SIGNIFICANCE OF ADDITIVE HEAT EFFECT IN THE THERAPEUTIC GAIN FACTOR IN COMBINED HYPERTHERMIA AND RADIOTHERAPY: MURINE TUMOR RESPONSE AND FOOT REACTION

The thermal enhancement ratio (TER) and therapeutic gain factor (TGF) were evaluated for combined hyperthermia and radiation treatments of a murine flbrosarcoma, FSa-II. The TER is the ratio of the radiation dose that induces a given reaction without hyperthermia to that with hyperthermia. The TGF is deiined as the ratio of TER for tumor response to TER for normal tissue response. Tumors in the subcutaneous tissue of the right foot were h-radiated with graded radiation doses when they reached an average diameter of 6 mm (110 mm’). Hyperthermia was given by immersing animal feet in a constant temperature water bath 10 mht before or after irradiation. The tumor growth time to reach 500 mm3 was obtained for each tumor and the median tumor growth thne was calculated for each treatment group. For the normal tissue study, the non-tumor bearing murhte foot was treated, as was the tumor, and the foot reaction was scored after treatment, according to our numerical score system for radiation damage, until the 35th post-treatment day and averaged. Using the fraction of animals showing a given average foot reaction score in a treatment group, the RDsO, or the radiation dose to induce the given foot reaction or greater, was calculated. A single heating at 455°C for 10 mm and a step-down heating (first heat at 45.5’C for 10 min immediately followed by the second heat at 41.5“C for 60 min) prolonged the tumor growth time, indicating that hyperthermia per se resulted in some cell killing. The prolongation was greater following step-down heating than following single heating. These heat treatments alone induced no noticeable heat damage on the foot, but decreased the threshold dose observed on the radiation dose response curves for the foot reaction. Accordingly, TER and TGF were evaluated with or without normalizing this thermal effect. TER’s for both tumor and foot responses without normalization were greater than the TER’s after normalization and decreased with increasing radiation dose (between 1.9 and 7.1 or greater for tumor and between 1.3 and 4.3 or greater for foot reaction), whereas the normalized TER’s were relatively constant (between 1.6 and 1.7 for tumor and between 0.7 and 1.5 for foot reaction). TGF’s without normalization were greater than those obtained after normalization. The former was large at small doses and decreased with increasing radiation dose (between 1.5 and 4.0 or greater), whereas the latter was within 0.8 and 1.3 and relatively independent of radiation dose. TGF’s following step-down heating were greater than the TGF following single heating (> 3.0 and between 1.5 and 2.0 for SDH and single heating given before radiation). This greater non-normalized TGF is likely due to the additive effect of hyperthermia, that is, due to the greater thermal effect on the tumor than the normal foot. Similarly, greater TGF’s following step-down heating may be due to greater damage, induced by this heating, to the tumor. TGF following hyperthermia given before or after radiation appeared to depend on the heat dose applied.