Evidence-based medicine in the treatment of peritoneal carcinomatosis: past, present and future

Aviram Nissan1, Alexander Stojadinovic2, Alfredo Garofalo3, Jesus Esquivel4, Pompiliu Piso5

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 pseudomyxoma-peritonei (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, non-metastatic 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 intra-peritoneal 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 intra-peritoneal 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 (420C-430C) 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 post-operative 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,

regional 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 peri-operative 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/m2 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/m2 IV bolus) and Leucovorin (80 mg/m2 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, treatment-related 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<20 and a good performance status. Patients will be randomly assigned to either best available systemic therapy or cytoreductive surgery + HIPEC followed by systemic therapy. Patients that will fail systemic therapy will be allowed to cross over to the surgical arm (figure 2).

Main endpoint of this multicenter trail is overall survival with secondary endpoints of progression-free survival, peritoneal progression-free survival and quality of life. This study will define the role of CRS+HIPEC in the management of PC of colorectal origin. Clinical trials: Gastric Cancer

Adenocarcinoma of the stomach is the fourth most common cancer and the second leading cause of cancer death worldwide, with almost a million new cases per year (table 1). The incidence of the disease decreased in the United States and other parts of the world, mainly of distal, intestinal type gastric cancer. On the other hand, the incidence of proximal diffuse type adenocarcinoma of the gastric cardia has been increasing, particularly in the western countries [85].

Peritoneal dissemination of adenocarcinoma of the stomach is common. Either at presentation, in the form of MA, macroscopic tumor deposits or microscopic dissemination detected by peritoneal washings or as a manifestation of recurrent disease. A large portion of recurrent disease will be either locoregional or peritoneal [86,87].

Peritoneal cancer cells detected by intra-operative washings are associated with higher rates of recurrence of gastric cancer [88]. Tumor cells spread by the mechanisms described above are entrapped within fibrin exudates, which protect them from host defences. These events are referred to as the “tumor cell entrapment" [89]. Not only is it important in understanding of the pathogenesis of both resection site and peritoneal surface recurrence, but also in an appreciation of the beneficial effects of adjuvant perioperative intraperitoneal chemotherapy.

As mentioned, peritoneal dissemination is a major pattern of therapeutic failure, and its recurrence rate ranges from 38% to 60%, being 53,3% in a recent large cohort of patients [90,91]. Serosal invasion, scirrhous-type stromal reaction and female gender were three independent factors found to be associated with peritoneal dissemination. In a study conducted in resected gastric cancer patients, the detection

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 5-year 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]. Fifty-eight 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 evidence-based 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 5-fluorouracil 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 fluorouracil-leucovorin 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 high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume 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 intra-operative 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 Worldwide

incidence (new cases/year)

% peritoneal dissemination††

Expected incidence of peritoneal carcinomatosis (new cases/year)

Primary peritoneal carcinoma

20,000 100% 20,000

Peritoneal mesothelioma

2000 100% 2000

Primary PSM*

Desmoplastic small round cell tumor

100 100% 100

Colorectal cancer¶

1023152 15% 153,472

Gastric Cancer

933937 40% 373,574

Ovarian Cancer

204499 60% 122,699

Secondary PSM†

Pancreatic cancer

232306 25% 58,076

Total 709,941

* Incidence estimation form literature reports † Incidence report from: Global cancer statistics 2002, GLOBCAN (http://www-

dep.iarc.fr/GLOBOCAN_frame.htm) †† peritoneal dissemination at diagnosis and at disease recurrence ¶ Including appendecial cancers and pseudomyxoma peritonei PSM = peritoneal surface malignancies

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

Secondary Outcomes 1. PFS

2. Toxicity burden 3. QOL appraisal 4. CTC during Rx

Cross Over

At Progression

Figure 3: Study design of the EUNE clinical trial.

Overall survival Completion of systemic therapy

D2 gastrectomy+HIPEC

D2 gastrectomy

Randomization

3 cycles of platinum-based therapy

Primary gastric cancer with either:

• Serosal invasion

• Positive cytology

• N1 disease

Staging by video laparoscopy

Overall survival Completion of systemic therapy

D2 gastrectomy+HIPEC

D2 gastrectomy

Randomization

3 cycles of platinum-based therapy

Primary gastric cancer with either:

• Serosal invasion

• Positive cytology

• N1 disease

Staging by video laparoscopy