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: BackgroundIntraperitoneal chemotherapy administration results in high drug concentration locally with low systemic toxicity. Using a rat model we compared the pharmacokinetics and tissue absorption of docetaxel infused intraperitoneally in two isotonic carrier solutions; 1.5% dextrose peritoneal dialysis solution (peritoneal dialysis solution) and hetastarch (6% hydroxyethyl starch), a high molecular weight solution.: Materials and methodsSixty Sprague–Dawley rats were randomized into groups according to the carrier solution administered. Rats were given a single dose of intraperitoneal docetaxel (80 mg/m2) in 0.1 ml/g body weight of each carrier solution. Each group was further randomized according to the intraperitoneal dwell period (3, 6, 12, 18, and 24 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and the volume recorded. Blood and tissues were sampled using a standardized protocol. Drug concentrations in peritoneal fluid, plasma, and tissues were determined by high-performance liquid chromatography.: ResultsHetastarch clearance from the peritoneal cavity was reduced when compared to peritoneal dialysis solution. The mean volumes remaining in the peritoneal cavity were significantly higher with hetastarch at 6 h (P = 0.022) and 12 h (P = 0.0012). Plasma docetaxel concentrations were similar for both carrier solutions. The mean total amount of docetaxel remaining in the peritoneal cavity was significantly greater with hetastarch at 3 h (P = 0.0022), 6 h (P = 0.0043), and 12 h (P = 0.0023). There was a 39% increase in the area under the curve ratio of peritoneal fluid to plasma docetaxel concentrations with hetastarch (227) versus peritoneal dialysis solution (163). Docetaxel concentrations were significantly greater with hetastarch in colonic tissue at 18 and 24 h, and in gastric tissue at 6, 12, and 18 h.: ConclusionThe use of intraperitoneal docetaxel with a hetastarch carrier solution provides a pharmacologic advantage for a local-regional killing of residual intraperitoneal tumor cells without increasing systemic toxicity. [Copyright &y& Elsevier]

Purpose. Docetaxel (Taxotere) has been shown to possess a broad spectrum of antitumor activity against various malignancies such as breast and lung cancers, but also against intraabdominal malignancies such as mesothelioma and ovarian cancer. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal chemotherapy is the prolonged high drug concentration that can be achieved locally with low systemic toxicity. Using a rat model, this study was designed to compare the pharmacokinetics and tissue distribution of intraperitoneal versus intravenous docetaxel. Methods. The study animals were comprised of 15 Sprague Dawley rats. They were randomized into three groups according to dose and route of administration (15 mg/kg intravenously, 15 mg/kg intraperitoneally, or 150 mg/kg intraperitoneally) and then given a single dose of docetaxel. Blood and peritoneal fluid were sampled using a standardized protocol for 90 min. At the end of the procedure the rats were killed and docetaxel concentrations in peritoneal fluid, plasma and selected tissue samples were determined by high-performance liquid chromatography (HPLC). Results. When docetaxel was delivered at 15 mg/kg the area under the curve (AUC) of the peritoneal fluid was significantly higher with intraperitoneal administration (110.6 µg/ml·min) as compared to intravenous administration (0.043 µg/ml·min; P=0.0079). This represents more than a 2500-fold increase in exposure for tissues at peritoneal surfaces after intraperitoneal administration. Conversely, at the same dose the AUC of the plasma was significantly lower with intraperitoneal administration (0.11 µg/ml·min) as compared to intravenous administration (4.25 µg/ml·min; P=0.0079). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 976 for intraperitoneal administration as opposed to 0.01 for intravenous delivery. The AUC ratio for intraperitoneal docetaxel at 150 mg/kg was 3004. There were significantly different concentrations in the heart and the abdominal wall (P=0.0079) and in the stomach and colon (P=0.0159) when intraperitoneal versus intravenous docetaxel were compared. Conclusions. The exposure of the peritoneal surface to docetaxel is significantly increased and the systemic exposure decreased with intraperitoneal docetaxel administration. Also, high concentrations of drug were observed in the abdominal wall and in the colon after intraperitoneal delivery. This experiment suggests the need for clinical studies to evaluate intraperitoneal administration of docetaxel in humans. [ABSTRACT FROM AUTHOR]

Purpose: In the treatment of gastrointestinal malignancies with dissemination to peritoneal surfaces the principal advantage of intraperitoneal chemotherapy over intravenous chemotherapy is the high drug concentration achieved locally with low systemic toxicity. This advantage can be optimized by maintaining a large area of contact between the chemotherapy solution and the surfaces within the abdomen and pelvis over a prolonged time period. Using a rat model we compared the pharmacokinetics of two drugs infused intraperitoneally, 5-fluorouracil and gemcitabine, in five different carrier solutions.Methods: A total of 120 Sprague Dawley rats were randomized into groups according to the carrier solution and the drug administered. Rats were given a single dose of intraperitoneal 5-fluorouracil (20 mg/kg) or gemcitabine (12.5 mg/kg) in 0.1 ml/g body weight of each carrier solution. The carrier solutions used varied in their tonicity (0.3%, 0.9% or 3% sodium chloride), or were isotonic and varied in molecular weight (0.9% sodium chloride, 4% icodextrin and 6% hetastarch). With the hypotonic, isotonic and hypertonic sodium chloride solutions, only 5-fluorouracil was used. Each group was further randomized according to the intraperitoneal dwell period (1, 3 or 6 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and the blood was sampled using a standardized protocol. The volume of the peritoneal fluid was recorded, and the drug concentrations in the peritoneal fluid and plasma were determined by high-performance liquid chromatography.Results: Measurements of peritoneal fluid volume showed a more rapid clearance of hypotonic and isotonic sodium chloride solutions from the peritoneal cavity as compared to hypertonic sodium chloride and high molecular weight solutions. When comparing the remaining intraperitoneal volumes at 6 h, the differences were statistically significant for both 5-fluorouracil and gemcitabine when hetastarch (P < 0.0001 and P = 0.0004) and icodextrin (P = 0.002 and 0.008) were compared with isotonic sodium chloride solution. Similarly, there was a significant difference in the volumes recorded at 6 h when hypotonic (P < 0.0001) and isotonic sodium chloride solutions (P = 0.0002) were compared with hypertonic sodium chloride solution. The concentrations of chemotherapy in the different carrier solutions varied little. The total amount of drug in the peritoneal cavity decreased with all solutions and more quickly with 5-fluorouracil than with gemcitabine. There was a significant difference in the total intraperitoneal 5-fluorouracil between hypotonic and isotonic sodium chloride solutions at 1 h (P = 0.0003) and 3 h (P = 0.0043), as well as between the isotonic and hypertonic sodium chloride solutions at 1 h (P = 0.03) and 3 h (P < 0.0001). Similarly, there was a significant difference in the total peritoneal gemcitabine at 6 h between icodextrin and isotonic sodium chloride solution (P = 0.01) and between hetastarch and isotonic sodium chloride solution (P = 0.05). There were no significant differences in plasma 5-fluorouracil and plasma gemcitabine concentrations obtained with the five solutions.Conclusions: These findings show that the clearance of 5-fluorouracil and gemcitabine from the peritoneal cavity can be significantly modified by varying the tonicity or the molecular weight of the carrier solution. Peritoneal fluid clearance was slower with hypertonic sodium chloride and high molecular weight solutions and this resulted in a reduced clearance of chemotherapy. By using a high molecular weight carrier solution the exposure of intraperitoneal cancer cells to gemcitabine was prolonged and drug availability at the peritoneal surface was increased. Similarly, by using a hypertonic carrier solution the exposure to 5-fluorouracil was prolonged and drug availability at the peritoneal surface was also increased. [ABSTRACT FROM AUTHOR]

Peritoneal surface malignancy is a common manifestation of intra-abdominal malignancies. Systemic chemotherapy offers no long-term survival and poor quality of life for these patients in their terminal stages of disease. By contrast, cytoreductive surgery combined with perioperative intraperitoneal and intravenous chemotherapy has resulted in encouraging clinical results. Further improvements should come from both clinical phase II/III studies and pharmacologic research. This article reviews the current pharmacologic data and controversies regarding the perioperative intraperitoneal and intravenous application of chemotherapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The peritoneal surfaces of the abdomen and pelvis are important sites for the dissemination of gastrointestinal and gynecologic malignancy. Transcoelomic dissemination of cancer cells gives rise to carcinomatosis, which, without special treatment, is a fatal manifestation of these diseases. To treat peritoneal carcinomatosis, cytoreductive surgery removes gross disease plus perioperative intraperitoneal and perioperative intravenous chemotherapy eradicates microscopic residual disease and chemical compatibilities. Chemotherapy agents are administered either 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 of the intraperitoneal chemotherapy is facilitated by moderate hyperthermia (41-42°C). Targeting of intravenous chemotherapy to the peritoneal surface is facilitated by the intraperitoneal heat. 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 hyperthermic chemotherapy as a scheduled part of the surgical procedure to uniformly expose all peritoneal surfaces is crucial to success.

Postoperative adhesions remain the leading cause of small bowel obstruction. Peritoneal adhesions were induced in 180 rats by scraping the cecum and burning the adjacent parietal peritoneum by electrocoagulation. The adhesions were scored 14 days later in a blinded manner. All four types of intraperitoneal instillations significantly reduced the extension and the severity of the adhesions, at both schedules, when compared to the control group. The use of 5-fluorouracil at 20 mg/kg in peritoneal dialysis solution during 5 days significantly decreased the global score (P = 0.04), the extension (P = 0.04), and the severity (P = 0.04) of adhesions when compared to the 5-day instillation of peritoneal dialysis alone. Lavage of the abdomen with peritoneal dialysis solution or hetastarch decreased the formation of adhesions. Instillation of 5-fluorouracil in a large volume of peritoneal dialysis solution could be novel and promising treatments for prevention of postoperative adhesions.

Peritoneal mesothelioma is a rare disease, but increasing in frequency. The incidence is approximately one per 1,000,000 and about one fifth to one third of all mesotheliomas are peritoneal. Because of its unusual nature, the disease has not been clearly defined either in terms of its natural history, diagnosis, or management. This article reviews a single institution's experience with 51 patients prospectively treated over the past decade with increasingly aggressive local/regional protocols. Peritoneal mesothelioma patients generally present with two types of symptoms and signs; those with abdominal pain, usually localized and related to a dominant tumor mass with little or no ascites and those without abdominal pain, but with ascites and abdominal distention. Pathologically, a positive immunostain for calretinin has markedly increased the accuracy of diagnosis. Prognosis as determined by clinical presentation, the completeness of cytoreduction, and gender (females survive longer than males) appears to be improved by the use of intraperitoneal chemotherapy. Over the past decade, the management of these patients has evolved similarly to ovarian cancer treatment and now involves cytoreductive surgery, heated intraoperative intraperitoneal chemotherapy (HIIC) with cisplatin and doxorubicin, and early postoperative intraperitoneal paclitaxel. These perioperative treatments are followed by adjuvant intraperitoneal paclitaxel and second-look cytoreduction. Prolonged disease-free survival and reduced adverse symptoms with the current management strategy are documented by a high complete response rate as assessed by a negative second-look. This multimodality treatment approach with cytoreductive surgery and intraperitoneal chemotherapy has resulted in a median survival of 50 to 60 months. Peritoneal mesothelioma is an orphan disease that is treatable with expectations for "potential" cure in a small number of patients if diagnosed and treated early with definitive local/regional treatments. A prolonged high quality of life is possible in the majority of patients., (Copyright 2002 by W.B. Saunders Company.)