HYPERTHERMIC INTRAOPERATIVE
INTRAPERITONEAL CHEMOTHERAPY
TUTORIAL

Authors: Arvil D. Stephens
Susan K. White, RN, CNOR
Jesus Esquivel, MD
O. Anthony Stuart
Paul H. Sugarbaker, MD


Washington Cancer Institute, CG-185
Washington Hospital Center
110 Irving St., NW
Washington, D.C. 20010
Phone (202) 877-3908
Fax (202) 877-8602


This publication has been sponsored by:
The Foundation for Applied Research in Gastrointestinal Oncology (FARGO)
and Sugarbaker Oncology Associates, P.C.

Contents

Coliseum Technique for Hyperthermic Intraoperative Intraperitoneal Chemotherapy

Nursing Considerations for the Administration of HIIC

Anesthesiology for Cytoreductive Surgery and HIIC Administration

Safety Considerations for HIIC Administration

Conclusions

Materials List

References

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 43^oC. Temperatures were measured with a Labcraft digital thermometer (Curtin Matheson Scientific, Jessup, MD). The temperature at the In-Flow line was approximately 44^oC. The Tenckhoff temperature probe was maintained between 42 and 43^oC. 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:

For gastric, pancreatic and ovarian cancer, mesothelioma, and sarcoma:

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.


Nursing Considerations for the Administration of HIIC

Health care providers in the operating room are subjected daily to occupational health risks such as exposure to hepatitis, HIV, tuberculosis, any infectious process, inadvertent inhalation of anesthetics and exposure to intraoperative X-rays. Another current concern is the exposure to cytotoxic agents. With the prospect of use of intraoperative chemotherapy, questions have been raised regarding the long term, low-dose daily exposure and the cumulative effects. Clinical research protocols are based on the understanding of the known toxicities of these drugs at therapeutic levels^(7,20). Conservative policies regarding occupational exposure have been implemented based on the possibility that some of these toxic manifestations may present themselves with the low dose chronic exposure. The paramount considerations of institutional policies should include: protection of the patient, protection of the health care providers and protection of the environment⁽²¹⁾.


Anesthesiology for Cytoreductive Surgery and HIIC Administration

Hyperthermic intraoperative intraperitoneal chemotherapy is administered after a major abdominal procedure that may be accompanied by massive fluid shifts, moderate blood loss, plasma electrolyte changes and changes in coagulation parameters. During the cytoreductive surgery, it is very important for the anesthesia care team to be vigilant in replacing fluids, correcting electrolyte changes and other therapies as deemed necessary per laboratory results (ABG, hemoglobin, glucose, sodium, potassium, calcium and lactate). As the surgeons prepare for the heated chemotherapy, a prothrombin time (PT) and a partial prothrombin time (PTT) are evaluated. Prior to the perfusion of heated chemotherapy, the patient's blood is evaluated and abnormalities are immediately corrected. Table 1 lists the fluid replacement required for ten patients who received HIIC with mitomycin C.

During the preparatory phase for HIIC, the anesthesia personnel evaluate the routine monitoring and support equipment. Table 2 lists the equipment typically used for cytoreductive surgery and HIIC at the Washington Hospital Center. Several prophylactic actions may be employed to avert heat related problems during the perfusion such as: placement of the warming blanket above the foam padding, use of the smoke evacuator at a higher setting, and adequate patient hydration. As the heated chemotherapy administration is begun, all patient warming devices are turned off, the operating room is maximally cooled, and the upper body Bair hugger is set to blow ambient air over the patient. An intravenous drip with sufenta, versed and Pavulon is used for paralysis. The dose of these drugs administered may be diminished during HIIC as there is minimal stimulation.

Adequate patient hydration prior to beginning the HIIC perfusion is mandatory. Our data indicate that a major problem encountered during the HIIC perfusion is the patient’s peripheral vasodilatation⁽²²⁾. Peripheral vasodilatation is manifest first in decreased urine output (typically at 60 minutes), then hypotension and tachycardia. It is critical for the perfusionist and anesthesiologist to be aware of the "heat stroke syndrome" and to be prepared to implement the necessary steps to correct the situation. If the patient is allowed to progress into a heat stroke like reaction, the patient’s core temperature (esophageal temperature) may continue to increase even after the heated perfusate is removed. Emergency procedures such as packing ice around the patient’s head and flushing the abdominopelvic cavity with cool saline may be necessary. During the HIIC 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 at least 400 cc per hour during the ninety minutes of the hyperthermic perfusion and for one hour thereafter.

Hespan is strongly contraindicated for any patient undergoing a peritoneal stripping procedure. Hetastarch is a chemically modified complex polysaccharide with a molecular weight of approximately 4.5 x 10⁵ daltons⁽²³⁾. Hetastarch has been reported to cause coagulopathy in a dose-related manner by three mechanisms^(24,25). First, hetastarch reduces the stability of blood clots by accelerating the conversion of fibrinogen to fibrin. Second, hetastarch macromolecules coat the platelet outer membrane, thus decreasing adhesiveness and increasing bleeding time. And third, an acquired von Willebrand’s syndrome may develop, with reduced levels of factor VIII activity. Seven patients from this surgical oncology service experienced coagulopathies during this period that were attributable to hetastarch administration. Two of these seven patients underwent cytoreductive surgery with HIIC and are included in the analysis above. Hetastarch is no longer administered to any patient on this service who is expected to undergo any peritonectomy procedure.


Safety Considerations for HIIC Administration

Blood and body fluids from patients receiving chemotherapy are considered contaminated for 48 hours after the last dose is administered⁽²³⁾. The precautions described below emphasize the safety considerations of intraoperative chemotherapy administration; however, they should be applied to any patient who has received chemotherapy within 48 hours. Routes of exposure for health care providers include: inhalation, contact, ingestion and injection. It is essential that certain equipment be available and appropriately utilized by personnel who come in contact with cytotoxic agents. This equipment includes: unpowdered latex gloves, impervious sterile gowns, protective eye wear, respirator mask (if a spill occurs), a spill kit, an impenetrable hazardous waste container, specially marked linen bags and appropriate cytotoxic agent labels.

Three major regulatory groups provide guidelines for the use of cytotoxic agents. Each institution that uses these agents is expected to develop individual policies and procedures. The major regulatory groups are: Occupational Safety and Health Administration (OSHA)⁽²³⁾, the National Cancer Institute (NCI)⁽²⁴⁾, and the Joint Commission on Accreditation of Health Care Organizations (JCAHO)⁽²⁵⁾. A summary of each group's guidelines is presented below (Table 4), however the complete references should be considered required reading for all personnel involved with cytotoxic agents.

Hyperthermic intraoperative intraperitoneal chemotherapy can be administered in a safe occupational environment, provided certain basic rules are followed. First and foremost is strict adherence to Universal Precautions. Any blood, body fluid or tissue from any patient should be considered potentially contaminated. Gloves, gowns, masks and eye protection should always be used to prevent contact between any contaminated object and the staff. Items not included under Universal Precautions include:

• Use of unpowdered latex gloves.
• Use of the smoke evacuator to remove aerosols and vapors.
• Modifications to the routine operating room clean up.
• Recommended procedures for clean up of chemotherapy spills.

All staff should wear unpowdered latex gloves any time cytotoxic drugs may be encountered. Powderless gloves are less permeable than powdered gloves and latex is a better barrier than most other glove materials. Our laboratory studies of glove permeability to chemotherapy drugs support the NCI’s recommendation that gloves should be changed every 30 minutes, and OSHA’s recommendation for double-gloving when possible (unpublished data). Our standards require that surgeons use a powderless latex under glove with an elbow-length over glove. We also recommend the use of Coban around the cuff of the elbow-length glove to prevent the glove from rolling down the surgeon’s arms.

Air samples were obtained during ten HIIC procedures with mitomycin C in an attempt to determine if chemotherapy vapors or aerosols are present with the Coliseum Technique. Air was sampled from approximately 5cm above the plastic sheet, using hospital wall suction at -200 mm Hg. Air was aspirated through a methanol trap for the duration of the 90 minute HIIC procedure. The methanol was then concentrated and analyzed for the presence of mitomycin C by HPLC. Traces of mitomycin C or a decomposition product were detectable in 6 of the 10 experiments. The total mitomycin C detected by this technique was 0.12 - 3.0 m g per HIIC perfusion. Positive tests correlated with HIIC perfusions in which the smoke evacuator was not running prior to the introduction of chemotherapy into the abdomen. We have now implemented a policy of running the smoke evacuator on a high setting throughout the HIIC administration. Repeat studies of mitomycin C vapors and the mutagenicity potential (using the Ame’s Test) are underway.

Routine operating room clean up is safe and effective if strict adherence to Universal Precautions is maintained. Any material in contact with chemotherapy should be separated from the standard trash and linen and placed in appropriate receptacles by the operating room staff. Chemotherapy waste should be stored on-site for 48 hours, then disposed by a licensed hazardous waste facility. All instrument trays should be labeled by the nursing staff with "Cytotoxic Agent" prior to leaving the operating room. All blood and pathology specimens obtained after the start of chemotherapy perfusion should also be labeled with "Cytotoxic Agent". Bactericidal solutions should not be used to clean contaminated items because they may cause chemical reactions with the chemotherapy agent and they do not inactivate the chemotherapy⁽²³⁾. OSHA recommends 70% isopropyl alcohol for clean up.

Clean up of chemotherapy spills should be directed by specific hospital policies and procedures that are based upon OSHA, JCAHO and NCI guidelines. All spills should be contained and cleaned up immediately by the circulating nurse. The procedures will be dictated by the size of the spill. If any personnel make direct contact with cytotoxic agents, they should immediately remove the contaminated apparel and discard in a hazardous waste container. The affected skin should be immediately washed with pure soap. If the eyes are affected, they should be immediately flooded with water or isotonic saline for five minutes. The personnel should then report to occupational health or to the emergency room. If only the clothing is contaminated, the article should be removed as soon as possible and placed in a cytotoxic linen bag.

OSHA defines a small chemotherapy spill as less than 5 grams or 5 mL of undiluted drug⁽²³⁾. Personnel should wear impervious gowns, double powderless surgical latex gloves and eye protection when cleaning any chemotherapy spill. Liquids should be blotted dry with absorbent pads and solid spills should be wiped with wet absorbent pads. The spill area will then be washed three times with 70% isopropyl alcohol or pure soap followed by clean water. After decontamination of the spill area, routine cleaning procedures may be used.

A large spill mandates the use of a spill kit which should be readily available wherever chemotherapy is handled. Large spills should be immediately contained with absorbent pads, towels, etc. to prevent spreading. A respirator mask should be worn in addition to the standard protective clothing. Care must be taken to prevent the formation of aerosols. Access to the spill area should be restricted.

Chemotherapy spill kits should be clearly labeled and are commercially available (Codan Medlon Inc., Burbank, CA). A spill kit should include a respirator mask, goggles, powderless latex surgical gloves, an impervious gown, impervious shoe covers, at least two sheets of absorbent material, Solusorb, a small scoop and brush, 70% isopropyl alcohol and/or pure soap, cytotoxic agent labels, a "caution" sign and large waste-disposal bags.

Because the toxicities of low level cumulative exposure are not well defined, personnel who have specific medical concerns should be excluded from the chemotherapy environment. This includes, but is not limited to; pregnant or breastfeeding women, men or women who are planning a family in the near future, personnel with known blood dyscrasias or who are immunocompromised and personnel taking hematologically toxic medications. The NCI recommends that personnel involved with cytotoxic agents on a full time basis be given periodic health examinations in accordance with institutional policy⁽²⁴⁾.

Figure 4 Patient Temperatures at Three Anatomic Sites,
Heat Exchanger and the In-Flow Line.

Intraabdominal and esophageal temperatures for a single patient. Data presented are typical temperatures observed during the hyperthermic perfusion. Note the differences in area under the temperature curves between In-Flow and Tenckhoff lines (at resection site), a Distant intraabdominal site and Esophageal (core body) temperatures. This figure demonstrates the localized administration of heat with this procedure.

Conclusions

Changes in the use of chemotherapy in patients with peritoneal carcinomatosis and sarcomatosis have been reported previously along with early favorable results of treatment⁽³²⁾. Chemotherapy is more often administered intraperitoneally, or by combined intraperitoneal and intravenous routes. Also, a shift in the timing of chemotherapy administration has occurred. It is now possible to administer chemotherapy in the operating room. Intraoperative administration using the Coliseum Technique provides several advantages:

• Residual cancer cells in the tumor bed, or free in the peritoneal cavity can be eradicated before postoperative changes in tumor cell kinetics occur, and while tumor burden is minimal.
• Favorable drug distribution to all surfaces at risk can be achieved before cancer cells are entrapped by wound healing or covered by surgical tissue reconstruction.
• Provide dose intensive, timely, regional chemotherapy with a level of drug not achievable by intravenous administration.
• Increase residual cancer cell’s exposure to non-cell-cycle specific drug by administration of regional hyperthermia.
• Minimize the possibility of toxicity by close monitoring of all physiologic parameters.
• Administer reasonable adjuvant treatment with minimal extra cost and without additional hospitalization.

Cytoreductive surgery with hyperthermic intraoperative intraperitoneal chemotherapy using the Coliseum technique is a reasonable treatment for selected patients with malignancies that present within the abdominopelvic cavity. Malignancies that have spread to the peritoneal surfaces have been uniformly lethal conditions until the advent of specialized surgical and chemotherapy techniques. Now selected patients with these diagnoses can be salvaged with acceptable morbidity, mortality and good quality of life. Cytoreductive surgery and mitomycin C HIIC using the Coliseum Technique have demonstrated 27.0% morbidity and 3.0% mortality in 200 treatments. We have shown that HIIC using the Coliseum technique in a gastrointestinal cancer population does not increase the morbidity or mortality of this dose-intensive clinical pathway.


Materials List

References

1. Jones S, Henry W: Hippocrates. Cambridge, Harvard University Press, 1959 to 1962.
2. Busch W: Uber den Einflus Weichen Heftigere Erysipelen Zuweilen auf Organisierte Neubildungen Ausuken Verhandl, Rheinisch-Westfael. Akad Wiss Nat Lng Wirtschaftswiss Vortr 23: 28, 1866.
3. Coley WB: The treatment of malignant tumors by repeated inoculations of erysipelas with a report of ten original cases. Am J Med Sci 105: 487, 1893.
4. Vidal E: Cancer et Traumatism, Alcan F. (ed). Assoc Franc de Chirurgie, Paris, 1907.
5. Jensen CO: Experimentelle Untersuchunger Uber Krebs bei Mausen. Zentralbl Parasitenkd Infektionskr 34: 28, 1903.
6. Loeb L: Transplantation von Tumoren. Virchows Arch Pathol Anat Physiol 172: 345, 1903.
7. The Chemotherapy Source Book. Michael Perry (Ed). Williams & Wilkins Publishers, Baltimore, MD, 1993.
8. Hornback NB: Historical aspects of hyperthermia in cancer therapy. Radiol Clinics of North America 27: 481, 1989.
9. Barlogie B, Corry PM, Drewinko B: In-vitro Thermochemotherapy of human colon cancer cells with cis-dichloroammineplatinum (II) and mitomycin C. Cancer Res 40: 1165-1168, 1987.
10. Los G, van Vugt MJH, den Engelse L, Pinedo HM: Effects of temperature on the interaction of cisplatin and carboplatin with cellular DNA. Biochem Pharmacol 46: 1229-1237, 1993.
11. Los G, van Vugt MJH, Pinedo HM: Response of peritoneal solid tumors after intraperitoneal chemohyperthermia treatment with cisplatin or carboplatin. Br J Cancer 69: 235-241, 1994.
12. Los G, Sminia P, Wondergem J, et al.: Optimisation of intraperitoneal cisplatin therapy with regional hyperthermia in rats. Eur J Cancer 27: 472-477, 1991.
13. Shimm DS, Gerner EW: Hyperthermia in the treatment of malignancies. in Therapeutic Heat and Cold. Justus Lehmann (Ed), Williams & Wilkins Publishers, Baltimore, MD, 1990.
14. Dedrick RL, Myers CE, Bungay PM, DeVita VT: Pharmacokinetic rationale for peritoneal drug administration in the treatment of ovarian cancer. Cancer Treat Rep 62: 1-9, 1978.
15. Lukas G, Brindle SD, Greengard P: The route of absorption of intraperitoneally administered compounds. Pharmacol Exp Ther 178: 562-566, 1971.
16. Torres IL, Litterst CL, Guarino AM: Transport of model compounds across the peritoneal membrane in the rat. Pharmacology 17: 330-340, 1978.
17. Sugarbaker PH, Stuart OA, Vidal-Jove J, Pessagno AM, DeBruijn EA: Studies of the peritoneal plasma barrier after systemic mitomycin C administration. Reg Cancer Treat 4:188-194, 1993.
18. Sugarbaker PH: Peritonectomy Procedures. Ann Surg 221:29-42, 1995.
19. Barnhart ER: Physicians’ Desk Reference.. Medical Economics Data, Publisher, Oradell, NJ 1997.
20. DeVita VT, Hellman S, Rosenberg SA (eds) Principles and Practice of Oncology, 3rd Edition, J.B. Lippincott Co., Philadelphia, PA 1989.
21. White SK, Stephens AD, Sugarbaker PH: Hyperthermic intraoperative intraperitoneal chemotherapy safety considerations, AORN 63:716-724, 1996.
22. Esquivel J, Angulo F, Bland RK, Stephens AD, Sugarbaker PH: Hemodynamic and cardiac function parameters during heated intraoperative intraperitoneal chemotherapy using the open "Coliseum Technique" Ann Surg Oncol 7(4):296-300, 2000.
23. Tansung T, Sugarbaker PH: Management of pancreatitis due to pancreatic injury in cytoreductive surgery. Reg Cancer Treatment 8:180-184, 1995.
24. Gold MS, Russo J, Tissot M, Weinhouse G, Riles T: Comparison of Hetastarch to albumin for perioperative bleeding in patients undergoing abdominal aortic aneurysm surgery. Ann Surg 211(4):482-485, 1990.
25. Strauss RG: Review of the effects of hydroxyethyl starch on the blood coagulation system. Transfusion 21:299-302, 1981.
26. OSHA Work-practice Guidelines for Personnel Dealing with Cytotoxic (Antineoplastic) Drugs. Am J Hosp Pharm 43:1193-1204, 1986.
27. National Study Commission on Cytotoxic Exposure. Recommendations for Handling Cytotoxic Agents, 1984.Joint Commission on Accreditation of Health Care Organizations. Accreditation Manual for Hospitals, 1989.