Experimental Basis for the Use of Hyperthermia in Oncology

Abstract

This review presents the results of experimental studies on the effects of hyperthermia, at a temperature of 40–45 °C, in normal and tumor tissues. These results show that there is a strong rationale for using hyperthermia in addition to radiotherapy and/or chemotherapy in patients with cancer. The following study results are summarized. Hyperthermia has cell killing effects which specifically occur in tumor regions with hypoxia and low pH. In well perfused and well oxygenated tissues, cell damage is usually not observed at temperatures of up to 43 °C. This cell killing effect of hyperthermia is complementary to the effects of radiotherapy and chemotherapy, which treatment modalities are less effective in hypoxic or insufficiently perfused areas. In combination with radio- or chemotherapy, hyperthermia further has sensitizing effects, partly through an increase in blood flow. An important feature in radiosensitization is the inhibition of DNA repair pathways. Radiosensitizing is stronger in tumor tissue than in normal tissue when radiation and hyperthermia are given with a time interval, leading to therapeutic gain. The interaction with various drugs is related to changes in pharmacokinetics, enhancement of drug accumulation and a decrease in intracellular detoxification and damage repair. It was also observed that hyperthermia can overcome chemoresistance associated with multidrug resistance, by influencing transmembrane transport, metabolism, and the functioning of involved proteins. The effects of hyperthermia are stronger with higher temperatures and longer exposure times. Treatment with hyperthermia induces heat shock proteins (HSP’s). These may lead to thermotolerance to the next treatment when that is applied too soon. On the other hand it was found that HSP’s induce an antitumor immune response which may further add to the therapeutic effect. A stimulating effect of hyperthermia on the development of metastases could not be demonstrated in most studies. Studies with drugs in thermosensitive liposomes show that the uptake of drugs in tumor tissues can be largely enhanced. Further, it has been shown that hyperthermia considerably increases the sensitivity of cancer stem cells to radiotherapy and chemotherapy. Sofar, there is limited experience with the combination of hyperthermia and targeted agents. Nanoparticles which can be used for local heat treatment and local drug delivery are under investigation.