gpm principles

I. PRINCIPLES OF INTRAPERITONEAL CHEMOTHERAPY

Intraperitoneal chemotherapy gives high response rates within the abdomen because the peritoneal space to plasma barrier provides dose intensive therapy (1). Figure 1 shows that large molecular weight substances, such as mitomycin C. are confined to the abdominal cavity for long time periods (2). This means that the exposure of peritoneal surfaces to pharmacologically active molecules can be increased considerably by giving the drugs via the intraperitoneal as opposed to intravenous route.

Large molecular weight compounds when instilled into the peritoneal cavity are sequestered at that site for long periods. The physiologic barrier to the release of intraperitoneal drugs is called the peritoneal space to plasma barrier. In this experiment, 15 mg of mitomycin C was infused into the peritoneal cavity as rapidly as possible. Intraperitoneal, intravenous, portal venous and urine mitomycin C concentrations were determined by HPLC assay. (From Sugarbaker PH, Graves T, DeBruijn EA, Cunliffe WJ, Mullins RE, Hull WE, Oliff L, Schlag P: Rationale for Early Postoperative Intraperitoneal Chemotherapy (EPIC) in patients with advanced gastrointestinal cancer. Cancer Research 50:5790-5794, 1990.

For the chemotherapy agents used to treat peritoneal carcinomatosis or peritoneal sarcomatosis, the area under the curve (AUC) ratios of intraperitoneal to intravenous exposure are favorable. Table 1 presents the AUC IP/IV for the drugs in routine clinical use in patients with peritoneal seeding (2,3). In our studies, these include 5-fluorouracil, mitomycin C, doxorubicin, and cisplatin.

TABLE 1
Area under the curve ratios of peritoneal surface exposure to systemic exposure for drugs used to treat intraabdominal cancer
Drug	Molecular Weight	Area Under the Curve Ratio
5-Fluorouracil Mitomycin C Doxorubicin Cisplatin	130 334 544 300	250 75 500 20

Sugarbaker and colleagues have advanced the tumor cell entrapment hypothesis to explain the high incidence of peritoneal seeding in patients who undergo the surgical treatment of intraabdominal adenocarcinoma or sarcoma. This theory relates the high incidence of tumor implantation to one or more of the following mechanisms:

a. free intraperitoneal tumor emboli as a result of full thickness invasion of the bowel wall by cancer;

b. leakage of malignant cells from transected lymphatic channels;

c. dissemination of malignant cells from trauma as a result of surgical dissection;

d. blood clots that remain in the abdomen or pelvis that contain viable cancer cells;

e. fibrin entrapment of intraabdominal tumor emboli on traumatized peritoneal surfaces;

f. tumor promotion of these entrapped cells through growth factors involved in the wound healing process.

In order to interrupt implantation of tumor cells on intraabdominal and pelvic surfaces, the abdominal cavity may be flooded with chemotherapy in a large volume of fluid prior to surgery (induction chemotherapy). during surgery (heated intraoperative intraperitoneal chemotherapy) and in the postoperative period (early postoperative intraperitoneal chemotherapy). Some patients with a poor prognosis may be recommended for adjuvant systemic chemotherapy. These strategies may be used to treat peritoneal surface malignancy or to prevent it in groups at high risk. In this approach to peritoneal surface malignancy, there is a change in the route (intraperitoneal vs. intravenous) and timing (perioperative vs. postoperative) of chemotherapy delivery.

This new approach to the surgical treatment of intraabdominal malignancy begins in the operating room after a complete resection of a primary cancer or after the cytoreduction of a cancer with carcinomatosis or sarcomatosis. The intraoperative chemotherapy is performed prior to construction of suture lines. A proper placement of tubes, drains and temperature probes is needed prior to initiation of intraperitoneal chemotherapy. Before abdominal closure, the temperature probes are removed, but the tubes and drains may be required for early postoperative intraperitoneal lavage and chemotherapy.

In the operating room, heated intraperitoneal chemotherapy is used. Heat is part of the optimizing process and is used to bring as much dose intensity to the abdominal and pelvic surfaces as is possible. Hyperthermia with intraperitoneal chemotherapy has several advantages. First, heat by itself has greater toxicity for cancerous tissue than for normal tissue. This predominant effect on cancer increases as the vascularity of the malignancy decreases. Second, hyperthermia increases the penetration of chemotherapy into tissues. As tissues soften in response to heat, the elevated interstitial pressure of a tumor mass may decrease allowing improved drug penetration. Third, and probably most important, heat increases the cytotoxicity of selected chemotherapy agents. This synergism occurs only at the interface of heat and body tissue, at the peritoneal surface. The benefits of heat and the intraoperative timing of intraperitoneal chemotherapy are listed in Table 2.

In the immediate postoperative period, an abdominal lavage removes tissue debris and blood products from the abdominal cavity to minimize fibrin accumulation. Also, the lavage maintains the patency of the closed suction drains.

Tumor cells that remain in the abdominal cavity can be destroyed by the pharmacologic concentrations of intraperitoneal chemotherapy instilled on postoperative days 1 through 5. The timely use of intraperitoneal chemotherapy in the early postoperative period eliminates tumor cells from the abdomen before they are fixed within scar tissue that results from wound healing.

The chemotherapy not only directly destroys tumor cells but it also eliminates viable platelets, neutrophils and monocytes from the peritoneal cavity. This diminishes the promotion of tumor growth associated with the wound healing process. However, removal of the white blood cells also decreases the ability of the abdomen to resist infection. For this reason, strict aseptic technique is imperative when administering the chemotherapy or handling abdominal tubes and drains.

TABLE 2

Benefits of intraoperative timing of intraperitoneal chemotherapy

Heat increases drug penetration into tissue.
Heat increases the cytotoxicity of selected chemotherapy agents.
Heat has anti-tumor effects by itself.
Intraoperative chemotherapy allows manual distribution of drug and heat uniformly
to all surfaces of the abdomen and pelvis.
Renal toxicities of chemotherapy can be avoided by careful monitoring of urine output during chemotherapy perfusion.
Nausea and vomiting are avoided because the patient is under general anesthesia.
The time that elapses during the heated perfusion allows a normalization of many functional parameters (temperature, blood clotting, hemodynamics, etc.).

Prognostic groups of patients with peritoneal carcinomatosis

The prognostic features that control the results of treatment in patients with peritoneal carcinomatosis have been determined. Prognostic indicators include: (1) the grade of the malignant tumor, (2) the presence or absence of lymphatic or hematogenous metastases, and (3) the completeness of the surgical removal of cancer from the abdomen and pelvis. Table 3 presents the prognostic groups for peritoneal carcinomatosis from colon cancer, rectal cancer, and appendiceal cancer now being used clinically to predict outcome. For invasive malignancy, a complete cytoreduction indicates that no visible nodules of cancer remain after surgery. For noninvasive malignancy such as pseudomyxoma peritonei, complete cytoreduction may include residual tumor nodules up to 2.5 mm in diameter.

TABLE 3
Prognostic groups for peritoneal carcinomatosis
Prognostic Group	Mucinous Tumor Grade	Metastases	Completeness of Cytoreduction	Expected 5-Year Survival
I	I	None	Complete	90%
II	II or III	None	Complete	60%
III	Any	Present	Complete	30%
IV	Any	Any	Incomplete	10%

Predicting outcome for mucinous adenocarcinoma by preoperative CT of the abdomen and pelvis

CT is an inaccurate test by which to quantitate peritoneal carcinomatosis from adenocarcinoma (4). The malignant tissue progresses on the peritoneal surfaces and its shape conforms to the normal contours of the abdominal and pelvic structures. This is quite different from the metastatic processes in liver or lung, which progress as 3-dimensional tumor nodules.

The CT has been of greater help in locating and quantifying mucinous adenocarcinoma within the peritoneal cavity (5). These tumors produce a copious colloid material that is readily distinguished by shape and by density from normal structures. Using two distinctive radiologic criteria, those patients with resectable mucinous peritoneal carcinomatosis can be selected from those with non-resectable malignancy. This spares patients who are unlikely to benefit from reoperative surgery from unnecessary procedures.

The two radiologic criteria found to be most useful are: (1) Segmental obstruction of small bowel, and (2) Presence of tumor more than 5 cm in greatest dimension on the small bowel surface or directly adjacent to small bowel mesentery. These criteria reflect radiologically the biology of the mucinous adenocarcinoma. The obstructed segments of small bowel signal an invasive character of malignancy that is unlikely to be cytoreduced completely. The mucinous cancer on small bowel and small bowel mesentery indicates that the mucinous cancer is no longer redistributed. This means that small bowel surfaces will have residual disease after cytoreduction, for this surface is difficult to peritonectomize (see Figures 2 and 3).

A patient with noninvasive mucinous adenocarcinoma of appendiceal origin (pseudomyxoma peritonei) who had a complete cytoreduction and remains disease-free at four years postoperatively. The mucinous tumor is very extensive but the small bowel loops are of normal caliber and are not distended by air. Also, the small bowel has become "compartmentalized" by the mucinous tumor. The small bowel surfaces and small bowel mesentery remain free of tumor.

A patient with aggressive mucinous adenocarcinoma who recurred after extensive prior cytoreductive surgery. Small bowel loops are slightly distended, contain small volumes of air, and its mesenteric surface is coated by mucinous tumor nodules. This patient has less than 5% likelihood of a complete cytoreduction.