Rationale for an intraperitoneal gemcitabine chemotherapy treatment for patients with resected pancreatic cancer.

Currently, the surgical management of pancreas cancer is recognized around the world as inadequate. Long-term survival is rare even though there is a potentially curative R0 resection. There is a strong rationale for the use of chemotherapy in the operating room to reduce local-regional and hepatic sites of recurrent/progressive disease. Gemcitabine monotherapy administered by an intraperitoneal route in the operating room with hyperthermia and then for long-term treatment postoperatively has a strong pharmacologic basis. The exposure of peritoneal surfaces to intraperitoneal gemcitabine is approximately 500 times the exposure that occurs within the plasma. By analogy to another lethal disease, ovarian cancer, intraperitoneal gemcitabine chemotherapy used following potentially curative resection is supported. Data that shows a superiority of multiagent chemotherapy to gemcitabine monotherapy has not been reported. A standardized treatment with intraoperative chemotherapy monitoring of gemcitabine would greatly facilitate further improvements in pancreas cancer treatment and lead the way to an evolution of more successful treatment strategies of this dread disease. The aim of this review is to present the recent available medical information and patents applicable to patients with resected pancreatic cancer.

Pharmacokinetics and pharmacodynamics of perioperative cancer chemotherapy in peritoneal surface malignancy.

The peritoneal surface remains an important failure site for patients with gastrointestinal and gynecologic malignancies. During the last 2 decades, novel therapeutic approaches, combining cytoreductive surgery with intraoperative intracavitary and intravenous chemotherapy, have emerged for peritoneal carcinomatosis patients. This has resulted in remarkable clinical successes in contrast with prior failures. Although further clinical data from phase II and III trials supporting this combined treatment protocols are necessary, an optimalization of the wide variety of different perioperative cancer chemotherapy protocols used in these treatment regimens is equally important. To this date, a clear understanding of the pharmacology of perioperative chemotherapy is still lacking. The efficacy of intraperitoneal cancer chemotherapy protocols is governed as much by nonpharmacokinetic variables (tumor nodule size, density, vascularity, interstitial fluid pressure, and binding) as by the pharmacokinetic variables (dose, volume, duration, pressure, and carrier solution). Our recent data support the importance of the tumor nodule as the most meaningful pharmacologic end point. Timing of perioperative intravenous chemotherapy may substantially influence the pharmacokinetics. This review aims to clarify the pharmacokinetic and pharmacodynamic data currently available regarding the intraperitoneal delivery of cancer chemotherapy agents in patients with peritoneal carcinomatosis.

Perioperative intraperitoneal chemotherapy for peritoneal surface malignancy.

The treatment of peritoneal surface malignancy mainly focuses on diffuse malignant peritoneal mesothelioma, pseudomyxoma peritonei from appendiceal cancer, and peritoneal dissemination from gastrointestinal and ovarian cancers. Cancer progression causes peritoneal implants to be distributed throughout the abdominopelvic cavity. These nodules plus the ascitic fluid result in abdominal distension. As the disease progresses, these tumors cause intestinal obstruction leading to debilitating symptoms and a greatly impaired quality of life. In the past, the prognosis of patients with peritoneal surface malignancy was regarded dismal and cure was not an option. Recently, cytoreductive surgery combined with perioperative intraperitoneal chemotherapy has shown an improved survival in selected patients with this disease. To date, multiple different treatment regimens of perioperative intraperitoneal chemotherapy have been used. This review focuses on the perioperative intraperitoneal chemotherapy currently in use in conjunction with cytoreductive surgery for the treatment of peritoneal surface malignancy at the Washington Cancer Institute.

Avoiding carcinogen exposure with intraperitoneal paclitaxel.

PURPOSE/OBJECTIVES: Diethylhexylphthalate (DEHP) is a lipid-soluble plasticizer commonly used in the manufacture of polyvinyl chloride- (PVC-) based plastics. Previous studies have documented the leaching of DEHP from PVC-based containers and extension sets during the IV administration of paclitaxel. DESIGN: Study of the leaching of DEHP from infusion bags and peritoneal dialysis solution transfer sets and clinical study of DEHP was proposed. SETTING: The experiments were performed in a laboratory with plastic ware normally used for intraperitoneal chemotherapy delivery. SAMPLE: Samples were taken from fluids that had been in contact with the plastic ware. Also, blood, peritoneal fluid, and urine were collected from a patient. METHODS: In a controlled laboratory environment, the authors used an established high-performance liquid chromatography assay to determine the rate and extent of DEHP leaching from infusion bags and in the solution transfer set used for early postoperative intraperitoneal chemotherapy (EPIC) administration of paclitaxel. Paclitaxel was tested at a concentration of 40 mg/L to simulate the median dose used for EPIC. In a single patient receiving 34 mg paclitaxel in 1 liter of 1.5% dextrose peritoneal dialysis solution (Dianeal), the presence and concentration of DEHP in samples of peritoneal fluid and urine were determined during the first 24-hour EPIC administration. MAIN RESEARCH VARIABLES: DEHP levels in fluids exposed to plastic ware and in the patients blood, peritoneal fluid, and urine were determined. FINDINGS: The in vitro studies showed that a solution of 40 mg paclitaxel dissolved in a 1 liter bag of Dianeal resulted in the extraction of approximately 26 mg DEHP over 24 hours. Approximately 2 mg DEHP was leached during the first hour and approximately 1 mg per hour over the following 23 hours. Equivalent results were obtained when 20 mg paclitaxel was dissolved in a 500 ml bag of 6% hetastarch (Hespan) with a leaching of approximately 13 mg DEHP in 24 hours. Using the same paclitaxel concentration, the chronic ambulatory peritoneal dialysis solution transfer tubing with a total capacity of 10 ml produced approximately 2 mg DEHP over 24 hours, of which approximately 0.5 mg was produced during the first four hours. Samples from a single patient showed that immediately prior to administration, a 1 liter bag of Dianeal containing 34 mg paclitaxel had about 3.3 mg DEHP. Approximately 3% (110 mcg) of unchanged DEHP was recovered from the peritoneal fluid at 24 hours. Total DEHP excreted in urine over the 24-hour period was approximately 900 mcg (27%). CONCLUSION: This study showed that the carcinogen DEHP is leached after preparation of paclitaxel from PVC-based containers and DEHP constantly accumulates in the solution transfer tubing. IMPLICATIONS FOR NURSING: Unless precautionary steps are taken, DEHP can be transferred to patients receiving intraperitoneal paclitaxel. Steps to minimize patient exposure to DEHP during EPIC with paclitaxel are necessary. In the ideal situation, no DEHP-containing plastic should be used for chemotherapy delivery. If that is not possible, (a) paclitaxel solution should be administered as soon as possible after preparation by the pharmacy, (b) infusion should proceed as rapidly as possible via the Tenckhoff catheter, and (c) the Tenckhoff catheter and extension tubing should be cleared by draining ascites fluid through these tubes prior to subsequent intraperitoneal infusions.