Arrhenius relationships from the molecule and cell to the clinic

There are great differences in heat sensitivity between different cell types and tissues. However, for an isoeffect induced in a specific cell type or tissue by heating for different durations at different temperatures varying from 43–44°C up to about 57°C, the duration of heating must be increased by a factor of about 2 (R value) when the temperature is decreased by 1°C. This same time–temperature relationship has been observed for heat inactivation of proteins, and changing only one amino acid out of 253 can shift the temperature for a given amount of protein denaturation from 46°C to either 43 or 49°C. For cytotoxic temperatures <43–44°C, R for mammalian cells and tissues is about 4–6. Many factors change the absolute heat sensitivity of mammalian cells by about 1°C, but these factors have little effect on Rs, although the transition in R at 43–44°C may be eliminated or shifted by about 1°C. R for heat radiosensitization are similar to those above for heat cytotoxicity, but Rs for heat chemosensitization are much smaller (usually about 1.1–1.2). In practically all of the clinical trials that have been conducted, heat and radiation have been separated by 30–60 min, for which the primary effect should be heat cytotoxicity and not heat radiosensitization. Data are presented showing the clinical application of the thermal isoeffect dose (TID) concept in which different heating protocols for different times at different temperatures are converted into equivalent minutes (equiv) min at 43°C (EM43). For several heat treatments in the clinic, the TIDs for each treatment can be added to give a cumulative equiv min at 43°C, namely, CEM43. This TID concept was applied by Oleson et al. in a retrospective analysis of clinical data, with the intent of using this approach prospectively to guide future clinical studies. Considerations of laboratory data and the large variations in temperature distributions observed in human tumors indicate that thermal tolerance, which has been observed for mammalian cells for both heat killing and heat radiosensitization, probably is not very important in the clinic. However, if thermal tolerance did occur in the clinical trials in which fractionation schemes were varied, it probably would not have been detected because with only the two–three-fold change in treatment time that occurs when comparing one versus two fractions per week, or three versus six total fractions, little difference would be expected in the response of the tumors since both thermal doses were extremely low on the dose-response curve. Data are shown which indicate that in order to test for thermal tolerance in the clinic and to have a successful phase III trial, the thermal dose should be increased about five-fold compared with what has been achieved in previous clinical trials. This increase in thermal dose could be achieved by increasing the temperature about 1.5°C (from 39.5 to 41.0°C in 90% of the tumor) or by increasing the total treatment time about five-fold. The estimate is that 90% of the tumor should receive a cumulative thermal dose (CEM43) of at least 25; this is abbreviated as a CEM43 T90 of 25. This value of 25 compares with 5 observed by Oleson et al. in their soft tissue sarcoma study. Arguments also are presented that thermal doses much higher than the CEM43 T90 induce the hyperthermic damage that causes the tumors to respond, and that the minimum CEM43 T90 of 25 only predicts which tumors that receive a certain minimal thermal dose in <90% of the regions of the tumors will respond. For example, in addition to a minimal CEM43 T90 of 25 a minimum CEM43 T50 of about 400 also may be required for a response. Finally, continuous heating for ∼2 days at about 41°C during either interstitial low dose-rate irradiation or fractionated high dose-rate irradiation, which we estimate could give a CEM43 of 75, should be considered in order to enhance heat radiosensitization of the tumor as well as heat cytotoxicity. In order to exploit the use of hyperthermia in the clinic, we need a better understanding of the biology and physiology of heat effects in tumors and various normal tissues. As an example of an approach for mechanistic studies, one specific study is described which demonstrates that damage to the centrosome of CHO cells heated during G1 causes irregular divisions that result in multinucleated cells that do not continue dividing to form colonies. This may or may not be relevant for heat damage in vivo. However, since normal tissues vary in thermal sensitivity by a factor of 10, similar approaches are needed to describe the fundamental lethal events that occur in the cells comprising the different tissues.