CHANGES IN TUMOR TISSUE OXYGENATION DURING MICROWAVE HYPERTHEP~MIA CLINICAL RELEVANCE

Haim I. Bicher, M.D. and Nodar P. Mitagvaria~ Ph.D.*, Valley Cancer Institute, 6917 Valjean Avenue Van Nuys, CA, USA, *Institute of Physiology Georgian Academy of Sciences, Tbilisi, USSR

Accepted for publication 4th International Symposi~im Hyperthermic Oncology Aarhus, Denmark, July ]984

ABSTRACT

A~ previously described (Bicher 1981) Tp02 and blood flow increase in tumor as temperature increases until 41C and decrease thereafter

(mlcrocirculation "breaking point"). In the present clinical study using 02 microelectrodes this response was reproduced in over 54 treatment sessions. However, it was found that as treatment progresses (patients are treated for one hour I0 times, twice weekly, and concomitantly receive 4000 rads of ionizing radiation) the initial increase of blood flow and TpO2 is reduced and there is immediate decrease in tissue oxygenation. -A correlation between microvascular tumor physio!ogical changes and tumor treatment responses is >~ing developed.

iKeywords: Hyperthermla, Radiation, Microclrculation, Oxygen

1. INTRODUCTION

The clinical use of microwave induced hyperthermia for cancer treatment is increasingly accepted. Several hypothetical mechanisms have been

described to th~s specific effect. In previous publications (Bicher 1977, 1978, 1980) we have demonstrated hyperthermia induced changes in In

microcirculation, tissue oxygenation, local blood flow and tissue pH.

order to elucidate the potential co~relation between microvasculsr changes and tumor response to the hyperthermia.treatments we undertook to record tissue oxygen levels in human tumors as a function of temperature during routine clinical hyperthermia treatments,, repeating this determination

for each of the 10 sequential heat fractions usually administered patient.

to each

2. METHODS

Microthermocouples:

Tissue temperatures were d~termined using

copper-conatantan clinical microthermocouples manufactured by PDM, 6917 Valjean Avenue, Van Nuys, CAo Each 75 micron wire of the thermocouple pair is insulated by teflon and the sensor is mounted in a triple suture which carries it in place when introduced using a miniature needle system. Through~ut treatment, temperature readings were taken at 5-min intervals under "power off" conditions. Temperatures were recorded using a modified microprocessor with a special interface controlling the microwave "on-off" cycle. A minimum of 4 probes were used in each treatment. Oxygen microelectrodes: A 25 micron gold wire, insulated in teflon, was prepared for use as an oxygen mlcroelectrodes by forming a "

Rhoplex-Formvar membrane over the exposed tip as described in previous publications (Bicher 1980). These electrodes are activated according to activators

polarographic pminciples and recorded through appropriate

microprocessors and A-D converters to the same~computer system described above; Oxygen readings were performed under "power off" conditions in the same manner describ~ electrodes were calibrated values- as described by for the temperature measurements. The 02

in buffered saline solutions of known pO2 Silver (1963). The temperature artifact was All results were

determined and found to be 5% per degree Celsius.

corrected by taking this artifact into account. The electrodes were mounted in the same suture as used for the thermocouples ~ich then became a dual pO2 temperature sensor, ~that was introduced into tissues in the same way as the routine PDM clinical thermocoupleso Equipment consists of a dual microwave generator operating at 915 or 300 ~z (PDM, Van Nuys, CA). Microwaves are delivered using air cooled microwave applicators of the Sandhu-Bicher type. Hyperthermia treatments

consisted of I0 fractions of heat delivered at 42 C for one hour. Treatments were separated by 72 hours. Hyperthermia immediately follows

radiation treatments. Each patient received a total of 4000 rads given in 200 rad fractions four times a week." Physiological determinations were successfully completed in a total of 54 treatments ~n 6 patients. All tumors included in this series had complete responses.

3. RESULTS
The typical changes of tumor oxygen levels during a heating period are d~vided into three phases. First there is an increase in TpO2 to more than double its original value. Thereafter the "critical point" is

reached, about 10-30 minutes into the treatment, and the oxygen levels begin to decrease. The third phase is one of stabilization, which usually occurs above the original baseline in previously untreated patients. Thesetrlphaslc responses have been~descrlbed in previous publications (Bicher 1978, 1980) and was confirmed in the present series, in all cases ~ during the first treatment (see Figure IA and Table I)~ As additional hyperthermla fractions are given there is a marked change

in the

trlphaslc TpO2 hyperthermlc

response.

The initial TpO2

increase gradually disappears and the stabilization occurs below the

initial TpO2 baseline. (Figure I, B and C and Table I). By the 10th treatment the initial size is always absent and the stabilization occurs below the initial level.

TpO; OIANBES DURING HYPERTHEP~IA HU,",AN IU~ORS

~o. OF TRFAT~E~TS - ~

T~ ~GES
I

15T 2-5Tff TREATmEnT , TP, FJ, T~ENT

TREAII"N1 ,

1.I I[IITIAL RISE IOOX

!

8.5%

2.I STABILIZATION. I BELOW INITIAL 2.5X IFVEL

- !

Table

4. DISCUSSION

As previously described (Bicher 1980, Eglund 1976, Sutton 1976) TpO2 and blood flow increase in tumor as temperature increases until 41C and decrease thereafter ("breaking point"). These changes are followed by a

decrease in tissue pH which is of long duration. 1980).

(Bicher 1980, Song

The pH changes have considerable effect on hyperthermla cell

killing, which is increased fivefold at low pH values (Gerweck 1974). The present results clearly indicate that fundamental changes in the

mlcrocirculation ability to perfuse tumors occur during the multifraction radiation-hyperthermia treatments.

As the series progresses the initial 02 increase, an obvious active compensating physiological response, is obliterated. Also, the fact that
pO2 levels decrease during the treatment to below the initial levels indicates that the microcirculation is unable to compensate for increased

02 demand due to increased metabolic activity probably induced by the raised tissue temperatures,
In this respect, routine TpO2 monitoring during treatment c~uld ~e of

clinical value.

BErber, B.. Betzel. F. and DAgostino.L., 1977, Changes n tu~or tissue Oxygenation induced by microwave hyperthemie. Internatlonal Journal Radiation Oncolo~ Biology Ph~slcs~ 2, 157. Bicher, H.. 1978, Increase in brain rissue oxygen availability induced by localized mlcrovave hyperrhermla. In Silver Ernclnska! and Bicher, Oxygen transport to tissue; Vol. flip ~7-353, NY, gicher, H., et el~ 1980, Effects o[ hypertherm[a o~ normal end tumor microenvlro~en~. R~dlarlon !~7, 52~-5~0. Bicher, ~., Hitagveria, N.; end Hetzo~.F., 1980. hyperthe~[a, Ann, NY Acad. Sci, 33~:21o Engined N., Ballbook T.~ Ling, L., 1974, Skin end m~scle blood flo~ durln~ re&ional perfusloa ~ith hyperthe~al p~rfusa~e. Scandinavian Journal Thorac Cardiovascular Surgery. 8. Gerweck, L., 19IY, Hodlfication of cell lethality ar elevated temperatures: The pH effect. Radlstioo Al~era~[ons in tumor t[asue oxygenation by microwave

Reinhold, H., et al, 1979, Reoxygenat[on of turbots in sandwich chamber. ~uropean Journal of Cancer~ 15,

Silver, I., 1963, A Simple mlcroelecrrode for measuring pO2 in gas or fluid, Medical Electronlc_x ~ En~neerlng, 1, ~7-551.
Song, C., Kang, M., Rhee, J., 1980, Effect of hyperrher=ia on vascular function p8 and cell suruival. Radiol_~!z 137, 795-803.

glio=a. ~nerican Association of Cancer Research (abstract).