The importance of thermotolerance for the clinical treatment with hyperthermia.

Thermotolerance (i.e. a temporary heat resistance following a prior heat treatment) is a general phenomenon occurring in both normal tissues and tumours. Besides affecting a fractionated heat treatment, thermotolerance may also influence the effect of fractionated combined heat and radiation. The importance of thermotolerance for fractionated clinical hyperthermia is discussed on the basis of a series of in vitro experiments in L1A2 cells and in vivo studies of a C3H mouse mammary carcinoma. If maximal tumour interaction is wanted, thermotolerance should be avoided, but it would be preferable in normal tissues in order to reduce the amount of damage. Unfortunately, there is a considerable variation in the kinetics and magnitude of thermotolerance between different tissues, and it is currently not possible to predict how thermotolerance will develop in a given tumour or normal tissue. However, both the magnitude and the kinetics appear to depend on the heat damage induced by the priming heat treatment. Thus, in a given tissue, thermotolerance will develop later, but will reach a higher maximum by a larger priming heat treatment. It follows that if a homogeneous temperature cannot be applied to a given tissue, different parts will develop thermotolerance at different kinetic patterns. Therefore, at the time of subsequent heat treatment, the tissue may express different heat sensitivities in different areas. With the current knowledge, the best way to overcome the problems of thermotolerance when heat is given alone or sequentially with radiotherapy will be by application of a single or few, but large heat fractions given with an interval that allows thermotolerance to develop and decay before the next hyperthermic treatment is given. With a simultaneous heat and radiation treatment which optimally requires heating in association with all radiation fractions, the fractionation interval should also be long, which is complicated by the fact that such long fractionation intervals may not result in an optimal radiation treatment.