HIPEC plus EPIC paclitaxel for maximal perioperative treatments of advanced epithelial ovarian cancer. Long-term results of a pilot study.

BACKGROUND: A unique time in which to effectively treat an intraabdominal malignancy is the time at which the surgeon attempts complete removal of the malignant process. Although surgery is effective for visible disease, micrometastases or multiple small cancer nodules are not amenable to resection. Alternative interventions to deal with residual disease disseminated on peritoneal surfaces are needed. MATERIALS AND METHODS: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can be combined with early postoperative intraperitoneal chemotherapy (EPIC) in order to maximally treat gross disease within the abdomen and pelvis and also the minimal residual disease that exists in many patients after resection. The third component of this treatment for ovarian malignancy was EPIC paclitaxel in this study. The clinical features, pharmacologic assessments, and survival were determined in ovarian cancer patients in whom EPIC was added to the perioperative treatment plan. RESULTS: Patients with high grade serous ovarian cancer underwent CRS, HIPEC with cisplatin/doxorubicin, and EPIC paclitaxel. These treatments combined as a single intervention were studied in 10 patients. The median number of peritonectomy procedures was 1, the median number of visceral resections was 5, and the median time required in the operating room was 8 h. Two patients had a class 3 adverse event. The median survival of patients was 50 months. Pharmacokinetic analysis of the intraperitoneal paclitaxel showed 252 ± 153 times exposure of peritoneal surfaces as compared to intravenous exposure when the drug was instilled into the peritoneal space. CONCLUSIONS: EPIC paclitaxel was successfully combined with CRS and HIPEC in 10 patients with ovarian cancer. The treatment was tolerated approximately the same as other major cytoreductive surgical procedures for ovarian cancer or other malignancies. Survival of these ovarian cancer patients seemed unusually prolonged as compared to other patients with stage 3b or recurrent disease. In this pilot study CRS, HIPEC and EPIC were safe and effective.

Pharmacology of perioperative intraperitoneal and intravenous chemotherapy in patients with peritoneal surface malignancy.

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.

Changes induced by surgical and clinical factors in the pharmacology of intraperitoneal mitomycin C in 145 patients with peritoneal carcinomatosis.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are a combined treatment modality considered for selected patients with peritoneal carcinomatosis from colorectal and appendiceal cancer. Mitomycin C is a drug often used in this clinical setting. The surgical and clinical factors that may influence the pharmacokinetics of hyperthermic intraperitoneal chemotherapy should be further elucidated. MATERIALS AND METHODS: The patients included were 145 who had colorectal or appendiceal carcinomatosis resected using cytoreductive surgery prior to treatment with hyperthermic intraperitoneal chemotherapy with mitomycin C as part of a multidrug regimen. The effect of clinical and surgical factors on drug distribution after single intraperitoneal bolus administration with mitomycin C was determined. RESULTS: The pharmacokinetics of 145 patients treated with intraperitoneal mitomycin C showed a 27 times greater exposure to peritoneal surfaces when compared to plasma. At 90 min, 29% of the drug remained in the chemotherapy solution, 62% was retained in the body, and 9% was excreted in the urine. The extent of peritonectomy increased the clearance of mitomycin C from the peritoneal space (p = 0.051). A major resection of visceral peritoneal surface and a contracted peritoneal space reduced drug clearance. A contracted peritoneal space significantly reduced (p = 0.0001) drug concentrations in the plasma. CONCLUSIONS: Surgical and clinical factors may require modifications of drug dose or timing of chemotherapy administration. A large visceral resection and a contracted peritoneal space caused a reduced mitomycin C clearance. Total diffusion surface is an important determinant of mitomycin C pharmacokinetics.

Optimizing the factors which modify thermal enhancement of melphalan in a spontaneous murine tumor.

BACKGROUND: Hyperthermia enhances the cytotoxicity of some chemotherapeutic agents. Both clinical and laboratory studies suggest melphalan may be an important drug when hyperthermia is added to chemotherapy treatments. Factors that may modify the thermal enhancement of melphalan were studied to optimize its clinical use with hyperthermia. METHODS: The tumor studied was an early-generation isotransplant of a spontaneous C3Hf/Sed mouse fibrosarcoma, Fsa-II. All studies were performed under supervision of the Animal Care and Use Committee. Hyperthermia was administered by immersing the tumor-bearing foot into a constant temperature water bath. Four factors were studied: duration of hyperthermia, sequencing of hyperthermia and melphalan, intensity of hyperthermia, and tumor size. To study duration of hyperthermia tumors were treated at 41.5 degrees C for 30 or 90 min immediately after intraperitoneal administration of melphalan. For sequencing of hyperthermia and melphalan, animals received hyperthermia treatment of tumors for 30 min at 41.5 degrees C immediately after drug administration, both immediately and 3 h after administration of drug or only at 3 h after administration of drug. Intensity of hyperthermia was studied using heat treatment of tumors for 30 min at 41.5 or 43.5 degrees C immediately following drug administration. Effect of tumor size was studied by delaying experiments until three times the tumor volume (113 mm3) was observed. Treatment of tumors was for 30 min at 41.5 degrees C immediately following drug administration. Tumor response was studied by the mean tumor growth time. RESULTS: Hyperthermia in the absence of melphalan had a small but significant effect on tumor growth time at 43.5 degrees C but not at 41.5 degrees C. Hyperthermia at 41.5 degrees C immediately after melphalan administration doubled mean tumor growth time at 30 min and caused a threefold increase at 90 min (P=0.0002) when compared to tumors treated with melphalan alone at room temperature. Application of hyperthermia for one-half hour immediately following drug administration was the most effective in delaying tumor growth. No significant difference in mean tumor growth time was observed with an increase in temperature from 41.5 to 43.5 degrees C. For large tumors heat alone and melphalan alone caused a moderate increase in tumor growth delay. These effects in large tumors were greatly increased by a combination of chemotherapy and hyperthermia. CONCLUSIONS: From our data it would appear that the administration of intraperitoneal melphalan immediately prior to 90 min of heat at 41.5 degrees C may optimize anti-neoplastic activity. These data may be useful in formulating clinical protocols in which melphalan and heat are combined.

Pharmacokinetic changes induced by the volume of chemotherapy solution in patients treated with hyperthermic intraperitoneal mitomycin C.

BACKGROUND: The rationale supporting the use of intraperitoneal chemotherapy in peritoneal surface malignancy relates to a large local-regional effect and low systemic toxicity. While optimizing the use of this treatment strategy, little information regarding the effect of volume of chemotherapy solution is available. OBJECTIVE: The goal of this study was to provide data regarding the effect of volume of chemotherapy solution on the pharmacokinetics of intraperitoneal chemotherapy. Data by which to optimally adjust this parameter during intraperitoneal chemotherapy treatments were sought. METHODS: Forty-eight patients with peritoneal surface malignancy were treated with hyperthermic intraperitoneal mitomycin C chemotherapy after a complete cytoreduction to remove all visible evidence of mucinous tumor. The dose of mitomycin C was always 12.5 mg/m(2) in males and 10 mg/m(2) in females. The first 12 patients were treated with 6 l of 1.5% dextrose peritoneal dialysis solution. The next 14 patients were treated with 4 l of fluid and then ten patients were treated with 2 l. In the last 12 patients the volume of fluid was 1.5 l/m(2) . Blood, peritoneal fluid, and urine samples were obtained every 15 min for 90 min; additional blood and urine samples were obtained at 120 min. Mitomycin C concentrations, urine volumes, and final intraperitoneal fluid volume were obtained. RESULTS: The intraperitoneal and the plasma concentrations were highest in the 2-l group, less in the 4-l group, and least in the 6-l group. All differences were statistically significant. Also, the percent of mitomycin C absorbed decreased significantly from 2, to 4, to 6 l of fluid. The area under the curve (AUC) ratio of intraperitoneal concentration times time to intravenous concentration times time was 27.01+/-4.92 for 2 l, 22.22+/-7.95 for 4 l, and 24.01+/-8.46 for 6 l. These differences were not statistically significant. If both the volume of chemotherapy solution and the total dose of mitomycin C were determined from the body surface area, the pharmacokinetics of intraperitoneal mitomycin C were more consistent. CONCLUSIONS: In order to prescribe a uniform treatment for patients receiving hyperthermic intraperitoneal mitomycin C, the total dose of the drug and the total volume of chemotherapy solution should be determined from the body surface area. If the volume of chemotherapy solution is not based on patient body surface area, predictions regarding toxicity are less precise.

Strategies for management of the peritoneal surface component of cancer: cytoreductive surgery plus perioperative intraperitoneal chemotherapy.

BACKGROUND: A prominent part of treatment failure of gastrointestinal and gynecologic malignancy is dissemination to peritoneal surfaces. This has been associated with a limited survival and no reliable treatment strategies. METHODS: A review of the natural history of carcinomatosis was performed and a rationale for intraperitoneal chemotherapy was sought. The pharmacology of chemotherapy administration into the peritoneal cavity was reviewed. RESULTS: The technology of perioperative intraperitoneal chemotherapy requires the administration of drugs along with moderate hyperthermia in the operating room as a planned part of the surgical procedure. The solution in which the chemotherapy is diluted has an effect upon the drug clearance from the peritoneal cavity. Also, the volume of the carrier solution affects the exposure of cancer nodules on peritoneal surfaces . CONCLUSIONS: New combinations of intraperitoneal chemotherapy administration when combined with optimal surgical technology for maximal chemotherapy effects should result in benefit to patients with peritoneal surface dissemination of gastrointestinal and gynecologic malignancy.

Docetaxel and hyperthermia: factors that modify thermal enhancement.

BACKGROUND: Hyperthermia enhances the cytotoxicity of some chemotherapeutic agents and recent studies suggest that docetaxel may show improved response at elevated temperatures. Factors that may modify the thermal enhancement of docetaxel were studied to optimize its clinical use with hyperthermia. METHODS: The tumor studied was an early-generation isotransplant of a spontaneous C3Hf/Sed mouse fibrosarcoma, Fsa-II. All studies were approved by the Animal Care and Use Committee. Docetaxel was given as a single intraperitoneal injection. Hyperthermia was achieved by immersing the tumor-bearing foot into a constant temperature water bath. Four factors were studied: duration of hyperthermia, sequencing of hyperthermia with docetaxel, intensity of hyperthermia, and tumor size. To study duration of hyperthermia tumors were treated at 41.5 degrees C for 30 or 90 min immediately after intraperitoneal administration of docetaxel. For sequencing of hyperthermia and docetaxel, animals received hyperthermia treatment of tumors for 30 min at 41.5 degrees C immediately after drug administration, hyperthermia both immediately and 3 hr after docetaxel administration and hyperthermia given only at 3 hr after administration of docetaxel. Intensity of hyperthermia was studied using heat treatment of tumors for 30 min at 41.5 or 43.5 degrees C immediately following docetaxel administration. Effect of tumor size was studied by delaying experiments until three times the tumor volume (113 mm(3)) was observed. Treatment of tumors lasted for 30 min at 41.5 degrees C immediately following drug administration. Tumor response was studied using the mean tumor growth time. RESULTS: Hyperthermia in the absence of docetaxel had a small but significant effect on tumor growth time at 43.5 degrees C but not at 41.5 degrees C. Hyperthermia at 41.5 degrees C for 90 min immediately after docetaxel administration significantly increased mean tumor growth time (P = 0.0435) when compared to tumors treated with docetaxel at room temperature. Treatment for 30 min had no effect. Application of hyperthermia immediately and immediately plus 3 hr following docetaxel was effective in delaying tumor growth. Treatment at 3 hr only had no effect. No significant difference in mean tumor growth time was observed with docetaxel and one half hour of hyperthermia at 41.5 or 43.5 degrees C. For larger tumors, hyperthermia alone caused a significant delay in tumor growth time. Docetaxel at 41.5 degrees C for 30 min did not significantly increase mean tumor growth time compared to large tumors treated with docetaxel at room temperature. CONCLUSIONS: Docetaxel shows a moderate increase in anti-tumor activity with hyperthermia. At 41.5 degrees C the thermal enhancement of docetaxel is time dependent if hyperthermia is applied immediately following drug administration. With large tumors docetaxel alone or docetaxel plus hyperthemia showed the greatest delays in tumor growth time in the experiments.

Extent of parietal peritonectomy does not change intraperitoneal chemotherapy pharmacokinetics.

PURPOSE: To measure the clearance intraperitoneal mitomycin C and doxorubicin in patients having peritonectomy and analyze the impact of the extent of peritoneal resection on pharmacokinetics. METHODS: A group of 15 patients with peritoneal carcinomatosis were submitted to cytoreductive surgery and heated intraperitoneal chemotherapy. Ten patients received mitomycin C and five, doxorubicin. Six patients underwent total parietal peritonectomy and nine had less-extensive peritonectomy. Pharmacokinetics were determined by sampling peritoneal fluid and blood. Drug concentrations over time, area under the curve ratios and the amount of drug recovered from the peritoneal cavity were calculated and compared between the groups. RESULTS: The concentrations of mitomycin C over time in the peritoneal fluid and plasma were similar in five patients with total parietal peritonectomy as compared to five patients with less-extensive peritonectomy ( P=0.5350 and 0.6991; Mann-Whitney test). Mitomycin C area under the curve ratio in total peritonectomy patients was 20.5 and 25.7 in patients with less-extensive peritonectomy. The difference in total amount of drug recovered from the peritoneal cavity was not significant (30.6+/-6.188% versus 22.6+/-3.84%, P=0.095). In the studies with doxorubicin, one patient underwent total parietal peritonectomy with similar pharmacokinetics to four patients submitted to partial peritonectomy. CONCLUSIONS: The extent of parietal peritoneal resection did not affect the pharmacokinetics of intraoperative intraperitoneal chemotherapy. The pharmacological barrier between the abdominopelvic cavity and plasma is not directly related to an intact peritoneum.

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.

Safety monitoring of the coliseum technique for heated intraoperative intraperitoneal chemotherapy with mitomycin C.

BACKGROUND: Treatment of carcinomatosis may involve the use of heated intraperitoneal chemotherapy; the cytotoxic solution is administered in the operating room with the abdomen open so that manual distribution results in uniform treatment. The potential risk of this procedure to the operating room personnel has not been previously investigated. METHODS: Mitomycin C was perfused through the peritoneal cavity, which was partially covered by a plastic sheet. Large volumes of air were suctioned from 5 and 35 cm above the abdominal skin edge. Urine from the surgeon and from the perfusionist were assayed. Sterile gloves worn in the operating room for manipulating the viscera during treatment were assayed for their permeability to mitomycin C. All samples were analyzed by high-performance liquid chromatography. RESULTS: Analysis of samples of operating room air and urine from 10 procedures showed no detectable levels of mitomycin C. Six tests of three different types of gloves showed a 10-fold range of mitomycin C penetration. The least permeable gloves leaked a mean of 3.8 parts per million over 90 minutes. CONCLUSIONS: No detectable safety hazard to the surgeon or other operating room personnel was demonstrated.