pathophysiology.
Peritoneal carcinomatosis (PC) is defined as the spread and implementation of
cancer cells in the peritoneal cavity resulting in malignant tissue deposits involving
parietal peritoneum surfaces or the visceral peritoneum lining abdominal and pelvic
organs. Peritoneal carcinomatosis may be associated with accumulation of fluid in the
peritoneal cavity containing cancer cells, a condition known as malignant ascitis
(MA).
Primary neoplastic diseases of the peritoneum are rare and include peritoneal
mesothelioma and primary peritoneal carcinoma. However, Peritoneal metastasis
originating from colorectal carcinoma, ovarian carcinoma, gastric carcinoma,
pancreatic carcinoma, and appendiceal carcinoma are more common [1]. Peritoneal
surface malignancies (PSM) can present in the form of MA, multiple small tumor
nodules, tumor masses in various sizes, layers of tumor tissue enveloping peritoneal
surfaces and organs, or mucin deposits, a condition known as pseudomyxomaperitonei
(PMP).
Pathophysiology
The peritoneum is a thin layer of mesothelial cells supported by a network of
lymphatics and blood vessels. The pathophysiology and the molecular mechanisms
underlying the formation of PC are generally unknown. Metastatic tumor deposits
spread within the peritoneal cavity by a different and unrelated mechanism compared
to the hematogenous spread of malignant diseases resulting in visceral metastasis or
lymphatic spread of tumor cells resulting in regional lymph node metastasis. Several
theories were proposed to explain the formation of PC [2].
A "tumor rupture" physical theory was proposed by several investigators.
According to the "tumor rupture" theory, a tumor of gastrointestinal or gynecological
origin infiltrating the serosal layer can exfoliate neoplastic cells into the peritoneal
cavity , resulting in PC; this process can be made easier by the surgical manipulation.
[3,4]. Although this theory may applied to some tumors, such as ruptured
gastrointestinal stromal tumors (GIST) or other large solid tumors, it is very difficult
to explain how low rectal cancers with no direct communication to the peritoneal
cavity can still result in PC. Also the observation that the incidence of PC following
perforated adenocarcinoma of the colon is not significantly different than the
incidence of PC following non-perforating tumors contradicts this theory . Exfoliation
of cancer cells from a tumor would create a random pattern of PC. However, in most
cases the pattern of PC spread is predictable [5].
Mucin production is the hallmark of many secondary PSMs. Extracellular or
intracellular mucin secretion by cancer cells is associated with higher incidence of
peritoneal spread. These observations are the basis of the "secretion theory" which
suggests that the peritoneal cavity is a hostile environment for cancer cells and acts as
a barrier for systemic cancer spread. However, secretion of growth factors, nutritional
factors, or other substances alone or embedded in mucinous substance by the tumor

cells, should be able to turn the peritoneal surface from a hostile environment into a
fertile area for the growth of tumor deposits.
Recent studies by Yonemura et al [6,7] provide new histological description of
the peritoneal lymphatic system. They described lymphatic stomata, peritoneal
lymphatic orifices connecting the peritoneal surface with subperitoneal lymphatic
system and the "milky spots", small aggregates of lymphatic vessels, lymphocytes and
macrophages present in the peritoneum and omentum. According to several
independent observations [8-11], cancer cells can pass through milky spots and
lymphatic stomata, to be trapped and proliferate in the subperitoneal lymphatic
system.
In summary, the pathophysiology of PC is a multi step process involving
cancer cells either exfoliated from tumors with direct communication to the peritoneal
cavity or delivered by the lymphatic system into the peritoneal cavity and
submesothelial spaces. Growth factors, angiogenic factors either embedded in mucin
or secreted directly into the peritoneal cavity allow the implementation of cancer cells
on the peritoneal surface. The implementation usually starts in areas rich in lymphatic
stomata such as the greater omentum, diaphragm and pelvis [12].
Epidemiology
Primary PSMs are rare tumors and include peritoneal mesothelioma and
primary peritoneal carcinoma.
Peritoneal mesothelioma is a rare tumor, more common in females than males.
According to the SEER data the overall incidence of mesothelioma in the US is 1.1
cases per 100,000 population at risk and peritoneal mesothelioma consists about 10%-
20% of all mesothelioma cases [13,14]. There are three subtypes of peritoneal
mesothelioma; epithelial, multicystic, and biphasic.
Primary peritoneal carcinoma (PPC), is a papillary carcinoma involving the
peritoneal cavity in the absence of an obvious primary site [15]. It is considered a
variant of ovarian cancer and accounts for 7%~13.8% of ovarian carcinomas [16].
There are three types of PPC; serous papillary carcinoma, mixed epithelial carcinoma,
and malignant mixed Mullerian tumor. Secondary PSMs are more common (table 1),
[17].
Current management
The current treatment of PSM is conducted according to guidelines and
consensus statements based on retrospective data and very few prospective clinical
trials. Since primary PSM is rare, extrapolation of data was obtained from clinical
trials of related disease. For example, the data obtained from clinical trials conducted
on pleural mesothelioma are used to treat peritoneal mesothelioma and the data
obtained from ovarian cancer trials are used for the treatment of PPC [14,17]. These
data should be interpreted with caution, the differences studied in detail and new
treatment guidelines should be established accordingly. However, it is unlikely that
prospective, Phase III, clinical trials will ever be conducted in such rare diseases.

As far as secondary PSM is concerned , despite the larger number of patients
treated, there are very few clinical trials. In PC originating from CRC most patients
are treated either by supportive care with a nihilistic approach or by palliative
systemic therapy regimes obtained from clinical trials reporting the results of
treatment in visceral metastasis and not PC. Surgery is performed only for palliation
or emergencies such as obstruction or perforation. Because of the poor outcome and
the low response rates of PC to systemic therapy, these nihilistic and palliative
approaches are slowly being replaced by a combined modality therapy approach of
cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal
chemotherapy (HIPEC) and systemic therapy [18]. This approach is discussed in
detail below.
The current treatment of gastric cancer is based mainly on surgery combined
with either chemotherapy or chemoradiation in cases were the tumor has not been
spread outside the stomach and regional lymph nodes. Peritoneal spread of gastric
cancer is common and currently treated mainly by systemic therapy. Despite several
clinical trials showing the efficacy of various forms of intraperitoneal (IP)
chemotherapy, this form of therapy is rarely used. The topic of clinical trials
comparing IP to systemic therapy in gastric cancer was recently reviewed by Yan et al
[19].
Adenocarcinoma of the exocrine pancreas is associated with high rates of PC
and with poor outcome. The minority of cases are amenable to surgical resection and
even in the face of R0 resection and administration of systemic adjuvant therapy, the
outcome is poor. Most of the cases are diagnosed at a stage where surgical resection is
futile and are treated either by systemic therapy or best supportive care [20,21]. The
overall 5-year survival rate is 5% and requires novel therapeutic approaches.
Ovarian cancer is usually diagnosed in advanced stages where peritoneal
dissemination is present. The current treatment varies between institutions and
countries. Debulking surgery for PC originating form ovarian cancer is advocated by
many [22]. However, the extent or timing of surgery is controversial and the
definition of "optimal debulking" also varies between institutions [23]. The good
response rates of ovarian cancer to platinum based therapy advocates neo-adjuvant
administration of systemic therapy followed by debulking surgery. However, despite
the good initial response rates, recurrence rates are high and platinum resistant tumors
are unlikely to respond to any current form of therapy. The role of IP therapy in
ovarian cancer was established by several clinical trials. In a recent report of a
prospective randomized clinical trial, IP chemotherapy was found to be superior to
systemic therapy [24]. This disease may be managed with better outcome by
CRS+HIPEC but this approach was never tested in a large scale clinical trial.
The rational for cytoreductive surgery and hyperthermic intraperitoneal
chemotherapy
Surgical therapy was traditionally used for the treatment of primary, nonmetastatic
solid tumors. Successful treatment of epithelial tumors is highly dependent
on their resection with surrounding healthy tissue without involvement of the
resection margins (R0 resection). Surgical treatment of metastasis in the liver, lung or
other organs was shown to be of benefit and was accepted as a standard of care
mainly in colorectal cancer but also in several other kinds of tumor, always respecting
the R0 resection criteria. In traditional surgical oncology the R0 resection concept is
mandatory for successful treatment, but not enforceable in the treatment of PC.

The principles of a new surgical technique for resection of peritoneal surfaces
and organs covered by tumor-bearing visceral peritoneum for the radical treatment of
PSM were first reported by Sugarbaker et al [25], introducing the new concept of
cytoreductive surgery, a new staging system of PC, and a scoring system to define the
completeness of cytoreduction. (CCR) [26]. (Table 2).
Confinement of disease to the parietal peritoneal surface, in absence of
systemic metastasis, was the basis for surgical eradication of disease through
aggressive cytoreduction. However, surgery alone has not achieved significant
improvement in survival in patients with peritoneal carcinomatosis, as grossly
apparent or microscopic disease inevitably remains after even aggressive
cytoreduction [27]. Viable tumor cells become sequestered in avascular intraperitoneal
adhesions explaining the resistance to and the ineffectiveness of systemic
chemotherapy for peritoneal carcinomatosis [28]. Since R0 resection is not feasible in
PSM and the relative tissue concentration of agents delivered systemically is
relatively low in peritoneal tumor deposits, better methods for eradicating residual
peritoneal disease were pursued.
Animal studies showed that the direct intraperitoneal administration of
cytotoxic agents results in significantly higher tissue concentrations as compared to
systemic intravenous administration of the same agents. However, the penetration of
the drugs into the tissue is limited to a 2-3mm superficial layer. The presence of an
anatomic barrier, the peritoneal-plasma partition, has enabled the exposure of the
peritoneal surface to high local concentrations of chemotherapy far in excess of
systemically administered agents when drug delivery is intra-peritoneal [29-34]. High
molecular weight drugs such as Mitomycin C (334 Da), and Oxaliplatin (397 Da),
have favorable pharmacokinetic profiles (AUC peritoneal fluid relative to plasma:
Mitomycin C, 75:1, Oxaliplatin, 25:1) permitting dose-dense intra-peritoneal therapy
over prolonged periods with rapid tissue concentration (in residual tumor deposits and
peritoneum), but limited systemic absorption or toxicity [35-37]. This particular
therapeutic approach addresses the problem of systemic chemotherapy resistance and,
with its reduced systemic toxicity, provides distinct pharmacological advantage over
systemic drug delivery [38, 39].
The cytotoxic effect of hyperthermia is well known. However, effective killing
of cancer cells is only possible at temperatures that will irreversibly damage
surrounding normal tissues. Intra-peritoneal hyperthermia, shown to be technically
feasible [40], was integrated into the treatment paradigm of cytoreduction and intraperitoneal
chemotherapy for peritoneal carcinomatosis in order to increase tissue
penetration and cytotoxicity of the delivered anti-neoplastic agent [41,42].
Hyperthermia itself is cytotoxic mainly by inhibition of functions essential to DNA
replication, transcription and repair [43,44]. However, the combined anti-tumor effect
of heat and intra-peritoneal chemotherapy is the basis for the current treatment
approach to peritoneal carcinomatosis [41,45]. The synergistic killing effects of
hyperthermia (42 0 C-43 0 C) and cytotoxic agents can provide an effective method of
eradicating residual disease up to 2.5mm left in the abdomen after CCR0-1
cytoreductive surgery. Although hyperthermic intra-peritoneal chemotherapy allows
high local drug concentrations to exposed peritoneal surface tumors, one important
limiting factor is the narrow depth of tissue penetration by the delivered cytostatic
agent [46]. Depth of drug peritoneal penetration is limited to ≤ 3 mm from the parietal
peritoneal surface [47,48]. Hence, the efficacy of hyperthermic intra-peritoneal
chemotherapy is inversely proportional to the volume of residual disease; thereby,

therapeutic benefit is maximized when all grossly apparent disease is resected
(complete cytoreduction).
Optimal therapeutic efficacy is achieved when intra-peritoneal heated
chemotherapy is administered immediately following maximal cytoreduction (CCR 0-
1), thereby minimizing trapping of viable peritoneal tumors cells in fibrin and postoperative
adhesions, and maximizing kill of tumor cells shed during resection [49].
Adhesions are lysed during cytoreduction to facilitate uniform distribution of
perfusate, maximize direct contact of drug with residual peritoneal tumor cells, and
harness the advantage of “thermo-chemotherapeutic” anti-tumor synergism [50-52].
Clinical trials: colorectal cancer
Despite advances in early detection of colorectal carcinoma, peritoneal disease
spread continues to be a common mode of disease progression, as 8% of patients with
colorectal adenocarcinoma have synchronous peritoneal spread of disease at time of
primary resection, and up to 25% of patients with recurrent colorectal cancer have
disease confined to the peritoneal cavity [53,54]. Peritoneal carcinomatosis represents
a major treatment challenge in oncology. Once considered a variant of systemic
spread of disease, peritoneal carcinomatosis of colorectal origin was treated with
systemic chemotherapy. Systemic multi-drug chemotherapy has not altered the natural
history of peritoneal carcinomatosis, as patients suffer disease progression and
functional deterioration due to visceral obstruction, malignant ascites and cancer
cachexia over a limited median survival of 6 to 9 months [54-56].
Novel first-line 5-Fluorouracil/Leucovorin-based chemotherapeutic regimens
to treat metastatic (liver and lung) colorectal carcinoma, including Oxaliplatin
(FOLFOX) and Irinotecan (IFL, FOLFIRI) with or without targeted antibody therapy
utilizing Bevacizumab (IFL/Bevacizumab) or Cetuximab, have increased response
rates (figure 1) and median survival (12 months to 20 months) significantly over what
has been the benchmark over the past four decades - 5-FU or 5-FU/LV [57-67].
However, long-term survival for patients with systemic disease spread remains poor,
and the outcomes for patients with advanced disease confined to peritoneal surfaces
treated with these modern agents, indeterminate.
Peritoneal carcinomatosis of colorectal cancer origin has long been considered
to have poor prognosis. A multi-center prospective study determined median survival
in this group of patients to be 5 months [55]. A retrospective analysis of patients with
colorectal carcinoma reported median overall survival of 7 months in patients with
peritoneal carcinomatosis [54]. The therapeutic paradigm to peritoneal carcinomatosis
consisting of cytoreductive surgery followed by hyperthermic intra-peritoneal
chemotherapy has shown promising oncological outcomes.
A recently published multi-center registry study of over 500 patients with
peritoneal carcinomatosis of colorectal origin treated with this approach reported
median overall survival of 19.2 months, and 3- and 5-year overall survival rates of
39% and 19%, respectively [68]. For patients with no macroscopic residual disease
after cytoreduction (CCR0) in that study, 3- and 5-year overall survival was 47% and
31%, with median survival of 32.4 months, similar to outcomes following complete
resection of colorectal liver metastases. Treatment with adjuvant systemic
chemotherapy after cytoreduction and peri-operative hyperthermic chemotherapy was
an independent predictor of improved survival on multivariate analysis. This study,
though retrospective in nature, suggested that improved outcomes were possible with
a combined modality treatment approach incorporating cytoreductive surgery,

egional intra-peritoneal chemotherapy with or without adjuvant systemic therapy in
patients that could otherwise expect limited survival ranging from 5-8 months [53-
55]. Overall survival in a large international registry study was consistent with that
reported in prior smaller Phase II studies of combined cytoreduction and perioperative
hyperthermic intra-peritoneal chemotherapy for peritoneal carcinomatosis
of colonic origin [69-80]. A single-institution, randomized controlled (Phase III) trial
demonstrated the superiority of this combined modality approach for patients with
colorectal peritoneal carcinomatosis over adjuvant systemic therapy with or without
surgical palliation [81].
One hundred five patients with colorectal peritoneal carcinomatosis were
randomly assigned to receive “standard,” 5-FU/LV, systemic chemotherapy or
hyperthermic intra-peritoneal chemotherapy with Mitomycin C (HIPEC; Mitomycin
C, 35 mg/m 2 at 41°C for 90 minutes) following aggressive cytoreduction. After a
median follow up time of 22 months, median survival was increased significantly in
the HIPEC arm of the study: 22.4 vs. 12.9 months; hazard ratio = 0.55: 95% CI, 0.32-
0.95. The analysis was conducted on an intent-to-treat basis and study design required
randomization prior to operation such that only 37% underwent complete
cytoreduction (CCR0); considering that the maximum benefit achieved with HIPEC
comes from a complete cytoreduction, the results of the experimental arm should be
considered underestimated. This was the first randomized trial which showed
survival benefit in patients with colorectal carcinomatosis treated with cytoreduction
and HIPEC when compared to palliative chemotherapy [81]. However, the study
utilized a systemic therapy regimen in the form of 5FU (400 mg/m 2 IV bolus) and
Leucovorin (80 mg/m 2 IV) administered weekly for 26 weeks or until progression,
intolerable toxicity or death, with or without palliative surgery.
The absolute survival benefit of ~10 months in that study was offset by
considerable treatment-related morbidity (Grade 4 morbidity = 45%) and mortality
(8%) in the study arm. A significant proportion of treatment-associated complications
(median operative blood loss 4,000 ml; small bowel fistula, 15%; operative site
infection, 6%; renal failure, 6%; pancreatitis, 2%) have been hypothesized to be due
to the high dose of intra-peritoneal hyperthermic Mitomycin C, which was
administered in the context of the trial. Reductions in intra-peritoneal Mitocycin doses
have been recommended on that basis. Others have demonstrated significantly lesser
treatment-related morbidity (23%-35%) and mortality (0-4%) with HIPEC utilizing
reduced Mitomycin doses [82,83].
The NKI trial demonstrated benefit of cytoreductive surgery with HIPEC for
patients with colorectal carcinomatosis, and it challenged the predominant therapeutic
nihilism that has been the norm for patients with this disease [81]. The actual
contribution of the regional therapy (HIPEC) to the observed survival benefit, despite
the considerable cost in terms of treatment-related morbidity evident in that trial,
remains in question; however, acceptable therapeutic toxicity has been reported in
other studies with relatively lower doses of intra-peritoneal Mitomycin without
apparent compromise in treatment efficacy.
Modern systemic therapy with combination cytotoxic and biological agents
resulted in a median survival exceeding 20 months for Stage IV colorectal cancer.
However, the most common mode of distant disease spread in these studies has been
hematogenous dissemination. Patients with peritoneal carcinomatosis with metastatic
disease confined to the peritoneal surface treated with complete (CCR0) cytoreduction
and HIPEC showed median survival exceeding 40 months (range 28-60 months) [50].
The benefit of modern systemic chemotherapy incorporating combinations of 5-FU,

Leucovorin, Oxaliplatin, Irinotecan, Capecitabine, Bevacizumab, Panitumumab, and
Cetuximab for patients with advanced colorectal carcinoma confined to the peritoneal
surface is unknown.
A standardized, evidence-based approach is currently lacking for patients with
peritoneal surface malignancy from colorectal origin. A collaborative trial with
surgical quality assurance and modern multi-drug chemotherapy incorporating critical
assessment of disease burden, determinants of complete cytoreduction, treatmentrelated
toxicity, quality of life and survival is imperative. The NKI trial, although not
perfect, has provided the basis and impetus for further study utilizing a new reference
study arm for future randomized trials of appropriately selected patients with
potentially curable regionally advanced colorectal carcinoma confined to the parietal
peritoneal surface.
Based on the consensus statement of the Peritoneal Surface Oncology Group
(PSOG) published in 2007 [84], a prospective randomized clinical trial was designed
by the PSOG and the United States Military Cancer Institute (USMCI). This,
multicenter clinical trial will start accruing patients in 2009. Included will be patients
with PC of colorectal origin with a PCI

of free tumor cells in peritoneal washings was proven to be an independent
unfavourable prognostic factor [92].
Surgical treatment is the mainstay of gastric cancer treatment. Outcome after
complete resection is mainly related to serosal penetration and the extent of regional
lymph node involvement. The extended lymphadenectomy (D2 resection) is accepted
as standard of care in East Asia. However it is still controversial in western countries
where D2 dissection is considered an appropriate option where surgeons can
demonstrate low operative mortality.
Adjuvant systemic chemotherapy following surgery with curative intent is a
viable option for the reduction of disease recurrence and disease related mortality. In a
meta-analysis of 14 randomised trials evaluating the role of adjuvant chemotherapy,
only a small survival advantage was found compared to surgery alone [93].
A neo-adjuvant regimen of epirubicin, cisplatin, and infused fluorouracil (ECF)
was shown in a prospective randomized trial (MAGIC trial) to increase 5-year overall
survival by 13% (36% Vs. 23%) as compared to surgery alone [94]. This approach of
neoadjuvant therapy was adopted by many medical centres mainly in Europe.
Combined modality therapy with chemotherapy and external beam radiation was
shown in a large prospective randomized clinical trial (intergroup 0116) to improve 5year
overall survival [95]. Despite the criticism on this trail showing poor quality of
surgical resection (54% D0 resections) and the fact that prior clinical trials showed no
benefit for either radiation therapy alone or combined with chemotherapy, this form
of pre-postoperative combined modality therapy was widely adopted, mainly in North
America and Europe.
Many cytotoxic agents have been studied for the treatment of metastatic
adenocarcinoma of the stomach. Multiple clinical trials evaluating the efficacy and
toxicity of various regimens showed good response rates. However, the median
survival remains in the range of 6-16 months [96]. Since the most common site to
harbour metastasis of gastric origin is the peritoneal cavity combined with
locoregional disease-recurrence, most patients with advanced gastric cancer may
benefit from intra-peritoneal therapy.
Most studies comparing IP chemotherapy to systemic therapy or surgery alone
were conducted in the adjuvant setting. Yan et al [19] recently reviewed all clinical
trials studying IP chemotherapy in its different forms in resectable gastric cancer.
Searching all public domains, they found 106 reports, of which 14 prospective
randomized clinical trials were identified. One trial was excluded from the analysis
because it compared hyperthermic IP chemotherapy to normothermic IP
chemotherapy. In the 13 clinical trials analysed, 1648 patients were randomly
assigned to receive either IP chemotherapy (n=873) or no IP therapy (n=775). Results
of this analysis are summarized in table 3. All but one clinical trial evaluating the role
of HIPEC in gastric cancer compared Surgery + HIPEC to surgery alone. Therefore,
the next step is the design of a clinical trial comparing the addition of HIPEC to
surgery with adjuvant or neoadjuvant systemic chemotherapy.
Based on the data accumulated so far from Phase II and small Phase III trials, a
multicenter prospective randomized clinical trial is currently designed by the
European Union Network of Excellence on Gastric Cancer (EUNE). This trial will
study the added value of HIPEC to the current paradigm in the treatment of gastric
cancer set by the MAGIC trial. Patients with serosal invasion (T3-4), lymph node
metastasis (N1) or patients with positive peritoneal cytology will be included.

All patients will receive three cycles of platinum-based therapy as set by the
principals of the MAGIC trial (Figure 3), followed by D2 resection. Patients will be
then randomized either to undergo surgery with HIPEC or surgery alone.
Clinical trials: Ovarian cancer
Ovarian cancer is a major heath problem worldwide, with an estimated 205,000
new cases year [17]. Therapy for OC is dependent on the stage of diagnosis. Most of
the cases are diagnosed at advanced stage of disease [97]. Therefore, therapy for
newly many diagnosed OC cases (frontline therapy) includes SRC followed by
systemic therapy combining platinum compound and taxens [98-102]. For those
patients for whom primary surgery is not feasible, primary chemotherapy is given,
followed by interval debulking after 3 cycles of therapy. However, 60-70% of patients
will suffer disease recurrence [98-99]. The two most frequent recurrence patterns are
locoregional (lymph node) recurrence or peritoneal dissemination. Cytoreductive
surgery may be applied as frontline therapy, interval debulking or at the time of
recurrence. The principal goal of cytoreductive surgery is to remove all of the primary
disease and, if possible, all metastatic disease since the size of the remaining disease
is related to survival [103,104]. The high percentage of recurrent disease despite
optimal treatment can be explained by residual tumor nodules remain following CRS
resistant to systemic chemotherapy.
Intraperitoneal chemotherapy is attractive for the treatment of ovarian
carcinoma, which remains confined to the peritoneal cavity for most of its natural
history. In a phase III clinical trial (GOG 172) reported by Armstrong et. Al, [24] IP
chemotherapy combined with intra-venous therapy was shown to be superior to
systemic chemotherapy alone. Catheter related problems remain the highest obstacle
for EPIC or DPIC as shown by another report of the same clinical trial [105]. Fiftyeight
percent of the patients did not complete six cycles of IP therapy. Thirty-four
percent of these patients discontinued IP treatment due to catheter related
complications. Altogether, postoperative intraperitoneal chemotherapy was shown by
three randomized controlled trials, to result in an overall and progression-free survival
benefit when cisplatin is administered by the IP route in patients with stage III,
optimally resected disease [24,100,101]. In the study reported by Alberts et al [100]
optimally debulked patients (n=546) with stage III ovarian carcinoma were
randomized between intra-venous cyclofosphamide and cisplatin versus intra-venous
cyclofosphamide and IP cisplatin (100 mg/m2). An estimated median survival of 41
vs. 49 months was achieved in favor of the IP treated group. In the study reported by
Markman et al [101], patients (n=462), with optimally debulking surgery, were
randomized between either IV paclitaxel followed by IV cisplatin, or IV carboplatin ,
then IV paclitaxel followed by IP cisplatin 100 mg/m2 every 3 weeks for 6 courses. A
progression free survival of 22.2 vs. 27.9 months was seen in favor of the IP treated
group (p=0.01). These studies show that a combination of CRS, DPIC, and systemic
therapy has an advantage over CRS and systemic therapy alone.
Hyperthermic intraperitoneal chemotherapy (HIPEC) was reported as a frontline
therapy for OC only in small scale trials [106-109]. Large scale Phase II and III
clinical trials are mandatory to establish a role for HIPEC as a frontline therapy in
addition to CRS in stage III and IV OC.
Neoadjuvant chemotherapy followed by interval debulking surgery may
improve results of CRS in patients presenting with advanced peritoneal disease [110].

This approach of adding HIPEC to interval or second look surgery was reported by
several groups in small numbers of patients [107, 111-112].
A prospective, multicenter clinical trial is currently conducted by the
Netherlands Kanker Institute (NKI). |Patients are treated by three cycles of systemic
therapy followed by interval debulking surgery with or without HIPEC.
A number of retrospective studies and phase II studies reported treatment of
patients with recurrent and heavily pre-treated ovarian carcinoma with HIPEC and
CRS [113-. Chemotherapeutic agents that were used are mainly cisplatin varying in
dose from 25-150 mg/m2; duration of perfusion ranged from 60 to 90 minutes and
temperature of the abdominal cavity was maintained at 39 to 42.5oC. From these
studies it can be concluded that this treatment regimen is feasible with acceptable
toxicity. Morbidity and mortality rates in these studies with heavily pre-treated
patients vary between 0-17% and 0-4% respectively. In addition, factors which affect
the outcome in terms of overall survival or median time to progression, are platinum
resistance, completeness of cytoreduction, extension of peritoneal carcinomatosis,
patient age, and interval between diagnosis of and CRS.
Currently, there is no prospective clinical trial evaluating the effect of
CRS+HIPEC in the treatment of recurrent or heavily-treated OC patients. A large
scale clinical trial designed to address the role of CRS and HIPEC in recurrent OC is
warranted.
Summary
Current treatment of PC, with the exception of a single institution Phase III trial in
CRC, is based mainly on retrospective data with small prospective phase II clinical
trials. There is no doubt that in order to establish guidelines that will be accepted by
the medical and the surgical oncology communities, large scale clinical trials should
be conducted in PC originating form colorectal, gastric, and ovarian cancer. Smaller,
phase II clinical trials combined with international and national prospective registries
will provide the data for the treatment of diseases with lower incidence and will
establish the efficacy of different HIPEC regimens. The main obstacles for conducting
such clinical trials are funding and supporting organizations, So far, the main
oncology groups showed reluctance in organizing or even supporting clinical trials
studying HIPEC or CRS.
Therefore, large scale clinical trials will have to be conducted by international
groups interested in improving the outcome of peritoneal carcinomatosis.
References
1. Esquivel J. Cytoreductive surgery for peritoneal malignancies--development of standards
of care for the community. Surg Oncol Clin N Am. 2007 Jul;16(3):653-66, x.
2. Al-Shammaa HA, Li Y, Yonemura Y. Current status and future strategies of cytoreductive
surgery plus intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis.
World J Gastroenterol. 2008 Feb 28;14(8):1159-66.
3. Eggermont AM, Steller EP, Sugarbaker PH. Laparotomy enhances intraperitoneal tumor
growth and abrogates the antitumor effects of IL-2 and lymphokine-activated killer cells.
Surgery 1987; 102:71-78.

4. Averbach AM, Jacquet P, Sugarbaker PH. Surgical technique and colorectal cancer: impact
on local recurrence and survival. Tumori 1995; 81:65-71.
5.Sugarbaker PH. Observations concerning cancer spread within the peritoneal cavity and
concepts supporting an ordered pathophysiology.
Cancer Treat Res. 1996;82:79-100.
6.Yonemura Y. Hyperthermo-chemotherapy for the treatment of peritoneal dissemination. In:
Yonemoura Y, editor. Contemporary approaches toward cure of gastric cancer.
Kanazawa:Maeda Shoten, 1996: 105-116.
7. Yonemura Y, Bandou E, Kawamura T, Endou Y, Sasaki T. Quantitative prognostic
indicators of peritoneal dissemination of gastric cancer. Eur J Surg Oncol. 2006
Aug;32(6):602-6.
8. Tsujimoto H, Hagiwara A, Shimotsuma M, Sakakura C, Osaki K, Sasaki S, Ohyama
T, Ohgaki M, Imanishi T, Yamazaki J, Takahashi T. Role of milky spots as selective
implantation sites for malignant cells in peritoneal dissemination in mice.
J Cancer Res Clin Oncol. 1996;122(10):590-5.
9. Tsujimoto H, Takhashi T, Hagiwara A, Shimotsuma M, Sakakura C, Osaki K, Sasaki
S, Shirasu M, Sakakibara T, Ohyama T, et al. Site-specific implantation in the milky spots of
malignant cells in peritoneal dissemination: immunohistochemical observation in mice
inoculated intraperitoneally with bromodeoxyuridine-labelled cells.
Br J Cancer. 1995 Mar;71(3):468-72.
10. Shimotsuma M, Shields JW, Simpson-Morgan MW, Sakuyama A, Shirasu M, Hagiwara
A, Takahashi T. Morpho-physiological function and role of omental milky spots as
omentum-associated lymphoid tissue (OALT) in the peritoneal cavity.
Lymphology. 1993 Jun;26(2):90-101. Review.
11. Hagiwara A, Takahashi T, Sawai K, Taniguchi H, Shimotsuma M, Okano S, Sakakura
C, Tsujimoto H, Osaki K, Sasaki S, et al. Milky spots as the implantation site for malignant
cells in peritoneal dissemination in mice.
Cancer Res. 1993 Feb 1;53(3):687-92.
12. Carmignani CP, Sugarbaker TA, Bromley CM, Sugarbaker PH. Intraperitoneal cancer
dissemination: mechanisms of the patterns of spread. Cancer Metastasis Rev 2003; 22:465-
472.
13. Deraco M, Bartlett D, Kusamura S, Baratti D. Consensus statement on peritoneal
mesothelioma. J Surg Oncol. 2008 Sep 15;98(4):268-72.
14. Deraco M, Baratti D, Zaffaroni N, Cabras AD, Kusamura S. Advances in clinical research
and management of diffuse peritoneal mesothelioma. Recent Results Cancer Res.
2007;169:137-55.
15. Bloss JD, Liao SY, Buller RE, Manetta A, Berman ML, McMeekin S, Bloss LP, DiSaia
PJ. Extraovarian peritoneal serous papillary carcinoma: a case-control retrospective
comparison to papillary adenocarcinoma of the ovary. Gynecol Oncol. 1993 Sep;50(3):347-
51.
16. Fromm GL, Gershenson DM, Silva EG. Papillary serous carcinoma of the peritoneum.
Obstet Gynecol. 1990 Jan;75(1):89-95.

17. Parkin DM, Bray F, Feraly JPP: Global cancer statistics. Ca Cancer J Clin 2005;55: 74-
108.
18. Esquivel J, Elias D, Baratti D, Kusamura S, Deraco M. Consensus statement on the loco
regional treatment of colorectal cancer with peritoneal dissemination.
J Surg Oncol. 2008 Sep 15;98(4):263-7.
19. Yan TD, Black D, Sugarbaker PH, Zhu J, Yonemura Y, Petrou G, Morris DL.
A systematic review and meta-analysis of the randomized controlled trials on
adjuvant intraperitoneal chemotherapy for resectable gastric cancer.
Ann Surg Oncol. 2007 Oct;14(10):2702-13.
20. Regine WF, Abrams RA. Adjuvant therapy for pancreatic cancer: current status, future
directions. Semin Oncol. 2006 Dec;33(6 Suppl 11):S10-3.
21. Stojadinovic A, Brooks A, Hoos A, Jaques DP, Conlon KC, Brennan MF. An evidencebased
approach to the surgical management of resectable pancreatic adenocarcinoma.
J Am Coll Surg. 2003 Jun;196(6):954-64.
22.
23. Helm CW, Bristow RE, Kusamura S, Baratti D, Deraco M. Hyperthermic intraperitoneal
chemotherapy with and without cytoreductive surgery for epithelial ovarian cancer.
J Surg Oncol. 2008 Sep 15;98(4):283-90.
24. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ,Walker
JL, Burger RA; Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in
ovarian cancer.
N Engl J Med. 2006 Jan 5;354(1):34-43.
25. Sugarbaker PH. Peritonectomy procedures. Ann Surg. 1995 Jan;221(1):29-42.
26. González-Moreno S, Kusamura S, Baratti D, Deraco M.
Postoperative residual disease evaluation in the locoregional treatment of peritoneal surface
malignancy.
J Surg Oncol. 2008 Sep 15;98(4):237-41.
27. Loggie BW, Fleming RA, McQuellon RP, Russel GB, Geisinger KR. Cytoreductive
surgery with intraperitoneal chemotherapy for disseminated peritoneal cancer of
gastrointestinal origin. Am Surg 2000; 66(6): 561-568.
28. Stewart JH, Shen P, Levine EA. Intraperitoneal hyperthermic chemotherapy for peritoneal
surface malignancy: Current status and future directions. Ann Surg Oncol 2005; 12(10):756-
777.
29. Speyer JL, Collins JM, Dedrick RL, et al. Phase I and pharmacological studies of 5fluorouracil
administrated intraperitoneally. Cancer Res 1980; 40:567-72.
30. Flessner MF, Dedrick RL, Schultz JS. A distributed model of peritoneal-plasma transport:
analysis of experimental data in the rat. Am J Physiol 1985; 248: F413-F424.
31. Dedrick RL. Theoretical and experimental basis of intraperitoneal chemotherapy. Semin
Oncol 1985; 12 (3 Suppl 4): 1-6.
32. Dedrick RL. Interspecies scaling of regional drug delivery. J Pharm Sci 1986; 75: 1047-
52.
33. Kuzuya T, Yamauchi M, Ito A, Hasegawa M, Hasegawa T, Nabeshima T.
Pharmacokinetic characteristics of 5-flourourcil and mitomycin C in intraperitoneal
chemotherapy. J Pharm Pharmacol 1994; 46:685-9.

34. Dedrick RL, Flessner MF. Pharmacokinetic problems in peritoneal drug administration:
Tissue penetration and surface exposure. J Natl Cancer Inst 1997; 89: 480-487.
35. Elias D, Bonnay M, Puizillou JM, et al. Heated intra-operative intraperitoneal oxaliplatin
after complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue
distribution. Ann Oncol. 2002; 13(2):267-72.
36. Elias D, Matsuhisa T, Sideris L, et al. Heated intra-operative intraperitoneal oxaliplatin
plus irinotecan after complete resection of peritoneal carcinomatosis: pharmacokinetics, tissue
distribution and tolerance. Ann Oncol. 2004; 15(10):1558-65.
37. Sugarbaker PH, Stuart OA, Carmignani CP. Pharmacokinetic changes induced by the
volume of chemotherapy solution in patients treated with hyperthermic intraperitoneal
mitomycin C. Cancer Chemother Pharmacol. 2006; 57(5):703-8.
38. Sugarbaker PH, Graves T, DeBruijn EA, et al: Rationale for early postoperative
intraperitoneal chemotherapy (EPIC) in patients with advanced gastrointestinal cancer.
Cancer Res 1990; 50:5790-5794.
39. Katz M, Barone R: The rationale of perioperative intraperitoneal chemotherapy in the
treatment of peritoneal surface malignancies. Surg Oncol Clin N Am 2003; 12:673-688.
40. Spratt JS, Adcock RA, Muskovin M, Sherrill W, McKeown J. Clinical delivery system for
intraperitoneal hyperthermic chemotherapy. Cancer Res 1980; 40: 256-60.
41. Teicher BA, Kowal CD, Kennedy KA, Sartorelli AC. Enhancement by hyperthermia of
the in vitro cytotoxicity of mitomycin C toward hypoxic tumor cells.
Cancer Res. 1981; 41(3):1096-9.
42. El-Kareh AW, Secomb TW. A theoretical model for intraperitoneal delivery of cisplatin
and the effect of hyperthermia on drug penetration distance.
Neoplasia 2004; 6(2):117-27.
43. VanderWaal R, Thampy G, Wright WD, Roti Roti JL. Heat-induced modifications in the
association of specific proteins with the nuclear matrix. Radiat Res. 1996; 145(6):746-53.
44. Roti Roti JL, Kampinga HH, Malyapa RS, et al. Nuclear matrix as a target for
hyperthermic killing of cancer cells. Cell Stress Chaperones. 1998; 3(4):245-55.
45. Pelz JO, Doerfer J, Hohenberger W, Meyer T. A new survival model for hyperthermic
intraperitoneal chemotherapy (HIPEC) in tumor-bearing rats in the treatment of peritoneal
carcinomatosis. BMC Cancer 2005; 5(1):56
46. van Ruth S, Verwaal VJ, Hart AA, van Slooten GW, Zoetmulder FA. Heat penetration in
locally applied hyperthermia in the abdomen during intra-postoperative hyperthermic
intraperitoneal chemotherapy. Anticancer Res 2003, 23:1501-8.
47. Kerr DJ, Kaye SB. Aspects of cytotoxic drug penetration, with particular reference to
anthracyclines. Cancer Chemother Pharmacol 1987; 19:1–5.
48. Los G, Mutsaers PH, et al. Direct diffusion of cis-diamminedichloroplatinum(II) in
intraperitoneal rat tumors after intraperitoneal chemotherapy: a comparison with systemic
chemotherapy. Cancer Res 1989; 49:3380–4.
49. Zoetmulder FA. Cancer cell seeding during abdominal surgery: experimental studies. In
Sugarbaker PH (ed.): Peritoneal Carcinomatosis: Principles of Management. Boston: Kluwer
Academic Press 1996; 155–162.
50. YanTD, Black D, Savady R, Sugarbaker PH. 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.
51. Hahn GM, Braun J, Har-Kedar I. Thermochemotherapy: synergism between hyperthermia
(42–43 degrees) and adriamycin (of bleomycin) in mammalian cell inactivation. Proc Natl
Acad Sci U S A 1975; 72:937–40.
52. Barlogie B, Corry PM, Drewinko B. In vitro thermochemotherapy of human colon cancer
cells with cis- dichlorodiammineplatinum (II) and mitomycin C. Cancer Res 1980; 40:1165–
8.

CRC
53. Chu DZ, Lang NP, Thompson C, et al: Peritoneal carcinomatosis in nongynecologic
malignancy: A prospective study of prognostic factors. Cancer 1989; 63(2):364-367.
54. Jayne DG, Fook S, Loi C, et al: Peritoneal carcinomatosis from colorectal cancer. Br J
Surg 2002; 89:1545-1550.
55. Sadeghi B, Arvieux C, Glehen O, et al: Peritoneal carcinomatosis from non-gynecologic
malignancies: Results of the EVOCAPE 1 multicentric prospective study. Cancer 2000;
88:58-63.
56. Jacquet P, Vidal-Jove J, Zhu B, Sugarbaker P. Peritoneal carcinomatosis from
gastrointestinal malignancy: natural history and new prospects for management. Acta Chir
Belg. 1994; 94(4): 191-7.
57. Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for
metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000; 343(13):905-14.
58. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil
compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a
multicentre randomised trial. Lancet 2000; 355(9209): 1041-7.
59. Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter randomized trial of
oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of
metastatic colorectal cancer. J Clin Oncol. 2000; 18(1): 136-47.
60. Rothenberg ML, Oza AM, Bigelow RH, et al. Superiority of oxaliplatin and fluorouracilleucovorin
compared with either therapy alone in patients with progressive colorectal cancer
after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol.
2003; 21(11): 2059-69.
61. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil
plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated
metastatic colorectal cancer. J Clin Oncol 2004; 22(1):23-30.
62. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse
sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;
22(2):229-37.
63. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil,
and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350(23):2335-42.
64. Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized trial of FOLFIRI versus
FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo
Oncologico Dell'Italia Meridionale. J Clin Oncol. 2005; 23(22):4866-75.
65. Goldberg RM, Sargent DJ, Morton RF, et al. Randomized controlled trial of reduced-dose
bolus fluorouracil plus leucovorin and irinotecan or infused fluorouracil plus leucovorin and
oxaliplatin in patients with previously untreated metastatic colorectal cancer: a North
American Intergroup Trial.J Clin Oncol. 2006; 24(21):3347-53.
66. Tabernero J, Van Cutsem E, Díaz-Rubio E, Cervantes A, Humblet Y, André T, Van
Laethem JL, Soulié P, Casado E, Verslype C, Valera JS, Tortora G, Ciardiello F, Kisker O, de
Gramont A. Phase II trial of cetuximab in combination with fluorouracil, leucovorin, and
oxaliplatin in the first-line treatment of metastatic colorectal cancer.
J Clin Oncol. 2007 Nov 20;25(33):5225-32.
67. Willet CG, Tepper JE, Cohen AM, et al: Failure patterns following curative resection of
colonic carcinoma. Surgery 1984; 200:685-690.
68. 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.

69. Fujimura T, Yonemura Y, Fujita H, et al: Chemohyperthermic peritoneal perfusion for
peritoneal dissemination in various intraabdominal malignancies. Int Surg 1999; 84:60-66.
70. Cavaliere F, Perri P, Di Filippo F, et al: Treatment of peritoneal carcinomatosis with
intent to cure. J Surg Oncol 2000; 74:41-44.
71. Pestieau SR, Sugarbaker PH: Treatment of primary colon cancer with peritoneal
carcinomatosis: Comparison of concomitant vs. delayed management. Dis Colon Rectum
2000; 43:1341-1346.
72. Beaujard AC, Glehen O, Caillot JL, et al: Intraperitoneal chemohyperthermia with
mitomycin C for digestive tract cancer patients with peritoneal carcinomatosis. Cancer 2000;
88:2512-2519.
73. Culliford A, Brooks AD, Sharma S, et al: Surgical debulking and intraperitoneal
chemotherapy for established peritoneal metastases from colon and appendix cancer. Ann
Surg Oncol 2001; 8: 787-795.
74. 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.
75. 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.
76. Cavaliere F, Perri P, Rossi CR, et al: Indications for integrated surgical treatment of
peritoneal carcinomatosis of colorectal origin: Experience of the Italian Society of
Locoregional Integrated Therapy in Oncology. Tumori 2003; 89:21-23.
77. Pilati P, Mocellin S, Rossi CR, et al: Cytoreductive surgery combined with hyperthermic
intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis arising from colon
adenocarcinoma. Ann Surg Oncol 2003; 10:508-513.
78. 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 carcinomatosis. Arch Surg 2003; 138:26-33.
79. Elias D, Pocard M: Treatment and prevention of peritoneal carcinomatosis from colorectal
cancer. Surg Oncol Clin N Am 2003; 12:543-559.
80. Glehen O, Mithieux F, Osinsky D, et al: Surgery combined with peritonectomy
procedures and intraperitoneal chemohyperthermia in abdominal cancers with peritoneal
carcinomatosis: A phase II study. J Clin Oncol 2003; 21:799-806.
81. Verwaal V, Ruth S, 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. J Clin Oncol 2003; 21:3737-3743.
82. Glehen O, Cotte E, Schreiber V, et al: Intraperitoneal chemohyperthermia and attempted
cytoreductive surgery in patients with peritoneal carcinomatosis of colorectal origin. Br J
Surg 2004; 91:747-754.
83. Pilati P, Mocellin S, Rossi CR, et al: Cytoreductive surgery combined with hyperthermic
intraperitoneal intraoperative chemotherapy for peritoneal carcinomatosis arising from colon
adenocarcinoma. Ann Surg Oncol 2003; 10:508-513.
84. Esquivel J, Sticca R, Sugarbaker P, Levine E, Yan TD, Alexander R, Baratti D,
Bartlett D, Barone R, Barrios P, Bieligk S, Bretcha-Boix P, Chang CK, Chu F, Chu
Q, Daniel S, de Bree E, Deraco M, Dominguez-Parra L, Elias D, Flynn R, Foster J,
Garofalo A, Gilly FN, Glehen O, Gomez-Portilla A, Gonzalez-Bayon L,
Gonzalez-Moreno S, Goodman M, Gushchin V, Hanna N, Hartmann J, Harrison L, Hoefer
R, Kane J, Kecmanovic D, Kelley S, Kuhn J, Lamont J, Lange J, Li B, Loggie B,
Mahteme H, Mann G, Martin R, Misih RA, Moran B, Morris D, Onate-Ocana L, Petrelli
N, Philippe G, Pingpank J, Pitroff A, Piso P, Quinones M, Riley L, Rutstein L,
Saha S, Alrawi S, Sardi A, Schneebaum S, Shen P, Shibata D, Spellman J,
Stojadinovic A, Stewart J, Torres-Melero J, Tuttle T, Verwaal V, Villar J,
Wilkinson N, Younan R, Zeh H, Zoetmulder F, Sebbag G; Society of Surgical

Oncology Annual Meeting. Cytoreductive surgery and hyperthermic intraperitoneal
chemotherapy in the management of peritoneal surface malignancies of colonic origin: a
consensus statement. Society of Surgical Oncology.
Ann Surg Oncol. 2007 Jan;14(1):128-33.
85. Crew KD, Neugut AL. Epidemiology of Gastric Cancer. World J Gastroenterol 2006. Jan,
12(3): 354-62
86. Roviello F, Marrelli D, de Manzoni G, Morgagni P, Di Leo A, Saragoni L, De Stefano A;
Italian Research Group for Gastric Cancer.
Prospective study of peritoneal recurrence after curative surgery for gastric cancer.
Br J Surg. 2003 Sep;90(9):1113-9.
87. Maehara Y, Emi Y, Baba H, Adachi Y, Akazawa K, Ichiyoshi Y, Sugimachi
K.Recurrences and related characteristics of gastric cancer.
Br J Cancer. 1996 Sep;74(6):975-9.
88.Kodera Y, Yamamura Y, Shimizu Y et al. Peritoneal washing cytology: prognostic value
of positive findings in patient with gastric carcinoma undergoing a potentially curative
resection. J Surg Oncol 1999; 72: 60-64
89. Sugarbaker PH, Cunliffe WJ, Belliveau J et al. Rationale for integrating early
postoperative intraperitoneal chemotherapy into the surgical treatment of gastrointestinal
cancer. Semin Oncol 1989; 16(4 suppl 6): 83-97
90. Bando E, Yonemura Y, Takeshita Y, Taniguchi K, Yasui T, Yoshimitzu Y et al.
Intraoperative lavage for cytological examination in 1,297 patients with gastric carcinoma.
Am J Surg 1999; 178: 256-62
91Cheng-Wun WU, Su-Shun Lo, King-Han Shen et al. Incidence and factors associated with
recurrence patterns after intended curative surgery for gastric cancer. World J Surs 1003; 327:
153-58
92. Bentrem D, Wilton A, Mazumdar M, Brennan M, Coit D. The value of peritoneal
cytology as a preoperative predictor in patients with gastric carcinoma undergoing a curative
resection. Ann Surg Oncol 12: 347-53, 2005
93. Earle CC, Maroun JA. Adjuvant chemotherapy after curative resection for gastric cancer
in non-Asian patients: revisiting a meta-analysis of randomised trials. Eur J Cancer 1999; 35:
1059-64.
94. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M,
Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua
YJ, MAGIC Trial Participants.Perioperative chemotherapy versus surgery alone for resectable
gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20.
95. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN,
Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA. Chemoradiotherapy after
surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal
junction. N Engl J Med 2001; 345: 725-730.
96. Cervantes A, Roselló S, Roda D, Rodríguez-Braun E. The treatment of advanced gastric
cancer: current strategies and future perspectives.Ann Oncol. 2008 Jul;19 Suppl 5:v103-7.
Ovary
97. Olivier RI, Lubsen-Brandsma MAC, Verhoef S, van Beurden M. CA125 and transvaginal
ultrasound monitoring in high-risk women cannot prevent the diagnosis of advanced ovarian
cancer. Gyn Onc 2006; 100(1):20-26.

98. McGuire W, Hoskins W, Brady M, Kucera P, Partridge E, Look K et al.
Cyclophosphamide and Cisplatin Compared with Paclitaxel and Cisplatin in Patients with
Stage III and Stage IV Ovarian Cancer. NEJM 1996; 334(1):1-6.
99. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA et al. Phase
III Trial of Carboplatin and Paclitaxel Compared With Cisplatin and Paclitaxel in Patients
With Optimally Resected Stage III Ovarian Cancer: A Gynecologic Oncology Group Study.
100. Albers DS, Liu PY, Hannigan EV, O'Toole R, Williams SD, Young JA et al.
Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus
intravenous cyclophosphamide for stage III ovarian cancer. NEJM 1996; 335:1950-1955.
101. Markman M, Bundy B, Albers DS, Fowler JM, Clark-Pearson DL, Carson LF et al.
Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately highdose
carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in smallvolume
stage III ovarian carcinoma: an intergroup study of the gynecologic oncology group,
southwesters oncology group, and eastern cooperative oncology group. J Clin Oncology
2001; 19:1001-1007.
102. Muggia FM, Braly PS, Brady MF, Sutton G, Niemann TH, Lentz SL, Alvarez
RD,Kucera PR, Small JM. Phase III randomized study of cisplatin versus paclitaxel versus
cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: a
gynecologic oncology group study. J Clin Oncol. 2000 Jan;18(1):106-15.
103. Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian
carcinoma. National Cancer Institute monograph 1975; 42:101-104.
104. Bristow R, Tomacruz R, Armstrong D, Trimble E, Montz FJ. Survival Effect of
Maximal Cytoreductive Surgery for Advanced Ovarian Carcinoma During the Platinum Era:
A Meta- Analysis. Journal of Clinical Oncology 2002; 20(5):1248-1259.
105. Walker JL, Armstrong DK, Huang HQ, Fowler J, Webster K, Burger RA et al.
Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal
chemotherapy in optimal stage III ovarian and primary peritoneal cancer: A Gynecologic
Oncology Group Study. Gyn Onc 2006; 100(1):27-32.
106. Steller MA, Egorin MJ, Trimble EL, Bartlett DL, Zuhowski EG, Alexander HR et al. A
pilot phase I trial of continuous hyperthermic peritoneal perfusion with high-dose carboplatin
as primary treatment of patients with small-volume residual ovarian cancer. Cancer
Chemother Pharmacol 1999; 43(2):106-114.
107. de Bree E, Rosing H, Beijnen JH, Romanos J, Michalakis J, Georgoulias V et al.
Pharmacokinetic study of docetaxel in intraoperative hyperthermic i.p. chemotherapy for
ovarian cancer. Anticancer Drugs 2003; 14(2):103-110.
108. Piso P, Dahlke MH, Loss M, Schlitt HJ.
Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal
carcinomatosis from ovarian cancer.
World J Surg Oncol. 2004 Jun 28;2:21.
109. Rufián S, Muñoz-Casares FC, Briceño J, Díaz CJ, Rubio MJ, Ortega R, Ciria R, Morillo
M, Aranda E, Muntané J, Pera C. Radical surgery-peritonectomy and intraoperative
intraperitoneal chemotherapy for the treatment of peritoneal carcinomatosis in recurrent or
primary ovarian cancer.J Surg Oncol. 2006 Sep 15;94(4):316-24.

110. Bristow RE, Eisenhauer EL, Santillan A, Chi DS. Delaying the primary surgical effort
for advanced ovarian cancer: a systematic
review of neoadjuvant chemotherapy and interval cytoreduction.
Gynecol Oncol. 2007 Feb;104(2):480-90.
111. Reichman TW, Cracchiolo B, Sama J, Bryan M, Harrison J, Pliner L et al. Cytoreductive
surgery and intraoperative hyperthermic chemoperfusion for advanced ovarian carcinoma. J
Surg Oncol 2005; 90(2):51-56.
112. Gori J, Castano R, Toziano M, Habich D, Staringer J, De Quiros DG et al.
Intraperitoneal hyperthermic chemotherapy in ovarian cancer. Int J Gynecol Cancer 2005;
15(2):233-239.
113. van der Vange N, van Goethem AR, Zoetmulder FA, Kaag MM, van de Vaart PJ,
Bokkel Huinink WW et al. Extensive cytoreductive surgery combined with intraoperative
intraperitoneal perfusion with cisplatin under hyperthermic conditions
(OVHIPEC) in patients with recurrent ovarian cancer: a feasibility pilot. Eur J Surg
Oncol 2000; 26(7):663-668.
114. Deraco M, Rossi CR, Pennacchioli E, Guadagni S, Somers DC, Santoro N et al.
Cytoreductive
surgery followed by intraperitoneal hyperthermic perfusion in the treatment of
recurrent epithelial ovarian cancer: a phase II clinical study. Tumori 2001; 87(3):120-
126.
115. Chatzigeorgiou K, Economou S, Chrysafis G, Dimasis A, Zafiriou G, Setzis K et
al. Treatment of recurrent epithelial ovarian cancer with secondary cytoreduction and
continuous intraoperative intraperitoneal hyperthermic chemoperfusion (CIIPHCP).
Zentralbl Gynakol 2003; 125(10):424-429.
116. Lucas WE, Markman M, Howell SB. Intraperitoneal chemotherapy for advanced
ovarian cancer. Am J Obstet Gynecol 1985; 152(4):474-478.

Table 1: The incidence of peritoneal surface malignancies
Primary PSM*
Secondary PSM†
Primary peritoneal
carcinoma
Peritoneal
mesothelioma
Desmoplastic small
round cell tumor
Colorectal cancer
Gastric Cancer
Ovarian Cancer
Pancreatic cancer
Worldwide
incidence
(new cases/year)
% peritoneal
dissemination††
20,000 100% 20,000
2000 100% 2000
100 100% 100
1023152 15% 153,472
933937 40% 373,574
204499 60% 122,699
232306 25% 58,076
Total 709,941
* Incidence estimation form literature reports
† Incidence report from: Global cancer statistics 2002, GLOBCAN (http://wwwdep.iarc.fr/GLOBOCAN_frame.htm)
†† peritoneal dissemination at diagnosis and at disease recurrence
Including appendecial cancers and pseudomyxoma peritonei
PSM = peritoneal surface malignancies
Expected incidence of
peritoneal carcinomatosis
(new cases/year)

Table 2: Completeness of cytoreduction (CCR) score
CCR category Tumor remaining following resection
0 No visible residual tumor present
1 Residual tumor of < 2.5 mm is present
2 Residual tumor of >2.5 mm< 2.5cm is present
3 Residual tumor of >2.5 cm is present

Table 3: Results of prospective randomized clinical trials evaluating adjuvant
intraperitoneal chemotherapy for gastric cancer (Yan et al Ref. 19).
Study arm Control arm HR 95% C.I. P Value
Surgery+HIPEC Surgery alone 0.60 0.43-0.83 0.002
Surgery+HIPEC+EPIC Surgery alone 0.45 0.29-0.68 0.0002
Surgery+NIPEC Surgery alone 0.67 0.44-1.01 0.06
Surgery+EPIC Surgery alone 0.64 0.37-1.10 0.11
Surgery+DPIC Surgery alone 0.89 0.51-1.55 0.68
HR= Hazard ratio
C.I= Confidence intervals
HIPEC=hyperthermic intraoperative intraperitoneal chemotherapy
EPIC= early postoperative intraperitoneal chemotherapy
NIPEC= normothermic intraoperative intraperitoneal chemotherapy
DPIC= delayed postoperative intraperitoneal chemotherapy

Figure 1: The improvement in response rates of stage IV colorectal cancer to systemic
therapy.
Figure 1 legend: This bar graph represents a summary of clinical trials reporting response rate
to systemic therapy in adenocarcinoma of the colon and rectum. Study subjects included
mainly patients with liver and lung metastasis.
11%
22%
40%
45%
48%
53%
74%
81%

Figure 2: Study design of the PSOG-USMCI clinical trial.
Limited
Peritoneal Surface
Malignancy of
Colonic
Origin
with
No prior
Cytoreduction
S
T
R
A
T
I
F
Y
Sync
Vs
Met
Measurable
Vs
Not meas.
R
A
N
D
O
M
I
Z
E
Best Systemic
Therapy
N=155
Cytoreduction
+ HIPEC (MMC)
+ Best Systemic
Rx
N=155
Primary Outcome
1.Overall Survival
Cross
Over Secondary Outcomes
At 1. PFS
Progression
2. Toxicity burden
3. QOL appraisal
4. CTC during Rx

Rando
Overall Completion D2 3 Overall Completion D2 3 cycles of
of platinum- gastric of platinum- gastric systemic
survival
therapy gastrecto
based cancer survival
therapy gastrecto
based cancer
my+HIPE my mizati
therapy with my+HIPE my mizati
therapy with
C either: C either:
ary
on
Seros
al
invasi
on
Positiv
e
cytolo
gy
N1
diseas
e
ing by
video
laparo
scopy
Figure 3: Study design of the EUNE clinical trial.