Prior Limited Benefits With Intraperitoneal Chemotherapy
Many oncologists seeing a resurgence of interest in intraperitoneal chemotherapy are skeptical of its possible benefits. They cite 2 decades of work in this field that have yielded only modest improvements. Those who have previously used intraperitoneal chemotherapy usually conclude that the difficulties with this route of administration outweigh any small benefits. However, prior use of intraperitoneal chemotherapy may have been flawed for three prominent reasons.
Limited Drug Penetration
First, intracavitary chemotherapy instillation produces a limited penetration of drug into tumor nodules. Only the outermost layer (approximately 1 mm) of the cancer nodule is exposed to the high concentration of drug delivered local-regionally. Also, as soon as chemotherapy enters any tissue, it is rapidly cleared into the systemic circulation. This means that only minute tumor nodules or individual cancer cells can be definitively treated. In most patients, oncologists have attempted to treat established disease with visible nodules. This improper selection of patients has resulted in disappointment with intraperitonealdrug use. Microscopic residual disease is the theoretically reasonable target for intraperitoneal chemotherapy.
Nonuniform Drug Distribution
Second, drug distribution with intraperitoneal chemotherapy is nonuniform. A majority of patients treated in this manner have undergone extensive prior surgery, which invariably results in the scarring of peritoneal surfaces. The adhesions create multiple barriers to the free access of fluid. Although the instillation of a large volume of fluid will partially overcome the problems of nonuniform drug distribution, large surfaces inevitably have no access or limited access to the chemotherapy solution. Unfortunately, this limited access due to adhesions is impossible to predict, and it generally worsens with repeated cycles of chemotherapy.
Not only do adhesions interfere with the distribution of chemotherapy, they also prevent the chemotherapy solution from achieving direct contact with the cancer. Surgery causes fibrin deposits on the surfaces that have been traumatized by the resection. Free intraperitoneal cancer cellsbecome entrapped within the fibrin. As collagen is laid down within fibrin, the tumor cells become entrapped within a scar tissue matrix that is dense and impenetrable by intraperitoneal chemotherapy.
Another aspect of nonuniform intraperitoneal drug distribution can be attributed to gravity. Water-density fluid placed within the peritoneal cavity will displace the lipid-density bowel and find a pool for the accumulation of chemotherapy solution within the pelvis and other dependent areas, including the paracolic gutters and right retrohepatic space. Unless the patient actively pursues frequent and radical changes in position (thereby affecting gravity distribution), the surfaces between the small bowel loops and especially between the small bowel loops and the anterior abdominal wall will remain untreated.
A final obstacle to the successful use of long-term intraperitoneal chemotherapy concerns the problematic technology for administration. With such chemotherapy treatments continuing for many weeks and months, the maintenance of long-term peritoneal access has proven difficult, and no optimal technical solution has been developed. Repeated instillations of large volumes of chemotherapy solution can be achieved through repeated paracentesis. However, bowel perforation, pain upon instillation, and failure to gain intraperitoneal access have frequently occurred.
Insertion of a permanent intraperitoneal port is an option. Failure to infuse, pain upon instillation, and a gradual reduction of free intraperitoneal space due to an indwelling foreign body have all been problematic.Infection of the intraperitoneal port occurs especially in patients with ascites. At present, prolonged peritoneal access is a logistic challenge with no known solution.
Rationale for Intraperitoneal Chemotherapy in Gastrointestinal Cancer
Conceptual Changes in Chemotherapy Administration
Systemic chemotherapy has produced increasingly higher response rates in patients with gastrointestinal cancer and has become a standard part of the treatment of unresectable metastatic disease and of adjuvant treatment following complete resection of the primary malignancy. In order to modify the use of chemotherapy in patients with carcinomatosis, conceptual changes regarding its use have been proposed.
First, a change in the route of drug administration is necessary. Chemotherapy is administered intraperitoneally or perhaps with multidrug therapy, both intraperitoneally and intravenously. Intravenous chemotherapy for carcinomatosis has not been shown to prolong survival. Currently, systemic chemotherapy is sometimes used as induction therapy in carcinomatosis patients with a poor prognosis, to reduce the volume of disease prior to definitive cytoreductive surgery plus intraperitoneal chemotherapy.
A second conceptual change involves the timing of drug administration. With carcinomatosis, the only successful management plans employ perioperative intraperitoneal chemotherapy. Usually, drug administration is initiated in the operating room using a heated chemotherapy solution. The drugs selected for intraoperative use are synergized by hyperthermia, and most frequently include mitomycin (Mutamycin), doxorubicin, cisplatin, and oxaliplatin (Eloxatin). In the early postoperative period, drugs that require cell replication are most appropriate. These drugs are administered in a large volume of fluid for the first 5 to 7 days postoperatively and include 5-FU, paclitaxel, and docetaxel (Taxotere).
A third conceptual change involves patient-selection criteria. The greatest benefit will be observed in patients with noninvasive mucinous appendiceal tumors and the less aggressive peritoneal mesotheliomas. Of the minimally invasive cancers, even large-volume carcinomatosis not located on small bowel surfaces can be definitively eradicated by peritonectomy. For malignancies that have invasive capabilities, the lesion size and distribution of the peritoneal implants are of great importance. Patients with small peritoneal tumor nodules that have limited distribution within the abdomen and pelvis can sometimes be made visibly free of disease by surgical resection. A proportion of these patients show long-term benefits when cytoreductive surgery is combined with perioperative intraperitoneal chemotherapy. However, aggressive treatment of an advanced and widely distributed invasive cancer on peritoneal surfaces is unlikely to produce any long-term benefits; the cytoreduction will be incomplete and intraperitoneal chemotherapy ineffective.
Also, these surgically heroic procedures result in a high incidence of morbidity and mortality. From a technical perspective, treatment of peritoneal carcinomatosis must be initiated as early as possible in the natural history of the disease in order to provide the greatest benefit (Figure 2).
Peritoneal Space-to-Plasma Barrier
Selected chemotherapy agents demonstrate a prolonged retention within the abdominopelvic space. Therefore, the exposure of peritoneal surfaces to a high concentration of drug over a long period will be much greater than systemic drug exposure. This marked difference in drug exposure results in a much higher response rate at the peritoneal surface. For intraperitoneal chemotherapy, the differences in drug exposure at the peritoneal surface vs systemic exposure in the treatment of gastrointestinal cancer are shown in Table 2.
The common adverse effects of chemotherapy, even when delivered via the intraperitoneal route, are bone marrow and gastrointestinal mucosaldamage. Indeed, one should not assume that intraperitoneal administration of chemotherapy eliminates systemic toxicity. Although the drugs are sequestered for prolonged periods within the peritoneal space, they are cleared into the systemic circulation. For this reason, the safe dose of most drugs instilled into the peritoneal cavity is similar to the intravenous dose. The exceptions are drugs with hepatic metabolism, such as 5-FU and gemcitabine (Gemzar). The dose of 5-FU can be increased by approximately 50% with intraperitoneal vs intravenous administration. The intravenous dose of 5-FU for 5 consecutive days is approximately 500 mg/m2/d; for intraperitoneal 5-FU, it is 750 mg/m2/d.
Two drugs that have vesicant effects locally are doxorubicin and mitoxantrone (Novantrone). For doxorubicin, the intraperitoneal dose is limited to 15 mg/m2 in 3 L of dialysis solution with manual distribution in the operating room. This dose, when used with moderate heat (41-42oC) for 90 minutes, will produce a tolerable level of peritoneal fibrosis. Multiple cycles of doxorubicin or higher doses of intraperitoneal drug will produce profound intestinal fibrosis and may dramatically interfere with normal peristalsis.
Intraperitoneal mitoxantrone has been extensively used to treat malignant ascites. Link and colleagues have reported success in the elimination of excess peritoneal fluid in 90% of 143 patients. The dose of mitoxantrone was 30 mg/m2, and up to three treatments were necessary to achieve the desired effect. Systemic toxicity was rarely seen (2.0%).
If a surgeon elects to manage patients with a peritoneal surface component of gastrointestinal cancer, it is imperative that the technical skills required for completion of the peritonectomy be mastered. During the peritonectomy, all visible cancer is removed in an attempt to leave the patient with only microscopic residual disease. Knowledge of the dissemination patterns of gastrointestinal cancer to peritoneal surfaces is essential, andunless all sites are rigorously inspected and all foci of cancerous implants removed, patients will be left with gross disease and a poor long-term outcome.
Isolated tumor nodules are removed using electroevaporation. Normal peritoneum is not excised; only the peritoneum involved by the malignant process is electrosurgically resected. If the visceral peritoneum requires removal and if a complete cytoreduction is contemplated, then resection of portions of the small bowel, colorectum, or stomach is indicated.
Common Anatomic Sites of Visceral Involvement
Mucinous peritoneal carcinomatosis has its greatest propensity for a large volume of visceral involvement at three definite anatomic sites. These are the sites where the bowel is anchored to the retroperitoneum, and motion resulting from peristalsis is restricted. The force of gravity also causes cancer cells to accumulate.
The most common intestinal resection required with peritonectomy involves the rectosigmoid colon. The peritoneal surfaces of the distal colon are nonmobile portions of bowel fixed within a dependent site. This dependent portion of the bowel is, therefore, frequently layered by carcinomatosis. A complete pelvic peritonectomy, which requires stripping of the abdominopelvic sidewalls, the peritoneum overlying the bladder, the culdesac of Douglas, and resection of approximately 18 in. of rectosigmoid colon, is necessary.
The ileocecal valve and terminal ileum constitute a second area where limited mobility may lead to a large volume of carcinomatosis and the need for a bowel resection. Resection of the terminal ileum and a small portion of the right colon are often necessary.
A final site frequently requiring gastrointestinal resection is the antrum or the entire stomach. The antrum is fixed to the retroperitoneum at the pylorus. Large volumes of tumor may accumulate on the pylorus and gastric antrum extending from the hepatoduodenal ligament across the stomach to the greater omentum. Also, tumor may enter the lesser sac through the foramen of Winslow and accumulate in the subpyloric space. Tumor at these two sites surrounding the gastric outlet may cause outlet obstruction. Large volumes of tumor in the lesser omentum combined with disease in the subpyloric space will sometimes cause a confluence of disease involving the left gastric artery, necessitating a total gastrectomy with lesser omentectomy for complete cytoreduction.
In order to adequately perform cytoreductive surgery with peritonectomy, the surgeon must use an electroevaporative technology. Electroevaporative surgery involves a high voltage from an electrosurgical generator, a pure cut mode, and a ball electrosurgical tip. An attempt at peritonectomy using the traditional scissor- and-knife dissection will result in unnecessary blood loss. Also, the highvoltage electrosurgery creates a margin of heat necrosis that is devoid of viable tumor cells and less likely to develop recurrence.
The peritonectomy procedures can be briefly described as follows. After abdominal exposure is achieved with a long midline abdominal incisionand a self-retaining retractor, a greater omentectomy and splenectomy are performed. If the spleen and undersurface of the left hemidiaphragm are layered by tumor, then a left subphrenic peritonectomy is necessary. This dissection elevates the spleen and distal pancreas prior to the division of the splenic artery and vein. The third peritonectomy is usually a right subphrenic peritoneal stripping. Electroevaporative surgery is also used to strip away Glisson's capsule and the tumor layered on the liver surface.
Following these upper abdominal dissections, the surgeon generally initiates a complete pelvic peritonectomy; ie, a peritoneal stripping of the pelvic sidewalls and the bladder and resection of the female internal genitalia and the rectosigmoid colon along with the adjacent cul-de-sac. The vaginal cuff is copiously irrigated and must be closed prior to initiating heated intraoperative intraperitoneal chemotherapy, or leakage of the chemotherapy solution will occur. Usually, the final peritonectomy involves a cholecystectomy, lesser omentectomy, and stripping of the omental bursa.
It should be emphasized that no intestinal suturing is performed prior to the completion of heated intraoperative intraperitoneal chemotherapy. The only closure that is indicated is closure of the vaginal cuff to eliminate the loss of chemotherapy solution through this dependent site.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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