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Basic principles in hyperthermic tumor therapy.


Literature on hyperthermic tumor therapy in the past 10 years has grown exponentially. Since 1975 three international symposia on cancer therapy by hyperthermia have been held. Hyperthermia is of clinical interest in the temperature range of 40 degrees-43 degrees C. Higher temperatures of 44 degrees-46 degrees C are not clinically realizable. With local heat application a higher elevation of tissue temperature is possible. Whole-body hyperthermia in men is limited physiologically, as the rate of complications increases exponentially above 42 degrees C. The heat dose normally is defined by temperature degree and time of temperature elevation. Hyperthermia has several effects on tumor cells. It influences proliferation activity; within the mitotic cycle, preferentially the M-phase cells and S-phase cells are thermosensitive. It is possible to synchronize tumor proliferation by heat. Hyperthermia inactivates tumor cells in hypoxic condition as well. This was demonstrated in vitro with tumor cells under varying oxygenation and with spheroid experimental tumors. Experiments with solid tumors in animals had the same effect. Hyperthermia enhances the effect of radiation on tumors. In solid human tumors only 3%-5% of cells are in growth fraction; 95% of tumor cells are hypoxic or prenecrobiotic. Only well-oxygenated cells are sensitive to a sparsely ionizing radiation and can be killed. This selective radiosensitivity is the reason why other radiation qualities for radiotherapy, which are also effective on hypoxic cells, are examined. Neutrons and heavy ions are densely ionizing radiations, which inactivate hypoxic radioresistant cells. Hyperthermia in combination with sparsely ionizing radiations--e.g., X-rays or gamma rays--could be an alternative to neutrons or heavy ions. The main problem with heat application in clinical radiotherapy is the lack of heating methods which are able to heat the entire volume of a large solid tumor homogeneously. In small experimental animals there is a TER of about 1.5-2.0. The therapeutic gain of additional heat in radiotherapy is greatly dependent on localization of the tumor (skin, extremities) and on cooling of the skin. Hyperthermia enhances cytostatic drugs. Many investigations have been done on the interaction of heat and cytostatics; in vitro experiments evaluated three types. First, the activity of many drugs increases slightly with temperature; no special effects are observed above 42 degrees C. Examples of drugs of that pattern are the hypoxic sensitizer Ro-07-0582 and the alkylating agents thio-TEPA and CCNU. A second type of mechanism is seen with cytostatic drugs which exhibit greatly increased effectiveness at temperatures above 42 degrees C; adriamycin and bleomycin belong to this type.(ABSTRACT TRUNCATED AT 400 WORDS)

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