Hyperthermia on peritonealcarcinoses
What is hyperthermia?
The term hyperthermia refers to raising the temperature of a part of or the whole body above normal for a defined period of time. The amount of temperature elevation is on the order of a few degrees above normal temperature (41,0 - 42.5 C°).
Written reports concerning the use of increased temperatures in cancer treatment have existed for many centuries. Probably the oldest report was found in the Egyptian Edwin Smith surgical papyrus, dated around 3000 BC. Hyperthermia researchers like to cite Hippocrates (460-370 BC) in particular, although the method he describes in one of his aphorisms, i.e. hot irons, concerns higher temperatures, such as those used in cauterisation. In the 19th century Dr. W. Coley treated patients with an extracted bacterial toxin from erysipelas, which causes high fevers. This was after observations that some cancers appeared to resolve after prolonged infection with erysipelas. In 1898, a Swedish physician, Dr. Westermark described anecdotal incidences of local hyperthermia causing cervical cancer to regress.
Rationale for hyperthermia in cancer treatment
- Selective effect
A selective tumour cell killing effect is achieved at temperatures between 40 and 44°C, which is related to a characteristic difference between normal and tumour physiology. The architecture of the vasculature in solid tumours is chaotic, resulting in regions with hypoxia and low pH, which is not found in normal tissues in undisturbed conditions. These environmental factors make cells more sensitive to hyperthermia. The effect of hyperthermia depends on the temperature and the exposure time. Most normal tissues are undamaged by treatment for 1 h at a temperature of up to 44°C. Only nervous tissues appear more sensitive.
- Mechanism of cell death
The main mechanism for cell death is probably protein denaturation, observed at temperatures >40°C, which leads to alterations in molecular structures like cytoskeleton and membranes, and changes in enzyme complexes for DNA synthesis and repair.
- Combination of hyperthermia with chemotherapy
For the combination of hyperthermia and chemotherapy, spatial cooperation can explain the additive effects.
- the efficacy of many drugs is potentiated by heat.
- the addition of hyperthermia to chemotherapy can counteract drug resistance.
- Increase in intracellular drug uptake
- enhanced DNA damage
- increase in intratumour drug concentrations, resulting from an increase in blood flow.
Whether the clinical combination of hyperthermia and chemotherapy leads to therapeutic gain will depend on the temperature increase in the organs for which the used drug is toxic. Hyperthermia is thought to affect tumour sensitivity to other treatments mainly through microenvironmental factors such as pH. One hypothesis is that hypoxic and therefore resistant tumour regions are preferentially eliminated under hyperthermic conditions because associated hypovascularisation results in higher temperatures and higher sensitivity due to hypoxia.
Heat shock proteins
Heat shock proteins (HSPs) are synthesised in response to stress such as a hyperthermic treatment. After a non-lethal heat shock, HSPs were found to be expressed on the surface of malignant cells but not on normal cells. HSP-expressing cells are more susceptible to lysis by natural killer effector cells. HSPs are released following necrotic cell death, and released HSPs stimulate macrophages and dendritic cells to secrete cytokines, and activate antigen-presenting cells.
Normal tissue toxicity will result directly from hyperthermia when the tolerance limits are exceeded. Experimental studies have shown that most normal tissues are not damaged when the temperature over 1 h of treatment does not exceed 44°C. Whether the toxicity of chemotherapy is enhanced will depend on the temperature in the drug-sensitive tissues.
The cellular damage by hyperthermia is most dramatic when the temperature is elevated to 43° C or higher in the intended tissue. The cells are most sensitive to heat in the late S phase (DNA synthesis phase) of the cell cycle.