Arvil D. Stephens

Morbidity and Mortality Analysis of 200 Treatments With Cytoreductive Surgery and Hyperthermic Intraoperative Intraperitoneal Chemotherapy Using the Coliseum Technique

Background: Peritoneal carcinomatosis from gastrointestinal cancers is a fatal diagnosis without special combined surgical and chemotherapy interventions. Guidelines for cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) by using the Coliseum technique have been developed to treat patients with peritoneal carcinomatosis and other peritoneal surface malignancies. The purpose of this study was to analyze the morbidity and mortality of patients undergoing cytoreductive surgery and HIIC by using mitomycin C.Methods: Data were prospectively recorded on 183 patients who underwent 200 cytoreductive surgeries with HIIC between November 1994 and June 1998. Seventeen of the 183 patients returned for a second-look surgery plus HIIC. All HIIC administrations occurred after cytoreduction and used continuous manual separation of intra-abdominal structures to optimize drug and heat distribution. Origins of the tumors were as follows: appendix (150 patients), colon (20 patients), stomach (7 patients), pancreas (2 patients), small bowel (1 patient), rectum (1 patient), gallbladder (1 patient), and peritoneal papillary serous carcinoma (1 patient). Morbidity was organized into 20 categories that were graded 0 to IV by the National Cancer Institute’s Common Toxicity Criteria. In an attempt to identify patient characteristics that may predispose to complications, each morbidity variable was analyzed for an association with the 25 clinical variables recorded.Results: Combined grade III/IV morbidity was 27.0%. Complications observed included the following: peripancreatitis (6.0%), fistula (4.5%), postoperative bleeding (4.5%), and hematological toxicity (4.0%). Morbidity was statistically linked with the following clinical variables: duration of surgery (P < .0001), the number of peritonectomy procedures and resections (P < .0001), and the number of suture lines (P = .0078). No HIIC variables were statistically associated with the presence of grade III or grade IV morbidity. Treatment-related mortality was 1.5%.Conclusions: HIIC may be applied to select patients with peritoneal carcinomatosis from gastrointestinal malignancies with 27.0% major morbidity and 1.5% treatment-related mortality. The frequency of complications was associated with the extent of the surgical procedure and not with variables associated with the delivery of heated intraoperative intraperitoneal chemotherapy. The technique has shown an acceptable frequency of adverse events to be tested in phase III adjuvant trials.

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.

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

BackgroundTreatment 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.MethodsMitomycin 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.ResultsAnalysis 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.ConclusionsNo detectable safety hazard to the surgeon or other operating room personnel was demonstrated.

Hemodynamic and cardiac function parameters during heated intraoperative intraperitoneal chemotherapy using the open "coliseum technique".

Background: Heated intraoperative intraperitoneal chemotherapy achieves high peritoneal concentrations with limited systemic absorption and has become an important tool in the management of patients with peritoneal carcinomatosis from low-grade malignancies such as pseudomyxoma peritonei and in selected cases of high-grade tumors such as colon adenocarcinoma. When the closed abdomen technique is used, its perioperative toxicity seems to be related to the hemodynamic and cardiac function changes associated with increased body temperature and increased intra-abdominal pressure.Methods: Hemodynamic and cardiac function variables during heated intraoperative intraperitoneal chemotherapy, using an open abdomen “coliseum technique,” were measured in 15 patients with the use of a noninvasive esophageal Doppler monitor.Results: The hemodynamic and cardiac function changes were characterized by an increased heart rate, increased cardiac output and decreased systemic vascular resistance associated with an increased body temperature, and decreased effective circulating volume with the urinary output tending to decrease as the therapy progressed.Conclusion: Heated intraoperative intraperitoneal chemotherapy with the open abdomen coliseum technique induces a hyperdynamic circulatory state with an increased intravenous fluid requirement and avoids changes because of increased intra-abdominal pressure. Hemodynamic and cardiac stability, as documented by normal blood pressure and adequate urinary output, can be achieved by liberal intravenous fluids, titrated to frequent urinary output determination.

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].

Surgically directed chemotherapy: Heated intraperitoneal lavage with mitomycin C

This chapter reported the pharmacokinetics and the toxicities of mitomycin-c (MMC) when administered as a hyperthermic intraperitoneal lavage after surgical resection of advanced primary or recurrent gastrointestinal cancer. Pharmacologic studies were performed in 10 patients and all adverse reactions were recorded in 20 patients. These 20 patients had advanced gastrointestinal malignancies with peritoneal carcinomatosis and underwent cytoreductive surgery prior to intraperitoneal lavage. Heated (42 degrees C) intraperitoneal mitomycin C was used in a lavage technique with 30 mg/3 1 of drug for 2 hours. The fluid was distributed throughout the abdominal cavity by vigorous external massage of the abdominal wall. This resulted in approximately 70 percent (21 mg) drug absorption from the perfusate. Urine output of MMC averaged 2.5 mg during the 2 hour procedure. Median peak blood levels of 0.25 micrograms/ml (range 0.11-0.41 micrograms/ml) were observed at 45-60 minutes into the procedure. Morbidity was low and was mainly related to the surgical procedures (prolonged ileus, postoperative fistulas) with mild to moderate drug-related myelosuppression. This new method of delivery of MMC and 5-FU should be explored in phase II clinical trials.

Cancer recurrence following laparoscopic colectomy

PURPOSE: Use of laparoscopic techniques for resection of colon and rectal cancer has raised considerable controversy. There is increasing concern that wound recurrence and peritoneal dissemination may represent a potentially fatal complication of this technique. METHODS: The surgical literature was reviewed, and clinical course of two patients is presented. RESULTS: Our two patients had tumor recurrence in the laparoscopy port sites within one year after laparoscopic-assisted colectomy for Dukes B adenocarcinoma of the colon. At laparotomy, diffuse peritoneal carcinomatosis without lymph node or liver metastases were found in both patients. They were treated by surgical resection of recurrent disease combined with heated intraoperative intraperitoneal mitomycin C chemotherapy and five days of early postoperative intraperitoneal 5-fluorouracil. These patients are clinically free of disease at 1.5 years after treatment of peritoneal implants. CONCLUSIONS: Cancer recurrence in abdominal wall incisions after laparoscopic colectomy has been reported in an increasing number of patients. It is possible that this technique should be abandoned. Cytoreductive surgery combined with intraperitoneal chemotherapy may represent the most adequate treatment of recurrent cancer that occurs following laparoscopic colectomy.

Intraoperative hyperthermic lavage with cisplatin for peritoneal carcinomatosis and sarcomatosis

Intraoperative hyperthermic lavage with cisplatin was studied in 8 patients with peritoneal carcinomatosis and sarcomatosis. A dose of 50 mg/m2 of cisplatin used for 2 hours with an intraperitoneal temperature of 41 degrees to 43 degrees C was used. Pharmacokinetic studies showed that cisplatin left the abdomen and pelvis by simple diffusion with a half life of 48 minutes in the peritoneal fluid. Eighty-six percent of the drug was absorbed into the plasma within 2 hours but only 6.9% was excreted into the urine. The area under the curve ratio for peritoneal fluid to plasma was 6.9. The quantity of cisplatin in tissue from the abdomen or pelvis was extremely variable. It was 1.85-10.28 micrograms cisplatin/g tumor and < 0.57-7.90 micrograms/g normal tissue. Comparison of pharmacologic parameters of hyperthermic to normothermic cisplatin administration showed no significant differences.

Hyperthermic Intraoperative Intraperitoneal Chemotherapy Safety Considerations

Perioperative staff members encounter many occupational exposure hazards in the workplace. Cytotoxic agent exposure is a relatively new hazard that perioperative staff members are experiencing as more surgeons use hyperthermic intraoperative intraperitoneal chemotherapy (HIIC) to treat patients with abdominopelvic cavity malignancies. Routes of exposure include inhalation, ingestion, injection, and skin contact. The National Cancer Institute, the Occupational Safety and Health Administration, and the Joint Commission on Accreditation of Healthcare Organizations provide guidelines for the safe administration and handling of cytotoxic agents. Institutions in which cytotoxic agents are administered should use these guidelines to develop policies, procedures, and educational programs to protect surgical patients and perioperative staff members.

Radiofrequency hyperthermia in the palliative treatment of mucinous carcinomatosis of appendiceal origin: optimizing and monitoring heat delivery in western patients

rate of 62% was caused by the long-term indwelling temperature probe sheaths. Infection was observed in four patients, small bowel fistula in one, and dislodgement of the temperature probe sheath requiring repeat CT was necessary in seven patients. After maximal escalation of RF power in seven patients (33%), deep hyperthermia compatible with thermal destruction of tumour (43°C for 45 min) was recorded in all subsequent treatments. In eight patients (38%), heat generation compatible with chemotherapy augmentation (41.5-43°C) was consistently recorded. In six patients, non-therapeutic temperatures were recorded. There was no correlation of maximal tumour temperature, maximal subcutaneous tissue temperature and maximal RF power. With the use of skin anaesthetic there was no correlation of tumour temperature and the thickness of the subcutaneous layer of the skin. Progression was seen in 14 patients, and 11 of these patients died. No patients who showed disease stabilization have died with a minimum of 2 year follow-up. Approximately 2/3 of Western patients can safely tolerate deep hyperthermia compatible with thermal destruction or chemotherapy augmentation with the use of skin anaesthetics. Thermal monitoring remained a problem in this investigation, in that there was a high incidence of adverse events. Increased temperature measured in subcutaneous tissue and tumour did not show a correlation with each other, with RF power, or with occurrence of complications. With localized mucinous tumours of appendiceal origin, deep hyperthermia with escalations of heat to maximal levels tolerated by the patient should continue to be pursued for a remarkable prolonged survival and excellent quality of life was seen in selected patients.