A procedure known as heated intraoperative intraperitoneal chemotherapy was developed by Paul Sugarbaker at the Washington Cancer Institute.The surgeon removes as much of the tumor as possible followed by the direct administration of a chemotherapy agent, heated to between 40 and 48°C, in the abdomen. The fluid is perfused for 60 to 120 minutes and then drained.
This technique permits the administration of high concentrations of selected drugs into the abdominal and pelvic surfaces. Heating the chemotherapy treatment increases the penetration of the drugs into tissues. Also, heating itself damages the malignant cells more than the normal cells.
Dr. Paul Sugarbaker, renowned oncologic surgeon specializing in mesothelioma at the Washington Cancer Institute, developed a leading-edge surgical procedure to treat mesothelioma called heated intraoperative intraperitoneal chemotherapy. In this procedure, as much of the tumor as possible is first removed by the surgeon. Following the removal of the tumor, a chemotherapy agent heated to between 40°C and 48°C is administered into the abdomen. The fluid is perfused for anywhere between one and two hours and then it is drained.
High concentrations of selected drugs can be administered into the abdominal and pelvic surfaces using this technique. The other benefit associated with using this technique to treat peritoneal mesothelioma is that the heated chemotherapy treatment increases the level to which the drugs can penetrate the tissues and damages malignant cells more than normal ones.
Coliseum Technique for Hyperthermic Intraoperative Intraperitoneal Chemotherapy
Cytoreductive surgery was attempted to make each patient macroscopically disease-free. At the end of the procedure, four closed suction catheters (Zimmer Inc, Warsaw, IN) were placed through the abdominal wall, using stab incisions, to lie beneath each hemidiaphragm and two within the pelvis (Figure 2). A Tenckhoff catheter (Quinton Inc, Seattle, WA) was placed through the abdominal wall if early postoperative intraperitoneal chemotherapy (EPIC) is planned.
Otherwise, the Tenckhoff catheter was placed over the midline abdominal incision for use in HIIC. The Tenckhoff catheter functioned as an in-flow line. The closed suction catheters were used as drainage lines for intraoperative lavage and remained in place for postoperative abdominal drainage. Two temperature probes (Respiratory Support Products Inc. Irvine, CA) were then placed over the edge of the abdominal incision. One temperature probe was tied to the Tenckhoff catheter. The other temperature probe was tied to a closed suction drain at a distant location from the Tenckhoff. All transabdominal tubes were secured to the skin and to the peritoneum with purse string sutures to prevent fluid leakage.
The Thompson retractor (Thompson Surgical Instruments, Traverse City, MI) was then repositioned as in Figure 2. The abdomen was left open with the skin edges suspended to the Thompson retractor with a number 2 running nylon suture. To prevent spillage of the chemotherapy and to control potential chemotherapy vapors, a plastic sheet was sutured to the wound edges. A slit incision was then made in the center of the plastic sheet to allow the surgeon access to all intraabdominal surfaces and to manually control the fluid distribution. After the hyperthermic perfusion was complete, bowel anastomoses and other reconstructive procedures were performed.
The hyperthermic perfusion with mitomycin C was carried out for ninety minutes using a HIIC custom tubing pack (Bard Cardiology, Haverhill, MA), two cardiopulmonary bypass pumps (Travenol Labs, Morton Grove, IL) and a Sarns heater/cooler unit (3M Cardiovascular Systems, Ann Arbor, MI). Three liters of 1.5% dextrose peritoneal dialysis solution containing the appropriate cytotoxic drug(s) were heated and infused at approximately 1 liter per minute into the abdominal cavity. The perfusate was heated to approximately 43oC. Temperatures were measured with a Labcraft digital thermometer (Curtin Matheson Scientific, Jessup, MD). The temperature at the In-Flow line was approximately 44oC. The Tenckhoff temperature probe was maintained between 42 and 43oC. The temperature probes and all temporary 3-0 chromic sutures were removed at the end of the hyperthermic perfusion.
Urine output was monitored by the anesthesiologist. At his or her discretion fluid challenge, furosemide, renal dose dopamine or mannitol were instituted to maintain a brisk diuresis. Urine output was measured every 15 minutes. It was maintained at greater than 400 cc per hour during the ninety minutes of the hyperthermic perfusion and for one hour thereafter.
In addition to intraoperative hyperthermic perfusion, patients with high grade tumor or incomplete cytoreduction received five days of early postoperative intraperitoneal chemotherapy. These five days of chemotherapy were given on postoperative days 1-5. Each dose was prepared in 1000 to 2000 cc of 1.5% dextrose peritoneal dialysis solution, depending on body size. Each dose was infused as quickly as possible, allowed to dwell for 23 hours then drained for one hour prior to the next infusion.
Levels of 5-FU were monitored in the peritoneal fluid and plasma of 9 patients on the first postoperative day. Three patients received cytoreductive surgery, HIIC and early postoperative 5-FU. Six patients received only cytoreduction and early postoperative 5-FU. Samples were obtained at regular intervals from 0 to 180 minutes post infusion.
Drug doses were as follows:
For pseudomyxoma peritonei and adenocarcinoma from appendiceal, colonic and rectal cancer:
Drug Day Route Dose Mitomycin C 0 IP 12.5 mg/m2 (max. 25 mg) for males or 10.0 mg/m2 (max 20 mg) for females in 3 liters. 5-Fluorouracil 1-5 IP 15 mg/m2 x 5 days.
For gastric, pancreatic and ovarian cancer, mesothelioma, and sarcoma:
Drug Day Route Dose Cisplatin 0 IP 50 mg/m2 (max. 100 mg) Doxorubicin 0 IP 50 mg/m2 (max. 100 mg) Mitomycin C 0 IP 7 mg/m2 (max. 14 mg) Doxorubicin 1-5 IP 15 mg/m2 x 5 days.
Standardized dose reductions occurred as follows:
33% dose reduction for age > 65 years
33% dose reduction for patients with compromised renal function.
50% dose reduction for prior exposure to heavy chemotherapy or radiation therapy
Other dose reductions as deemed necessary by the Principal Investigator.
For patients undergoing pharmacokinetic monitoring, samples of plasma, urine and perfusate were obtained at fifteen minute intervals during the hyperthermic perfusion and at the end of the procedure. These measurements were used for pharmacokinetic calculations and to help relate possible complications to systemic and intraperitoneal drug levels.
Patients were monitored for complications associated with intraperitoneal hyperthermia including: enteral complications (fistulas, anastomotic leaks), wound complications (pancreatitis, bile leaks, wound dehiscence), hematologic toxicities, prolonged ileus and line sepsis.