Pharmacokinetics and tissue distribution of intraperitoneal paclitaxel with different carrier solutions.

BACKGROUND: For cancers that have disseminated to peritoneal surfaces, intraperitoneal chemotherapy administration results in high drug concentration locally with low systemic toxicity. Using a rat model we compared the pharmacokinetics and tissue absorption of paclitaxel 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. METHODS: A total of 60 Sprague Dawley rats were randomized into groups according to the carrier solution administered. Rats were given a single dose of intraperitoneal paclitaxel (40 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 At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and the volume recorded.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. RESULTS: Fluid clearance from the peritoneal cavity was lower in the presence of hetastarch than in the presence of peritoneal dialysis solution. The mean volumes remaining in the peritoneal cavity were significantly higher with hetastarch at 18 h (P=0.0079). No excess peritoneal fluid remained with peritoneal dialysis solution at 24 h. Mean plasma paclitaxel concentrations were significantly lower with hetastarch at 3 h (P=0.0079), 12 h (P=0.0079), and 18 h (P=0.0317). The mean total quantity of drug remaining in the peritoneal cavity was significantly greater with hetastarch at 12 h (P=0.0079) and 18 h (P=0.0317). There was a 105% increase in the area under the curve ratio of peritoneal fluid to plasma paclitaxel concentrations with hetastarch (391) vs peritoneal dialysis solution (191). Paclitaxel concentrations were significantly greater with peritoneal dialysis solution at 6 h in colon, abdominal wall, and myocardium. CONCLUSIONS: The use of intraperitoneal paclitaxel with hetastarch carrier solution provides a pharmacologic advantage for a local-regional killing of residual tumor cells with decreased systemic toxicity. Clinical investigations into the use of 6% hetastarch with high molecular weight chemotherapeutic agents are warranted.

Prognostic assessment of gastrointestinal stromal tumor.

The term "gastrointestinal stromal tumor" (GIST) has been applied to a collection of distinctive mesenchymal tumors occurring within the human gastrointestinal tract. As new drug therapy becomes available, data regarding the natural history of these unusual tumors are necessary to provide selection factors for treatment. Ninety-eight patients had light microscopy compatible with GIST at a single institution from 1989 to 2000. After immunostaining with c-kit and histopathologic review, 69 were judged to be GIST. All prognostic indicators were determined for gastric GIST, intestinal GIST, and all locations combined. The location of the GIST did not have a significant impact on survival. Clinically, tumor size, peritoneal cancer index, and completeness of cytoreduction had a significant impact on prognosis for GIST at all locations. Pathologically, cytologic atypia, necrosis, invasion and number of mitoses were significant prognostic indicators for GIST. Criteria to separate three pathologic groups of GIST according to the tumor size and the mitotic count were useful to evaluate the tumor behavior; in the borderline pathologic group invasion and cytologic atypia were statistically significant prognostic criteria. The cell phenotypes, as determined by immunostains, correlated with the prognosis of gastric GIST but not intestinal GIST. A correlation between the immunostain Ki-67 but not CD-34 or desmin and the prognosis was observed. It is possible to select clinical and pathologic parameters of GIST that impact on prognosis. Invasion and necrosis help to determine the prognosis with borderline tumors. The immunostain Ki-67 correlated with the prognosis and may be helpful to assess prognosis when dealing with small biopsy specimens.

Thermal enhancement of new chemotherapeutic agents at moderate hyperthermia.

BACKGROUND: Hyperthermia enhances the cytotoxicity of some chemotherapeutic agents. We have studied the effect of moderate hyperthermia (41.5 degrees C) on the cytotoxicity of five new chemotherapeutic agents (docetaxel, paclitaxel, irinotecan, oxaliplatin, and gemcitabine) and melphalan against a spontaneous murine fibrosarcoma. METHODS: The tumor was an early-generation isotransplant of a spontaneous C3Hf/Sed mouse fibrosarcoma, FSa-II. Hyperthermia was administered by immersing the tumor-bearing foot into a constant temperature water bath set at 41.5 degrees C for 30 minutes when the tumor reached 34 mm(3). Chemotherapy was administered intraperitoneally immediately before hyperthermia. Tumor response was studied by the mean tumor growth time and the mean tumor growth delay time. RESULTS: Hyperthermia significantly increased the tumor growth times of the animals treated with docetaxel, irinotecan, and gemcitabine at low dose and these drugs plus oxaliplatin at high dose. Docetaxel at high dose showed the greatest control of tumor growth by hyperthermia, with a 26% reduction. Concerning the taxanes, paclitaxel cytotoxicity was not enhanced by hyperthermia, but docetaxel was enhanced by hyperthermia at both doses of drug. CONCLUSIONS: Moderate hyperthermia increases the cytotoxicity of docetaxel, irinotecan, and gemcitabine on mouse fibrosarcoma. Paclitaxel did not show heat enhancement. Oxaliplatin and docetaxel showed greater heat enhancement when the drug dose was high.

Peritoneal cystic mesothelioma: a case series.

BACKGROUND: Cystic peritoneal mesothelioma is a rare disease associated with a favorable short-term prognosis. Longer follow-up documenting a persistence of symptoms and a high rate of recurrence after debulking surgery along with an uncertain natural history prompt a re-evaluation of prior treatment recommendations. No prior long-term clinical study of these patients is available. METHODS: The experience with five cases of cystic peritoneal mesothelioma, four females and one male, are reviewed. All of these patients were treated with cytoreductive surgery with peritonectomy procedures and heated intraoperative intraperitoneal chemotherapy. CT, pathology and current status were investigated in order to learn more about the natural history of this disease. RESULTS: All patients were symptomatic from abdominal distention and three of the four complained of severe pain. Female patients complained of long periods of recurrent abdominal and pelvic pain poorly managed by oral analgesics. In one patient prolonged conservative management over ten years resulted in transition to an invasive process with extensive lymph nodal metastases. Her prognosis for long-term survival is guarded because of mesothelioma extension into the chest. Disease control of both ascites and pain in the abdomen and pelvis was achieved in all five patients treated with cytoreductive surgery plus intraperitoneal chemotherapy. CONCLUSIONS: Cystic peritoneal mesothelioma should no longer be referred to as "benign" cystic mesothelioma. An aggressive approach with complete disease eradication is the correct goal of treatment. From our experience, cytoreductive surgery to remove all visible tumor and intraperitoneal chemotherapy to control microscopic residual disease will help patients with peritoneal cystic mesothelioma to remain symptom- and disease-free over an extended time period with a single surgical intervention. Disease eradication may prevent the transition to an aggressive and fatal disease process.

Prevention of intraperitoneal adhesions by intraperitoneal lavage and intraperitoneal 5-fluorouracil: experimental studies.

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.

Docetaxel: pharmacokinetics and tissue levels after intraperitoneal and intravenous administration in a rat model.

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 microg/ml.min) as compared to intravenous administration (0.043 microg/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 microg/ml.min) as compared to intravenous administration (4.25 microg/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.

Diagnosis and treatment of peritoneal mesothelioma: The Washington Cancer Institute experience.

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.