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Hyperthermia in cancer therapy: the biological basis and unresolved questions.

Summary The properties of a cell population which characterize it as malignant also render that cell population sensitive to hyperthermia. These heat-sensitizing properties are accessory, rather than intrinsic to the transformed state. The loss of normal growth control and enhanced rate of glycolysis of tumor cells gives rise in situ to a relatively rapidly proliferating, poorly perfused, acidic and energy-deprived cell mass, all with regional variation. Reduction in tissue blood flow limits the capacity of tissue to dissipate locally deposited heat and may permit selective tumor heating under certain circumstances. Elevated rates of glycolysis and lactic acid production probably give rise to a reduced pH, which is commonly observed in tumor tissue, and increase the sensitivity of tumor cells to hyperthermia. During tumor growth, the availability of glucose and oxygen does not match the demand for these ATP substrates. Moderate reductions in cellular energy status which are not toxic at 37°C increase the sensitivity of cells to hyperthermia. However, not all cells in tumors reside in a poorly perfused, acidic, or nutrient-deprived microenvironments. The thermal sensitivity of these “normal environment” tumor cells is probably no greater than that of corresponding normal tissue cells. Therefore, the total population of cells within a tumor will be most effectively treated by combining hyperthermia with other forms of therapy. Taken together, these considerations give rise to the expectation that hyperthermia will be useful in cancer therapy. In addition to these basic considerations, 3 promising avenues of research are addressed: the possibility of enhancing tumor thermal sensitivity by enhancing differences in tumor and normal tissue pH and energy status; the possibility of noninvasively predicting tumor thermal sensitivity based on tumor blood flow, pH, and energy status; and the possibility of structuring hyperthermia fractionation protocols which minimize damage to normal tissue and which maximize damage to tumor tissue, based on differences in thermotolerance decay kinetics.