Simultaneous and sequential hyperthermia and radiation treatment of an experimental tumor and its surrounding normal tissue in vivo

In order to optimize the therapeutic effect of a combined hyperthermia-radiation treatment, the influence of sequence and interval between the two modalities on local tumor control and normal tissue damage was studied during variation of heating time and temperature. A C3H mouse mammary carcinoma transplanted into the feet of C3D2F1 mice was used as a model. Local hyperthermia was given to unanesthetized mice by immersion of the tumor-bearing foot into a water bath. Radiation was given either before, during or after heating. After simultaneous treatment an increasing thermal enhancement ratio (TER) was observed with increasing temperatures and/or increasing heating time with TER values ranging from 1.2 at 41° C to about 5 at 43.5° c after a one hour heating. In all simultaneous treatment schedules, the TER values were almost similar in tumor and normal tissue; no improvement in therapeutic gain was observed. Different results were obtained by using an interval between the two modalities. Hyperthermic treatment (42.5° C/60 min) given with intervals up to 24 hours before radiation showed no definitive improvement in therapeutic ratio. However, if radiation was given before the heating, the normal tissue completely recovered from thermal sensitization within 4 hours, whereas a marked thermal enhancement was persistent in the tumor for more than 24 hours. Thus, an increased therapeutic ratio could be obtained if radiation was given before heat and an interval of 4 hours or more was allowed. This improved therapeutic ratio was dependent on the temperature and ranged from about 1.1 at 41.5° C to 2.1 at 43.5° C given for one hour. These data indicate that if both tumor and normal tissue are heated, the optimal tumor effect may not be a hyperthermic radiosensitization, but rather a direct heat killing of radioresistant tumor cells. This special heat sensitivity of radioresistant tumor cells may be explained by the characteristic environmental conditions (e.g. chronic hypoxia and acidity) influencing such cells.