PROCEEDINGS in the Treatment of

Jeanne L. DeMoss, Thomas G. Frazier, and Jeffrey C. Crowley PSI COR Br1ghton. M I

Introduction ______treated. Coley stressed the importance of maintaining the for several days at 39-40 oc tiJr effective Cancer cells, unlike normal cells, exhibit growth treatment. whereby sensitivity to normal controlling factors has The use of water-circulating cisterns and high fre­ been completely or partially lost. 11 Treatment is di­ quency currents was followed by the technique of elec­ rected towards eliminating these cancerous cells by tromagnetic heating, called , as a more exposure to cytotoxic agents. refined method to deliver heat locally to target tissue. Most recently hyperthermia has been added to the list Results published in 1974 by Pettigrew and associates of cytotoxic for treatment of cancer which demonstrated whole body hyperthermia to be a safe and also includes radiation, , and surgery. reliable technique for the treatment of cancer. 4 Although heat by itself is cytotoxic, hyperthermia is used most often as an adjunct to other types of treat­ Basic Principles ______ment. The use of an extracorporeal circuit may provide a method of heating blood and perfusing a tumor, a Heat itself is damaging to cells. Thermal damage is region, or the whole body to a level that may be toxic to dependent on both the temperature applied and the cancer cells but not to normal tissue. An awareness of duration of exposure. The goal of hyperthermic the principles of hyperthermic cancer therapy, as it may is to achieve cytotoxic temperatures in the tumor for a apply to the patient undergoing hyperthermic extracor­ sufficient length of time without damaging the sur­ poreal circulation, is beneficial to the understanding of rounding normal tissue. The rate at which blood flows cancer therapy. through any given area of tissue determines the amount of heat that may be carried away and therefore is a History ______major determinant of the temperature rise in that tis­ sue.7 In normal tissue, heat will cause vasodilation Evidence of the use of heat and caustic agents m (Fig. I). In a tumor, the microvasculature is made up of treating small non-ulcerating was obtained an overabundance of capillary beds which are unable to from translations of Ramajama (2000 B.C.), Hippocra­ dilate. Blood flow through the tumor is more sluggish, tes (400 B.C.), and Galen (200 A.D.f. Accounts of thus unable to dissipate heat applied to the area. The spontaneous tumor regressions following illness with inability to respond to heat by dilation as normal vascu­ lasting high fever such as smallpox, influenza, tubercu­ lature would, also subjects the tumor to hypoxia, anaer­ losis, and malaria were further supported in the late obic metabolism and local acidosis; these conditions in 1800's by documented evidence of disappearance of turn make the tumor tissue more vulnerable to thermal verified sarcomas following infection with . injury. 6 A description of microvascular pathology after Subsequently, Coley began treatments of malignant heat treatment of tumors showed microvascular throm­ tumors with febrile therapy using mixed toxins of erysi­ bosis presumably due to endothelial damage of the pelas to obtain several years of disease-free survival in tumor capillaries. 16 one-third of inoperable carcinomas and sarcomas There is some indication of an enhanced cytotoxic effect with the combined use of heat and chemothera­ Direct communications to: Jeanne L. DeMoss, C.C.P., peutic drugs; however, it is not clear if this effect is PSICOR, 810 E. Grand River, Brighton, MI 48116 Presented at AmSECT's Third National Symposium on differentially cytotoxic to tumors compared with nor­ Thermal Regulation, August 27-29. 1984, Boston, MA mal tissue. 1 It is known that the activity of many drugs

Volume 17, Number I. 1985 The Journal of Extra-Corporeal Technology 37 RF Heat Effects on Tissue the effect of by inhibiting the cell's recovery from sublethal radiation damage.Y NORMAL TISSUE VESSELS TE The amplified cytotoxic action due to combination of heat and chemotherapeutic drugs and radiation can be ~ partially explained by examining the effect of each therapy on parts of the replication cycle of cells. (Fig. T OPENS 2) The cell cycle of cancer cell is similar to that of NEO~ normal cells. Each cell begins its growth during G I ~·'";"" phase where enzymes necessary for DNA production, other proteins, and RNA are produced. S-phase follows

SOLID TUMOR as the time of DNA synthesis. When DNA synthesis is Figure 1: Heat Effects on Tissue Cell Cycle increases with heat, that drugs which are not active at G (Resting) normal temperatures may become more efficient at 0 0 ... . 42 oe, and a cell's ability to repair lethal damage is inhibited with heating. x Herman and associates demon­ Duration (Hr) 18-30 16-20 2-10 0.5-1 strated that the cytotoxicity of hyperthermia alone or Phase G, s Gz M together with some chemotherapeutic drugs may be Function RNA and DNA RNA and Mitosis diminished by slow rates ofhcating. 21 Protein Synthesis Protein Synthesis Synthesis Synergism has been demonstrated between hyper­ thermia and ionizing radiation. Results have shown Figure 2: Cell Cycle greater cytotoxicity with combination of these devices Manual o(Cancer Chemothempr. Roland T. SkeeL M.D .. Editor. Copyright 1982. p. 5. Used with permission of Little. than with the additive effects of each. Heat potentiates Brown and Company. Boston. MA.

0 200 400 600 800 1000 Dose {Rads)

Figure 3: Percent Cell Survival vs. Dose (Rads) at Various Temperatures "Basic Principles in Hyperthermic Tumor Therapy." F. DietzeL Recem Results ill Cmzcer Re.1earch- Vt:!scular Perji1sion in Ca11cer Therapr. Schwcmmle Vol. 86. 1983. Used with permission of Springer-Verlag Publishers. New York. NY and F. Dietzel

38 The Journal of Extra-Corporeal Technology Volume 17. Number 1. 1985 complete, the cell enters G2 (premitotic period) during Whole body hyperthermia techniques include immer­ which more protein and RNA synthesis occur. The G2 sion of the body in molten wax, hot water or hot air, phase is followed immediately by M-phase (mitosis) thermally controlled water circulating suits or blankets when cell division actually takes place. Each of the and extracorporeal circuits. newly formed cells enters G I. The G !-phase is in Hyperthermia is of clinical interest primarily in the equlibrium with a resting state called Go. Cells in Go­ temperature range of 40-43 oc.' Whole body hyper­ phase are relatively inactive with respect to syntheses thermia in humans is physiologically limited because and so are insensitive to many chemotherapeutic the rate of complications increase exponentially above agents. 42 oc.' Because of the narrow margin between the Certain drugs, however, show specificity in their effective temperatures to treat cancer cells and that of mechanism of cytotoxic action such that the cell is more increasing complications resulting from high levels of susceptible to drug damage at given times in this repli­ heat, it is imperative that temperature monitoring be cation cycle. Heat shows greatest effect during S-phase done from sites which will most accurately reflect the and M-phase, while cells are more susceptible to radia­ temperature of the tissues throughout the body. The tion damage during G 1-phase. 3 The asynchronous temperature measurement site will be intluenced by the combination of these susceptible times enhances the site of heat application. chance of affecting more cells for a given exposure. For In some modes of heating, particular areas of the example, beneficial effects can be obtained with inter­ body receive more heat than other areas resulting in mediate doses of radiation (2000-4000 rads) when burns. Areas susceptible to burns may include cannula­ combined with hyperthermia. (Fig. 3) This is of great tion sites used for extracorporeal circulation, skin when value to a patient unable to tolerate higher doses be­ in contact with hot wax, hot air or hot water, and cause of the cumulative effect of previous courses of cutaneous sites at pressure points such as the heels and radiation. 2 buttocks in contact with water blankets. In a cancer patient, burns may become a serious complication Regional (Local) and Total Body when the patient's resistance to infection is suppressed Hyperthermia ______by chemotherapy, radiation, or malignant disease. 17 Particular structures can tolerate temperatures up to Hyperthermia treatment techniques can be catego­ 45 oc without cell damage while systemically the limit rized as two types based on site of involvement: local is probably not more than 43 oc for 12 hours. 13 Skin, (regional) and whole body. esophageal, pulmonary artery, rectal and bladder tem­ Local hyperthermia involves externally applied heat­ peratures are the sites most often monitored. Skin ing by microwave, radio-frequency and ultra-sound or probes are superficial by comparison, therefore more internally applied heat by extracorporeal perfusion of greatly influenced by non core body temperature fac­ isolated sites. Microwave or radio-frequency sources tors. The induction of hyperthermia places the body in (2450 MHz microwaves to 500 KHz long wave a condition of quickly changing temperatures which diathermy) can be directed locally by insertion of nee­ need to be monitored closely and accurately. Rectal dle guides or implants into the tumor, whereas ultra­ temperature often lags behind other measured values sound can be focused and is better able to penetrate because of its location influenced by massive abdomi­ body mass to reach deep-seated tumors. nal viscera. Rectal temperature may be used for a The regional extracorporeal technique involves iso­ comparison temperature but not as the only index of lating the target site from the systemic circulation with total body temperature. Bladder temperature, measured tourniquets so that this area may be perfused with a by a thermistor tipped Foley catheter may be most high concentration of anticancer drug at high tempera­ accurate if one considers that urine transferred to the tures while avoiding systemic toxicity and leakage of bladder comes from the kidneys which receive a sub­ concentrated drug to the rest of the body. Local hyper­ stantial amount of flow from the extracorporeal system. thermia permits perfusion of given areas with drugs of Benzinger" discussed the use of the tympanic mem­ greater concentration and exposure to higher tempera­ brane as a site of measurement based on its agreement tures than can be tolerated systemically. with hypothalamic temperature and arterial blood tem­ Whereas local therapy may be used in isolated tumor perature enroute from the heart to the brain. There is, sites, metastatic disease requires a systemic approach.' however, a great amount of discomfort and risk of

Volume 17, Number I, 1985 The Journal of Extra-Corporeal Technology 39 damage to the membrane when a probe must rest groups have reported cases of patients with apparently against it. The esophageal measurement site has been nonsymptomatic mitral valve prolapse,not previously strongly advocated'" as most meaningful in quickly detected. These patients developed symptoms with in­ changing thermal conditions since it serves as the best duction of hyperthermia which included hypotension available index of aortic arch blood temperature. This and reduced cardiac output requiring termination of choice is based on the thought that the heart and lungs heat treatment. 26 The proposed mechanism for this function as a thermal mixer with the aortic arch tem­ observation was a failure to maintain adequate diastolic perature being most representative to changes in heat filing and therefore a failure to maintain stroke volume production and loss of the body." If a Swan-Ganz as heart rate increased in response to heat. thermodilution catheter is used, monitoring of pulmo­ In whole body hyperthermia, anticoagulation therapy nary artery temperatures becomes available as a site of is imperative and requires some particular consider­ measurement reflecting intracardiac blood temperature. ations. Anticoagulation is kept at adequate minimal doses. Suggested safe clotting times are 3.5 to 4 times Clinical Experiences ______baseline activated clotting time. In consideration of previously discussed possible mechanisms of thermal injury, since there is a vascular clotting response to heat Regional hyperthermic perfusion was reported to be which increases damage to tumor masses it may be of an effective treatment of melanoma and sarcoma by value to minimize anticoagulation. 17 Hyperthermia and Cavaliere in 1967. 211 Most recently it has been shown its tendency to increase the utilization of heparin, com­ that hyperthermic perfusion can further improve the bined with the minimal dose guideline for anticoagula­ prognosis for patients with malignant melanoma of the tion, requires extremely close monitoring of clotting limbs. 1H times. Frequent addition of heparin to the extracorpo­ Certain factors may be responsible for better results real circuit is common. seen with regional as compared The catabolic effect of previous anticancer therapy to results seen with systemic therapy. Patients selected and the nature of the disease process may place the for regional hyperthermic perfusion present isolated patient in need of plasma protein replacement. Al­ tumor sites in contrast to systemic tumor involvement bumin is the primary component of the plasma pro­ seen in patients requiring whole body therapy. Regional teins22 of the blood. It contributes approximately 62% perfusion permits isolated sites to be exposed to higher of total protein concentration and 70% of total colloid temperatures and greater drug concentrations without osmotic pressure. Albumin may be used as the protein systemic toxicity. These factors contribute to regional oncotic portion of the prime or replacement fluid dur­ perfusion being less systemically traumatic than whole ing therapy. Herman21 documents that severe general­ body therapy. In addition, more clinical experience has ized edema (anasarca) was found to be more prominent been gained in regional perfusion methods than in in patients whose fluid replacement consisted of a high systemic therapy. volume of crystalloid as opposed to patients who were Whole body hyperthermia was first documented as a pretreated with colloid solutions and then given smaller safe method in 1974. 4 Since then several methods of amounts of crystalloid during treatment. This observa­ inducing systemic hyperthermia have evolved. In 1979, tion occurred irrespective of method of hyperthermia Parks and associates documented treatment of advanced treatment ( extracorporeal or warm water blanket) or malignancy of extra-corporeal hyperthermia. 17 maximum temeprature reached. Herman found the oc­ Systemic hyperthermia places additional stresses on currence of pulmonary edema was less frequent and many systems of the body primarily the cardiovascular less severe when use of colloid, lower volumes of system which becomes a limiting factor to intensity of cyrstalloid, and positive end expiratory pressure (5-10 therapy. In order to avoid severe hypotension, good left em of H 0) was used. ventircular function is needed to increase the cardiac 2 output in response to heat induced vasodilation. 19 A In any method of hyperthermic therapy sweating review of literature reveals that at hyperthermic (41- causes a great amount of fluid loss from the patient. 1 As 42 oq conditions, heart rate increases to 150-170 beats mentioned previously, as body temperature rises, sys­ per minute, mean arterial pressure and pulmonary cap­ temic vasodilation occurs increasing volume uptake by illary wedge pressure decrease, and cardiac index in­ the patient. These factors in combination with urine creases. Cardiac arrhythmias rarely occur. Several output and effects of anesthetic agents collectively con-

40 The Journal of Extra-Corporeal Technology Volume 17. Number 1, 1985 tribute to the need for volume replacement to the mia treatments for a variety of malignant carcinomas. patient. Electrolyte studies should be monitored (Table I) Two types of hyperthermia techniques were throughout the therapy for evidence of need for electro­ used: whole body and peritoneal hyperthermia. Anes­ lyte replacement. thesia was by Ethrane or Halothane, oxygen and endo­ The choice of anesthetic technique is important for tracheal respiratory control. In all cases patient several reasons. The type of anesthesia used affects the temperatures were monitored by esophageal and rectal patient's systemic pH and vascular flow to visceral probes with maximum temperature attained at 41.5 °C organs. c3 Endotracheal respiratory gas anesthesia may rectally. At no time was the inflow (or arterial) temper­ 4 24 25 permit a more normal or acidic pH, · · while intra­ ature permitted to exceed 43 oc. venous sedative and spontaneous respiration produces a Although literature review of the results of other more alkalotic pH. 1 The safety of this latter technique is groups shows little problem with life threatening car­ based on heat being a potent ventilatory stimulant diovascular collapse. we designed an extracorporeal which increases both tidal volume and respiratory rate. circuit which would be able to sustain a patient on The level of narcotic and barbiturate is titrated to cardiopulmonary bypass if needed. The system con­ maintain reasonable arterial oxygen saturation and car­ sisted of Cobe Optiflo II" oxygenator with integral bon dioxide elimination. 26 cardiotomy reservoir through which we maintained 1.5 A series of hyperthermic perfusions was carried out liters of oxygen to preserve oxygenating function at our institution utilizing extracorporeal circulation. Thirteen patients received a total of fourteen hyperther- a Cobc Laboratories. Lakewood. CO 80245

Table 1 Table of Hyperthermia Treatments Rectal Peritoneal Temp Date of Pt Sex Age Tumor Site of Disease WBH Time Drug Treatment Result

F Ovarian Omentum Peritoneal N/A N/A J-80 5-80 Carcinoma ~ 2 F 61 Ovarian Peritoneal N/A cis-Platinum 6-80 2-81 Carcinoma ~ ] F 59 Breast Bone WBH 41.5 none 8-27-81 5-8] 2 hrs + 4 M 26 Hodgkins Stage IV WBH 41.5 none 10-8-81 ]-9-82 2 hrs + 5 M 29 Malignant Systemic WBH 41.5 OTIC 11-12-81 2-14-82 Melanoma I hr 1500 mg + 6 F 41 Ovarian Intra- Peritoneal 41.5 none 11-17-81 5-24-82 Abdominal 2 hrs ~ 7 M 33 Kaposi's Systemic WBH 41.5 Sarcoma 1.5 hrs none 2-16-82 8 F 52 Ovarian Liver & WBH 41.5 cis -Platinum J-4-82 5-6-82 Adeno- Peritoneum I hr 100 mg + Carcinoma 9 F 50 Colon Ovaries Peritoneal 41.5 cis -Platinum 4-22-82 'ee 13 Carcinoma I hr JOOmg ~ 10 F 56 Renal Lung WBH 41.5 none 5-17-82 ]-7-83 Carcinoma I .5 hrs + II F 45 Ovarian Pelvis Peritoneal 41.5 cis -Platinum 10-29-82 N/A I hr JOOmg 12 F 26 Mycosis Systemic WBH 41.5 none 12-14-82 1-25-83 Fungoides 1.5 hrs ! 13 F 50 Colon Ovaries WBH 41.5 5-FU I g 1-IJ-8] 4-20-8] Carcinoma I hr cis-Platinum + 50 mg 14 F 27 Ovarian Colon & WBH 41.5 cis-Platinum 3-17-8] ~ 6-3-83 Carcinoma Liver I hr 50 mg ~ =expired

Volume 17, Number I, 1985 The Journal of Extra-Corporeal Technology 41 should it be needed. The arterial pump used was a Bio­ Future ______Medicus Biopumph and arterial filtration with Pall Adult arterial blood filter.Arterial (inflow) and venous Results of regional and whole body hyperthermia (outflow) temperatures were monitored by usc of an show therapeutic value. Regional hyperthermia for electronic digital thermometer. Pressures and inflow many reasons has shown greater prospect. Whole body resistances were monitored at the arterial (inflow) side hyperthermia involves a much more complex system in of the circuit. itself and exposes the patient to greater systemic physi­ The whole body hyperthermia method included hep­ ologic stress. arinization with 3 mg/kg of porcine intenstinal mu­ Many topics in regard to hyperthermic treatment for cosca heparin and initiated through cannulations of cancer need to be studied. One major difficulty in femoral arterial and venous sites. Prime varied accord­ research of this subject is that no suitable animal model ing to patient requirements as to proportions of albumin has been found which has similar temperature toler­ (75 g), packed red cells (if needed), lactated Ringers, ances and response of humans.' Pharmacologic studies heparin I 0,000 units. Flows were directed towards may include what drugs are effective and how are their achieving a cardiac index flow of 2.4 liters/min/meterc actions modified at high temperatures. What tempera­ until maximum temperature was reached at which time ture levels are safe yet effective and at what duration of the flow was reduced to 2.0 liters/min/meterc. Acti­ exposure. Continued studies need to be done in the vated clotting times using the Hemochron method were areas of sequencing hyperthermia with other anticancer repeated at 15 minute intervals unless conditions re­ treatments and how these treatments affect its toxicity quired monitoring more closely. Protamine was given to the patient. following termination of extracorporeal circulation. More recently research has shown that bacteria and Peritoneal hyperthermia involves cannulation of op­ their toxins directly damage cancer cells and inhibit posite sides of the peritoneal cavity providing an inflow metastases. 27 Although reminiscent of effective therapy and outflow site for warm perfusate which consisted of by Coley using toxin innoculations in the late 1800's. 2000 ml of lactated Ringers solution. Flows generally the therapeutic value contributed by the individual com­ ranged from 1-2 liters/minute as consistent with out­ ponents of heat, bacterial products, and the immune flow return. Careful monitoring is needed to avoid system response in tumor regression have yet to be obstruction to peritoneal outflow and subsequent inflow defined.' pressure increase. Lab values monitored before, during, and after ther­ apy included CBC, CEA, SMA-12, and arterial blood gases. CEA (carcinoembryonic antigen) is used to References ______monitor response to therapy. I Bull JM: Whole Body H;perthermia as an Anticancer Agent. CA. 32:2. When drugs were added to the circuit, they were 123-127. 19X2. administered when maximum desired temperature was :2. Hyperthermia Cancer Treatment In-Focu~ Report #9303. Information Rc- :-.ourcc:-. International. Inc. 1983. achieved, and circulated for the prescribed time. Fol­ 3. Dichon JA: HYperthermia in the Treatment of Cancer. Lancet. Jan. 2.7. lowing systemic hyperthermia, blood from the circuit 1979. 202-205. was infused as needed following termination of extra­ 4. Pettigrew RT. Galt JM. Ludgate CM. eta!: Clinical Etkcts of Whole Bod} Hyperthermia in Advanced Malignancy. 81: Mcd . ./. 4:679-682. 1974. corporeal circulation. Following peritoneal hyperther­ 5. Dietzel F: Basic Principle~ in Hyperthermic Tumor Therapy. Recenr mia, the perfusate was drained from the peritoneal Rnults in Cancl'l' Rc.1mrch. X6 177-190. 1984. 6. Babbs C. DeWitt D: Physical Principles of Local f(Jr Cancer. cavity of the patient. The peritoneum was then irrigated Medical Instrumentation. 15(6) J67-J7J. 1981 with large amounts of normal saline solution. Patients 7. Voorhees WD. Babbs CF: Method to Determine the Importance of Blood Flow in Thermal Clearance from Deep Lying Normal Tis~uc in Dogs. Proc were passively allowed to return to normal body tem­ AAMI 16th Annual Meeting. 1981. perature in the following hours of recovery room obser­ g_ Hahn GM. Braun L Har-Kedar I: Thermochemotherapy: Synergism Be­ tween Hyperthermia (42-43 o C) and Adriamjcin (or Bleomycin) in Mam­ vation. malian Cell inactivation. Proc. Nat'/. Acad. Sci. USA. 72:9J7-940. 1975. Results of these hyperthermia treatments were con­ 9. Bcn-Hur E. Elkind M. Bron_ RV: Thermally F.nhanccd Radio-response of sistent with other groups' findings showing partial re­ Cultured Chinese Hamster Cells-lnhihition of Repair of Sublethal Dam­ age and Enhancement of Lethal Damage. Radiat. Res. 5H:J8-51. 1974. mission in treated patients. No deaths occurred as a 10. Herman T. et a!: Whole Body Hyperthermia and Chcmotherap) i(Jr result of these hyperthermia treatments. Treatment of Patient~ with Advanced Refractory malignancic~. Cancl'r Treatmem Reports. Vol66 No 2. 259-265. 1982. b Bio-Medicus, Minneapolis, MN 55344 II Skeel R: Manual r~f"Cancer Chemotherapy Bo~ton: Little. Brown and Co .. c Pall Biomedical Products, East Hills, NY 11548 1982.

42 The Journal of Extra-Corporeal Technology Volume 17. Number I. 1985 12. Haf~trom L. et al: Blood Leakage and Melphalan Leakage from the 21 Herman TS, et al: Differential Rates of Heating Influence Hyperthermia Perfusion Circuit During Regional Hyperthermic Perfu~ion f(lr Malignant Induced Cytotoxicity in Normal and Transformed Cclb in Vitro. Proc. Am. Melanoma. Cancer Treatment Reports. 68(6)·. 867-872. 1984. As.1oc. Cancer Res. and ASCO. 20:165. 1979. 13. Bligh J: Aspect~ of Thermoregulatory Phy~io1ogy Pertinent to Hyperther­ 22. Guyton AC: Capillary Dynamics: Fluid Exchange Between Blood and lllll' Treatment of Cancer. Cancer Research. 39:2307-2312. June 1979. Interstitial Fluid. Text hook of Medical Phvsiologr Sixth Edition. W. B. 1·+. Cran~ton W.. ct a1: Oral. Rectal and e~ophagcal temperatures and Some Saunders 392-396. 1981. Factor> Alkcting Them in Man. J. Phnio/. (Lund.) 126:347-358. 1954. 23. Lees DE. Kim YD. Dubois M. et al: Internal Organ Hypoxia During 15. Bcntinger T: On Phy~ica1 Heat Regulation and Sense of Temperature in Hyperthermia Cancer Therapy in Humans. Proceedings of the Third Man. Proc. Nat"!. Acad. Sci. USA 45:645-659. 1959. International Symposium in Cancer Therapy by Hyperthermia. Drugs. and 16. Eddy H: tumor Microva~cular Re~ponse-Hyperthermia. Drug. Radiation Radiation. June 1980. Canca Research, June 1980. Comhination~. 1. Nat'/. Cancn: /nsf. 19X I. 24. Blair RM. Levin W: Clinical Experience of Induction and Maintenance of 17. Parb L. et a1: Treatment of Far-Advanced Brochogenic Carcinoma hy Whole Body Hyperthermia, in Cancer 77u'rapy hy H_,perthermia and Extracorporeally Induced Sy~temic Hyperthermia. 1. 17Ioracic. Cardio\'0.\. Radiation. Baltimore. Munich: Urban and Schwarzcnberg Inc .. Streffer. Surg. 78:883-892. 1979. C. (Ed) 1978. p. 318-321. 18. Tonak J: Hyperthermic Pcrfu~ion in Malignant Melanomas~5 Year 25. Larkin JM. Edwards WS. SMith DE. et al: Systemic Thermotherapy: Re~ult~. Rec. Res. in Cancer Research.~Va~cular Perfu~ion in Cancer Description of a Method and Physiologic Tolerance in Clinical Subjects. Therapy Vol 86. 1983. Canca. 40:3155-3159, 1977. 19. Bull JM: Whole Body Hyperthermia: A Phase-) Trial of a Potential 26. Lees DE, Kim YD. Bull JM. Whang-Pcng J. Schuette W. Smith R. Adjuvant to Chemotherapy. Anna/.1 of !merna/ Medicine. 90:317-323. MacNamara T: Anesthetic Management of Whole Body Hyperthermia tor 1979. Treatment of Cancer. Anesthclio!ox.~' 52:418-428. 1980. 20. Cavaliere R'. et al: Selective Heat Sensitivity of Cancer Cells: Biochemical andCiinieal Studies. Cancer. 20:1351-1381.1967.

Volume 17, Number I, 1985 The Journal of Extra-Corporeal Technology 43