Pharmacokinetics of the peritoneal-plasma barrier after systemic mitomycin C administration.

The peritoneal plasma barrier (PPB) is a pharmacologic entity of importance for treatment planning in patients with malignant tumors confined to the abdominal cavity. We have examined the pharmacokinetics of the PPB by sampling abdominal fluid following intravenous mitomycin C (MMC) administration. The study included 15 cycles of treatment in seven patients with peritoneal carcinomatosis from colorectal cancer. Five patients were studied twice and one patient was studied three times for a total of 15 cycles. Patients were treated with intraperitoneal 5-fluorouracil (5-FU) at 20 mg/m2 in 11 of fluid. Between 250 and 500 ml of ascites remained after the 23 hour intraperitoneal dwell. On day 3, MMC (12 mg/m2) was administered intravenously as a 2-hour continuous infusion in 200 ml of dextrose solution. The concentration of MMC was determined in plasma, peritoneal fluid, and urine by high performance liquid chromatolography (HPLC) at frequent intervals for 8 hours. The area under the curve (AUC) for plasma as related to peritoneal fluid was three times greater for plasma in one cycle, two times greater for plasma in three cycles, 1.5 times greater for plasma in five cycles, and the same in six cycles. AUC ratios showed a correlation with the extent of peritoneal stripping at the prior surgical procedure 6 weeks to 14 weeks previously. We conclude that malignant ascites may be less exposed to chemotherapy than systemic tumor nodules when the intravenous route of drug administration is used. This inadequacy is even more pronounced in patients who have had extensive abdominal surgery.

Prognostic implications of chemoresistance-sensitivity assays for colorectal and appendiceal cancer.

A major problem with pharmacologic treatments for cancer is the unpredictable nature of the clinical response. Therefore, many patients are treated but few benefit from chemotherapy. Selection of patients for drug treatment would greatly benefit both responders and nonresponders. Mitomycin C (MMC) and 5-fluorouracil (5-FU) are important drugs widely used in the treatment of patients with gastrointestinal malignancies. In a prospective study, an in vitro chemoresistance-sensitivity assay (CR-SA) was performed for 95 patients at the time of surgery for peritoneal carcinomatosis from colorectal and appendiceal cancer. Following cytoreductive surgery, all of these patients had minimal-to-moderate residual disease. All patients were treated with the same chemotherapy regimen regardless of the results of the in vitro assay in the postoperative period. Clinical status of patients was correlated to the assay predictions, and the results were statistically evaluated. When resistance was correlated with outcome, there was no statistical difference. In addition, the mean percentage of growth inhibition was not increased when responders and nonresponders were compared. Finally, more patients who had > or = 95% in vitro growth inhibition of cancer did not survive than did those with < or = 95% growth inhibition. The in vitro test did not predict sensitivity or resistance to cancer when regional chemotherapy was administered in a clinical setting of peritoneal carcinomatosis.

Peritoneal carcinomatosis from gastrointestinal malignancy: natural history and new prospects for management.

Peritoneal carcinomatosis represents regional spread of gastrointestinal, gynecological and other malignancies with or without evidence of systemic metastases. The authors reviewed the natural history and the different types of peritoneal carcinomatosis. A new treatment approach that combines cytoreductive surgery and intraperitoneal chemotherapy is described. The principles of this surgery and the pharmacology principles of intraperitoneal drug administration are explained. The major attraction of intraperitoneal therapy is that following intracavitary drug administration, the peritoneal cavity is exposed to higher concentrations than the rest of the body. A total of 100 patients with peritoneal carcinomatosis followed from one to ten years were treated by this approach. Patients were divided into four prognostic groups according to the histologic findings, extent of diseases, distant metastases and the completeness of cytoreductive surgery. This new cytoreductive approach is particularly effective for patients with low-grade malignancies confined to the abdominal cavity and who had a complete cytoreductive surgery.

Morbidity and mortality of cytoreductive surgery and intraperitoneal chemotherapy.

BACKGROUND: Peritoneal carcinomatosis has been regarded as a uniformly lethal clinical entity. Recently, dose-intensive treatments combining cytoreductive surgery and intraperitoneal chemotherapy have resulted in long-term survival in selected patients. METHODS: This article reports the morbidity and mortality associated with this new treatment strategy in 45 consecutive treatments of 43 patients with peritoneal carcinomatosis treated during an 18-month interval. RESULTS: The duration of median postoperative ileus was 21 days, and increased age of the patient and extent of cytoreduction caused an increased incidence of ileus. Twenty-one complications occurred in 17 patients (37.7%). Complications related to enteric function included fistula (n = 4), bile leak (n = 1), pancreatitis (n = 1), and anastomotic disruption (n = 1). There were two early and two late episodes of postoperative bleeding requiring reoperation. Six patients had pneumonia and one had deep vein thrombosis. There were no deaths. Six of the seven complications related to enteric function occurred in patients who had undergone induction intraperitoneal chemotherapy before cytoreductive surgery plus early postoperative intraperitoneal chemotherapy. CONCLUSIONS: As a result of these findings, induction intraperitoneal chemotherapy is only recommended for patients with low-volume intraabdominal cancer. In most patients surgical removal of peritoneal carcinomatosis before intraperitoneal chemotherapy is recommended. Because of the significant morbidity related to treatment of peritoneal carcinomatosis, careful patient selection and favorable long-term results of treatment are required.

Preoperative radiological evaluation of the liver by computerized tomographic portography in patients with hepatic tumors.

The main objective of preoperative imaging studies is to define as accurately as possible the number, size, location, and relationship of tumor masses in the liver to pertinent portal and hepatic venous vasculature. Computerized tomographic portography images hepatic veins and segmental portal vein branches and identifies the anatomical location of tumor nodules with excellent sensitivity and a low false-positive rate. The intraoperative correlation of computerized tomographic portography on 30 patients in the last 20 months at this institution shows a sensitivity of 88 per cent with a low rate of false-positivity. The ability to detect metastatic lesions in the liver by computerized tomographic portography diminishes when the lesions are noted to be less than 1 cm. The authors conclude that the preoperative interpretation of the computerized tomographic portogram provides valuable information not previously available to the surgeon operating on the liver.