**2.1. The use of hyperthermia**

The concept of using heat to destroy cancerous tissue has been attempted multiple times in the past. It was, however, difficult to develop a mechanism of heat delivery to the affected tissues that would allow controlled ablation of tissues in question. One of the earliest references to the efficacy of mild hyperthermia in cancer destruction is found in 1891 in the report by Dr. Coley, an orthopedic surgeon, who made an observation of complete resolution of an inoperable sarcoma in a patient after *Streptococcus pyogenes* infection [9]. He suggested that the high fevers that accompany the illness injured cancer cells sufficiently to destroy them. He followed up that work by describing a series of 10 patients that were successfully treated with "bacterial toxin therapy" [9]. Unfortunately, his results were not reproduced by others.

In the years to come, radiation therapy and chemotherapy have established themselves as mainstream treatments for cancer. It was not until 1967 when Cavaliere et al. demonstrated selective sensitivity to heat of cancer cells, thus suggesting the use of hyperthermia as part of cancer therapy [10]. Follow-up work in animal models corroborated that notion. It was demonstrated that hyperthermia preferentially affects glioma cells compared to surrounding brain tissue. Local hypoxia and more acidic microenvironment within tumor contributes to this selective sensitivity to heat of glioblastoma [11]. Furthermore, hyperthermia potentiates the effects of radiation and chemotherapy observed in vitro [12–14].

Other factors, however, influence the effectiveness of hyperthermia. In vitro experiments showed that only 50% of sarcomas were responsive to hyperthermia resulting in tumor remission, whereas the other 50% had no response to elevated temperatures [15]. The threshold temperature at which irreversible damage occurs is different across species. While cell cycle arrest and increased cell death in rodent cell lines occurs at 43°C, in human cell lines that threshold is at 41°C [16].

The mechanism by which mild hyperthermia induces damage to cancer cells may involve activation of apoptosis pathways in a temperature dependent fashion, resulting in changes of expression of heat shock proteins such as HSP 27 and 72. The latter display antitumor properties by initiating immunologic response resulting in activation of natural killer cells directed against tumor cells [17].
