[CANCER RESEARCH 39, 2245-2251 , June 1979]0008-5472!79!0039-0000$02.0O

Normal Tissue and Solid Tumor Effects of Hyperthermia in Animal Modelsand Clinical Trials'

F. Kristian Storm,2 William H. Harrison, Robert S. Elliott, and Donald L. Morton

Division of Oncology. Department of Surgery, UCLA School of Medicine [F.K.S., W.H.H., D.L.M.Jand School of Engineering (R.S.E.J, University of California, LosAngeles, California 90024, and the Surgical Service, Veterans Administration HospitalfF.K.S. , D.L.M.], Sepulveda, California 91343

Abstract

Localized hyperthermia therapy by high-energy radio-frequency waves was evaluated in malignant and adjacent normaltissue of 30 patients with 10 types of cancer. Hyperthermiawas delivered to superficial and deep visceral cancers in awakepatients who had refractory disease. Histological and clinicalresponses were recorded serially.

Toxicity tests in dogs, sheep, and pigs showed that progressive necrosis of normal and cancer tissue occurred at temperatures above 45°C(113°F).However, as normal tissues approached this temperature, intrinsic heat dissipation occurred(possibly due to augmented blood flow) so that temperaturesbelow 45°Ccould be maintained, whereas most solid tumorsdid not have this adaptive capacity and could be heated to50°C(122°F)with virtually no injury to normal organs, s.c.tissue, or skin. To date, 69 treatments have been administeredto 36 tumors in the 30 patients. Selective heating was observedin both primary and metastatic tumors located in surface tissuesand internal organs. Response appeared to be related to tumorsize in that differential heating was possible more often in thelarger lesions. In tumors successfully heated, moderate tomarked necrosis occurred.

Radio-frequency hyperthermia appears to be a safe andpotentially useful form of therapy for selected cancer patienta.While other cancer treatments are more effective for smalltumors, hyperthermia may be uniquely beneficial against largerlesions.

Introduction

Most hyperthermic research has concentrated on the tumoricidal effects of heat at 42—44°C,since at these temperaturesmalignant cells have been found to be slightly more sensitiveto heat than are their normal cell counterparts (1—3,7, 8, 10,12—14, 17, 20). Higher temperatures may be of greater therapeutic benefit, but above 45°C(113°F),irreversible damageto both normal and neoplastic tissue progresses in a lineardose-time relationship, and host tolerance becomes a limitingfactor (2, 5, 8, 9, 19, 20). Recent investigations (11) havesuggested, however, that many solid tumors may act as a heatreservoir because their neovascularity is incapable of augmenting blood flow in response to heat. Thus, these tumorsmay be heated independently above 45°C(Chart 8). Severaltreatment centers have reported selective heat destruction of

I Supported in part by grants from the National Cancer Institute, Department

of Health, Education and Welfare, and the Medical Research Service of theVeterans Administration. Presented at the Conference on Hyperthermia in CancerTreatment, September 15 and 16, 1978, San Diego, Calif.

,To whom requestsforreprintsshouldbe addressed,at54—140 CenterforHealth Sciences, University of California, Los Angeles, Calif. 90024.

tumor by radio-frequency waves (6, 7, 11, 20); however, normal tissue thermal tolerance and local hyperthermic cancertherapy have yet to be tested adequately in animals or humans.

Our study was designed to evaluate the effects of radiofrequency hyperthermia in the range of 42—50°Con bothsurface and deep visceral normal tissues as well as on spontaneously arising cancers in animals and humans. We presenta brief summary of our findings to date to demonstrate thathyperthermia has potential as an effective treatment for manysolid tumors without injury to normal tissue. With temperaturesat or above 50°C(122°F),marked tumor necrosis has beenobserved. Implications for human cancer therapy are discussed.

Materials and Methods

The effects of localized hyperthermia on normal skin, s.c.tissue, extremitas, viscera, and spontaneously arising tumorswere evaluated in anesthetized large animals. Clinical trialswere undertaken in patients with histologically proved cancerwho had progressive local or metastatic disease despite allstandard forms of therapy (surgery, radiation, chemotherapy,or combination therapy). During all phases of animal investigation and clinical trials, both an oncologist and an electricalengineer were present to evaluate continually the effects ofhyperthermia.

Hyperthermia was produced by crystal-controlled radio-frequency waves of 13.56 MHz. A prototype impedance-matchingnetwork provided an absorbed power accuracy of >95% at arange of 10 to 1000 watts. Heat was delivered to superficialtumors by contact electrodes, with or without surface cooling.Intrathoracic and intraabdominal heating was achieved using aMagnetrode, a prototype nonsurface contact electrode systemof our design created specifically for deep visceral hyperthermia with minimal preferential surface heat absorption.

Temperatures in solid tumors and normal adjacent tissueswere recorded serially during brief periods of wave cessationusing commercial needle thermistors (Yellow Springs Instrument Co., Yellow Springs, Ohio).

Thermal effects were evaluated by serial clinical examinationand needle biopsy. Systemic effects of heat were monitoredthroughout treatment by changes in pulse, blood pressure,respiratory rate, and core temperature readings. All patientshad pre- and posttherapy complete blood count, differentialcount, electrolytes, sugar, creatinine, and urate tests, andurinalysis. Patients undergoing deep intrathoracic hyperthermia also had electrocardiogram and cardiac isoenzyme determinations. Patients undergoing deep intraabdominal hyperthermia had liver function and amylase tests. Tumor size wasdetermined by direct measurement, or by radiographs or tomographic scans.

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F. K. Storm et al.

Results

Thermal Response in Normal Animals

Skin. Graded radio-frequency doses of 1 to 10 watts/sq cmapplied to canine skin produced occasional transient first-degree burns (erythema) at 42°C,second-degree burns (edemaand bullae) at 46°C,and third- and fourth-degree burns (fullthickness skin and muscle necrosis) at and above 50°C(Chart1).

Extremity. Dog, sheep, and pig extremities were heateddeeply to 41 —44°Cto determine muscle, nerve, and vesselthermal tolerance. At these temperatures, histological examination failed to reveal abnormalities, and in no instance wasmotor or vascular functional injury apparent over an observation period of 1 to 6 weeks.

Sequential temperature recordings at constant heat dosageshowed that when normal muscle reached 43—44°C,abrupttemperature reduction occurred which could not be overcomewithout a substantial increase in applied heat (Chart 2).

Viscera. Dogs were subjected to graded deep heat, anddirect temperature measurements were taken from heart, lung,esophagus, liver, stomach wall, stomach contents (solid andliquid), gallbladder, bile, spleen, pancreas, kidney, small bowelwall and contents, colon, and stool to determine whether ornot any particular normal organ was subject to specific heating.It is noteworthy that no preferential heating or ‘‘hotspots―occurred at temperatures of 37—49°C.

Dogs were subjected to external hyperthermia equivalent to42—45°C internal heat dosage for 1 5 mm over the upper chest,

lower chest-upper abdomen, and lower abdomen-spinal cord. and then observed for 2 to 3 weeks. During this interval, there

was no clinical evidence of internal organ injury. Posttreatmentcardiac enzymes were transiently elevated, but no abnormalities were apparent by electrocardiogram. Hepatic transaminases and amylase were transiently elevated, but no signs ofcompromise became manifest. However, prolonged continuousheating at these temperatures universally resulted in fatal cardiac tachyarrhythmias.

Thermal Response of Canine Tumors.

Investigation of several spontaneously arising tumorsshowed that i.t.3 temperature could be raised to a potentiallylethal level while preserving physiological temperature in surrounding normal tissues. Chart 3 illustrates the thermal profileof a sarcoma which occupied two-thirds of a dog's hemithoraxthat was heated to 51°Cwhile adjacent normal lung remainedat 42.5°C.

Three histologically different tumors were heated to >50°C,and at the termination of radio-frequency hyperthermia, eachtumor dissipated heat very slowly when compared to adjacentnormal muscle (Chart 4).

Human Clinical Trials

To date, 69 treatments have been administered to 36 tumorsin 30 patients with refractory cancer. Tumor heating @5O°Cwas observed in 17 of 36 tumors (47%); 45—49°Cin 3 of 36(8%), and 42—44°Cin 8 of 36 (22%). In 8 of 36 tumors, (22%),

3 The abbreviation used is: it., intratumoral.

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temperatures above 42°Ccould not be achieved without violating adjacent normal tissue tolerance.

Tumor Histology. Ten varieties of cancer have been evaluated. Selective heating @45°Cwas possible in 20 of 36 tumors(55%), and appeared to be independent of histology (Table 1).

Tumor Size. Selective heating @45°Cwas possible in 43%of tumors <5 cm in greatest diameter and in 73% of tumors

@5cm (Table 2).Superficial Tumors. Nineteen tumors arising in skin or s.c.

tissue were evaluated, and selective heating @45°Cwas observed in 14 (74%). Temperatures (i.t.) as high as 70°Chavebeen achieved, with up to 57°Cat 10-cm i.t. depth. Surfacetumors treated @50°Cfor 15 mm on one or more occasionsgenerally showed histological evidence of coagulative necrosisand would slough within 10 to 14 days.

Visceral Tumors. Seventeen intrathoracic or intraabdominaltumors have been evaluated. Selective heating @45°Cwaspossible in 6 tumors (35%), and all were @5cm in size. Chart5 illustrates the temperature profile in a patient who had arecurrent 10- x 15- x 30-cm primary intraabdominal sarcomathat progressed despite surgical resection, radiation, andchemotherapy. Chart 6 shows the temperature profile of a 10-x 10-cm hepatic metastasis in a patient with colon carcinoma.

While i.t. temperatures frequently were not uniform, tumorsheated @5O°Cfor 15 mm on one or more occasions generallyshowed coagulative necrosis and intravascular thrombosis.These tumors usually were replaced by varying degrees offibrosis with little change in volume (Fig. 1). Occasional centralliquefaction was observed.

Toxicity. Hyperthermia generally has been well tolerated inthe mildly sedated, awake patient. Normal tissues in the treatment field adjacent to tumors, including skin, s.c. tissue, ab

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diaphoresis, skin flushing, a modest rise in core temperature(0.5—1°C),respiratory rate (2 to 12 rpm), systolic blood pressure (20 to 40 mmHg), and a moderate to marked rise in pulse(20 to 60 beats/mm) (Chart 7).

Nearly one-half of our patients have undergone intrathoracicor intraabdominal hyperthermia with no clinical or laboratoryevidence of internal organ injury. No significant arrhythmias,cardiac isoenzyme changes, or abnormal serum parameters ofinternal organ function have been found at heat sufficient toproduce marked tumor heating. No rise in serum creatinine orurate levels was observed in patients with large tumors heatedto 45—50°C;therefore, prophylactic i.v. hydration and uricosuric agents were discontinued after initial trials.

Three patients with superficial tumors heated to 50—70°Chad slough of immediately adjacent overlying skin; otherwise,injury to normal skin has not been observed. Two obesepatients (with 2 to 3 cm of s.c. tissue) had small localized areasof s.c. fibrosis gradually result at temperatures of 42—45°C;otherwise no adverse reactions in normal surface tissues havebeen observed after deep hyperthermia.

Discussion

Most studies to date have dealt with the effects of moderatehyperthermia in the range of 42—44°Calone or in combinationwith X-irradiation or chemotherapy, based upon evidence of

20 25 selective thermal sensitivity of tumor cells in this temperature

range(1,2, 7,8, 10, 12—14,17,20).Lethaltemperatureexposure time relationships have been established for manytumor cell lines, and it appears that even higher temperaturesmay be of greater potential therapeutic value, since the required heating time for tumor destruction is approximatelyhalved (6). However, high-temperature hyperthermia was notconsidered to be feasible since the differential thermal sensitivity between malignant and normal cells is lost above 45°C, andprogressive and irreversible protein denaturation occurs inboth normal and malignant tissue (2, 5, 8, 9, 19, 20). Manysolid tumors have a relatively poor and physiologically unre

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Hyperthermia in Cancer Treatment

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dommnarand thoracic musculature, esophagus, lung, liver, andgut, ordinarily could be maintained at a physiological temperature of <45°C with appropriate radio-frequency applicationsince all these tissues were observed to be capable of thermaladaptation.

In patients undergoing deep visceral hyperthermia at 500 to1 000 watts absorbed power density, we frequently observed

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RF Heat:Deep MUSCLE

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Selective heating (@45°C)by tumor type (human)Selectively

heatedHistology

No. of tumors No.%Melanoma

17 9 53Sarcoma 6 6 100Colon carcinoma 4 1 25Epidermold carcinoma 2 1Teratocarcinoma 2 2Other 5 120Total

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Table1 thoracic and intraabdominal heating were achieved by a shortwave radio-frequency Magnetrode of our design which permitted efficient localized internal heating with minimal preferentialheat absorption by skin or s.c. tissue (Charts 5 and 6).

Initial experiments on the thermal tolerance of animal skin,extremities, and viscera supported the safety of temperatures

OCsponsive blood flow (11, 18), suggesting that tumors mightretain more heat than would normal tissue whose adaptivevasculature would allow heat dissipation (15) (Chart 8). On thebasis of this hypothesis, several investigators applied radiofrequency hyperthermia and found that while a tumor could beheated to 45—50°C,most normal tissues remained within aphysiologically acceptable temperature range (6, 7, 11). However, even with the most sophisticated equipment available,preferential heat absorption occurred within skin and s.c. tissues, which often resulted in injury (6, 11). Thus, virtually nodata have been available on the effects of localized deephyperthermia, and most cancer research has been limited tothe study of surface tumors.

Our investigation was designed to evaluate the effects oflocalized hyperthermia on superficial normal tissues, on visceral organs, and on solid tumors arising in these sites. Forthis purpose, superficial hyperthermia was applied by variousprototype electrodes, with and without surface cooling. Intra

patient GDSarcoma10x15z30cm9—77

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[ ‘rOWERIHyperthermia in Cancer Treatment

Heating i.t. above 45°Cwas achieved most often in tumors5:5 cm in diameter (Table 2). Most of the tumors that could notbe heated to 45°Cdisplayed physiological adaptation to heatsimilar to that of adjacent normal tissues. Thermal adaptationwas most often observed in lesions <5 cm in size, and rarelyin lesions @5cm, probably due to a diminished vascular integrity in the larger tumors. While standard methods of cancertherapy (surgery, X-irradiation, and chemotherapy) are most

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Chart 6. Heat profile of metastatic colon carcinoma in liver, 10 x 10 cm,showing selective tumor heating (human).

of <45°C(4, 9, 20). Interestingly, when animal muscle reached43—44°C,spontaneous cooling occurred which maintained thetissue well below its thermal tolerance limit (Chart 2). Thisphenomenon has been observed by others (4), supports thehypothesis of normal tissue physiological adaptation to hyperthermia, and is consistent with augmented blood flow (Chart8).

When external radio-frequency hyperthermia was applied tocanine normal viscera, no selective heating of any normalorgan occurred. However, when hyperthermia was applied tospontaneously arising dog tumors, it resulted in solid tumorheating above 45°C,while normal adjacent tissues remainedat physiological temperatures (Chart 3). These results supported the work of others showing that selective solid tumorheating was possible (6, 7, 11, 20). Moreover, at treatmenttermination, effectively heated tumors dissipated heat muchmore slowly than did adjacent normal muscle (Chart 4). Thesedata again suggested that normal tissues and tumors have adifferent capacity to dissipate incident heat.

Initial clinical trials in patients with refractory cancer revealedthat intratumor temperatures of 42—50°Ccould be achieved inmore than three-fourths of the tumors evaluated with virtuallyno normal tissue injury. Selective hyperthermia was possiblewith both primary and metastatic solid tumors (Charts 5 and6), and appeared to be independent of tumor histology (Table1).

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Chart 8. Postulated mechanism of selective solid tumor heating. Normal tissueblood flow augmentation with heat, not present in solid tumors. Tumors act asrelative heat reservoir.

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F.K.Stormeta!.

effective for smaller tumors, our data suggest that hyperthermiamay be uniquely effective against larger tumors.

Tumor necrosis was marked in lesions heated @5O°Cfor 15to 60 mm on one or more occasions. Such treatment causedrapid coagulative necrosis and vascular thrombosis (Fig. 1, Aand B). Superficial tumors generally would slough within 10 to14 days of therapy. However, effectively heated visceral tumorswould remain intact with little change in size and with noevidence of systemic tumor breakdown products by serumcreatinine, urate, or urinary protein determinations. Serial biopsies of these internal tumors revealed few functional vesselsand progressive tumor replacement by scar (Fig. 1C), as othershave noted (16). We postulate that the attendant vascularnecrosis and thrombosis which occur at these high temperatures prevent absorption of the tumor and allow only fibrousreplacement over a prolonged interval. Therefore, direct biopsyrather than size measurement appears to be necessary toassess therapeutic benefit in visceral cancers treated by hyperthermia.

Radio-frequency hyperthermia with an absorbed power density to 1000 watts generally was well tolerated in our patients,with virtually no normal tissue injury. Our patients appeared todissipate localized heat by evaporation (diaphoresis) and increased peripheral blood flow (flushing and pulse rise), ratherthan by increased ventilation (Chart 7).

All superficial normal tissues and viscera that were evaluatedhad the capacity to adapt to heat and, with proper radiofrequency application, could be maintained within a physiologically safe temperature range. Slough of normal skin overlyingsuperficial tumors that were heated to 50—70°Cwas probablythe result of either direct heat conduction or vacular compromise. Localized s.c. fibrosis that occurred at 42—45°Cin someobese patients was probably due to the extremely poor vascularity of such tissue.

The results of our animal research and initial clinical trials,associated with our development of safe and effective equipment, indicate that hyperthermia may become a potentiallyuseful form of local cancer therapy when fully evaluated. Clinical trials are now underway to determine the most therapeuticdose-time regimen. We are also investigating toxicity and therapeutic enhancement ratios of combined chemotherapy and Xirradiation with hyperthermia, as well as any changes in thehost immune system with such therapies. At present, we donot regard hyperthermia as an appropriate alternative to anystandard treatment modality, but rather a highly experimentalmodality to consider when other modes fail.

Acknowledgments

Continuing progress in this endeavor has been made possible by technicaladvice and instrumentation from the following contributors: Association for Ad

vancement of Medical Instrumentation; Bureau of Medical Devices, U.S. Foodand Drug Administration; Federal Communications Commission; Fred StormIndustrial Design, Inc., Los Angeles, California; Gaymar Industries, Inc., NewYork, New York; Henry Radio, Inc., Los Angeles, California; Hughes AircraftCorp., Los Angeles, California; Martin-Marietta Aerospace Corp., Denver, Cobrado; Metalized Products/King-Seeley Co., Boston, Massachusetts; Oftice ofTelecommunications Policy, The White House; Texas Instruments, Dallas,Texas;Trent-Wells, Inc., Los Angeles, California; Wavecom, Inc., Los Angeles, California.

This investigation has been undertaken with the able assistance of BeverlyDrury, Linda Holcomb, and Dr. Harold Snow.

References

1. Bender, E., and Schramm, T. Untersuchungen sur Thermosensibilitat vonTumor und Normalzellen in vitro. Acta Biol. Med. Ger., 17: 527—543,1966.

2. Cavaliere, R., Ciocatto, E. C., Giovanebla,B. C., Heidelberger, C., Johnson,R. 0., Margottini, M., Mondovi, B., Maricca, G., and Rossi-Fanelli, A.Selective heat sensitivity of cancer cells: Biochemical and clinical studies.Cancer, 20: 1351-1 381 , 1967.

3. Crile, G., Jr. Heat as an adjunct to the treatment of cancer: experimentalstudies. Cleve. Clin. 0.. 28: 75—89,1961.

4. De Lateur, B. J., Lehmann, J. F., Stonebridge, J. B., Warren, C. G., andGuy, A. W. Muscle heating in human subjects with 915 MHz microwavecontact applicator. Arch. Phys. Med. Rehabil., 5 1: 147—151, 1970.

5. Dickson, J. A., and Muckle, D. S. Total body hyperthermia versus primarytumor hyperthermia in the treatment of the rabbit VX2 carcinoma. CancerRes., 32: 1916—1923,1972.

6. Dickson, J. A., and Shah, S. A. Technology for the hyperthermic treatmentof large solid tumors at 50°C.Clin. Oncol., 3: 301—318, 1977.

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8. Giovanella, B. C., Morgan, A. C., Stehlin, J. S., and Williams, L. J. Selectivelethal effect of supranormal temperatures on mouse sarcoma cells. CancerRes., 33: 2568—2578,1973.

9. Hardy, J. D., Stobwijk, J. A. J., Hammel, H. T., and Murgatroyd, D. Skintemperature and cutaneous pain during warm water immersion. J. AppI.Physiol., 20: 1014—1021 , 1965.

10. Larkin, J. M., Edwards, W. S., and Smith, D. E. Total body hyperthermia andpreliminary results in human neoplasms. Surg. Forum, 27: 121—122, 1976.

11. Le Veen, H. H., Wapnick, S., Piccone, V., Falk, G., and Ahmed, N. Tumoreradication by radiofrequency therapy. J. Am. Med. Assoc., 235: 2198—2200, 1976.

12. Mendecki, J., Friedenthal, E., and Botstein, C. Effects of microwave-inducedlocal hyperthermia on mammaryadenocarcinoma in C3H mice. Cancer Res.,36: 2113—2114,1976.

13. Mondovi, B., Strom, A., Rotilio, G., Agro, A. F., Cavaliere, A., and RossiFanelbi,A. The biochemical mechanismof selective heat sensitivity of cancercells: studies on cellular respiration. Eur. J. Cancer, 5: 129—136, 1969.

14. Muckle, D. 5., and Dickson, J. A. The selective inhibitory effect of hyperthermia on the metabolism and growth of malignant cells. Br. J. Cancer, 15:771—778,1971.

15. Natadze, T. G. Regulation of blood circulation in malignant tumors. Vopr.Onkol. (Leningr.), 5: 14—23,1959.

16. Overgaard, K., and Overgaard, J. Investigations on the possibility of athermic tumor therapy: shortwave treatment of a transplanted isobogousmouse mammary carcinoma. Eur. J. Cancer, 8: 65—78,1972.

17. Pettigrew, R. T., Gait, J. M., Ludgate, C. M., and Smith, A. N. Clinical effectsof whole-body hyperthermia in advanced malignancy. Br. Med. J., 4: 679—682, 1974.

18. Shibata, H. R., and MacLean, L. 0. Blood flow to tumors. Prog. Clin. Cancer,2:33-47, 1966.

19. Stolwljk, J. A. Physiological response to whole body and regional hyperthermia. In: M. J. Wizenberg and J. E. Robinson (eds). Proceedings of theInternational Symposiumon Cancer Therapy by Hyperthermia and Radiation.pp. 163—167. Baltimore: American College of Radiology Press, 1976.

20. Westermark, H. The effect of heat upon rat tumors. Scand. Arch. Physiol.,52: 257—322,1927.

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1979;39:2245-2251. Cancer Res   F. Kristian Storm, William H. Harrison, Robert S. Elliott, et al.   Animal Models and Clinical TrialsNormal Tissue and Solid Tumor Effects of Hyperthermia in

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