Henry Ford Hospital Medical Journal

Volume 29 Number 1 Clinical Today Article 2

3-1981

Hyperthermia

F. K. Storm

Follow this and additional works at: https://scholarlycommons.henryford.com/hfhmedjournal

Part of the Life Sciences Commons, Medical Specialties Commons, and the Public Health Commons

Recommended Citation Storm, F. K. (1981) "Hyperthermia," Henry Ford Hospital Medical Journal : Vol. 29 : No. 1 , 5-9. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol29/iss1/2

This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Henry Ford Hosp Med J Vol 29, No 1, 1981

Hyperthermia F. K. Storm, MD*

This report describes the history of hyperthermia and re­ out preferential surface tissue heating, further clinical in­ views current forms of treatment at both low (42°-43°C) vestigation of both superficial and deep internal solid and higher (<45°C) temperatures. Hyperthermia treatment tumors is now possible. at low temperatures includes fluid immersion and irriga­ Recent data suggest that hyperthermia may be an espe­ tion, regional perfusion with heated fluids, and electro­ cially effective form of for larger tumors that resist magnetic radiofrequency waves. Low-temperature hyper­ standard forms of treatment. Clinical trials are now under­ thermia has also been combined with way to determine the most therapeutic dose/time regimen, and with in recent clinical trials. At higher to determine toxicity and therapeutic enhancement ratios temperatures, we and other investigators have also had of combined chemotherapy and x-irradiation with hyper­ promising, preliminary results in treating tumors safely. thermia, and to evaluate any changes in the host immune With the specialized radiofrequency instrumentation we system with such . have developed to apply hyperthermia at any depth with­

Th e use of heat in treatment dates back to the At temperatures between 41°-45°C (106°-113° F), cancer ancients with the application of red-hot irons by Ramajama cells are slightly more sensitive to heat than their normal (2000 BC), Hippocrates (400 BC), and Galen (200 AD). In cell counterparts. In vitro and in vivo tumor models have more recent times, Westermark (1898) placed hot-water shown irreversible damage and complete regression of circulating cisterns into advanced carcinomas ofthe uterus various tumors at 42°-45°C, while normal cells were killed and found palliative shedding of some tumors. Coley at temperatures at least one degree higher, or more than (1927) introduced "toxin" therapy for cancer, but stated twice the duration of heating (1-4). that responses were associated with temperatures of Heat causes progressive necrosis to tumor cells at these 39°-40°C of several days' duration, suggesting that the temperatures but not in stromal or vascular cells within febrile reaction might have been caused by the tumericidal tumors, nor in normal surrounding tissues (5). Autolytic dis­ agent. Simultaneously, Keating-Hart and Doyen (1910) in­ integration of heat-damaged cells is followed by a marked troduced electrocoagulation of tumors, which is still in use increase in connective tissue stroma and scar formation (6). today. Warren (1933) was one ofthe first to apply heat from Interestingly, this process occurs in tissue cultures of tumor- infrared and high-frequency currents to tumors and found derived and tumor-producing cells, but not in normal and remissions of some . With the subsequent develop­ non-tumor-producing cells. When a cell subline derived ment and popularity of x-irradiation therapy, hyperthermia from a non-tumor-producing line acquires high tumor- research was all but abandoned until modern times when producing capacity, it also acquires greater thermosen­ the selective thermosensitivity of tumor cells was more fully sitivity. Thus, malignant potential, both in vivo and in vitro, appreciated. is accompanied by decreased thermotolerance (7-8).

* Department of Surgery, Division of Oncology, Center for Health Hyperthermia alters both DNA and RNA synthesis and Sciences, University of California, Los Angeles depresses cellular enzymatic systems required for cell me­ Address reprint requests to Dr. Storm, Center for Health Sciences, Room tabolism and division. Its major mode of action may be to 54-140, University of California, Los Angeles CA 90024 increase cell and lysosome membrane permeability, caus- Storm

ing selective internal destruction of the cancer cell. Cells the extremities. All evidence of gross tumor disappeared in that are less well oxygenated seem to be most vulnerable to 10 patients, five had regressions, three failed to respond, thermic injury. and four could not be evaluated. The complication rate was high, with six deaths and three immediate amputations; however, massive tumor necrosis was demonstrated (4). Modern Concepts of Total body hyperthermia Low-Temperature Hyperthermia Pettigrew, in 1974, reported on 38 terminal cancer cases Hyperthermia has been applied by various means, includ­ treated by total body hyperthermia at 41.8°C for an average ing fluid immersion and irrigation, regional perfusion with of four hours, which was applied by emersion in molten heated fluids, and by electromagnetic radiofrequency wax. An objective response, weight gain, or relief from waves. pain, as well as measured tumor regression or histologic All frequencies of radiofrequency waves appear to heat evidence of necrosis, was seen in 18 of 38 cases, wfth tissues in a similar way. Energy is transferred into tissue by four patients dying from disseminated intravascular coag­ field interaction that causes ions in the tissue to oscillate or ulation (9). produces changes in the magnetic orientation of mole­ Larkin and Edwards, in 1976, reported their experience cules, which are locally converted into heat. Because the with total body hyperthermia applied by a water-circulat­ energy of a shortwave or microwave quantum is only about ing suit. Nineteen patients were maintained at 41.5°-42°C 10'' eV, it cannot produce ionization or excitation. The for two to five hours, with an objective tumor response biological effects of radiofrequency waves are primarily noted in 70%. Complications included one death, transient and perhaps solely due to heat production. However, the cardiac arrhythmias in 15%, superficial burns in 15%, and absorption and penetration characteristics of electromag­ transient respiratory distress in 11%, which have been netic waves are markedly dependent upon tissue composi­ attributed to the seven to eight hours of anesthesia time tion and interfaces (i.e., skin/muscle/fat/bone). Moreover, required to raise and maintain body temperatures in these the depth of penetration is often limited. Incident energy critically ill patients (11). absorption is a function of tissue resistance, so that tissues with high values (skin, subcutaneous tissue, bone) prefer­ The rmo rad iot he rapy entially absorb heat in amounts 10-150 times greater than tissue with low values (muscle, organs, tumors). Therefore, Hyperthermia has been combined with radiation therapy if skin or subcutaneous tissue must be penetrated to heat in the hope of producing a synergistic and augmented deeper tissue, a high and potentially dangerous degree of response. Since hypoxic cells are more radioresistant than surface energy deposition-would be needed to produce aerobic cells (11), several investigators have concluded that deep heat effectively. hypoxic cells may be at least as sensftive to hyperthermia as aerobic cells. Others have suggested that the primary At present, satisfactory heating is limited to depths of 2-3 effect of hyperthermia is to inhibit cellular recovery from cm with commercially available apparatus. In sublethal radiation damage (12). an attempt to overcome this limitation, several investigators have designed specialized equipment in the range of 915 When tumor cells were exposed to hyperthermia followed MHz and 2450 MHz microwave bands. However, even by 600 rad radiation, the result was a three-log increase in with surface cooling, documented temperatures of cells killed as compared to their survival at 37°C to 43°C. 42°-44°C have been possible only at 2-3 cm depth, with Clinical doses for local and regional treatment wfth the the thermal gradient continuously decreasing as depth combined treatment may lie in the range of 200-600 increases. For this reason, clinical trials wfth standard rad/fraction (13). microwave techniques have been limited to superficial tumors. In an effort to produce deep internal hyperthermia, Clinical trials several approaches have been used, particularly limb per­ In 1977, K im reported his experience using hyperthermia fusion, total body hyperthermia, and combination and radiation for cutaneous cancers in man. With frac­ therapies. tionated doses of 800-2400 rad followed by 43.5°C surface heating by water bath or microwaves, 7 of 10 patients Isolated limb perfusion showed significant prolonged benefits wfth combination therapy when compared to radiation alone (14). In 1967, Caval iere performed regional limb perfusions with pre-warmed blood at 41.5°-43.5°C in 22 patients wfth Hornback has treated 70 patients with advanced malig­ large, recurrent, or single metastatic cancers localized in nancy with a combination of microwave (heating) and Hyperthermia

standard radiation. Of 21 patients who received a full tolerance becomes the prime consideration (1,4,7). course of therapy, 16 (80%) had complete regression of all Therapeutic hyperthermia in this higher temperature range local tumor, and nine of them remained free of disease was not thought feasible until the realization that some from nine to 14 months (15). solid tumors might act as a heat reservoir and retain heat due to abnormal vascularity and relatively poor blood flow. The Radiation Therapy Oncology Croup has recently es­ When Shibata and MacLean evaluated cancers in man, tablished a controlled study among 14 institutions to ex­ they found that the blood supply was poorer in all tumors plore the efficacy of such combined therapy. Phase 1 studied (21). Using isotope dilution techniques, LeVeen studies suggest that effective thermal doses are probably in found that tumor blood flow was only 2-15% that of the range of 43°-45°C, combined with higher doses of surrounding tissue and concluded that tumors retain more radiation equivalent to 4,000 rad in four weeks (Boone heat than normal tissue whose adaptive vasculature allows MLN, Gerner EW, personal communication, 1976). heat dissipation (22).

The rmoc hemothe rapy Our evaluation of thermal tolerance on animal skin, ex­ The combination of hyperthermia and chemotherapy has tremities, and viscera supported the safety of temperatures also been investigated, since heat is thought to alter tumor of<45°C (23). Interestingly, when normal animal muscle cell membrane permeability and enhance uptake of reaches 43°-44°C, spontaneous cooling occurs that main­ chemotherapeutic agents. tains the tissue well below its thermal tolerance limit. This phenomenon, which has been observed by others, sup­ In 1970, Giovanella found a four-log kill in leukemia cells ports the theory of normal tissue adaptation to hyperther­ at 42°C in three hours. With the addition of dihydroxy- mia that is consistent with augmented blood flow (22). butylaldehyde, a 100-fold kill enhancement was observed When external, radiofrequency hyperthermia is applied to with no increase in toxicity. DL-glyceralydehyde, canine normal viscera, no selective heating ofany normal melphalan, sodium oxyamate, and actinomycin-D were organ occurs. also active in combination with heat (16). In vitro data also suggest benefits from hyperthermia combined with Animal tumor investigations adriamycin (17). Using shortwave-induced hyperthermia, Dickson reported In 1976, Goss reported on the survival of four human that 7 of 10 rabbits bearing VX2 carcinoma had complete fibroblast strains and seven melanoma cell lines after ex­ tumor regression with cure ofthe host. The temperature of posure to various concentrations of melphalan alone and skin and normal muscle remained 3°-4°C lowerthan mini­ in combination with heat at 42°C for four hours. He found mal tumor temperatures, and no injury occurred (23). that combined treatment was not only synergistic but in­ creased the differential between fibroblast and melanoma In our experience, hyperthermia applied to spontaneously lines (18). arising dog tumors results in solid tumor heating above 45°C, with normal adjacent tissues remaining at phys­ When Stehlin, et al treated locally recurrent and intransit iologic temperatures. Moreover, when treatment ends, melanoma ofthe extremities using hyperthermic limb per­ heated tumors dissipate heat much more slowly than adja­ fusion, they found an increased response from 35% to 80% cent normal muscle, which shows that normal tissues and by adding heat (41°C) to melphalan perfusion (19). tumors differ in their capacity to dissipate incident heat.

Human clinical trials Modern Concepts of High-Temperature LeVeen applied shortwave hyperthermia to 21 patients and Local Tumor Hyperthermia produced tumor temperatures over 46°C, which is 8°-10°C higher than in adjacent normal tissue. Tumor necrosis or Most studies so far have dealt with moderate hyperthermia substantial regression of cancer was noted in each case of 42°-43°C alone or combined with x-irradiation or with minimal destruction of normal tissue. However, he chemotherapy, based upon the evidence of selective ther­ found that for internal tumors, it was best to transmit energy mal sensitivity of tumor cells. Lethal temperature/exposure to lesions that were surgically exposed to avoid heating time relationships have been established for many cell and occasional burning of surface tissues (22), as others lines. However, several investigators have found that at have experienced. temperatures approaching 45°C a linear kill takes place dueto progressive and irreversible protein denaturation. At With the specialized radiofrequency instrumentation we such high temperatures the differential susceptibility be­ have developed to apply hyperthermia at any depth with­ tween malignant and normal cells decreases, and host out preferential surface tissue heating, further clinical in- Storm

vestigation of both superficial and deep internal solid are available. Goldenberg found that the growth of human tumors is now possible (23-25). colonic tumors in hamster cheek pouches was inhibited In 30 patients with 36 refractory cancers, we found that after he applied shortwave diathermy heating; the growth intratumor temperatures of 42°-50PC could be achieved in of contralateral, presumably normothermic, cheek pouch more than three-fourths, wfth virtually no injury to normal tumors was also inhibited (20). Hahn found that sarcomas tissues. Selective hyperthermia was possible with both implanted in mice were highly sensitive to cure by radiofre­ primary and metastatic solid tumors and appeared to be quency heating. However, cell-kill as assessed by cloning independent of tumor histology. Intratumor heating above efficiency of treated and immediately excised tumors was 45°C was achieved most often in tumors < 5cm in diam­ insufficient to account for the in vivo cures. This suggested eter. Most of the tumors that could not be heated to 45°C that delayed killing might be the result of stimulation of a displayed physiologic adaptation to heat, similar to that of tumor-directed immune response, secondary to the direct adjacent normal tissues. effects of low or high dose hyperthermia.

While standard methods of cancer therapy (surgery, x- irradiation, chemotherapy) are most effective for small Future Prospects tumors, our data suggest that hyperthermia may be The results of animal research and initial clinical trials, uniquely effective against larger tumors. Tumor necrosis associated with our development of safe and effective was marked in lesions heated<50°C for 15-60 minutes on equipment, indicate that hyperthermia may become a po­ one or more occasions. Such treatment caused rapid coag- tentially useful form of local cancer therapy when fully ulative necrosis and vascular thrombosis. Superficial tu­ evaluated. Clinical trials are now underway to determine mors generally would slough within several days of the most therapeutic dose/time regimen, to determine tox­ therapy. However, effectively heated visceral tumors would icity and therapeutic enhancement ratios of combined remain intact with little change in size and with no evi­ chemotherapy and x-irradiation with hyperthermia, and to dence of systemic tumor breakdown products by serum evaluate any changes in the host immune system with such creatinine, urate, or urinary protein determinations. Serial therapies. biopsies of these internal tumors revealed few functional vessels and progressive tumor replacement by scar. All Patients with advanced cancer that resists standard meth­ superficial normal tissues and viscera that were evaluated ods of therapy, or those wfth cancers for which no standard had the capacity to adapt to heat and, with proper radio- therapy exists, are candidates for experimental hyperther­ frequency application, could be maintained within a phys­ mic therapy. iologically safe temperature range (23-26).

Hyperthermic immune enhancement Several investigators have suggested that selective tumor regression after hyperthermia may be due, in part, to some augmentation of the immune system, although few studies Hyperthermia

References

1. Westermark H. The effect of heat upon rat tumors. Skand Arch Physiol 14. Kim JH, Hahn EW, Tokita N, et al. Local tumor hyperthermia in 1927;52:257-322. combination with radiation therapy. Cancer 1977;40:161-69.

2. CrileCJr. Heat as an adjunct to the treatment of cancer: Experimental 15. Hornback NB, Shupe RE, Shidnia H, Joe BT, et al. Preliminary clinical studies. Cleveland Clin Q 1961;28:75-89. results of 433 megahertz microwave therapy and radiation therapy on patients with advanced cancer. Cancer 1977;40:2854-63. 3. Bender E, Schramm T. Untersuchungen zur thermosensibilitat von tumor und normalzellen in vitro. Acta Biol Med Germ 1966; 16. Giovanella BC, Lohman WA, Heidelberger C. Effects of elevated 17:527-43. temperatures and drugs on the viability of L1210 leukemia cells. Cancer Res: 1970;30:1623-31. 4. Cavaliere R, Ciocatto EC, Giovanella BC, et al. Selective heat sen­ sitivity of cancer cells: Biochemical and clinical studies. Cancer 17. Hahn GM, Braun J, Har-Kedar I. Thermochemotherapy: Synergy 1967;20:1351-81. between hyperthermia (42°-43°C) and adriamycin (or bleomycin) in mammalian cell inactivation. Proc Natl Acad Sci (USA) 1975;72: 5. Muckle DS, Dickson JA. The selective inhibitory effect of hyperther­ 937-40. mia on the metabolism and growth of malignant cells. Br J Cancer 1978;15:771-78. 18. Goss P, Parsons PG. The effect of hyperthermia and melphalan on survival of human fibroblast strains and melanoma cell lines. Cancer 6. Overgaard K, Overgaard J. Investigations on the possibility of a Res 1977;37:152-56. thermic tumor therapy: Shortwave treatment of transplanted isologous mouse mammary carcinoma. Europ J Cancer 1972;8:65-78. 19. Stehlin HS, Giovanella BC, Ipoiyi PD, et al. Results of hyperthermic perfusion for melanoma of the extremities. Surg Gynecol Obstet 7. Giovanella BC, Morgan AC, Stehlin JS, et al. Selective lethal effect of 1975,T40:339-48. supranormal temperatures on mouse sarcoma cells. Cancer Res 1973;33:2568-78. 20. Goldenberg DM, Langner M. Direct and abscopal antitumor action of local hyperthermia. Z Naturforsch 1971;266:359-61. 8. Mendecki J, Friendenthal E, Botstein C. Effects of microwave-induced local hyperthermia on mammary adenocarcinoma in C3H mice. 21. Shibata HR, Maclean LD. Blood flow to tumors. Prog Clin Cancer Cancer Res 1976;36:2113-14. 1966;2:33-47.

9. Pettigrew RT, Calf JM, Ludgate CM, et al. Clinical effects of whole 22. LeVeen HH, Wapnick S, Piccone V, et al. Tumor eradication by body hyperthermia in advanced malignancy. Br Med J 1974; radiofrequency therapy JAMA 1976;235:2198-2200. 4:679-82. 23. Storm FK, Harrison WH, Elliott RS, Morton DL. Hyperthermia in 10. Larkin JM, Edwards WS, Smith DE. Total body hyperthermia and cancer treatment: Normal tissue and solid tumor effects in animal preliminary results in human neoplasms. Surg Forum 1976;27:121-22. models and clinical trials. Cancer Res 1979;39:2245-51.

11. Gerweck LE, Gillette EL, Dewey WC. Killing of Chinese hamster cells 24. Storm FK, Harrison WH, Elliott RS, Hatzithelofilou C, Morton DL. in vitro by heating under hypoxic or aerobic conditions. Europ J Human hyperthermic therapy: Relationship between tumor type and Cancer 1974;10:691-93. capacity to induce hyperthermia by radiofrequency. Am J Surg 1979; 138:170-74. 12. Ben-Hur E, Elkin MM, Bronk BV. Thermally enhanced radio response of cultured Chinese hamster cells: Inhibition of repair, sublethal 25. Storm FK, Elliott RS, Harrison WH, Morton DL. damage, and enhancement of lethal damage. Radiat Res 1974; for human neoplasms: Thermal death time. Cancer (in press). 58:38-51. 26. Dickson JA, Shah SA, Waggott D, Whalley WB. Tumor eradication in 13. Connor WG, Gerner EW, Miller RC, Boone MLM. Prospects for the rabbit by radiofrequency heating. Cancer Res 1977;37:2162-69. hyperthermia in human cancer therapy, II. Presented at the RSNA Symposium on Hyperthermia, 1975 (in press).