HYPERTHERMIC ENHANCEMENT OF HIGH-DOSE-RATE IRRADIATION IN 9L GLIOSARCOMA CELLS

Purpose: Long duration-mild temperature hyperthermia has previously been shown to be an effective potentiator of low-dose-rate irradiation. An in vitro investigation was initiated to determine if 41 degrees C hyperthermia could be useful in sensitizing high-dose-rate (HDR) brachytherapy. Experiments were designed to determine the optimal length of heat treatments to be applied with a twice daily 5 Gy times five fraction high-dose-rate protocol. Methods and Materials: Rat 9L gliosarcoma cells growing exponentially in flasks were exposed to X-irradiation and 41 degrees C hyperthermia. Irradiation was applied in 5 Gy fractions two times per day to a total dose of 25 Gy. Hyperthermia consisted of combinations of 1 or 4 hr beatings before and/or after each of the radiation exposures. In addition, a set of cells was heated continuously at 41 degrees C starting 6 hr before the first fraction and continuing to 4 hr after the 5th fraction. Cell survival was assayed by colony formation. Results: Sensitization of high-dose-rate increased linearly with increasing length of 41 degrees C heating over the entire range of heat exposures applied. Maximum sensitization was produced by continuous heating for 58 hr throughout the entire radiation course. Heating for 4 hr before fractions two through five produced less sensitization to these later fractions than was expected if each heat-radiation fraction had acted independent of the other fractions. Conclusion: Continuous 41 degrees C heating eliminated split dose sparing during high-dose-rate. The apparent development of thermotolerance during the course of heat and high-dose-rate resulted in reduced sensitization in the later fractions when 4 hr pre- and/or post-heat were applied. This tolerance was overcome if heat was applied continuously between radiation fractions. The clinical relevance of these in vitro data is that 41 degrees C hyperthermia should be applied for as long as is possible during this type of high-dose-rate protocol. This combined hyperthermia-high-dose-rate treatment may enhance the efficacy of interstitial irradiation in situations such as boost irradiation of high grade glioma.