I. Introduction

Peritoneal carcinomatosis represents a significant adverse step in the natural history of any gastrointestinal cancer using conventional management. It eliminates any hope of cure and with disease progression leads to poor quality of life. Patients who relapse through peritoneal seeding will experience a succession of complications secondary to the progressive carcinomatosis. Those patients who present with peritoneal implants with the primary cancer in place may suffer not only from progressive carcinomatosis but also from the complications of the primary tumor, most commonly obstruction, bleeding and perforation.

A. Colorectal carcinomatosis

Despite advances for early diagnosis of colorectal cancer, peritoneal carcinomatosis persists as a major problem. Peritoneal implants are present in 10% of patients with colorectal cancer at the time of diagnosis and are the second cause of death after liver metastasis (Sugarbaker, 1990). In contrast to the other two main sites of colorectal cancer metastasis, liver and lymph nodes, peritoneal seeding is considered a condition uniformly lethal with no perspective of cure. From a database of 3019 colorectal cancer patients, Jayne and colleagues identified 349 patients with peritoneal carcinomatosis (Jayne et al, 2002). The median survival of this group was 7 months. Unfortunately this recent data showed no improvement in the survival of these patients if compared with the first study of the natural history of peritoneal carcinomatosis published 13 years before (Chu et al, 1989). Also, a European multicenter trial (EVOCAPE 1) evaluated prospectively 118 patients with peritoneal carcinomatosis arising from colorectal cancer. The mean survival of those patients was 6.9 months (Sadeghi et al, 2000).

B. Gastric carcinomatosis

In the United States 20 to 30% of patients with gastric cancer being explored for potentially curative resection will be found to have peritoneal seeding at the time of surgical exploration (Sugarbaker, 2003 or 2004). Current standard treatment is systemic chemotherapy which may delay onset of symptoms but is not curative. The median survival of these patients is 5 months with virtually no long-term survivors (Sadeghi et al, 2000). Yoo and colleagues reviewed 2328 patients with gastric cancer who underwent curative resection with at least 5-years follow-up (Yoo et al, 2000). Documented evidence of relapse of the disease was found in 508 patients. Isolated peritoneal recurrence was noted in 34% of patients who relapsed. Hematogenous recurrence occurred in 26% and local-regional persistence of the tumor was seen in 19%. Two or more sites of recurrence were documented in the remaining patients. Serosal invasion and lymph node metastasis were risk factors of relapse in all patterns of recurrence.

This high incidence of peritoneal carcinomatosis following curative resections is shared by others, with an average incidence between 20% and 50% (Gunderson and Sosin, 1982; Koga et al, 1984; Wisbeck et al, 1986; Landry et al, 1990). These data show that in an impressive number of patients the recurrence is isolated within the peritoneal cavity. It also suggests that if an effective treatment could be targeted toward peritoneal dissemination, at least a third of the patients with advanced gastric cancer could experience a better outcome.

Systemic chemotherapy for gastric patients presenting with peritoneal seeding at the time of abdominal exploration or as a manifestation of disease recurrence after a curative surgery is uniformly disappointing. Preusser and colleagues published a response rate for advanced gastric cancer of 50%; nevertheless patients with peritoneal dissemination obtained the worst response (Preusser et al, 1989). Ajani and colleagues, treated patients prior to gastrectomy (Ajani et al, 1991). At exploration, peritoneal carcinomatosis was the most common cause of failure of intensive neoadjuvant chemotherapeutic treatment. Also, radiation showed limited results in this situation and is expected to cause significant morbidity when applied to such a large field.

C. Rationale for peritoneal surface malignancy treatments

However, during the last two decades new concepts have arisen with the intent to develop treatment options for carcinomatosis patients. Recognition of the peritoneal layer as the first defense barrier to tumor progression allows one to assume that cure might be possible if tumor nodules were eradicated from all peritoneal surfaces (Sugarbaker, 1990). Also in 1984, Flessner and colleagues showed in pharmacokinetics experiments that the clearance of a drug from the peritoneal cavity is inversely proportional to its molecular weight (Flessner et al, 1984). This new pharmacologic concept, known as Peritoneal-Plasma Barrier, represents the basis of intraperitoneal use of chemotherapeutic agents. In 1995, Sugarbaker published new surgical strategies collectively referred to as peritonectomy procedures (Sugarbaker, 1995). These surgical techniques allow the resection of all parietal peritoneum involved by peritoneal seeding. Visceral peritoneum invaded by tumor may require organ resection.

When the concept of peritonectomy is combined with new pharmacokinetics studies, strategies for the effective management of peritoneal surface malignancies can be formulated for a significant proportion of patients. Accumulated experience shows that success against carcinomatosis from gastrointestinal tumors depends on a coordinated and dose intensive effort. That means maximal surgical cytoreduction plus maximal chemotherapy delivered directly into the abdominal and pelvic cavity during the perioperative period. Unless both strategies are used as a planned part of the surgical intervention little success can be expected.

The most direct test of this new concept of the peritoneum as the first line of defense against peritoneal dissemination is pseudomyxoma peritonei arising from an appendiceal adenoma. It represents a paradigm of this new approach to peritoneal surface malignancies with approximately 85% 5-year survival (Sugarbaker et al, 1999). No other treatments for this group of patients have been shown to be curative. From the remarkable results achieved in appendiceal mucinous tumors using this new combined treatment a rationale for the treatment of peritoneal carcinomatosis from colorectal cancer and gastric cancer emerges. The treatment modalities are further described, selection criteria discussed, results of clinical studies presented and morbidity, mortality and quality of life among treated patients evaluated.

II. Peritonectomy procedures

Until recently any patient with peritoneal seeding from a gastrointestinal primary had no surgical option with intent to cure. This was based on the assumption that even if the peritoneal nodules were the only anatomical sites of advanced disease, they were untreatable by conventional surgical techniques. However, the study of the pathobiology of the peritoneal surface component of cancer and also of the patterns of this dissemination allowed the evolution of six surgical procedures for the treatment of macroscopic disease spread on peritoneal surfaces (Sugarbaker, 1995).

An important concept regarding tumor behavior derives from the studies of Weiss. He showed that even though a large number of malignant cells reached the liver through the blood stream only a few adhere to the endothelium and develop into true metastasis. This phenomenon known as “metastatic inefficiency” characterizes hematogenous dissemination of disease (Weiss, 1986). In contrast, free cancer cells in the peritoneal cavity implant and grow with great efficiency. Schott and colleagues evaluated the prognostic significance of isolated tumor cells detected in the bone marrow and in the peritoneal lavage of 84 patients with gastric cancer and in 109 patients with colorectal cancer (Schott et al, 1998). Although cancer cells identified in the bone marrow showed little prognostic significance, free cancer cells in the peritoneal cavity were highly correlated with limited long-term survival.

From observations collected from reoperative surgical procedures, Sugarbaker, (1996) described four patterns of intracoelomic cancer dissemination. In the absence of peritoneal fluid aggressive tumors tend to spread randomly to the peritoneum surrounding the primary tumor. However, tumors that are mucus producing or those that lead to ascitic fluid accumulation, present a characteristic redistributed pattern. The tumor cells tend to adhere at the peritoneal resorption sites in the greater omentum and beneath the diaphragm. Also, gravity is a determinant in tumor distribution since the peritoneal fluid accumulates in the pelvis creating a fluid rich in tumor contamination. Thus, these malignant cells have the opportunity to implant and progress on pelvic peritoneal surfaces.

The third pattern of intracoelomic cancer dissemination was described by Carmignani and colleagues (2003). They documented the influence that peritoneal motion has on tumor distribution. Many structures in the abdomen are stationary, whereas others such as the jejunum and ileum are in continuous peristalsis. When cancer cells are present within the peritoneal space, especially when ascitic or mucoid fluid is present, the malignant cells tend to deposit within non-mobile anatomic sites such as the rectosigmoid junction, around the cecum and the appendix, over the liver and in the subpyloric space. In contrast, the surfaces of the small bowel and its mesentery may remain almost free of disease. This is one of the observations that led to a rationale for peritonectomy procedures and a curative approach to peritoneal surface malignancies.

A fourth mechanism influencing tumor distribution into the abdominopelvic cavity occurs as a result of surgical manipulation and is called “tumor cell entrapment.” The malignant cells present in the peritoneal cavity at the time of the first surgery have a tendency to implant on wounded surfaces such as the laparotomy scar, along the bed of the resected primary tumor, or in suture lines. These cells become entrapped by fibrin and are stimulated by inflammatory growth factors released during the healing process. The concept that tumor cell entrapment and enhancement can result from surgical procedures should profoundly affect the practice of cancer surgery (Sugarbaker, 1990).

Considering that a significant proportion of patients with carcinomatosis arising from gastrointestinal cancer have a preponderance of spread on parietal peritoneum and have limited disease over their small bowel surfaces, Sugarbaker described the peritonectomy procedures with the intent to reduce peritoneal surface dissemination to a microscopic level (Sugarbaker, 1995). These procedures are used for resection of peritoneum involved by cancer. On the small bowel surface tumor nodules are electroevaporated and normal peritoneum is spared in order to preserve gastrointestinal function. These techniques are summarized as follows:

· Epigastric peritonectomy: includes any prior midline scar in continuity with preperitoneal epigastric fat pad, the xiphoid process and the round and falciform ligaments of the liver.

· Anterolateral peritonectomy: removes the greater omentum with the anterior layer of the peritoneum from the transverse mesocolon. If the spleen is involved it is resected. The peritoneum of the right paracolic gutter along with the appendix, the spleen and in some patients, the peritoneum covering the left paracolic gutter must be stripped.

· Subphrenic peritonectomy: the peritoneum underneath the right and left portions of the diaphragm is removed along with the left triangular ligament of the liver; this includes the peritoneum lining the retrohepatic space. Glisson’s capsule is removed in part or completely as required by cancer implants.

· Omental bursa peritonectomy and lesser omentectomy: begins with the cholecystectomy and is followed by removal of the peritoneum of the porta hepatis, anterior and posterior aspects of the hepatoduodenal ligament, hepatogastric ligament and the peritoneal floor of the omental bursa, including the peritoneum overlying the pancreas.

· Pelvic peritonectomy: removes the peritoneum from the rectovesical or rectouterine space (pouch of Douglas) and usually the rectosigmoid colon must be resected. In women, both ovaries and the uterus are also removed.

· Partial/total gastrectomy: if the subpyloric space is involved an antrectomy may be enough to eliminate the disease. However, especially in mucinous tumors, the entire lesser curvature of the stomach may be encased by tumor and only a total gastrectomy allows complete removal of disease.

III. Intraperitoneal chemotherapy

A. Rationale

Cytoreductive surgery alone can treat gross and macroscopic disease. However, it leaves behind microscopic disease which will progress not only on the peritoneal surfaces, but also within the scar tissues. Residual disease will be stimulated by growth factors released during the healing process (Sugarbaker, 1990). This iatrogenic mechanism for tumor dissemination (tumor cell entrapment and enhancement) is a major cause for both systemic and intraperitoneal chemotherapy failure.

Intraperitoneal chemotherapy was designed to treat the entire abdominal and pelvic cavity using high drug concentrations locally with reduced systemic toxicities. As would be expected, the results of intraperitoneal chemotherapy administered alone for the treatment of established peritoneal metastasis are disappointing. This failure occurs as a result of the very limited penetration of the drugs into tumor nodules. Experimental studies show that only the outer layers of the cancer implants will achieve cytotoxic concentrations of the chemotherapeutic agent (Ozols et al, 1979; Los and McVie JG, 1990). The most optimistic studies suggest a maximum of 3 mm depth of penetration by the cytotoxic drugs (van de Vaart, 1998). These data establish that intraperitoneal chemotherapy should be used only after complete cytoreduction.

Another important limitation for the use of intraperitoneal chemotherapy alone for the treatment of peritoneal surface malignancies is the non-uniform distribution of the drug inside the abdominal and pelvic cavity. The tumor itself may cause extensive adhesions; also, a significant number of these patients have had prior surgical interventions leading to scar formation. Thus, unless all adhesions are taken down one cannot expect a uniform distribution to all peritoneal surfaces (Elias et al, 2000).

B. Hyperthermia

Hyperthermia alone already has some cytotoxic properties that can be summarized as follows: inhibition of angiogenesis, induction of apoptosis, denaturation of essential proteins, impaired DNA repair and induction of heat-shock proteins which can be receptors for natural-killer cells (Christophi et al, 1999; Dahl et al, 1999).

Perhaps more important, chemotherapy has been shown to be potentiated by hyperthermia. The ideal temperature for specific chemotherapy agents have not been precisely determined, but it is between 41^oC and 44^oC. Above this temperature the heat will be cytotoxic to non-cancerous cells and cause destruction of the chemotherapy agents (Shimizu et al, 1991).

Hyperthermia decreases interstitial pressure of the tumor nodules to a level expected for normal tissues. It also increases cell membrane permeability allowing a higher drug concentration inside tumor nodules (Storm, 1989; Leunig et al, 1992; Jacquet et al, 1998). Although hyperthermic enhancement of penetration deep into the cancer nodule has only been demonstrated for cisplatin and doxorubicin, it should occur also with other cytotoxic drugs (van der Vaart et al, 1998).

Another benefit of higher temperatures is heat augmentation with selected drugs such as mitomycin C, cisplatin and doxorubicin (Storm, 1989). Some chemotherapy agents such as melphalan, cyclophosphamide and ifosfamide are synergized by heat to a great extent (Urano et al, 1999, 2002; Mohamed et al, 2003; Glehen et al, 2004).

C. Technique

The timing of drug delivery can be classified as preoperative intraperitoneal chemotherapy; intraoperative intraperitoneal chemotherapy, usually associated with hyperthermia (HIIC); early postoperative intraperitoneal chemotherapy (EPIC); and long-term intraperitoneal chemotherapy (LTIC).

Preoperative intraperitoneal chemotherapy has been used by Yonemura (Japan), for the treatment of gastric cancer presenting with established peritoneal metastasis. This group also utilizes HIIC and EPIC in the same patients trying to improve the results in this poor prognosis clinical entity (Yonemura et al, 2003).

The use of intraperitoneal chemotherapy just after the cytoreduction, but before the construction of the anastomosis; HIIC, is the most widely used method (Glehen et al, 2004). In addition to the advantages of the route of administration of the chemotherapeutic agent (intraperitoneal) and the association of hyperthermia, all adhesions are eliminated at this point in the surgery allowing the distribution of the fluid to the whole peritoneal cavity. Another major benefit of HIIC utilized after maximal cancer resection with peritonectomy is related to the reduction of tumor burden to a microscopic level. The cytotoxic drugs can eliminate free cancer cells before they implant deep in scar tissue and away from the effects of both systemic and intraperitoneal chemotherapy.

There are four techniques by which to perform the HIIC: closed, partially closed, open and by a peritoneal expander. In the closed technique the intestinal anastomoses, the fascia and skin of the abdominal wall are closed prior to the HIIC. In the partially closed technique the skin of the abdominal wall is closed with a running suture. After the chemotherapy treatment the abdominal skin is reopened and intestinal anastomoses performed. However, these methods do not guarantee a uniform drug and heat distribution as shown through radiological exams and dye studies (Hughes et al, 1992; Elias et al, 2000). The open technique or “Coliseum technique” (Figure 1) was described by Sugarbaker and is performed by elevating the skin edges of the midline abdominal incision on a self-retaining retractor (Sugarbaker, 1999). This method, in spite of greater heat-loss and the theoretical problem of environmental chemotherapy contamination, has the advantage of allowing the surgeon to manipulate the fluid inside the abdominal cavity in order to optimize heat and drug distribution. Yonemura et al. also described an open technique with the help of a peritoneal expander which, as the coliseum method, permits the surgeon to distribute the fluid (Yonemura, 2003). The peritoneal expander technique is performed through the closure of the proximal and distal portions of the abdominal incision, leaving a central gap for a plastic cylinder. Through this opening the surgeon’s hand can manipulate the abdominal contents. The peritoneal expander is attached to a self-retaining retractor. This method was designed to accelerate the heating process inside the abdomen and diminish the heat loss (De Simone et al, 2003).

Some groups use HIIC and also EPIC in the same patient; only a few groups utilize EPIC alone as a preferential route of drug administration (Glehen et al, 2004). HIIC plus EPIC may have some disadvantages when compared with EPIC alone:

· Hyperthermia is usually not used in EPIC;

· Drug distribution depends on gravity;

· This technique is more associated with a greater incidence of wound healing complications.

The delayed delivery of intraperitoneal chemotherapy produces the worst results (Sautner et al, 1994). In addition to the disadvantages presented by the closed technique, in this method the drugs are delivered after adhesion formation. This not only prevents treatment of the entire abdominal and pelvic cavity, but also allows viable tumor cells to become imbedded inside the scar of healing tissue. Trapped in scar tissue and under the stimulus of growth factors released by inflammatory cells, these cancer cells are in a sanctuary site and cannot be reached by chemotherapeutic drugs (Sugarbaker, 1990; Sugarbaker, 1996).

The duration of the peritoneal washing with chemotherapy solution varies greatly. In the HIIC techniques, this period varies between 60 to 90 minutes. The volume and flow employed are also differences encountered among the groups; 3 liters of fluid, with a flow of 2L/minute can be considered an average (Glehen et al, 2004).

In the EPIC technique the drug is administered as fast as possible and remains within the peritoneal cavity for 23 hours. An additional chemotherapy instillation occurs the next day. The EPIC usually is performed during the first five post-operative days. Changes in patient position facilitate drug distribution.

D. Drugs

The pharmacokinetics characteristics of intraperitoneal administration of chemotherapeutic agents are of great importance in the choice of drugs. Selected chemotherapy agents have a prolonged retention within the peritoneal cavity. In 1978 Dedrick and colleagues demonstrated that the peritoneal clearance of a drug is inversely proportional to its molecular weight. Further investigation confirmed that certain agents delivered into the peritoneal cavity will maintain higher levels inside the abdomen compared to the plasma levels. This finding is known as the peritoneal-plasma barrier. This is an inaccurate nomenclature; even after extensive stripping of the peritoneal surfaces there are no large changes in the clearance of the drugs. There is an increase in the barrier with complete healing of the abdomen and scar tissue accumulation after peritonectomy procedures (Sugarbaker et al, 1990).

The peritoneal-plasma barrier has an important practical utility since it maintains a high concentration of the drug inside the peritoneal cavity with a lower plasma concentration. This diminishes the systemic toxicities that accompanies cancer chemotherapy treatment. From this data the ideal drug to be used should have the following characteristics: high molecular weight, fast systemic clearance and water solubility. For use as HIIC augmentation by hyperthermia and non-cell cycle specific cytotoxicity is desired.

A large number of chemotherapeutic agents have been used for the treatment of peritoneal surface malignancies arising from gastrointestinal tumors. Mitomycin C is the most frequently used agent. The synergism between hyperthermia and mitomycin C has been demonstrated in the laboratory. Clinically, it has been found to be effective in the control of cancer lines with low growth rates and high chemotherapy resistance such as the mucinous appendiceal adenocarcinomas (Sugarbaker et al, 1999).

Five-fluorouracil is an ideal agent to be used in EPIC, but not in HIIC, since the 5-fluorouracil does not show augmentation with hyperthermia and its cytotoxicity is cell-cycle related (Storm, 1989).

Doxorubicin has proven to be an excellent drug to be used in HIIC. In a rat model, when used at 43^oC, this drug showed a marked deep penetration without increasing plasma concentrations (Jacquet et al, 1998). These positive characteristics make this drug an appropriate choice in many tumors. At high doses and repeated treatments, peritoneal sclerosis is a limiting factor in dose escalation.

Synergism between cisplatin and hyperthermia has been shown in several clinical trials. In animal models this finding was considered to be a consequence of higher and selective uptake of the drug by the cancer cells (Los et al, 1993). Thus, cisplatin clearly deserves special attention from investigators for use in HIIC.

Oxaliplatin, used for several years in Europe, but only recently approved in the United States, was the subject of a pharmacokinetics study by Elias and colleagues (Elias et al, 2002). Their report showed that this agent achieved high tumor and intraperitoneal concentrations without toxic plasma levels. Since this drug has shown an impact in the systemic treatment of advanced colorectal cancer, it must be explored in the treatment of carcinomatosis secondary to colorectal tumors.

IV. Quantitative prognostic indicators

When confronted in the operating room with peritoneal seeding from gastrointestinal cancer, the surgeon must make a decision regarding the possible risks and benefits of a definitive treatment versus supportive care. Although this combined treatment has proven to be the only possibility of cure for patients presenting with peritoneal carcinomatosis, one cannot forget the morbidity, mortality and cost that accompany the combined treatment. With the combined treatment strategy a proportion of patients will be free of disease and a second group will experience a better outcome with longer survival. However, as in most gastrointestinal cancer treatments, there will be a group of patients that will be treated with minimal benefit. The disease will continue to progress despite the treatment provided; sometimes these patients will have a worse clinical course due to the inappropriately excessive treatment. In an attempt to offer a suitable treatment for individual patients quantitative prognostic indicators have been developed.

The peritoneal surface malignancy literature supports three pre-operative quantitative prognostic indicators: tumor histopathology, radiological features and prior surgical score. In the operating room after complete exploration of the abdomen and pelvis, the surgeon has another prognostic indicator that is an index to measure the tumor burden within the peritoneal surfaces. This is called the peritoneal cancer index (PCI). Unfortunately, the most reliable prognostic indicator to date can be assessed only after the surgical procedure. The completeness of cytoreduction score indicates the amount of tumor that could not be surgically resected.

A. Tumor histopathology

The biologic behavior of the peritoneal surface malignancy is a major determinant of prognosis in these patients. Pancreatic adenocarcinomas with peritoneal seeding exemplify one clinical situation in which combined treatment is of no known value due the extremely aggressive behavior of this neoplasm. Gastric cancer patients represent another major challenge to the combined treatment since only those presenting small volume of peritoneal surface disease seems to have an improved life expectancy. Colon cancer patients are in an intermediate position. Even though these patients have a moderate amount of disease, if a complete cytoreduction is achieved, improvement in life expectancy may be observed. On the other hand there are the non-invasive tumors such as pseudomyxoma peritonei arising from an appendiceal adenoma. These tumors may have extensive intraperitoneal accumulation without local invasion, lymphatic infiltration or hematogenous dissemination. Thus, the use of peritonectomy procedures, even in bulky tumors, can eradicate all macroscopic disease and when combined with perioperative intraperitoneal chemotherapy leads to long-term survival.

B. Prior surgery score

The occurrence of prior abdominal surgeries greatly influences the likelihood of complete cytoreduction. During surgery, cancer cells free in the peritoneal space have a tendency to adhere to raw surfaces such as sites of surgical dissection. These entrapped tumor cells may now grow along retroperitoneal structures such as the ureters and the vena cava. Abraided and surgically traumatized small bowel surfaces also are favored sites for cancer cells to implant. This deeper non-anatomical cancerous dissemination caused by prior abdominal surgery represents a major cause of incomplete cytoreduction and thus of limited survival. The “Prior Surgical Score” (Table 1) was developed to quantitate the previous surgical trauma and to estimate the likelihood of a complete resection (Jacquet and Sugarbaker, 1996). This scoring system has proved to have a good correlation with prognosis in patients with mesothelioma (Sebbag et al, 2000) and pseudomyxoma peritonei (Sugarbaker and Chang, 1999) treated by cytoreductive surgery and intraperitoneal chemotherapy. Also, primary colon cancer with carcinomatosis may have a better prognosis that carcinomatosis with recurrent disease (Pestieau et al, 2000). Recommendations regarding primary gastrointestinal cancer operations need to change in order to minimize the prior surgical score.

One must conclude that if unexpected carcinomatosis is found, modification of the first surgical intervention is required. For example, if mucinous carcinomatosis arising from a ruptured appendiceal neoplasm is observed in a patient thought to have appendicitis, a minimal dissection should be undertaken. Beyond appendectomy, the surgeon is advised to aspirate the free mucoid fluid and to perform generous biopsies to plan a future definitive combined treatment (Gonzalez and Sugarbaker, 2004). A right colectomy should not be performed to avoid deep entrapment of tumor cells in the groove between the psoas muscle and vena cava. A more common situation is patients presenting with obstructing colonic malignancies with peritoneal seeding. If the patient has a good performance status, the only procedures indicated are a decompressing ostomy and biopsies.

Table 1. Prior surgical score (PSS)

PSS-0 (none)	Biopsy only
PSS-1 (minimal)	Exploratory laparotomy, one region dissected
PSS-2 (moderate)	Exploratory laparotomy, two to five regions dissected
PSS-3 (heavy)	Extensive prior cytoreduction, more than five regions dissected

Only the debilitated patient that will not be a candidate for the combined approach should undergo definitive resection.

C. Radiological features

Pre-operative CT of chest, abdomen and pelvis are performed in invasive tumors such as gastric and colorectal cancer patients to exclude systemic disease. Unfortunately, there is no reliable radiological examination able to predict the intraperitoneal tumor burden or its distribution in invasive tumors. This lack of accuracy occurs as a result of the pattern of the cancerous growth in the peritoneal cavity. In contrast with solid organs such as the liver in which metastasis grow as nodules, aggressive cancerous implants spread along the contours of the peritoneal surfaces. This means that a negative pre-operative CT may have little value in quantitating carcinomatosis in invasive tumors (Jacquet et al, 1993).

In contrast there are non-invasive malignancies for which CT represents a reliable tool to predict the success of a complete cytoreduction. In a retrospective analyses Jacquet et al, (1995) compared patients with mucinous tumors with complete and incomplete cytoreduction. The authors identified two radiological findings that were correlated with incomplete resection:

· Signs of segmental small bowel obstruction

· Tumor masses of 5 cm or greater diameter associated with the jejunum or the upper ileum or their mesentery.

The association of both findings in the same patient indicated a likelihood of less than 5% to achieve a complete cytoreduction. Masses along the terminal ileum are common findings and can be resected with the cecum. These poor prognosis findings suggest a more advanced disease with an invasive component. Also, the nodules associated with the small bowel surfaces reflect the failure of the redistribution phenomenon, usually a result of previous surgical trauma or from end-stage of the disease.

D. Peritoneal cancer index

The extent of carcinomatosis has proven to be directly related to the likelihood of a complete cytoreduction and thus with survival. With the intent to quantitate the extent of intraperitoneal disease Jacquet and Sugarbaker described the PCI.

The PCI (Figure 2) is a score obtained in the operating room with surgical exploration after the release of adhesions (Jacquet and Sugarbaker, 1996). The peritoneal space is divided into 13 abdominopelvic regions as seen in Table 2. Then, the largest tumor nodule within each anatomical location is measured. A value that goes from 0 to 3 is given to each of the 13 regions according to the size of the largest nodule found in the region. The number of nodules in each area is not counted but only the size of the largest nodule is registered. Then the PCI is calculated by the sum of the 13 values recorded; the PCI will range from 0 to 39 (13x3).

The PCI has two distinct roles. First, it provides an objective parameter for the surgeon that can be used in the decision-making process regarding the choice of the most suitable treatment for an individual patient. Second, the

However, many oncologists desire to have a second randomized trial. Unfortunately, previous experience has shown that the randomization of patients into this kind of study can be very difficult. In 1995, Elias designed a prospective randomized trial involving patients with colorectal peritoneal carcinomatosis. Systemic chemotherapy would be used in the control group to be compared to maximal cytoreduction plus EPIC. He reports that this trial was rapidly abandoned due to the great dissatisfaction with inclusion criteria in six of the first seven eligible patients; the patients were fully aware of the futility of the control arm of the study. Then, the design of the trial was modified. The control group would now receive maximal cytoreductive surgery and systemic chemotherapy while the experimental arm would be treated by cytoreductive surgery and EPIC plus similar systemic chemotherapy. However, during the 4 years of study only 35 patients were enrolled in this phase III randomized study in spite of the 90 patients that were necessary. There were enough eligible patients, but most of them refused to be randomized in the trial. They asked to be enrolled in the phase I-II trials involving HIIC (Elias and Pocard, 2003; Elias et al, 2004).

The experience of this French group reflects a changing proactive behavior of patients who refuse to be randomized in a control group with well-known established poor prognosis. Future trials will probably be designed to standardize the most effective features of the combined approach instead of denying an effective treatment for the control group.

However, one should not assume that this combined treatment is suitable for all patients with peritoneal carcinomatosis arising from colorectal cancer. As in all surgical treatments for cancer it is important to exercise proper patient selection. Several quantitative prognostic indicators have been identified. For colorectal tumors there are two prognostic indicators that have shown to be reliable; the PCI and the CCS.

In patients with colorectal carcinomatosis, Pestieau and Sugarbaker reported that a PCI of 10 or less was associated with a five-year survival rate of 50%; a PCI between 10 and 20 carried a 5-year survival of 15%; a PCI greater than 20 resulted in no 5-year survivals (Pestieau and Sugarbaker, 2000). Elias in 2001, also using mitomycin C as the intraperitoneal chemotherapy agent, reported an improved prognosis when the PCI was lower than 16. Patients with PCI below 16 had a 3-year survival rate of 60.3% versus 32.5% in patients with PCI above this cutoff (Elias et al, 2001). More recently, the same French group using intraperitoneal oxaliplatin combined with systemic 5-fluorouracil and leucovorin used a PCI of 24 to separate patients with good prognosis from those with restricted long-term survival (Elias et al, 2002). These studies demonstrate that the PCI be used to separate patients who are likely to benefit from this aggressive combined treatment from those patients who should be treated with palliative intent. The numerical value for this PCI cutoff must be determined for a particular treatment regimen in a specific carcinomatosis disease state. In other words the critical PCI for colorectal cancer, gastric cancer and appendiceal cancer will all be different. Most likely, the more aggressive the cancer and the more heavily pretreated the patient, the lower the PCI that will be associated with long-term survivors.

The second quantitative prognostic indicator of predictive value in colorectal carcinomatosis in CCS. In the multicentric analysis performed by Glehen, the actuarial survival rate at 1-year, 3-years and 5-years for patients classified as CC-0 or CC-1 were 87%, 47% and 31%, respectively (Glehen et al, 2004). Shen and colleagues reported on 77 colorectal cancer patients treated by the combined approach. The 5-year survival rate for complete resection of all visible disease was 34% with a median survival of 28 months (Shen et al, 2004). In 2000, Sugarbaker reported the results of 104 patients with peritoneal seeding from colorectal cancer. The median overall survival for patients with complete cytoreduction was 24 months with a 30% 5-year survival, whereas patients with incomplete cytoreduction had a median survival of 12 months and 0% 5-year survival (Pestieau and Sugarbaker, 2000).

Other prognostic factors to be recognized in colorectal carcinomatosis patients were the use of neoadjuvant chemotherapy, lymph node involvement, presence of liver metastasis, poor histological differentiation, presence of signet ring cell type and location of the primary tumor in the rectum. The presence of these clinical features has been associated with poor prognosis (Gomez-Portilla et al, 1999; Marcus et al, 1999; Elias et al, 2001; Carmignani et al, 2004; Glehen et al, 2004; Knorr et al, 2004).

Gomez-Portilla et al, (1999) evaluated 86 patients with peritoneal carcinomatosis from colorectal origin with a median follow-up of 36.2 months. These authors showed that second-look operations were more likely to be successful if patients had a complete cytoreduction at the time of first surgery. They concluded that second-look surgery should be considered a treatment option in patients who could fulfill two criteria: First, they had a complete initial cytoreduction and second, a new complete resection was judged possible (Gomez-Portilla et al, 1999). Similar findings were reported by Verwaal et al, (2004).

C. Gastric cancer

1. Background and rationale

Among gastrointestinal cancers discussed in this paper, gastric cancer with peritoneal seeding deserves special attention because of its aggressive behavior and short median survival. In most gastric carcinomatosis patients this new combined treatment should first of all be considered a good palliation; in a small percentage of patients hope for cure may be realistic.

A review of multiple journal articles over the last 20 years supports palliative resections, even total gastrectomy if necessary, as the treatment of choice in selected patients with stage IV gastric cancer (Table 5). Complete removal of the primary cancer has a statistically significant improvement not only in survival, but also a better quality of life for these patients.

The rationale for palliative resection of the primary gastric cancer is to eliminate the serious complications that can result from the primary malignancy. These are most

commonly obstruction, perforation and bleeding. Another rationale for the resection of the primary tumor is more theoretical. By Skipper’s log-kill hypothesis, if a significant proportion of the tumor burden is removed, then both systemic and intraperitoneal chemotherapy are expected to show a greater response (Skipper et al, 1952). This may have a particular importance in gastric cancer because it is a chemotherapy-resistant tumor.

In the absence of liver or systemic metastases, the primary gastric tumor should not be considered unresectable prior to laparotomy. As long as the primary lesion and the organs it invades can be removed without significant morbidity, an attempt should be made to resect regardless of size. Leaving the gastric mass behind not only allows obstruction, bleeding and perforation during the chemotherapy treatment, but also diminishes the likelihood of a meaningful response from the chemotherapeutic drugs. Peritonectomy can be used to further reduce and, in some patients, even eliminate all visible carcinomatosis. In this situation, the response to subsequent intraperitoneal and systemic chemotherapy should be maximized.

Sugarbaker reported, (1995) the use of five different peritonectomy procedures for carcinomatosis from gastric cancer. The goal of these procedures is to reduce the intraperitoneal burden of tumor to a microscopic level, which can then be knowledgeably treated by both intraperitoneal and systemic chemotherapy. The peritonectomy procedures utilized for gastric cancer patients have been described previously.

In discussing the peritonectomy procedures for gastric cancer it needs to be emphasized that these resections are performed selectively; rarely are all procedures performed in a single patient. Peritoneum that is involved by carcinomatosis is removed but normal peritoneum is spared. Unfortunately, peritoneum on the small bowel surface invaded by cancer nodules often cannot be removed.

Yonemura et al, (1999) expanded the visceral peritonectomy in gastric cancer with peritoneal dissemination. Beyond a subtotal or total gastrectomy, the peritonectomy may involve a total colectomy if it proves to be necessary for removal of gastric cancer implants. This combination of procedures allows the surgeon to perform a total parietal peritonectomy and a very extensive visceral peritonectomy which is limited most of times by the risk of short bowel syndrome.

Intraperitoneal chemotherapy has as its objective the eradication of the microscopic residual disease and tiny tumor nodules that the surgeon cannot see or cannot remove because of a diffuse involvement of small bowel peritoneum. Conceptually, the peritoneal cavity may qualify as a “pharmacologic sanctuary” because intravenously injected drugs penetrate poorly at this site (Dedrick et al, 1978). This limited access to peritoneal implants may be one reason why patients with gastric cancer presenting with peritoneal seeding respond so poorly to systemic chemotherapy.

2. Gastrectomy plus intraperitoneal chemotherapy

In 1988 Fujimoto and colleagues from Chiba, Japan presented their initial experience in patients with gastric cancer and peritoneal seeding treated with gastrectomy and intraperitoneal hyperthermic perfusion with mitomycin C and misonidazole. All 15 of their patients tolerated the procedure well. They maintained the temperature inside of the peritoneal cavity at 43^oC to 44.5^oC (Fujimoto et al, 1988).

One year later the same authors reported on 59 patients that received gastrectomy combined with intraperitoneal hyperthermic perfusion with mitomycin C (Fujimoto et al, 1989). Compared with historical controls, the patients of the protocol showed a statistically significant improvement in survival (p=0.001). The results were most impressive in patients who had demonstrated peritoneal seeding. Median survival of the untreated group was approximately 6 months. Median survival of the patients treated with intraperitoneal chemohyperthermia was approximately 18 months (p=0.001).

In 1990 Fujimura and colleagues from Kanazawa, Japan reported on continuous hyperthermic peritoneal perfusion for the treatment of peritoneal dissemination of gastric cancer. Thirty-one patients with gastric cancer and peritoneal dissemination received cisplatin and mitomycin C. All but one of these patients had peritoneal dissemination assessed as P3. The peritoneal fluid was heated between 41^oC and 43^oC. A special peritoneal cavity expander was used in an attempt to improve distribution of chemotherapy and heat so that the surgeon could manipulate the small bowel with his hand during the chemotherapy treatments. Two of their patients survived more than 2 years (6%).

Noh et al from Seoul, Korea reported on 23 patients who had gastric resection plus intraoperative intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy. These patients were compared to 17 who had no resection and systemic chemotherapy. Two patients died after resection. The mean survival in the resection group was 7 months as compared to 5 months in the non-resection group. These authors suggested that cytoreductive surgery plus intraoperative and early postoperative intraperitoneal chemotherapy appears to be relatively safe and provides an improved outcome (Noh et al, 1995).

Yu et al from Taegu, Korea reported on the treatment of 64 patients with resectable stage IV gastric cancer (Yu et al, 1998). Half of these patients had gastrectomy only and half underwent gastrectomy plus early postoperative intraperitoneal chemotherapy with mitomycin C and 5-fluorouracil. The median survival was 4.9 versus 27.8 months (p=0.0098).

These reports demonstrate the benefit in gastric cancer of treating patients with established peritoneal implants with gastrectomy plus intraperitoneal chemotherapy. However new data has supported the use of peritonectomy procedures in selected patients at the time of resection of the primary gastric cancer.

3. Gastrectomy plus peritonectomy procedures combined with intraperitoneal chemotherapy

In theory and in practice, the more complete the surgical eradication of gastric cancer prior to initiation of chemotherapy, the greater the likelihood of cancer eradication.

Yonemura and colleagues are the pioneers in the combination of gastrectomy plus cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for the treatment of gastric cancer with peritoneal dissemination. In 1991, these authors published results on 41 patients with peritoneal dissemination of gastric cancer in the absence of liver metastasis. The overall median survival was 14.6 months with a 3-year survival in 4 patients (9.8%). The procedure also had a favorable impact on the relief of symptoms. In 7 of 9 patients who had ascites, the ascites disappeared after continuous hyperthermic peritoneal perfusion. These authors suggest that continuous hyperthermic peritoneal perfusion with mitomycin C and cisplatin is of benefit in the treatment of gastric cancer patients with peritoneal dissemination (Yonemura et al, 1991).

Yonemura and colleagues updated their experience in 1995. They reported on 43 patients who had peritonectomy in addition to continuous hyperthermic peritoneal perfusion with mitomycin C, cisplatin and etoposide. Patients who had a complete cytoreduction had a mean survival of 419 days, a 1-year survival of 61% and a 5-year survival of 17%. Patients who had residual disease had a mean survival of 205 days, a 1-year survival of 30% and a 5-year survival of 2%. The survival of patients with complete cytoreduction (n=28) as compared to patients with residual disease (n=55) was significantly different (p=0.034). Twenty-eight patients underwent a second-look surgery. In 8 patients who had a complete response recorded at the time of the second-look operation, there was a 47% five-year survival. These authors concluded that chemotherapy was most effective in those patients who had a small tumor burden as a result of cytoreductive surgery because this is the clinical situation in which there is a maximal response to chemotherapy. They suggested that cytoreductive surgery and continuous hyperthermic peritoneal perfusion are an effective treatment strategy for peritoneal dissemination of gastric cancer (Yonemura et al, 1995). The findings of this study also show that the results of treatment are greatly affected by proper patient selection.

In 1995 these authors updated this information reporting on the effects of this treatment in 83 patients (Yonemura et al, 1995). The overall one-year survival was 43% and 5-year survival was 11%. Again, patients who underwent a complete cytoreduction survived significantly longer than those with residual disease and those with a complete response to chemotherapy as observed at the time of the second-look operation survived longer than those with a partial response or no response.

Hirose et al, (1999) from Fukui, Japan, reported on hyperthermic peritoneal perfusion to treat gastric cancer with peritoneal metastasis in 17 patients. Patients given the combined treatment had a significantly better survival than 20 control patients. There was an 11-month versus 6-month median survival time and a one-year survival rate of 44% versus 15% (p=0.00479). All 5 patients who had a complete cytoreduction prior to continuous hyperthermic peritoneal perfusion survived more than 14 months. A Cox multivariate regression analysis showed that complete resection of localized peritoneal metastasis was an independent prognostic factor (p=0.0062). In these patients, continuous hyperthermic peritoneal perfusion was not a statistically independent prognostic variable (Hirose et al, 1999).

Yoo and colleagues reported the effectiveness of early postoperative intraperitoneal chemotherapy on 91 patients with stage IV gastric cancer. Additional cycles of intraperitoneal chemotherapy were administered on a monthly basis for four cycles. The results were compared with those from 140 historical controls who had surgery only. The overall 3-year survival in the group treated with chemotherapy was 17.5% and in the surgery alone group it was 11.4% (Yoo et al, 1999).

4. Prevention of peritoneal carcinomatosis in patients with gastric cancer treated with intent to cure

Analyses of recurrence patterns after potentially curative resections of primary gastric cancer have shown that local and intra-abdominal sites of progressive disease have an impact on survival. They are the only site of first recurrence in approximately 50% of patients. Even at death, the tumor often remains confined to the abdomen (Gunderson and Sosin, 1982; Wisbeck et al, 1986; Landry et al, 1990). The anatomic sites of treatment failure with postoperative systemic adjuvant chemotherapy treatments or neoadjuvant chemotherapy are essentially the same as those observed after surgery alone (Bruckner and Stablein, 1983; Wils, Meyer and Wilke, 1994). After extended lymphadenectomy, the peritoneal surfaces and the liver remain the major sites of recurrence; the rate of local-regional relapse is considerably lower when compared to recurrence patterns with more limited surgery (Maruyama et al, 1987; Kaibara et al, 1990; Korenaga et al, 1992).

From this analysis of the clinical data on surgical treatment failure, perioperative intraperitoneal chemotherapy as an adjuvant to surgery may be considered a rational therapeutic modality. There is a strong theoretical basis for the use of perioperative intraperitoneal chemotherapy as a planned part of primary gastric cancer surgery. The tumor cell entrapment hypothesis suggests that surgical manipulation of the cancerous stomach, transection of lymphatic channels and blood loss from the cancer specimen result in free intraperitoneal cancer cells. These cells become fixed in fibrin and tumor progression is enhanced by the wound-healing process. All available data indicate that gastric cancer cells present in the peritoneal cavity are always lethal (Boku et al, 1990; Fujimura et al, 1997; Bando et al, 1999; Kodera et al, 1999).

Eight studies were identified reviewing publications over the last 20 years in the English language that reported on the use of perioperative intraperitoneal chemotherapy in patients who had potentially curative resection of their primary gastric cancer. Perioperative chemotherapy was used during the surgical procedures in seven studies and immediately after surgery in one trial. All eight studies were prospective and randomized.

Table 6 shows statistically significant data for a 3-year survival rate (p=0.01) in one study (Fujimura et al, 1994) and a 5-year survival rate in the three other studies (Hamazoe et al, p=0.02; Yu et al, p=0.0278; and Fujimoto et al, p=0.0362). A statistically significant survival advantage was not seen in three studies, but the trend with small number of patients was for benefit with adjuvant intraperitoneal chemotherapy. Moreover, peritoneal recurrence was shown to be lower in two study groups treated with perioperative intraperitoneal chemotherapy (Hamazoe et al, p=0.0854; Fujimoto, p<0.0001). Taken together, these reports strongly suggest improved overall survival in the adjuvant-treatment group, which received chemotherapy given intraoperatively or immediately following surgery, as compared with patients who underwent gastrectomy alone.

Of interest is a report by Sautner and colleagues who randomized patients to receive or not receive intraperitoneal cisplatin between postoperative days 10 and 28 after gastrectomy. No improvement in survival was seen (Sautner et al, 1994). It has been suggested that both the route (intraperitoneal vs systemic) and the timing (perioperative vs delayed) of this surgically directed chemotherapy were crucial factors in the benefits observed in adjuvant gastric cancer trials (Sugarbaker et al, 1990). The negative results of the Sautner study supports the tumor cell entrapment hypothesis as an important factor of failure in the treatment of peritoneal seeding. This study was not included in Table 6 or in the meta-analysis since it did not adhere to the principles required for the adequate treatment of peritoneal surface malignancies.

Certain groups of randomized patients benefited more from perioperative intraperitoneal chemotherapy than other groups. A study by Ikeguchi and colleagues did not show statistically significant benefits for all patients of the trial. However, in 72 patients who had 1-9 positive nodes, the survival rate was 44% in the control group and 66% in patients treated by intraperitoneal chemotherapy (Ikeguchi et al, 1995). In the study by Yu et al, (1998) patients with N2-positive lymph nodes had 5-year survival rate of 15% in the control group and 44% in patients treated by intraperitoneal chemotherapy (p=0.03). Patients with lymph nodes positive for gastric cancer may be at special risk for local-regional cancer dissemination, which perioperative intraperitoneal chemotherapy can eradicate.

Investigators must use some caution when interpreting the results of these randomized studies of adjuvant perioperative intraperitoneal chemotherapy. Because of the difficulty of accurately staging patients prior to treatment, some patients with resectable stage IV cancer were included in the randomization. Therefore, true adjuvant results are combined with the use of intraperitoneal chemotherapy in patients with stage IV cancer who were able to have a gastrectomy.

These eight prospective randomized trials for the adjuvant treatment of gastric cancer may be suitable for meta-analysis. They involved only patients with a well-defined clinical entity: resectable gastric cancer without visible peritoneal seeding. They represent all randomized clinical trials that have been presented to date, with no exclusions. Also, the trials were sufficiently similar in terms of treatment to make the calculation of average effects medically meaningful. The average treatment effect has a hazard ratio of 1.75. In other words, a patient with resectable gastric cancer treated by gastrectomy plus perioperative intraperitoneal chemotherapy was almost 2

In the prospective protocol used by Verwaal and colleagues the administration of a high dose of mitomycin C (35 mg/m²) was required. This may explain in part the 15% incidence of intestinal fistula (Verwaal et al, 2003). In another study with high rate of intestinal fistula (22.2%), oxaliplatin was the drug used (Elias et al, 2002). The high dosage or the type of intraperitoneal chemotherapy may contribute to an unexpected high incidence of anastomotic dehiscence and fistula.

The role of the type of irrigation technique (open versus closed) on the rate of anastomotic fistulas is controversial. The open technique has the theoretical advantage to distribute the heated chemotherapy solution more uniformly (Sarnaik et al, 2003). Stephens reported a rate of 4.5% of intestinal complications with the open “Coliseum Technique” (Stephens et al, 1999). However, possible disadvantages of a non-uniform heated irrigation on the anastomosis was not observed in the Glehen study which showed similar rate of intestinal fistula (6.5%) using the closed technique (Glehen et al, 2003).

The timing of development of intestinal fistulas in patients who underwent intraperitoneal chemotherapy can be later than usual in other operations on the gastrointestinal tract. In the study of Glehen et al, (2003) the mean time of occurrence of these fistulas was the sixteenth postoperative day.

Another major concern regarding combined treatment relates to the hematologic toxicity of intraperitoneal chemotherapy. The rate of hematological toxicity varies considerably between series. It depends on the chemotherapy dosage used and the extent of stem cell damage from prior systemic chemotherapy treatment (Schnake et al, 1999). The higher the dosage, the higher the rates of toxicity. Postoperative hematological toxicity rates varied among these studies from 3.1% to 47.8%. It is important to note that the toxicity due to chemotherapeutic agents may occur early in the postoperative course. In the study of Shen and colleagues, the two patients that died as a consequence of bone marrow suppression developed this complication within 72 hours after intraperitoneal chemotherapy (Shen et al, 2004).

vii. Quality of life

The quality of life after cytoreductive surgery plus perioperative intraperitoneal chemotherapy has been evaluated in only a few studies. Although this combined approach may confer long term survival for a proportion of patients suffering from peritoneal carcinomatosis secondary to invasive cancers, in a large percentage of patients it will be a palliative procedure. Especially in patients treated with palliative intent the quality of life is an important consideration.

McQuellon and colleagues reported on quality of life data prospectively obtained from 64 consecutive patients treated by the combined approach for peritoneal carcinomatosis. Within 3 to 6 months after the surgery, the quality of life, measured by questionnaires, returned to baseline (McQuellon et al, 2001). From the same group of patients, McQuellon focused on 17 patients who had survived more than 3 years after the cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Ten patients (65.5%) described their health as excellent or very good; 4 (25%) as good; and 2 (13%) as fair. In 94% of cases, no limitations on moderate activity were reported. When the authors analyzed the life satisfaction of the patients since their treatment, 76% indicated that everything was different, but better after the treatment (McQuellon et al, 2003).

Schmidt and colleagues, (2005) assessed the quality of life in 25 patients who were alive following treatment by cytoreductive surgery and heated intraperitoneal chemotherapy. The mean duration for these assessments following surgery was 4 years. The global health status score was 62.6% in the study group and 75.3% in the general population. The differences were not significant (p=0.07). However, there was a definite trend towards reduced quality of life in treated patients. Symptoms of nausea and diarrhea were significantly more frequent in operated patients. The data in patients undergoing cytoreductive surgery and heated intraperitoneal chemotherapy were far superior to those patients treated with Whipple procedure where the score was 40.

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Paul H. Sugarbaker, M.D.,

Regions	Anatomic structures
0 Central	Midline abdominal incision – entire great omentum – transverse colon
1 Right upper	Superior surface of the right lobe of the liver – undersurface of the right hemidiaphragm – right retrohepatic space
2 Epigastrium	Epigastric fat pad – left lobe of the liver – lesser omentum – falciform ligament
3 Left upper	Undersurface of the left hemidiaphragm – spleen – tail of pancreas – anterior and posterior surfaces of stomach
4 Left flank	Descending colon – left abdominal gutter
5 Left lower	Pelvic sidewall lateral to the sigmoid colon – sigmoid colon
6 Pelvis	Female internal genitalia with ovaries, tubes and uterus – bladder – Douglas pouch – rectosigmoid colon
7 Right lower	Right pelvic sidewall – cecum – appendix
8 Right flank	Ascending colon – right abdominal gutter
9 Upper jejunum	Including both bowel and its mesentery
10 Lower jejunum	Including both bowel and its mesentery
11 Upper ileum	Including both bowel and its mesentery
12 Lower ileum	Including both bowel and its mesentery

Author	Year	Institution	No. of Patients	Method	3 year survival	5 year	Morbidity	Mortality
Sugarbaker	1999	Washington DC	385	MMC	74%	63%	27%	2.7%
Witkamp	2001	Amsterdam	46	MMC	81%	NA	39%	8%
Piso	2001	Regensburg	17	Cisplatin	75%	NA	63%	11%
Shen	2003	Winston-Salem	23	MMC	61%	NA	NA	NA
Deraco	2004	Milan	33	Cisplatin/MMC	NA	96%	33%	3%
Guner	2004	Hanover	28	Cisplatin/MMC/5FU	NA	75%	36%	7%
Loungnarath	2005	Lyon	27	Cisplatin/MMC	80%	50%	44%	0%

Reference	Location	Treatment and no.	Survival
Ekbom and Gleysteen ^a	Milwaukee, WI	No resection, 20 Palliative gastrectomy, 147	0% (2 year minimum) 16% (2 year minimum)
GITSG	Washington, DC	No resection, 53 Palliative gastrectomy, 147	P < 0.05
Meijer et al. ^a	Amsterdam, Netherlands	No resection, 25 Palliative gastrectomy, 26	4.2 m (median) 9.6 m
Boddie et al. ^b	Houston, TX	No resection, 21 Palliative gastrectomy, 45	3.6 m (median) 10.4 m
Bozzetti et al.	Milan, Italy	No resection, 185 Palliative gastrectomy, 61	3.0 m 8.0 m
Hallissey et al.	Birmingham, UK	No resection, 9,597 Palliative gastrectomy, 884	P < 0.001
Butler et al. ^a	Torrance, CA	Palliative total gastrectomy, 27	15.0 m
Haugstvedt et al ^b	Norway	No resection, 311	4.0 m (median)
Monson et al. ^a	Rochester, NY	No resection, 226 Palliative gastrectomy, 53	3.5 m (median) 19.0 m
Ouchi et al. ^a	Natori, Japan	No resection, 31 Palliative gastrectomy,64	6.0 m P < 0.01 12.0 m
Kikuchi et al.	Kanagawa, Japan	No resection, 59 Palliative gastrectomy,63	5.5 m P < 0.0001 12.2 m

Reference	Location	No. of patients study/ control	Survival rates % study/ control	P	Study/ control morbidity %	Study/ control mortality %
Koga et. al.	Yonago	26/21	2.5-year 83/67.3	NS	3.1/7.1	NA
Hamazoe et al.	Yonago	42/40	5-year 61.3/52.5	0.02	4.8/7.50	0
Fujimura et al.	Kanazawa	22/18	3-year 68/23	0.01	36/NA	0
Yonemura et al.	Kanazawa	79/81	3-year 55/38	0.052	3/2.5	3/2.5
Ikeguchi et al.	Yonago	78/96	5-year 51/46	NS	1.2/2.08	1.2/2.08
Yu et al.	Taegu	125/123	5-year 54.1/38.1	0.0278	28.8/20.3	6.4/1.6
Fujimoto et al.	Chiba	71/70	5-year 69/55	0.0362	2.81/2.85	0
Kim et al.	Seoul	52/51	5-year 34.6/31.4	NS	NA	NA

Author	Journal, year	N	Morbidity (%)	Mortality (%)
Stephens	Ann Surg Oncol, 1999	200	27	1.5
Beaujard	Cancer, 2000	83	9.6	3.6
Elias	Cancer, 2001	64	54.6	9.3
Witkamp	Br J Surg, 2001	46	39.1	8.7
Butterworth	Am J Surg, 2002	11	56	9
Verwaal	J Clin Oncol, 2003	48	66	8
Glehen	J Clin Oncol, 2003	56	28.6	1.8
Elias	Gastroenteral Clin Biol, 2003	36	44	13.8
Pilati	Ann Surg Oncol, 2003	46	35	0
Glehen	Ann Surg Oncol, 2003	216	24.5	3.2
Glehen	J Clin Oncol, 2004	506	22.9	4
Guner	Int J Colorectal Dis, 2004	28	36	2/28
Zanon	World J Surg, 2004	30	16.7	3.3
Deraco	Ann Surg Oncol, 2004	33	18	3
Glehen	Br J Surg, 2004	53	23	4
Shen	Ann Surg Oncol, 2004	77	30	12

Review Article

Received: 25 March 2005; Accepted: 18 April 2005; electronically published: May 2005

A. Colorectal carcinomatosis

B. Gastric carcinomatosis

C. Rationale for peritoneal surface malignancy treatments

Survival

P

References

Author	Journal	Year	Median survival
Mahteme	Br J Cancer	2004	32
Glehen	Br J Surg	2004	32.9
Shen	Ann Surg Oncol	2004	28
Pilati	Ann Surg Oncol	2003	18
Glehen	J Clin Oncol	2004	32.4
Elias	Cancer	2001	35.9
Pestieau	Dis Colon Rectum	2000	24
Verwaal	Br J Surg	2004	21.6

Complication	Intestinal fistula	Hematologic toxicity	Dosage/drug
Author	n (%)	n (%)
Stephens, 1999	9/200 (4.5)	8/200 (4.0)	10/12.5 mg/m²/MMC
Beujard, 2000	2/83 (2.4)	3/83(3.6)	10 mg/L/MMC
Witkamp, 2001	6/46 (13)	22/46 (47.8)	35mg/m²/MMC
Elias, 2001	12/64 (18.7)	2/64 (3.1)	10 mg/m²/MMC
Butterworth, 2002		2/11 (18.1)
Verwaal, 2003	7/48 (15)	19%	Max 70 mg/MMC
Glehen, 2003	7/56 (12.5)	2/56 (3.6)	Max 60 mg/MMC
Pilati, 2003	2/46	4/46	26.2 mg (median)/MMC
Elias, 2003	8/36 (22.2)	7/36 (19.4)	460 mg/m²/oxaliplatin
Glehen, 2003	14/216 (6.5)	10/216 (4.6)	Max 60 mg/MMC
Guner, 2004	3/28 (10.7)	2/28 (7.1)	12.5 mg/m²
Zanon, 2004	1/30 (3.3)	1/30 (3.3)	Cisplatin
Deraco, 2004	2/33 (6)	7/
Ghehen, 2004	42/506 (8.3)	12/506 (2.4)
Shen, 2004	1/77 (1.3)	15/77 (19)	30-40 mg/m²/MMC