Arrhenius relationships from the molecule and cell to the clinic

With the rapid development of clinical hyperthermia for the treatment of cancer either alone or in conjunction with other modalities, a means of measuring a thermal dose in terms which are clinically relevant to the biological effect is needed. A comparison of published data empirically suggests a basic relationship that may be used to calculate a "thermal dose." From a knowledge of the temperature during treatment as a function of time combined with a mathematical description of the time-temperature relationship, an estimate of the actual treatment calculated as an exposure time at some reference temperature can be determined. This could be of great benefit in providing a real-time accumulated dose during actual patient treatment. For the purpose of this study, a reference temperature of 43 degrees C has been arbitrarily chosen to convert all thermal exposures to "equivalent-minutes" at this temperature. This dose calculation can be compared to an integrated calculation of the "degree-minutes" to determine its prognostic ability. The time-temperature relationship upon which this equivalent dose calculation is based does not predict, nor does it require, that different tissues have the same sensitivity to heat. A computer program written in FORTRAN is included for performing calculations of both equivalent-minutes (t43) and degree-minutes (tdm43). Means are provided to alter the reference temperature, the Arrhenius "break" temperature and the time-temperature relationship both above and below the "break" temperature. In addition, the effect of factors such as step-down heating, thermotolerance, and physiological conditions on thermal dose calculations are discussed. The equations and methods described in this report are not intended to represent the only approach for thermal dose estimation; instead, they are intended to provide a simple but effective means for such calculations for clinical use and to stimulate efforts to evaluate data in terms of therapeutically useful thermal units.

The two principal rationales for applying hyperthermia in cancer therapy are that: (a) the S phase, which is relatively radioresistant, is the most sensitive phase to hyperthermia, and can be selectively radiosensitized by combining hyperthermia with x-irradiation; the cycling tumor cells in S phase which would normally survive an x-ray dose could thus be killed by subjecting these cells to hyperthermia; and (b) the relatively radioresistant hypoxic cells in the tumor may be selectively destroyed by combinations of hyperthermia and x-irradiation. Both of these rationales have been mentioned as reasons for using high LET irradiation in cancer therapy; therefore where such irradiation may be of use, hyperthermia may also be advantageous.

There is now abundant evidence that apoptosis, the cell death mechanism responsible for physiological deletion of cells, can be triggered by mild hyperthermia. However, the overall importance of this mode of death in heated tumours has not yet been established. In this light and electron microscopic study, apoptosis induced by 43 degrees C or 44 degrees C water bath heating for 30 min in a range of murine and human tumours growing in vitro and in four murine tumours growing as solid nodules in vivo, was identified on the basis of its characteristic morphology, and the amount present quantified. Apoptosis was found to play a variable role in the response of tumours to heating, with the lowest levels produced in human melanoma lines (less than 1%) and the highest levels in some Burkitt's lymphoma lines (up to 97%). In these latter tumours the induction of apoptosis is clearly a major component of the hyperthermic response.