Oswald Anthony Stuart

Heated Intraoperative Intraperitoneal Mitomycin C and Early Postoperative Intraperitoneal 5-Fluorouracil: Pharmacokinetic Studies

Purpose: The purpose of this study was to report the pharmacokinetics of heated intraoperative intraperitoneal mitomycin C (MMC) and to analyze the impact of heat, extent of peritoneal resections, and effect of intraoperative hyperthermic chemotherapy on the pharmacological properties of the peritoneal plasma barrier. Methods: Sixty patients with peritoneal carcinomatosis were included in a phase I/II study combining cytoreductive surgery with 2 h of heated intraperitoneal mitomycin C in an intraoperative lavage technique and one cycle of early postoperative 5-fluorouracil (5-FU) given on postoperative days 1–5. Three pharmacokinetic analyses were performed: (1) pharmacokinetics of heated intraoperative intraperitoneal MMC was determined for 18 patients by sampling peritoneal fluid, plasma, and urine during the 2-h procedure; (2) impact of peritoneal resections on MMC pharmacokinetics was assessed by comparing a group of patients who underwent ≤1 peritonectomy procedure (minimal surgery) to a group of patients who underwent ≥2 peritonectomy procedures (extensive surgery), and (3) effects of heated intraoperative intraperitoneal chemotherapy on the pharmacokinetics of early postoperative intraperitoneal 5-FU by comparing a group of patients treated with heated intraoperative intraperitoneal MMC to a control group who did not receive heated intraoperative intraperitoneal chemotherapy. Results: The mean dose of heated intraoperative intraperitoneal MMC per patient was 22.5 ± 7.1 mg (12.9 ± 3.8 mg/m2). Drug absorption from perfusate was 14.3 ± 2.7 mg. The mean aeras under the curve (AUC) for perfusate and plasma were, respectively, 340 ± 138 and 15 ± 4 µg/ml × min. The mean AUC peritoneal fluid/plasma ratio was 23.5 ± 5.8. Patients who underwent extensive peritoneal resections exhibited a significantly (p = 0.037; Wilcoxon rank test) increased peak plasma concentration of MMC, a significantly (p = 0.029) increased AUC of plasma concentrations and a significantly (p = 0.034) decreased peritoneal fluid/plasma AUC ratio. Pharmacokinetic studies of early postoperative intraperitoneal 5-FU showed no significant difference in plasma AUC, perfusate AUC and AUC ratio between patients who received and those who did not receive heated intraoperative intraperitoneal MMC. Conclusions: Heated intraoperative intraperitoneal chemotherapy achieves high peritoneal concentrations of MMC with limited systemic absorption. Systemic drug absorption during heated intraoperative intraperitoneal chemotherapy is increased when extensive peritoneal resections are performed, but such slight increases are unlikely to change the risk of systemic drug toxicities. Heated intraoperative intraperitoneal chemotherapy does not alter the pharmacokinetics of early postoperative intraperitoneal 5-FU.

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.

A simplified approach to hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) using a self retaining retractor

There are both pharmacologic and practical reasons for recommending intraoperative intraperitoneal chemotherapy. From a pharmacologic point of view, direct installation of selected drugs into the peritoneal cavity results in a large increase in the amount of chemotherapy that reaches abdominal and pelvic surfaces. This pharmacologic advantage is the result of the peritoneal-plasma barrier. Molecules of large hydrophyllic drugs leave the peritoneal cavity more slowly than they are metabolized systemically. Three-fore, a great concentration difference exists at all times between drug concentration within the peritoneal cavity and drug concentration in the plasma [1,2].

Using Pharmacologic Data to Plan Clinical Treatments for Patients with Peritoneal Surface Malignancy

The surfaces of the abdomen and pelvis are an important anatomic site for the dissemination of gastrointestinal and gynecologic malignancy. This transcoelomic spread of cancer cells gives rise to peritoneal carcinomatosis which, without special treatments, is a fatal manifestation of these diseases. In order to control peritoneal carcinomatosis cytoreductive surgery to remove gross disease is combined with perioperative intraperitoneal and perioperative intravenous chemotherapy to eradicate microscopic residual disease. Chemotherapy agents are selected to be administered by the intraperitoneal or intravenous route based on their pharmacologic properties. A peritoneal-plasma barrier which retards the clearance of high molecular weight chemotherapy from the peritoneal cavity results in a large exposure of small cancer nodules on abdominal and pelvic surfaces. Tissue penetration is facilitated by moderate hyperthermia (41-42ºC) of the intraperitoneal chemotherapy solution. A constant dose of chemotherapy agent and volume of carrier solution based on body surface area allows prediction of systemic drug exposure and systemic toxicity. Timing of the chemotherapy as a planned part of the surgical procedure to maximize exposure of all peritoneal surfaces is crucial to success.

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.

Pharmacokinetics of the perioperative use of cancer chemotherapy in peritoneal surface malignancy patients.

Background. The peritoneal surface is an acknowledged locoregional failure site of abdominal malignancies. Previous treatment attempts with medical therapy alone did not result in long-term survival. During the last two decades, new treatment protocols combining cytoreductive surgery with perioperative intraperitoneal and intravenous cancer chemotherapy have demonstrated very encouraging clinical results. This paper aims to clarify the pharmacologic base underlying these treatment regimens. Materials and Methods. A review of the current pharmacologic data regarding these perioperative chemotherapy protocols was undertaken. Conclusions. There is a clear pharmacokinetic and pharmacodynamic rationale for perioperative intraperitoneal and intravenous cancer chemotherapy in peritoneal surface malignancy patients.

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.

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.

Bases farmacológicas de la quimioterapia perioperatoria en la carcinomatosis peritoneal

Resumen En los tumores digestivos y ginecologicos, la carcinomatosis peritoneal, sin tratamientos especiales, es una manifestacion fatal de estas enfermedades. La cirugia citorreductora, que extirpa la enfermedad microscopica, se combina con quimioterapia perioperatoria intraperitoneal e intravenosa para eliminar la enfermedad microscopica residual. Entender bien el efecto de la membrana peritoneal en la farmacocinetica de los quimioterapicos y los factores que la modifican permite elegir la combinacion de farmacos, calcular su dosis y el volumen de disolucion, lo que facilita predecir la exposicion peritoneal y sistemica al tratamiento y su toxicidad. Coordinar la quimioterapia como una parte programada del tratamiento quirurgico para obtener la maxima exposicion en toda la superficie peritoneal es crucial para el exito del tratamiento. En este articulo actualizamos las bases farmacocineticas de la quimioterapia perioperatoria de la carcinomatosis peritoneal.

Rationale for perioperative chemotherapy treatment in peritoneal carcinomatosis

Peritoneal carcinomatosis, without special treatment, is a fatal sign of gastrointestinal and gynaecological malignancy. Cytoreductive surgery to remove gross disease is combined with perioperative intraperitoneal and intravenous chemotherapy to eradicate the residual microscopic disease. Knowledge of the effect of the peritoneal barrier on the pharmacokinetics of the chemotherapy agents, and the factors that affect this, enables a good combination of drugs, dosage and solution volume to be selected, in order to predict peritoneal and systemic exposure to the treatment and its toxicity. Timing of the chemotherapy as a planned part of the surgical procedure to maximise exposure of all peritoneal surfaces is crucial to success. In this article we update the pharmacokinetic basis for perioperative chemotherapy treatment of peritoneal carcinomatosis of gastrointestinal or gynaecological origin.