Where, when and why hyperthermia went wrong way

‘Hyperthermia is generally regarded as an experimental treatment with no realistic future in clinical cancer therapy’ – Horsman and Overgaard said in 2007, though, trying to combat this statement. It’s difficult to find another method in medicine which remains experimental after 40 years of research and application. Hyperthermic community usually claims to technical problems of heating and heating control to justify this failure. To our mind, the problem is the ‘temperature concept’ of hyperthermia. Electromagnetic hyperthermia was finally derived from electromagnetic therapy near 1935, after 30-year fight between thermal and non-thermal concepts of electromagnetic fields application. It was based on a belief that only thermal effect has value, and temperature is the only parameter of efficacy (thermal/temperature dogma). Non-thermal (temperature independent) effects were denied. Initial concept of extreme hyperthermia of 1970th was based on the wrong premise of higher thermal susceptibility of malignant cells. Therefore, it was believed that hyperthermia has a broad therapeutic range which allows to kill tumor cells by abovethreshold (>43°C) temperature without damage of healthy tissues. Proofs of inadequacy of this concept were received already in 1980th when it become obvious that really this therapeutic gap is minor or absent, which makes the extreme hyperthermia impossible. To correct it, the concept of ‘thermal dose’ was introduced. This was based on ungrounded extrapolation of biochemical Arrhenius equation onto living matter. Series of randomized clinical trials of early 90s showed inefficacy of the extreme hyperthermia and called into question the thermal dose concept, but the latter was ignored. Instead of the extreme hyperthermia, the concept of moderate hyperthermia based on the same thermal dose concept was introduced in 2000s: it was believed that moderate hyperthermia could enhance tumor perfusion and subsequently enhances radioand chemo-efficacy. Though it’s declared that this approach was fruitful and its effect was confirmed in randomized clinical trials, it’s not correct. The careful analysis of these trials has shown multiple biases. After correction to the distortions, the efficacy of the moderate hyperthermia is not confirmed. Ignorance of the special features of tumor bloodflow was the reason of this failure. Therefore, there are some points when and where hyperthermia had gone the wrong way: 1) 1930s when temperature was equated to thermal energy and non-thermal (temperatureindependent) effects were denied; 2) 1960s when greater thermal sensitivity of tumor cells was incorrectly postulated; 3) 1980s when incorrect ‘thermal dose’ concept was introduced; 4) 1990th when obvious proofs of inconsistency of temperature concept were ignored; 5) 2000s when moderate hyperthermia concept was introduced. As a result, during the last 20 years, the ‘temperature’ hyperthermia is in stalemate. Since 1970s, growing evidence of non-thermal effects and their broad application in different fields (dielectrophoresis, bioelectric effect, electroporation, galvanotherapy, etc.) caused a development of some non-thermal field cancer treatment techniques. Hyperthermia concept should be cardinally re-evaluated now with respect to obvious bankruptcy of the temperature concept and development of non-thermal concept.