Int. J. Radiation Oncology Biol. Phys., Vol. 6, pp. 867-870 Pergamon Press Ltd., 1980. Printed in the U.S.A.

036~3016/80/070867~)4502.00/0

Brief Communication
HYPERTHERMIA AND RADIATION IN COMBINATION: A CLINICAL FRACTIONATION REGIME IqAIM I. BICFtER, M.D., Ph.D., TALJIT S. SANDHU, Ph.D., F~,ED W. HETZEL, Ph.D.
Division of Radiation Biology and Physics, Department of Therapeutic Radiology, Henry Ford Hospital, Detroit, Michigan 48202. A fractionation regime has been devised and clinically tested to use a combination of hyperthermia and low dose radiation therapy to treat tumors with a curative intent. Hyperthermia is induced using microwaves delivered to a defined tissue volume through specially designed applicators. Frequencies of 2450, 915 or 300 MHz are used according to the desired penetration depth. Each treatment lasts for 90 minutes. The skin is cooled by an air jet. Tissue temperature is kept at 45C when hyperthermia alone is used and at 42C in combination with radiation. Patients are treated twice a week with 72 hour intervals between treatments. The regime consists of 4 treatments of hyperthermia alone followed by a week of rest. Thereafter each hyperthermia treatment is preceded by a 400 rad fraction of x-irradiation delivered in 4 combined treatments to a total of 1600 rad. This low total radiation dose allows retreatment of previously irradiated areas or organs. No toxicity induced by this combination has been detected, even in areas previously radiated to high doses. Twenty-three patients have been entered into the protocol that encompasses 37 treatment fields. Most tumors respond to treatment, many of these with total disappearance; skin, brain, breast and spinal cord are among the treated areas. Melanomas and lymphomas are the most sensitive tumors, sarcomas the most resistant; adeno and squamous cell carcinoma in between.
Hyperthermia, Fractionatlon, Radiation therapy.

INTRODUCTION For over one hundred years results have been reported indicating that heat can modify tumor growth. The pioneer effort of Busch3 in 1866 verified the disappearance of a sarcoma in the fact of hyperpyrexia during erysipelas. Bruns2 and Coley5 had similar observations in different types of tumors. The past decade has seen a renewed interest in hyperthermia; both in the laboratory and in the clinic. Several investigators have reported cure attempts using hyperthermia in different forms.~13 Doss and coworkers89~7 used radiofrequency heating in animal and human tumors with excellent results; a method that was also tested extensively by LeVeen et al.t4 Recently, Hornback et al.2 reported their experience with the use of microwaves. Suit and Schwayder18~9 have reviewed the literature of recent experiences in hyperthermia. Suit18 demonstrated experimentally that the tumor cure dose (TCDs0) values for thermally resistant tumors were significantly reduced, therefore advocating a combination of hyperthermia and radiation therapy. Since the oxygen enhancement ratio (OER) for hyperthermic
Presented in part at American Society of Therapeutic Radiologists, New Orleans, October 1979. Work supported in part by grant CA 25780-01 awarded by the National Cancer Institute, Department of Health, Educa867

damage may be close to one there is a good possibility that the combination of x-irradiation and hyperthermia will lead to a specific effect on the hypoxic cells in the tumors. Westra and Dewey2 also indicate that because the hyperthermic sensitivity of mammalian cells is greater in the S phase of the cell replication cycle, which is also the most resistant to x-irradiation, this could also lead to further enhancement of the therapeutic effect of the combined modalit~es. Dramatic changes in cell survival during hyperthermia have also been observed when the pH of the cells is only slightly altered.~ Crile6 combined heat with radiation in the treatment of cancer of the rectum. He surgically proved that this combination was effective in eradication of metastases. Crile7 also demonstrated the effectiveness of hyperthermia in a mouse sarcoma and the dependence of cure on the temperature achieved and the length of the treatment period. He also combined radiation and hyperthermia in the treatments of sarcoma in humans. ~ Cavaliere et al.415 documented the effect of heat on tumor cells and the sparing of normal tissue in rats. In clinical studies, regional perfusion with heated blood between 41-43C

tion, and Welfare. Reprint requests to: Haim I. Bicher, M.D., Ph.D. Accepted for publication 19 March 1980.

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was used in recurrent tumors of the extremities, especially melanomas. Only 7 of 22 patients failed to show a definite response to this treatment. In this article we report preliminary results of the use of a unique protocol designed to rationally combined hyperthermia and radiation treatment modalities in a clinical setting. This protocol has been des!gned to take advantage of known effects of hyperthermia either alone or in combination with ionizing radiation. The temperatures employed and sequencing are based on data obtained by many scientific and clinical investigators as well as recent results obtained in our laboratory.~4 6-9,~ ~5.~7 20,. Skin cooling was implemented to prevent normal tissue damage whenever possible. The number of fractions and the duration of each treatment was arbitrarily chosen, taking into account factors such as patient compliance, patient comfort and possible biological factors including thermotolerance, vascular response and repair. In addition, the total dose of radiation employed is sufficiently low to allow retreatment of previously irradiated fields. METHODS AND MATERIALS Protocol Localized hyperthermia is induced in all patients by microwave radiation employing direct contact applicators. The tumor size, location and depth determine the applicator size and microwave frequency (2450, 915 or 300 MHz) that are employed. Heat is initially applied to the tumor in four fractions of 1~/2 hour duration at intervals of 72 hours. The temperature is monitored to maintain the tumor temperature at 45C _+ 0.5C while the overlying, normal skin is simultaneously maintained with air cooling at or below 36C. Following these 4 fractions the patient rests for one week. Finally, four more fractions of hyperthermia are given; this time in combination with radiation. Each of these 4 treatments consists of a dose of 400 rad to the tumor immediately followed (<20 min.) by hyperthermia to a temperature of 42.0C _+ 0.5C. These fractions are again separated by 72 hours: as before, skin cooling is used when necessary to maintain a temperature of 36C or lower at the surface. Table 1 is a schematic of this protocol. The nature of the procedure was explained to each patient and informed consent was obtained prior to any treatment. Equipment The microwave generator employed in these studies has a variable frequency plug in module for 200-3000 MHz with 100 W contim~pus wave (CW) power output. ,~,he ,direct contact applic~t-~rs have been designed and built in this department]6 ~Briefly, they are square or rectangular cross-section
*Unpublished results--Manuscript entitled: Effect of hyperthermia on tissue microenvironment: Normal and tumor.

Table 1. Proposed "curative" fractionation: Hyperthermia + radiation therapy 1. Hyperthermia only--4 Treatments 45C--90 Minutes, (skin 36C or below) treat every 72 hours 2. Rest 1 Week evaluate response to heat alone Radiation therapy and hyperthermia-4 Treatments--42C--90 minutes Heat follows radiation (20 minute interval) RT: 400 rad fractions--Each treatment Total--8 Hyperthermia treatments + 1600 rads/2 weeks/4 fractions

waveguides excited in the transverse electric TEl0 mode.16 Depending upon applicator size and the frequency to be employed the waveguides are either air-loaded or loaded with low loss dielectric materials (~=6.0). Thermometry is accomplished with both microthermistors and 30 guage thermocouples. Two thermistors are used on the surface of the patient, one at the center of the heat field and one over peripheral normal tissue. One or two thermocouples are also inserted depending upon the size and location of the tumor. In every case at least one 30 guage thermocoupie is inserted at the greatest depth of the tumor attempting to maintain it at right angles to the short axis of the antenna. This helps to reduce interference. A sequencer is employed to cycle the power; this allows for regular temperature readouts free of interference. All data is recorded simultaneously on a multichannel recorder. RESULTS At this time twenty-three patients have been treated with a total of 37 fields; Tables 2 and 3 summarize our results. A total response is observed in 23 treatment fields and a partial response in 14. No response was observed in only one patient who was available for follow-up, this was one of only two sarcomas. The only complications that were directly attributable to treatment were 2 skin burns, as a result of inadequate surface cooling, which healed completely. One patient with a history of epilepsy experienced a grand mal seizure during treatment of a neck tumor. Two marginal and one local recurrences have been noted, all are currently being retreated. Several other observations made during or following treatment are noteworthy. It has been possible to obtain actual thermometry for every treatment of every field (a total of 296 treatments) with minimum patient discomfort. It must be emphasized, however, that great care must be used during the initial planning and set up for the patient to achieve this goal. In almost all patients treated, it has been noted that
Submitted to Radiology.

Hyperthermia fractionation regime H. I. BICHER et al.

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Table 2. Results 37 Fields treated Total response Partial response No response Recurrence Complications 25 11 (9 less than 2 month follow-up) 1 Local Marginal Skin burns Grand seizure 23 Patients

Table 3. Results by histology

No. of fields Follow up (months)

Response

1 2 2 (completely healed) 1 (Neck treatment) (epileptic patient)

Malignant melanoma Malignant lymphoma Squamous cell CA

Adenocarcinoma

4 5 6 17 2 1 2

3 Total 1 Partial 5 Total 3 Total 3 Partial 12 Total 5 Partial 1 Partial-expired 1 No response ! Partial 2 Total

2 2 3-6 2 2-5 -4 2-4

Sarcoma Glioma Other (basal cell, transitional cell)

the microwave power required to maintain the desired treatment temperature declines following the first or second treatment of a given field. Finally, it appears that tumor regression following completion of treatment is very slow and requires approximately two months before the total effect is obtained. DISCUSSION Although it is still very early in this study and long term follow-up is not available yet, it is clear this treatment regime does produce striking results in a wide variety of cases. If only those fields which were treated completely and available for follow-up are considered, we can report 67.6% total response, 29.7% partial response and only 2.7% no response. In only one patient has a local recurrence been noted; possibly as a result of misalligned thermocouples that resulted in artifactual temperature readouts. The patient is currently being retreated. The observations on power required to maintain a constant temperature and on tumor regression time are

Total response: no tumor present at 2 months follow-up and thereafter. Partial response: Tumor decreased in size to half or less at 2 months follow-up. Partial response--Expired: Patient deceased during or within 8 weeks after treatment.

both quite interesting. Based on recent laboratory results, it is likely that both phenomena are related to heat induced, physiological changes within the tumor which are involved in the ultimate destruction of the tumor. Further physiological studies are currently in progress. It is also interesting to speculate on the possible meaning of the two marginal recurrences; they may indicate that this combined modality protocol is effective in the treatment of microscopic disease. More time for followup and the input of more patients will be required before a true evaluation of the clinical efficacy of this protocol can be made.

REFERENCES 1. Brenner, H.J., Yerushalmi, A.: Combined local hypertherhyperthermia of spontaneous malignant neoplasms of mia and x-irradiation in the treatment of metastatic animals. A preclinical study, presented at the American tumors. Br. J. Cancer 33: 91-95, 1975. Society of Therapeutic Radiologists, 18th Annual Meet2. Bruns, P.: Die heilwirung des erysipels auf geschwulste. ing. Atlanta, Georgia, Oct., 16, 1976. Beitr. Klin. Chir. 3: 443-466, 1887. 9. Doss, J.D., McCabe, C.W.: A technique for localized 3. Busch, W.: Uber den Einfluss welchen heftigere Erysipeln heating in tissue, an adjunct to tumor therapy. Med. Instr. zuweilen auf organistierte Neubildungen ausueben. Ver10: 133-136, 1975. handl. Naturh. Preuss. Thein. Westpahl. 23: 28-30, 1866. 10. Gerweck, L.E.: Modification of cell lethality at elevated 4. Cavaliere, R., Ciocatto, E.C., Giovanella, B.C., Heideltemperatures. The pH effect. Radiat. Res. 70: 224-235, berger, C., Johnson, R.O., Margottini, M., Mondovi, B., 1977. Moricca, G., Rossi-Fanelli, A.: Selective heat sensitivity for 11. Hartman, J.T., Crile, G.C., Jr.: Heat treatment of osteocancer cells. Cancer Philad. 20: 1351-1381, 1967. genic sarcoma, Report of five cases. Clin. Orth. Rel. Res. 5. Coley, W.B.: The treatment of malignant tumors by 61: 269-276, 1968. repeated inoculations of erispelas with a report of original 12. Hornback, N.B., Shupe, R,E~, Homayoon, S., Joe, B.T., Edgardo, S., Marshall, C.~ ~~liminary clinical results of cases. Am. J. Med. Sci. 105:487 512, 1893. 6. Crile, G. Jr.: Heat as an adjunct to the treatment of cancer. combined433 megahertz r~iizrowave therapy and radiation therapy on patients with advanced cancer. Cancet~.~40: Cleveland Clin. 28: 75-89, 1961. 7. Crile, G.J.: The effect of heat and radiation on cancers 2854-2863, 1977. implanted on the feet of mice. Cancer Res. 23: 372-380, i3. Johnson, R.J.R., Sandhu, T.S., Hetzel, F.W., Kowal, H.S., 1963. Bicher, H.I., Song, S.: A pilot study to investigate the 8. Day, P.W., Sternhagen, C.J., Doss, J.D., Edwards, S.: therapeutic ratio of hyperthermia 41.5-42.0C and radiaCombination radiation therapy and localized current field tion. Int. J. Radiat. Oncol. Biol. Phys. 5:947 954, 1979.

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14. Leveen, H.H., Wapnick, S., Piccone, V., Fald, G., Ahmed, N.: Tumor eradication by radiofrequency therapy. JAMA 235: 2198-2200, 1976. 15. Moricca, G., Cavaliere, R., Caputo, A., Bigotti, A., Colistro, F: Hyperthermic treatment of tumors: Experimental and clinical applications. Rec. Res. Cancer Res. 59:112152, 1977. 16. Sandhu, T.S., Kowal, H., Johnson, R.J.: The development of microwave hyperthermia applicators. Int. J. Radiat. Onc. Biol. Phys. 4: 515-519, 1978. 17. Sternhagen, C.J., Doss, J.D., Day, P.W., Edwards, W.S., Doberneck, R.C., Herzon, F.S., Powell, T.D., OBrien, G.F., Larkin, J.J.: Clinical use of radiofrequency current in

oral cavity carcinomas and metastatic malignancies with continuous temperature control and monitoring. In Proc. of Second Annual Int. Symp. on Can. Thera. by Hyperthermia and Rad., C. Streffer (Ed.) Baltimore-Munich, Urban & Schwarzenberg Inc. 1978, pp. 331-334. 18. Suit, H.D.: Hyperthermic effects on animal tissues. Radiology 123: 483-487, 1977. 19. Suit, H.D., Shwayder, M.: Hyperthermia: Potential as an anti-tumor agent. Cancer 34:122-129, 1974. 20. Westra, A., Dewey, W.C.: Variation in sensitivity to heat shock during the cell cycle of chinese hamster cells in vitro. Int. J. Radiat. Biol. 19: 467-477, 1971.