0103_HYPERTHERMIA IN RADIATION ONCOLOGY - 04.pdf

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PROCEEDINGS OF THE IsT MEETINGOF EUROPEAN GROUP OF

H Y P E R T H E R M IIN R D I T ION ON CO LOG YEdited byG. ARCANGELI and F. MAURO

Cam bridge 9- 10 September 1979

PHYSIOLOGICAL MECHANISMS OF LOCALIZEDMICROWAVE HYPERTHERMIAH. I. BICHER, P. W. VAUPEL

ABSTRACT

MASSON


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PHYSIOLOGICAL MECHANISMS OF LOCALIZEDMICROWAVE HYPERTHERMIAH. I. BICHER, P. W. VAUPE~ *)

SUMMARYTumor tissue responses to microwave induced hyperthermia is determi-ned using oxygen and Ph microeletctrodes as well as a hydrogen clearancetechnique to measure blood flow in microareas oJ tumors. Localized microwavehyperthermia causes an improvement in tumor oxygenation and a rise in localblood flow at temperatures up to 40-4I C, When heating is carried out up tohigher temperatures a distinct drop of the tissue oxygen tension and oJ micro-[low becomes obvious. Tissue pH is low and it decreases markedly duringhyperthermia. The mechanisms oJ these effects seem to be predominantly me-d, iated through the blood flow changes with temperature.

The renewed interest in hyperthermic treatment of tumors- either aloneor in combination with irradiation or chemotherapeutic agents- has its back-ground in old observations that moderate and tolerable levels of hyperthermiawhen applied locally to malignant tumors have been shown in many instancesto cause regression of the tumors. In some cases the regression has been per-manent and com plete.From earlier experiments there are conclusions that the response of thetumor cells to artificially induced high tissue temperatures are dependent to alarge extent upon the in vivo metabolic environment of the cells, i.e., oxyge-nation and tissue pH values. The microenviroment of the cancer cells againis mostly determined by the efficiency of blood flow through solid tumors. The-refore, the effect of temperature on blood flow through the tumor tissue is ofconsiderable importance.With a view to further understand the mechanisms of action of localizeahyperthermia we undertook to evaluate the ~ physiological ~ responses of tumo-rous tissues using microtechniques to measure tissue oxygen tensions, pH valuesand blood flow in microareas of the tissue.

(*) Henry Ford Hospital, Department of Therapeutic Radiology, Radiation Biologyand Physics Division, Detroit, Michigan 48202, USA.Investigations supported by grants awarded by: National Cancer Institute CA25780-01-- Haim I. Bicher Deutsche Forschungsgemeinschaft Va 57/1 -- Peter W. Vaupel.


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96 Bicher H. I., Vaupel P. W. aterials and methods

The measurements were performed in C3H mouse mammary adenocarci-noma 10-20 days after implantation of tumor cells into the hind leg. The ani-mals were anaetshetized with chlorpromazine- HC1 (50 mg/kg i.m.) and keta-mine- HC1 (40 mg/kg i.m.). Another series of experiments was conducted on15 patients with subcutaneous metatases of squamous cell carcinomas, adeno-carcinomas and melanomas.a) Measurem ent of t issue p02 ~alues using 02 m icroelectrodesThe micr0electrodes used were either of the ~ gold in glass >> type as pre-viously described Eli or microelectrodes as. developed by Erdmann etal. [2]. Silver print is applied to the shaft of the microelectrodes serving asthe reference electrode. During the hyperthermia experiments a temperatureeffect of 5% C for a given 02 tension was taken into consideration.The electronic circuitry to measure the polarographic current was pro-vided by a Model 1201 Chemical Microsensor System (Transidyne GeneralCorp., Ann Arbor, Mich., USA), and the results were recorded on a Model7 D Grass polygraph. The procedure for electrode calibration was the same aspreviously describeb [1].During the experiments on humans a platinum- iridium Teflon- coatedwire, 120~m in diameter, was used as the 02 electrode. Although its calibra:tion was not sufficiently reliable to determine actual tissue p02 values, is wasfound that for measuring transients the values obtained correlated well withthose from microeletctrodes.b) MeaSurements o[ tissue- pH values using spear- type glass micro-electrodesThe pH microelettrodes used were of the HINKE- type as described byHinke [4] and Herbert [3]. These sper-type glass microelectrodes had tipdiameters as small as 1 ~m so that tissue damage on penetration into the tissuewas minimized.c) Determ ination of local tumor blood ]low micro]low )Local tumor blood flow was determined utilizing the hydrogen clea-rance technique after electrochemical generation of H2 within the tissue [6].d) Application of localized tissue hyperthermia

Usually microwaves in the frequency of 2450 MHz were applied lo-cally (in some instances microwaves in a frequency of 9 5 MHz were used).The microwaves were delivered through a specially designed applicator [5]which was fed through a coaxial cable from a Raytheon model CMD- 10diathermy generator. Net power transmitted to the tissue was obtained bymeasuring the incident and reflected power using a Bird model 43 through-line wattmeter inserted between the generator and the applicator. ~In thecase of the mice tumors net power transmitted to the tissue varied be:t~C, een1.5 and 3.0 W.Mean tumor and mice rectal temperature were recorded using verysmall thermocouples. The thermocouple for monitoring the mean tumortissue temperature as well as the pH and 02 microeleetrodes were arrangedvery carefully such that they were aligned at rigth angles to the electricvector of the plane electromagnetic waves generated in the waveguide. Thishad to be done in order to minimize the interference effects in the mi-


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Physiological mechanisms of localized microwave hyperthermia 97crosensors: Thethermocouple inserted into the tumorous tissue was in closeproximity to the other microsensors.

Resultsa) Effects oJ local hyperthermia on tissue p02Starting from mean tumor tissue temperatures of 30-32C, there is arise in the tissue oxygen tensions that parallels the application of the mi-crowa.ve and follows, closely, changes in tissue temperatures up to about40C. The response was very fast, tissue p02 increasing shortly after the risein temperature. This effect was present when heating was carried out up to40-41C (Fig. 1). At higher temperatures there was a decrease in tissue p02values in 7 tumors. During 3 experiments further increase in tumor p02 va-lues could be observed. In one experiment, starting from very low initialp02 values (0-1 mmHg), there was no change at all during application oflocalized microwaves.EFF-E~P- 0F MICROWAVE HYP~RTHERMIAON AVERAGE Tp 02--HUMAN TUMO.RS

50 TpO2mm Hg )0

1

45

5IG. 1. ~ Effect 0f microwave hyperthermia On tissUe pOz value in C3H mouse fnammaryaden0carcinoma. There is a rise in tissue pOz Value (TpO~) that parallels the application ofthe microwaves (rnW) up to 40-41oC. The bar at the bottom indicates 1 min.Breathing pure oxygen for one minute usually causes a very small risein p02 readings within tumors. During local hyperthermia there was a ten-dency for an increase in these responses that was proportional to the localtumor temperature (Fig. 2). When oxygen was breathed at tumor tempera-tures above 41C the increase in the tissue 02 partial pressure became consi-derably less than below this temperature.b) Impact o] local hyperthermia on t issue pHThe mean tissue pH in C3H mouse mammary adenocarcinomas was

found to be 6.75. Upon local heating the tissue pH values slightly dropped


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98 Bicher H. I. Vaupe] P. W.until a tissue temperature of 39-40C war reached. Above this temperaturerange there was a distinct and con, tinuous drop of-the intratumor pH values;After 1 hour of 43C- hyperthermia an average pH drop of 0,55 pH- unitscoud be observed (see Fig. 3).

Tp 02 RISE INDUCED BY MICROWAVE HYPERTHERMIAEFFECT ON" 02 BREATHING - MOUSE TUMORS (mmHg)control

88

9 9 50

0

4

FIG. 2. -- Increase of tissue oxgen tension in tumors (TpOz) during microwave hyperthermiaand effect on oxygen breathing of the animals.c) Responses o] local tumor blood flow to hyperthermiaLocal tumor blood flow as measured with the local hydrogen clearancetechnique increased up to 40-41~C. When heating was carried out up. tohigher temperatures, a considerable fall of local tissue blood flow wasobvious.

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5.5 Inormothermia after 1 hr of43C hyperthermiaFIG. 3 --- Intratumor pH values before (normothermia/and after 1 hour of 43C-hyperthermia


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Physiological mechanisms of localized microwave hyperthermia 99Discus s ion

The present studies clearly demonstrate that localized microwave hy-perthermia causes a rise in tumor oxygen partial pressures and of local bloodflow up to 40-41C. When heating was carried out up to higher tempe-ratures a pronounced fall of both could be observed, pH decreases slightlyup to 39-40C with a steeper fall thereafter. These findings are valid eitherfor experimental mice tumors or spontaneous tumors in humans.The mechanism of these effects seems to be predominantly mediatedthrough ,the blood flow changes with temperature. The metabolic effect seemto be secondary. This result coincides very well with earlier findings ofVaupel et al. [7, 8] utilizing an isolated perfusion of tissue-isolated rat.tumors in situ. In these experiments total tumor blood flow increased signi-ficantly after an increase of the mean tumor temperature from 37 to 39.5C.At higher temperatures (42C) total tumor blood flow decreased to a levelsomewhat below the flow during normothermia. These changes in bloodflow were paralleled by variations of the 02- consumption and of the glucoseuptake of the tissue.Tumor microcirculation seems to be ~ activated ~ at moderate hyper-thermic temperatures (up to 40-41C) and deteriorated at higher tempera-tures. Whereas a vasodilation of tumor vessels appears to be an importantfactor for flow improvements, a reduction of red blood cell flexibility, mul-tiple microthromboses as well as occlusions of microvessels should betaken into consideration as factors at higher tumor temperatures.

REFERENCES

[1 ] BICHER H. I., MA RVIN P. : Pharmacological control of local oxygen regulation mechanismsin brain tissue - Stroke, 1976, 7, 469-472.[2 ] Em~MANN W., KREL~, W., METZ~ER H., NIX~ORF I. : Ein Verfahren zur Herstellung standar-disierter GoM -- Mikroelektroden fuer die p02 Messung im Gewebe - Pfluegers Arch.,

1970, 319, R 69.[3 ] H~RBnRT N . C . : Glass microelectrodeg for pH- Adv. Exp. Med. Biol., 1974, 50, 23-38.[4] H~N~=E J . A. M. : Cation-selective microeleetrodesfor intracellular use - In: Glass Electrodesfor Hydrogen and Other Cations, - G. Eisenman, ed., New York, 1967, Marcel Dekker Inc.[5] SANDrrU T. S., KowAg H. S., Joy,soy R. J. R. : The development of microwave hyperthermiaapplicators - Int. J. Radiat Oncol Biol. Phys., 1978, 4, 515-519.[6 ] S~OSSECK K . , L~JEB~nRS D. W . , CoxxI~ N. : Determination of local blood/tow (mieroflow)by electrochemically generated hydrogen - Pfluegers Arch., 1974, 348, 225-238.[7] VA gUEr, P., OSX nEI~mR K ., TI~O~E H. : Bloodflow, vascular, resis tance and oxygen congum ption of malignant tumors during normothermia and hyperthermia, - Microvasc. Res., 1977,13, 272.[8 ] VA~J~ P. , OSa~aEI~ER K. , Mtr~g~ER-K~,I~SER W. : Impact of hyperthermia oft blood flow,respiratory gas exchange and glucose uptake of malignant tumors Annual M eeting Internat.Soc. Oxygen Transport to Tissue, La JollaiCal., 1979.

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0103_HYPERTHERMIA IN RADIATION ONCOLOGY - 04.pdf