1111.J. Radiation Oncology Bid. Phys. Vol. 4, pp. l@S-I103 @ Pergamon Press Inc.. 1978. Printed in the U.S.A.

0

Technical

Innovation

and Note

MICROWAVE-INDUCED HYPERTHERMIA IN CANCER TREATMENT: APPARATUS AND PRELIMINARY RESULTS JOZEF MENDECKI, Ph.D., ESTHER FRIEDENTHAL,M.D. and CHARLES BOTSTEIN, M.D. Department

of Radiotherapy,

Montefiore

Hospital and Medical Center. Bronx. NY 10467. U.S.A.

and FRED STERZER, Ph.D., ROBERT PAGLIONE, M.S.E.E.,S MARKUS NOWOGRODZKI, M.E.E.S and ELVIRA BECK Microwave

Technology

Center. RCA Laboratories.

Princeton.

NJ 08540. U.S.A.

Apparatms for the controfled local heating of cutaneous and s&cutaneous tumors is described. This apparatus, rbkb uses mkrowsve radiatfon in tbe freqaency 915 MHz or 2450MHz, can raise the temperature of such tumors to tbe byprrtbermic range (42.5-43”C), i.e. tbe temperature range wbicb appears to be optimum for tbe Wabnent of maf@%ant tumors. EncouroSing results have been obtaked w+tbtbfs apparatus in treatbq,j maf@ancies in laboratory animafs and in man. Compkte eredicstion oftrpnspdonted-pdmoin the carcinoma was acidevcd in C3H mice. In severaf cfinkal cases, byperWrm ia appeared to he Wciaf treatment of hasaf.cefl carcinoma, malignant mefanoma, and skin meka&~~ of car&noms of tbe breast.

Microwave-induced beating, Localized hyperthermia.

INTRODUCTION Observations regarding malignant following exposure to elevated

tumor

regression

temperatures date back many decades. However, more rigorous research into the effects of induced hyperthermia as a modality of cancer treatment has been undertaken only recently. There is evidence that at least some types’ of malignancies respond to heat treatment as either a stand-alone therap$.“.“.‘” or in conjunction with radiation or chemotherapy.‘~‘.7~‘0 This response appears to be predicated on the higher thermosensitivity of neoplastic cells compared with normal cells.’ To achieve this selective destruction, the treatment temperature must be closely controlled to the range of about 42.5-43”C.4Y’3*‘6No therapeutic effects are observed at temperatures below this range, while significant damage to normal cells can occur at temperatures above this range. A number of approaches intended to produce whole body, regional or localized hyperthermia have been used in various trials. They comprise studies of tMSEE = Master of Science in Electrical Engineering. SMEE = Master of Electrical Engineering. Reprint requests to: J. Mendecki. Montefiore Hospital

spontaneous or induced tumors in experimental aniand in clinical settings.9.‘1,‘7~‘s Methods for inducing local hyperthermia include microwaves, radiofrequency, and ultrasound. This our experiences relates report with localized, controlled hyperthermia induced by means of microwaves. Unlike infrared radiation, micro-wave radiation can penetrate into lossy dielectrics such as living tissue and is therefore useful in the heating of tumor volumes. The experiments described demonstrate results obtained with apparatus that is specially developed for applications of our approach to the treatment of transplanted tumors in laboratory animals”.4.‘3 and in clinical settings.99”*‘7.‘8 mals3.4.‘3

METHODS

AND MATERIALS

Heating by microwaoes Electromagnetic radiation 10,000 MHz can penetrate

with

frequencies

below

significant distances into living tissues, and therefore can be used to induce heat in living organisms. The depth to which such and Medical Center, Bronx, NY 10467. U.S.A. Accepted for publication 32 March 1978.

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Radiation Oncology 0 Biology 0 Physics

November-December

radiation penetrates tissues is a function of the frequency of radiation, and of the properties of the tissues. In general, the lower the frequency, the greater the depth of penetration. However, the penetration into tissues at a given frequency is greater in tissues with lower water content (fat, bone, etc.) than in tissues with high water content (muscle, skin, etc.). In our experiments, we have used two frequency bands in the microwave range, namely 2450 + 50 MHz and 915 f 13 MHz. These two frequency bands are assigned by the Federal Communications Commission for industrial, scientific and medical use. With frequencies in these two bands one can obtain moderately deep penetration into tissues; at the same time precise, localized heating, can be achieved with applicators of convenient size. If depth of penetration (d) is defined as the depth where heating is reduced to 37% of the surface heating, then at 2450MHz d = 1.7 cm for muscle and d = 11.2 cm for fat. The corresponding values at 915 MHz are 3 cm for muscle and 17.7 cm for fat.’ The power density required to raise living tissue to a temperature of about 43°C was found experimentally to be approximately l-2 W/cm* of surface area upon which the wave impinges. Thus, depending on the particular experiment, powers ranging from a few to hundreds of watts may be required. Special transistorized portable generators were constructed for the lower power applications; commercially available generators using electron tubes were used when higher power levels were required.

1978. Vol. 4, No. 11 and No. 12

plicators l-3 are electrically matched to muscle tissue, i.e. they are designed to minimize the reflections of microwave energy from the interface between the applicator and muscle when the applicator is pressed against muscle. Typically more than 85% of the microwave energy entering these applicators can be transmitted into muscle. Applicators 4-7 must be matched with a separate coaxial tuner. This is done by pressing the applicator against the tumor to be treated and then adjusting the tuning elements of the tuner until the power reflected from the tumor is a minimum (reflected power is monitored by measuring the rectified current in a crystal detector that is attached to a directional coupler). Applicators l-3 are waveguides filled with solid dielectrics (see Fig. 1). These applicators are intended for treating small cutaneous or subcutaneous tumors. Applicator 4 is an air-filled wave-guide unit that can accommodate tumors protruding above the skin. Applicator 5 is useful for heating relatively large cutaneous or subcutaneous tumors. This applicator conforms closely to tumor and body contours. Applicators 6 and 7 use a coaxial geometry. This type of applicator consists of a coaxial cable terminating in a radiating antenna (Fig. 2a). It can induce heating within a spherical volume and is therefore particularly suitable for insertion into a body cavity, such as the bladder, esophagus, rectum. etc. possibly via a catheter. To obtain directive heating, a metallic reflector can be used opposite the area to be treated (Fig. 2b). Temperature

control equipment

In our experiments temperature measurements were carried out by using copper-constantan thermocouples. These devices do not affect the heating

Applicators Table 1 lists the various types of experimental applicators and indicates their principal use. Ap-

Table 1. Approximate Frequency

(MHz)

Type

working area

(mm)

1. Dielectric-filled

waveguide

2450

8x 12

2. Dielectric-filled

waveguide

915

10x22

3. Dielectric-filled

waveguide

915

35 x 35

4. Air-filled waveguide

2450

30x70

5. Conformal

2450

63x 114

applicators

6. Coaxial probes (various diameters)

24501915

not applicable

7. Coaxial probes (various) diameters)

245019 I5

not applicable

Primary use Cutaneous and subcutaneous tumors Cutaneous and subcutaneous tumors Cutaneous and subcutaneous tumors Cutaneous and subcutaneous tumors raised above skin Cutaneous and subcutaneous tumors Symmetrical heating, body cavities or interstitial use Directive reflector inside body cavities

Comments Pre-matched to muscle tissue Pre-matched to muscle tissue Pre-matched to muscle tissue Requires external matching network Requires matching Requires matching

external network external network

Requires external matching network

Microwave-induced

Fig.

1. Applicator

1097

hyperthermia in cancer treatment 0 J. MENDECKI et al.

for operation

at 2450 MHz

CENTER CONDUCTOR

(prematched

for muscle tissue).

CENTER CONDUCTOR

REFLECTOR

4 DIELECTRIC SHIELD

(b) (a) Fig. 2. Sketches of coaxial applicators: (a) multi-directional; (b) with directive reflector. pattern if placed perpendicular to the electric field created by the microwave radiation. At the frequencies used by us, thermocouples constructed of the thinnest possible wires are less subject to error resulting from stray pickup. At 915 MHz, readings were erratic and the microwave signal had to be interrupted when temperature readings were taken. The temperature control circuit described elsewhere” has been deveioped to overcome the above measurement problems and to provide accurate temperature control over extended periods (typical treatments may last about 1 hr at a time).

Multi-applicator It is possible

systems

to combine the heating effects of several applicators in order to achieve either more uniform heating or predetermined heating patterns within larger tumors. Preliminary experiments have been performed with same arrangements. Figure 3 presents a power-splitting and control unit using miniaturized microwave integrated circuit (MIC) technology and incorporating special microwave switching diode in every channel (developed by Dr. Martin Caulton, RCA Laboratories). This system permits automatic control of the heating provided by

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Radiation Oncology 0 Biology ?? Physics

1978. Vol. 4, No. 11and No. I?

November-December

RESULTS

OUTPUTS

/4

Applicator

PIN - DIODES

LANGE ? COUPLERS CERMET RESISTORS

1

INPUT

Fig. 3. Four-way power splitter and switch system using microwave integrated circuit technology (50 W, 2450 MHz).

each individual applicator, making it possible to maintain a particular heating pattern across the irradiated area. The multi-applicator system also can provide an intersecting pattern of heat, analogous to the “focusing” schemes used with ionizing radiation. In this case, the applicators are placed at an angle to one another at strategic points on the irradiated volume, resulting in crossing of the electromagnetic beams and maximum temperature rise at the desired focus. (The details are described in “Results” and illustrated in Fig. 8.) 43 F

performance

A number of experiments have been performed with various applicators in order to determine the power required to raise the temperature of the irradiated volume to the desired threshold of approximately 42.K and then to maintain it at this level. In general, a power density of about 1 W/cm’ of tumor surface area was necessary to operate the applicators effectively. For example, Fig. 4 illustrates the results of an experiment in which the pre-matched wave-guide applicator I was placed on the abdomen of an anesthetized mouse. approximately 0.5 cm above the rectum, where a thermocouple was inserted as a convenient means of measuring temperature rise at a fixed distance from the applicator while using different input powers. The rectal temperature of an anesthetized mouse ranges from 33 to 34°C. When 1.5 W/cm’ and a frequency of 2450 MHz were used, a temperature of 42°C was reached in 60 set, while 0.8 W/cm’ produced a rise only to 37°C without further increase, and 0.5 W/cm’ resulted in hardly any heating. A similar curve was obtained at 915 MHz with applicator 2. In another experiment. mammary adenocarcinoma approximately 6 mm in diameter in C3H mice was heated using applicator I;” a tumor surface temperature of 43°C was reached in about 90 seconds using 1.15 W of input power. The temperature in the center of the tumor was about 02°C higher. The heating effect of a non-directive coaxial applicator (Fig. la) is shown in Fig. 5: it traces the temperature rise in a mouse mammary adenocarcinema about 20 mm in diameter. The coaxial ap-

/* 2 45 GHZ

41 I5 WTS/etn* 40 39 i

if

/

i

1 0

0 8 WATTS /cm* _/

1

,

15 30 45

tectal temperature

,

,

60

,

,

,

,

(

,

,

1

,

,

,

75 90 105 I20 135 150 165 I80 195 210 225 24C TIME(SECONDS 1

of mouse during local hyperthermia (Applicator 1.)

Microwave-induced

47

I

hyperthermia

I

I

in cancer

II

I

I

46-

11

I

POWER

45_

2450

Mttz

-

1.25

??J.

treatment

WATTS

MFNIECKI

II

1099

et ~1.

1

I

OFF f

/I

4443-

G e kk w I-

’ 1

.

4; 40-

.

39.

/

/

37 ““I

/

, 34b

’ 30

0

’ 60

’ 90

’ 120

’ 150

’ 180

’ 210 TIME

Fig.

5. Temperature

inside

r

.

\

. \

. \

‘\;,

’ 300

’ 330

’ 360

’ 390

’ 420

. 450

(seconds)

mammary adenocarcinoma (approx. 20mm) applicator was used in experiment).

in

C3H mouse (omni-directional

cube of animal tissue, and the applicator was positioned to direct most of the heating at point lsimulating the heating of a tumor at this point. As Fig. 6 shows. selective heating is indeed obtained at point 1: a temperature of 43°C could be reached in about 3 min with an input power of 25 W, and could be maintained with 4 W of power. The other points remained at moderate temperatures. To measure heat distribution from a coaxial applicator in vascularized tissue, an inflated rubber sphere with a coaxial probe placed at its center was inserted through a midline incision into the abdominal cavity of a live. anesthetized rat whose intestines had been removed. The right half of the abdominal wall was folded backward, increasing its thickness for

plicator was inserted into the center of the tumor and energized with 1.25 W of input power. For this measurement, the applicator was matched with an external double-slug tuner and the thermocouple was placed within the tumor, approximately 3 mm from the applicator antenna-l4 Temperature rose gradually and reached 45°C within 4.5 min. With the power disconnected, it fell quickly to the initial level. Figure 6 presents the performance of a coaxial applicator equipped with a directive reflector (Fig. 2b). The body cavity was simulated by placing equal volume5 (1.5 cm’) of animal muscle symmetrically at four equidistant points 3 cm from the applicator antenna. within a Styrofoam cylindrical container.14 Thermocouples were inserted into the center of each

$ ” D

’ 240

I I i I I I I I I I I I I I I (1 270

\

i 35-

3.

f

_

/x-‘c-cc--z

;;~~y~+----

4

lip/-

m-3

& 25l

2

4

6

A CENTER B DIELECTRIC

CONDUCTOR SLEEVE

C REFLECTOR

E

IO

12

14

16

I8

20

MIN

Fig. 6. Temperature vs time, 3 cm from point of application of different values of microwave power.

Radiation Oncology ??Biology ??Physics

1100

November-December 1978, Vol. 4, No. 11 and No. 12

30

I

2

4

6

8

IO MIN

12

14

16

18

20

Fig. 7. Heating of abdominal wail of a rat by means of multi-directional coaxial applicator placed at center of abdominal cavity. the purpose of studying heat penetration. Thermocouples were placed at various points in the abdominal wall, as indicated in the inset of Fig. 7. The abdominal wall was reattached and the abdominal skin was sutured. Figure 7 shows the temperature measurements when the coaxial applicator within the cavity was energized. The animal’s oral temperature, shown for

reference, remained unchanged at 32°C throughout the experiment. A temperature of 42°C was reached within 3 min and could be maintained easily. The temperature within the inner aspect of the wall was somewhat higher than that of the skin surface, but lower than the temperature within the fold of the abdominal muscle. These differences possibly could be related to heat losses at the muscle-air interfaces or to compromised circulation within the fold. With a view toward possible use of coaxial applicators as interstitial implants, heat distribution was 44

A-RECTAL

43

41

2450

MHZ

40

UNDER SKIN

;;p.

CY

0

A

Fig. 8(a). Sketch of “intersecting mouse.

beam” experiment,

C3H

, , , , , / , , , , , , , , 60 I20160 240300360420 SECONDS

Fig. 8(b). Heating

effect of “intersecting

beam”

arrange-

Microwave-induced

hyperthermia

in cancer

measured by implanting a 0.8 mm thick coaxial applicator into the thigh of a live rat. Thermocouples were placed at three points: at the level of the applicator antenna, and at points 5 mm and 10 mm from the applicator within the muscle mass. The temperature rose to 43°C at the site of the applicator within 5 min (2.5 W) while the other thermocouples registered about 1°C less for each 5 mm of distance.” In a multi-beam experiment, two waveguide applicators 1 were placed on the abdomen of a mouse and directed toward the rectal region (see Fig. 8a). Temperatures were monitored in the rectum as well as on the surface under one of the applicators. When 0.5 W of power was applied to each of the applicators, the rectal temperature could be raised to 43’C, while the temperature within a single applicator “beam” remained at about 37°C (Fig. 8b). Clinical results In the original experiment using an applicator as shown in Fig. 1, mammary adenocarcinoma was induced in 72 C3H mice; 54 received 4 hyperthermia treatments localized to the tumor site (43”C, 45 min. every other day). while 18 served as controls. Complete eradication of tumors was achieved in all the treated animals and they showed no evidence of tumor recurrence over an observation period of 4 months, while all 18 controls died within 4 weeks post-inoculation.” This experiment served as the pilot for further studied, still in progress, and also defined the preliminary treatment regimens for subsequent initial clinical evaluation, four examples of which are described. Patient 1. A 66 year old woman presented with basal cell carcinoma of the left posterior neck, approximately 6 cm in diameter. The lesion was divided into two parts: one, about 1.5 cm in diameter, was exposed to hyperthermia (43°C. 45 min) using the applicator of Fig. 1, immediately followed by a dose of 3OOrad; the remainder of the lesion was treated

treatment

0 J. MENDECKI et al.

1101

with the same dose of radiotherapy alone. Both parts were treated three times weekly. The section treated with combined therapy showed complete resolution following six treatments (1800 rad), while the area subjected to radiotherapy alone required 12 sessions (6000 rad) to achieve tumor eradication. No recurrence was observed at 6 month follow-up visit. This is illustrated in Fig. 9. Patient 2. A male, age 67, with disseminated malignant melanoma of the skin, confirmed by biopsy, received radiation and/or thermotherapy to three separate lesions approximately 1.5 cm in diameter each, located on the left thigh. One lesion received hyperthermia alone (42.5”C. 45 min, induced by the applicator shown in Fig. 1 at 2450 MHz): the second lesion received the same thermal treatment followed by IOOOrad; and the third was treated with radiotherapy alone (1000 rad). Weekly treatments were administered. After five treatments the lesions treated with hyperthermia (either with or without radiotherapy) disappeared while the lesion treated with X-rays alone showed no apparent change. Treatments were discontinued after five sessions (total of 5OOOrad). On a follow-up visit 2 weeks later, the heat-treated area had the appearance of normal skin in respect to color and consistency, the lesion treated with heat plus radiation also subsided, leaving a depigmented area, while the third lesion, treated only with radiotherapy. showed considerable reduction in size. Two months post treatment, the third lesion also disappeared completely. Since melanoma lesions in this patient had proved resistant to radiotherapy on previous occasions and the heat treatment was at a site different from that treated with X-ray alone, the experiment not only appears to indicate the effectiveness of heat treatment (with or without Xrays). but it also suggests confirmation of findings by other investigators [ 181 on stimulation of immune responses resulting from thermic destruction of cancer cells. Patient 3. A 58-year-old woman had three lesions

Fig. 9. Effect of microwave heating on basal cell carcinoma: (a) before treatment;

(b) after six treatments.

1102

Radiation Oncology ??Biology 0 Physics

of metastatic breast cancer located on the chest wall approx. 2 cm in diameter treated with three different regimens: six weekly sessions of (I) Xradiation; (2) hyperthermia (43% 45 min): and (3) a combination of X-rays followed by hyperthermia, both as above. The lesions treated with heat alone and with heat plus radiation showed a visibly accelerated regression. Patient 4. Local recurrence developed in a 78 year old man 2 years following radical mastectomy for adenocarcinoma of the breast; it consisted of two nodules 1.5 X 1.5 cm and 0.7 x 0.8 cm. A course of 4300 rad with MCo to the involved area resulted in minimal decrease in the size of the nodules. One month later the entire area was treated with a total of 2000rad; only the larger nodule was subjected to microwave-induced hyperthermia (43°C x 60 min, four treatments, 2450 MHz) immediately prior to radiotherapy. On a follow-up visit 4 weeks later, the larger nodule had disappeared, leaving only a scab. The smaller nodule (which had received radiotherapy only) was reduced to one-half the. original size. Subsequently the patient moved away and was lost from follow-up. These preliminary encouraging results are presented in supportive evidence to reports from other centers on the effective use of hyperthermia in treatment of human neoplasms, especially in conjunction with ionizing radiation. A large scale evaluation of this treatment modality appears indicated. The variety of applicator designs at our disposal has permitted us to plan therapeutic programs for a number of superficial and deep seated tumors. These programs are presently being evaluated.

DISCUSSION Hyperthermia emerges as a potential therapeutic tool in the treatment of at least some malignancies, and microwave radiation appears to be a safe and relatively simple means of inducing localized and controllable heating of tumors. The availability of reliable and precisely controllable instruments for experimentation as well as treatment is essential to future efforts in this field.

November-December

1978, Vol. 4, No. 11 and No. 12

Thermotherapy has important advantages in the treatment of tumors. Among these. the most important are (a) the relative safety of this method compared with other treatment modalities (b) the selectively destructive effect of heat above the threshold level of about 42.5”C on malignant tissue compared to normal tissues; (c) the sensitizing effect of heat when it is used in conjunction with radiotherapy, leading to reduced radiation doses and increased therapeutic ratio; (d) the possible stimulation of immune processes by hyperthermia leading to increased host defenses against tumor growth.‘.” Possible additive and/or sensitizing effects of hyperthermia when it is used in conjunction with chemotherapy provide other potential advantages of this method of treatment.‘* Much clinical work remains to be done to optimize the therapeutic regimens, determine the possible extent to which concomitant ionizing-radiation treatments can be reduced, and catalog the responses of different tumors to the heat therapy. The microwave frequency and the applicator geometry must be chosen carefully for a specific experiment or clinical treatment. The use of electrically matched microwave systems permits control of the heat penetration by proper choice of frequency. Preliminary multi-beam arrangements have been demonstrated by which tissue within the body can be heated to elevated temperatures without heating the organs in the paths of the individual beams, although special precautions (such as specific phasing of the various signals) must be taken to prevent the formation of hot spots within the treated volume. Multiapplicator systems employed in conjunction with precontrol circuits permit the cise temperature achievement of predetermined heat-distribution patterns throughout the tumor mass. Finally, the coaxial applicator, on the basis of heat mapping experiments in both simulated body-cavity geometries and in uivo animal measurements, appears to have an important potential for the treatment of tumors contained in body cavities. The demonstration of directive heating using this type of applicator makes it particularly useful for clinical treatment of human malignancies.

REFERENCES Cavaliere. R.. Ciocatto, Giovanella, B.D., Meidelberger, versus primary tumor hyperthermia C., Johnson, R.O., Margottinim, M., Mondovi. B., Moricca. G., Rossi-Fanelli. A.R.: Selective heat sensitivity of cancer cells. Cancer 20: 1351-1381. 1967. Crile. G. Jr.: The effects of heat and radiation on cancers implanted on the feet of mice. Cancer Res. 23: 372-380. 1%3. Dickson, J.A., Shah, S.A., Waggott, D., Whalley, W.B.: Tumor eradication in the rabbit by radio-frequency heating. Cancer Res. 37: 2162-2169, 1977. Dickson, J.A., Mu&e, D.S.: Total body hyperthermia

in the treatment of the rabbit VC-2 carcinoma. Cancer Res. 32: 19161923. 1972. 5 Dietzel, _. F.: Tumor und Temperatur. Urban & Schwarzenberg, Munchen-Berlin-Wien. 1975. 101-I 10. 6. Friedenthal, E., Mendecki, M., Botstein, C.: Induction of hyperthermia in deep seated tumors by a special microwave applicator. Proc. 2nd Znt. Symp. Cancer Therapy by Hyperthemria and Radiation, Essen, Germany, 24 June 1977 in print. 7. Gerner, E.W., Connor. W.G.. Boone, M.L.M.. Doss,

Microwave-induced

hyperthermia

J.O., Mager E.G., Miller, R.C.: The potential of localized heating as an adjunct to radiation therapy. Radiobiology 116: 433439. 1974. 8. Goldenberg, D.M.. Langer, M.: Direct and abscopal anti-tumor action of local hyperthermia. 2. Nuturforschung. 26B: 359-361, 1971. 9. Johnson, C.C.. Guy, A.W.: Nonionizing electromagnetic wave effects in biological materials and systems.

in cancer

14.

15.

Proc. IEEE 60: 692-718. 1977. IO. Leith. J.T., Miller R.C., Gerner,

E.W.. Boone, M.L.M.: Hyperthermia potentiation: biological aspects and applications to radiation therapy. Cancer 39: 766-779. 1977. 11. LeVeen. H.H., Wapnick, S., Piccone, V.. Falk. B.. by radiofrequency Ahmed. N.: Tumor eradication therapy. J. Am. Med. Assoc. 235: 2198-2200 1976. 12. Marmor, J.B., Hahn, N., Hahn, G.M.: Tumor cure and cell survival after localized radiofrequency heating. Cancer Res. 37: 879-883. 1977. 13. Mendecki, J.. Friedenthal, E.. Botstein, C.: Effects of microwave induced local hyperthermia on mammary

16.

17.

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in C3H mice. Cancer Res. 36: 2113adenocarcinoma 2114, 1976. Mendecki, J., Friedenthal, E., Botstein, C., Sterzer, F., Paglione, R., Nowogrodzki. M., Beck, E.: Microwave applicators for localized hyperthermia treatment of malignant tumors. J. Bio-engng 1: 51 l-S18 1978. Mondovi. B.. Santoro, AS., Strom, R.. Faiola, R.. Fanelli, A.R.: Increased immunogenicity of Ehrlich ascites cells after heat treatment. Cancer 30: 885-888. 1974. Overgaard, K.. Overgaard, J.: Investigations on the possibility of a thermic tumor therapy-I. Shortwave treatment of a transplanted isologous mouse mammary carcinoma. Europ. J. Cancer 8: 65-78, 1972. Pettigrew, R.T.: Cancer therapy by whole body heating.

Pror. lnt. Symp. Cancer Therapy by Hyperthermia and Radiation. Washington, D.C.. 28-30 April 1975, pp.

282-288. 18. Stehlin, J.S., Giovanella, B.C., de Ipolyi, P.D., Muenz, L.R., Anderson, R.T.: Results of hyperthermic perfusion of melanoma of the extremities. Surg.. Gpnecol. & Ohstet. 140: 3X3-348, 1975.