Sugarbaker Oncology Associates
Specialty Section for the Treatment of Peritoneal Carcinomatosis
from Colorectal and Ovarian Cancer


 

Changes in the management of patients with peritoneal carcinomatosis from colorectal and ovarian cancer have occurred and shown favorable results. A change in ROUTE of chemotherapy administration has occurred. Cytostatic drugs are given intraperitoneally, or by combined intraperitoneal and intravenous routes. In this new strategy, intravenous chemotherapy alone is rarely indicated. Also, a change in TIMING has occurred in that chemotherapy begins in the operating room and may be continued for the first five postoperative days. Third, a change in selection criteria of treatment of cancer has occurred. Only patients with minute sized intraperitoneal tumor nodules with limited distribution within the abdomen and pelvis are likely to show prolonged benefit Meticulous cytoreductive surgery is necessary prior to the intraperitoneal chemotherapy instillation in order to reduce the tumor burden to its lowest level. Aggressive intraperitoneal chemotherapy treatments directed at large nodules of invasive intraperitoneal cancer will not produce long-term benefits, and are often the cause of excessive morbidity or mortality. Optimal treatments for peritoneal surface malignancy must occur as early as is possible in the natural history of these diseases in order to achieve the greatest benefits. A fourth change that now must occur with peritoneal surface malignancy regards the oncologists' attitudes toward these diseases. Patients may be cured if treated with aggressive local-regional treatment strategies without delay.

Most cancers that occur within the abdomen or pelvis will disseminate by 3 different. routes. These are hematogenous metastases, lymphatic metastases, and through peritoneal spaces to surfaces within the abdomen and pelvis. In substantial number of patients with abdominal or pelvic malignancy, surgical treatment failure may be isolated to the resection site or to peritoneal surfaces. This leads to a hypothesis that suggests that the elimination of peritoneal surface spread may have an impact on the survival of these cancer patients, and that a leading cause of death and suffering in patients with these malignancies is progression of peritoneal surface disease. Prior to the use of cytoreductive surgery and intraperitoneal chemotherapy, carcinomatosis was uniformly fatal, eventually resulting in intestinal obstruction over the course of months or years. Occasionally patients with low-grade malignancies such as pseudomyxoma peritonei survived for several years, but all end result reports have shown fatal outcomes.

TUMOR CELL ENTRAPMENT

The 'tumor cell entrapment" hypothesis explains the rapid progression of peritoneal surface malignancy in patients who undergo treatment using surgery alone. This theory relates the high incidence and rapid progression of peritoneal surface implantation to:

  1. free intraperitoneal tumor emboli as a result of serosal penetration by cancer;
  2. leakage of malignant cells from transected lymphatics;
  3. dissemination of malignant cells directly from the cancer specimen as a result of surgical trauma and back-flow of venous blood;
  4. fibrin entrapment of intraabdominal tumor emboli on traumatized peritoneal surfaces;
  5. promotion of these entrapped tumor cells through growth factors involved in the wound healing process.

     

This phenomenon causes a high incidence of surgical treatment failure in patients treated for primary gastrointestinal cancer. Also, the re-implantation of malignant cells into peritonectomized surfaces in a patient with carcinomatosis must be expected.

In order in interrupt this widespread implantation of tumor cells on abdominal and pelvic surfaces, the abdominal cavity is flooded with chemotherapy in a large volume of fluid during the operation (heated intraoperative intraperitoneal chemotherapy) and in the postoperative period (early postoperative intraperitoneal chemotherapy).

This new approach to the surgical treatment of abdominal and pelvic malignancy begins in the operating room after a complete resection of a primary cancer or after the complete cytoreduction of peritoneal carcinomatosis. The proper placement of tubes and drains and temperature probes is needed prior to initiation of intraperitoneal chemotherapy. Suture lines or repair of seromuscular tears occur after the intraperitoneal chemotherapy is completed. Before abdominal closure, the temperature probes are removed but the tubes and drains are left in place for early postoperative intraperitoneal chemotherapy.

The use of intraperitoneal chemotherapy in the past has met with limited success and acceptance by oncologists. There have been three major impediments to greater success. Intracavitary instillation allows very LIMITED PENETRATION of drug into tumor nodules. Only the outermost layers (approximately 1 mm) of a cancer nodule is penetrated by the chemotherapy. This means that only minute tumor nodules can be definitely treated. In most trials, oncologists have attempted to treat established disease, and this selection of patients has caused disappointment with intraperitoneal drug use. MICROSCOPIC RESIDUAL DISEASE is the ideal target for intraperitoneal chemotherapy protocols.

A second cause for limited success with intraperitoneal chemotherapy is a NON-UNIFORM DRUG DISTRIBUTION. Patients treated by drug instillation into the abdomen or pelvis uniformly have had prior surgery, which causes scarring. The adhesions create multiple barriers to the free access of fluid. Although the instillation of a large volume of fluid over a long time period will partially overcome the problems created by adhesions, frequently large surface areas will have no access to chemotherapy. In addition, limited access from adhesions may increase with repeated instillations of chemotherapy.

Tumor cells may be protected not only by adhesions, but also by surface scar. Surgery results in fibrin deposits on surfaces that have been traumatized by the cancer resection. Free intraperitoneal cancer cells become trapped within the fibrin. The fibrin is infiltrated by platelets, neutrophils and monocytes as part of the wound healing process. As collagen is laid down, the tumor cells are then entrapped by scar tissue. The scar tissue is marginally vascularized.  Neither intravenous or intraperitoneal chemotherapy has access to cancer cells trapped in scar tissue and adhesions.

A final obstacle to success with the administration of intraperitoneal chemotherapy that one encounters is the DIFFICULTY AND DANGERS OF LONG-TERM PERITONEAL ACCESS. There has been no technical solution to the requirement for reliable repeated access to the peritoneal space. Access in the operating theater is now completely safe. Also, temporary access in the early postoperative period is safe for the patient. However, repeated instillations of large volumes of chemotherapy solution causes great inconvenience and can result in a large number of serious complications. Whether the oncologist chooses repeated paracentesis or an indwelling catheter, complications such as pain upon instillation, bowel perforation, instillation into soft tissues or inability to infuse or drain occur repeatedly. At this time, prolonged peritoneal access remains a technical challenge.

The problems with prolonged peritoneal access have led numerous surgical oncologists to adopt what has been referred to as combined treatment. All visible abdominal or pelvic cancer should be completely extirpated by surgery. Then in the operating room, a high dose of heated chemotherapy is delivered to eradicate the remaining tiny tumor nodules or cancer cells that remain. This means that all abdominal and pelvic components of the cancer, including persistent peritoneal surface malignancy, are eliminated. Systemic components of the disease now can be more adequately treated by the medical oncologist.

SURGICAL TECHNIQUES

If a surgeon operates on a patient with peritoneal surface malignancy, certain requirements of his efforts are necessary. He must know how to perform peritonectomy procedures, dissect using electroevaporative surgery, and through the use of intraperitoneal chemotherapy prevent cancer implantation into traumatized peritoneal surfaces, suture lines, all transabdominal puncture sites, and the abdominal wound closure.

Peritonectomy procedures are necessary if one is to successfully treat peritoneal surface malignancies with curative intent. Peritonectomy procedures are used in the areas of visible cancer progression in an attempt to leave the patient with only microscopic residual disease. Small tumor nodules can be removed using electroevaporation. Involvement of the visceral peritoneum frequently requires resection of the organ or the structure. Peritoneal surface malignancy tends to involve the viscera at 3 definite sites. These are sites where the bowel is anchored to the retroperitoneum and a reduction in peristalsis causes less mobility of the visceral peritoneal surface. The rectosigmoid colon, as it comes up out of the pelvis, is a non-mobile portion of the bowel. Also, it is a dependent site; and therefore, frequently requires resection. Usually a complete pelvic peritonectomy involves stripping of the abdominal sidewalls, the peritoneum overlying the bladder, the cul-de-sac, and the rectosigmoid colon. The ileocecal valve is another area where there is limited mobility. Resection of the terminal ileum and a small portion of the right colon are often necessary. A final site often requiring resection is the antrum of the stomach or sometimes the entire stomach. The antrum of the stomach is fixed to the retroperitoneum at the pylorus. Tumor accumulates in the subpyloric space and may cause gastric outlet obstruction. Tumor in the lesser omentum may cause a confluence of disease on the lesser curvature. This may require a total gastrectomy because of encasement of the vascular supply to the stomach.

In order to adequately perform cytoreductive surgery, the surgeon must use electroevaporative surgery. Peritonectomies and visceral resections using the traditional scissors and knife dissection will unnecessarily disseminate a large number of tumor emboli within the abdomen. Also, clean peritoneal surfaces devoid of cancer cells are less likely to occur. Electroevaporative surgery leaves a margin of heat necrosis that is less likely to contain persistent malignant cells. Electroevaporation of tumor and normal tissue at the margins of resection minimizes both the blood loss with peritoneal stripping and the likelihood of persistent disease within a peritonectomy site.

Cytoreductions without chemotherapy washing may actually harm a patient in the long run rather than help them. Extensive removal of peritoneal surfaces in the absence of intraperitoneal chemotherapy will allow tumor cells to become implanted on a deeper surface of the abdomen and pelvis. This will lead to involvement of vital structures such as ureters. Also, deep involvement of the pelvic sidewall or tissues along vascular structures may occur. If a surgeon is to attempt to treat peritoneal surface malignancy, he must become thoroughly familiar with the techniques of intraoperative chemotherapy and early postoperative chemotherapy. Complete cytoreduction combined with aggressive perioperative intraperitoneal chemotherapy and proper patient selection are the three definite requirements of optimal treatment of peritoneal surface malignancy.

CHEMOTHERAPY TECHNIQUES

Heated Intraoperative Intraperitoneal Chemotherapy Administration

In the operating room, heated intraoperative 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 more 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 and allow 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.

Alter the cancer resection is complete, the Tenckhoff catheter and closed suction drains are placed through the abdominal wall and made watertight with a purse string suture at the skin. Temperature probes are secured to the skin edge Using a running 2 x 0 monofilament suture, the skin edges are elevated on a retractor. A plastic sheet is incorporated into these sutures to create a covering for the cavity. A slit in the plastic cover is made to allow the surgeon's double-gloved hand access to the abdomen and pelvis. (Figure 1) During the perfusion, all the anatomic structures within the peritoneal cavity are uniformly exposed to heat and to chemotherapy. The surgeon continuously manipulates abdominal and pelvic structures to dislodge cancer cells from peritoneal surfaces. A roller pump forces the chemotherapy solution into the abdomen through the Tenckhoff catheter and pulls it out through the drains. A heat exchanger keeps the fluid being infused at 44oC so that the intraperitoneal fluid is maintained at 41.5o-43oC. The smoke evacuator is used to pull air from beneath the plastic cover through activated charcoal, preventing any possible contamination of air in the operating room by chemotherapy aerosols.

Alter the intraoperative perfusion is complete, the abdomen is suctioned dry of fluid. The self-retaining retractor is repositioned and reconstructive surgery is performed. It should be reemphasized that no anastomoses are constructed until after the chemotherapy perfusion is complete.


Early Postoperative Intraperitoneal 5-Fluorouracil for Adenocarcinoma and Paclitaxel for Ovarian Cancer

In order to keep the catheters for drug instillation and abdominal drainage clear of blood clots and tissue debris, an abdominal drains are placed on suction in the operating room. This requires tubes and drains to be positioned prior to closure of the abdomen. All intraabdominal catheters are withdrawn before the patient is discharged from the hospital.  Intraperitoneal chemotherapy following complete cytoreduction in patients with appendiceal cancer, colonic cancer, or other gastrointestinal adenocarcinomas has utilized 5-fluorouracil.  For ovarian cancer and primary adenocarcinoma, paclitaxel has been utilized.

RESULTS OF TREATMENT

Patients with large volume of ascites are frequently encountered. This may be caused by breast cancer, gastric cancer, mucinous malignancies of the colon or appendix, and ovarian cancer. Intraperitoneal chemotherapy is uniformly successful in eliminating the debilitating ascites. This usually requires three or four instillations of a systemic dose of appropriate chemotherapy into the peritoneal cavity. In a few patients, persistent ascites will require a debulking in order to separate bowel loops, remove bulk disease, and allow the use of a single cycle of heated intraoperative intraperitoneal chemotherapy. The resection generally includes the greater and lesser omentum and pedunculated tumor masses. No attempt at a complete cytoreduction is made.


Results of treatment of peritoneal surface malignancy with cytoreductive surgery and perioperative intraperitoneal chemotherapy

Disease State

No. of Patients

10-Year Survival

Appendix cancer with carcinomatosis and pseudomyxoma peritonei syndrome after complete cytoreduction

900

65%

Primary and recurrent colon or rectal cancer with carcinomatosis and complete cytoreduction

70

25%

Recurrent abdominopelvic sarcoma with sarcomatosis following complete cytoreduction

50

43%

Peritoneal surface malignancy
  1. Peritoneal mesothelioma
  2. Papillary serous cancer
  3. Primary peritoneal adenocarcinoma

150

27%

Symptomatic malignant ascites

16

0%



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