There are two types of heat application: active hyperthermia, which provokes fever episodes by means of pyrogen administration, and passive hyperthermia, which raises the temperature of tissues or body fluids by various physical means.

The classic, pyrogen-induced fever therapy with target temperatures between 39–40 °C results in enhanced migration of leukocytes and monocytes from the peripheral blood into the tissues and also improves chemotaxis and activates phagocytosis. In addition, it activates metabolic processes, enhances the blood supply, and potentiates the effects of some cytostatic agents.

•   Extreme hyperthermia has direct cytostatic and cytotoxic effects, especially within the tumor tissue, and produces synergistic effects with cytostatic agents.

In principle, hyperthermia can be applied to all solid malignant tumors. Temperatures above approximately 42 °C have cytostatic or cytotoxic effects on cells in general. In malignant tissues, however, heat seems to be cytotoxic already at lower temperatures because of the altered microenvironment. Damages to membranes of the endoplasmic reticulum, to the cytoskeleton, and to the mitotic spindle are induced already at temperatures in the range of 41–42 °C. In addition, hyperthermia causes the induction of apoptosis.

During passive hyperthermia, the tumor tissue is warmed up by means of external energy sources. The temperature range differs depending on the type of application:

– 39–40 °C for moderate whole body hyperthermia

– 41–42 °C for extreme whole body hyperthermia

– 42–43 °C for superficial or deep hyperthermia

– 46–58 °C for transurethral hyperthermia.

Hyperthermia must be distinguished from thermoablative methods. These procedures induce coagulation necrosis at temperatures of above 90 °C. They are usually performed with interstitial techniques, but also with ultrasound and alternating magnetic fields.

The thermosensitivity of tumors depends on internal cellular factors and on the cellular environment (e. g., energy deficit, or low pO₂ and low pH). At low pH and low oxygen saturation, cells are more sensitive to higher temperatures. This might explain why malignant tissues are more sensitive to heat than healthy tissues with a normal blood supply. In addition to specific conditions of physical absorption and the altered microenvironment, the tumor’s blood vessels are probably less capable of thermoregulation. This creates higher temperatures within the tumor and stimulates some of the tumor cells to produce heat shock proteins (HSP). These proteins are then expressed on the cell membrane together with tumor-associated antigens (HSP-TAA), thus increasing the cell’s antigenicity and inducing additional local immuno-reactions that contribute to the destruction of the tumor cells (10, 14, 16). Depending on the temperature and duration of treatment, there may also be some regional overheating with increased blood flow in the healthy tissue surrounding the tumor, thus causing a reduction in the tumor’s blood supply.

The main problem with the sole application of high temperatures as cancer therapy lies in the technical area, i. e., in reaching sufficiently high and homogenous temperatures in tumors of well-vascularized organs or of deep location, and also in the prevention of so-called hot spots in healthy tissues.

In addition to having direct cytotoxic effects on the tumor tissue and making the tumor tissue more sensitive to chemotherapy or radiation therapy (e. g., by increasing membrane permeability), high temperatures also increase the cytotoxic effects of cytostatic agents and ionizing radiation. Hence, it makes sense to combine these methods. There are also clinical indications that the resistance to chemotherapy can be overcome by heat. The combined therapies may be performed simultaneously, or sequentially at defined alternating intervals.

The cytotoxic effects of hyperthermia are essentially based on molecular and metabolic changes in the cells. Due to the breakdown of molecular structures, the cells become more sensitive to heat not only during mitosis but also during S phase. This might explain the better response rate when radiation therapy and hyperthermia are combined—in addition to the changes in metabolic processes and blood supply–because cells in S phase and mitosis are certainly resistant to radiation. However, they are also especially thermosensitive. Another explanation for the potentiating effect of this combination therapy might be a thermal inhibition of the repair processes following radiation-induced DNA damage. In addition, hyperthermia is first of all effective in hypoxic areas, whereas radiation is more effective in oxygen-rich areas.

•   Infrared radiation Infrared A (IRA) radiation is generally used because it penetrates better into the tissue. In order to prevent skin burns resulting from intense absorption of some of the IRA radiation by water molecules in the uppermost layers of the skin, water-filtered infrared A (wIRA) radiation is sometimes applied. The most important fields of IRA application are superficial hyperthermia (e. g., Hydrosun irradiator) and whole body hyperthermia (e. g., IRATHERM 2000; Heckel hyperthermia bed).