**1.2. Medical history of hyperthermia in oncology**

Hyperthermia is really an ancient tradition of human medicine. It is one of the very first known medical therapies, more than 5000 years old, [7].It has been historically recognized that malignant and infectious diseases can be successfully treated by raising the body temperature.

It has been historically recognized that malignant and infectious diseases can be successfully treated by raising the body temperature. The first known oncotherapy by heat was made by an Egyptian priest/physician, Imhotep, in the 5th century BC. He exposed the tumors to "natural heat" (fever) before surgically removing them, which was in fact the very first immune approach as well.

Many ancient cultures used heat to treat diseases and to maintain health. The thermal baths for their curative properties were used by the Greeks, the pre-Christian Jews and the Romans too [8]. The Chinese treated many diseases including syphilis and leprosy by hot spring baths [9]. Taking regular, extremely hot baths from infancy is the block of developing rheumy, according to the ancient Japanese medical notes.

Naturally, this treatment had a sacral meaning in historic times, regarding the Sunlight, the fire and the heat as parts of the leading spiritual object in all ancient religions. This belief was behind when the heat was applied to locally affected parts of the body and to its entirety by means of hot water, steam, hot sand and hot mud baths. Natural hot air caverns connected with volcanic sources were also used. By the development of the medical knowledge, more and more heat applications were applied in practice. Later Hippocrates documented it [10], and he was convinced of its overall efficacy, telling when hyperthermia (fire) does not help, then the disease has to be declared as incurable. Hippocrates said: "Give me the power to produce fever and I will cure all diseases". His followers in line were Aurelius Cornelius Celsus and Rufus of Ephesus, who believed in the curative effect of fever. The progress continued in the Middle Ages [11], when the ablation techniques (burn out the tumor) and hot-bathes dominated the hyperthermia practices, while the temperature measurement was worked out step by step.


2 Hyperthermia

temperature. This whole-body heating can be unwanted, mainly accidental from environmental sources, and it might be accelerated by additional heavy muscular work or by extra metabolic activity. This is a life-threatening situation with the danger of a heatstroke [6]. Hyperthermia requests definite and effective medical treatment when it appears as a disease, having elevated body temperature and the patient suffers from its serious consequences. This medical intervention applies therapies to reestablish the normal temperature of the body keeping the healthy homeostasis (overall stability) and handling

The popular heat-treatment applications are types of "kitchen medicine": the old recipes are "sure", the patient follows them, and is cured when everything is done according to the auricular traditional regulations. The meaning of "kitchen medicine" is: do it like in the kitchen, reading the process from the cookery-book: "heat it on the prescribed temperature for the prescribed time and the success is guaranteed". This type of thinking has its origin in the ancient cultures, when the Sun - the fire, the heat - was somehow in the centre of the

Hyperthermia

**Therapy**  applied curatively or palliative for various diseases in households and in medicine

This idea of "take it for sure" is the disadvantage of the popular wisdom. It interprets this heating method as a simple causal process, "do it, get it", however, hyperthermia is not as

Hyperthermia is really an ancient tradition of human medicine. It is one of the very first known medical therapies, more than 5000 years old, [7].It has been historically recognized that malignant and infectious diseases can be successfully treated by raising the body

It has been historically recognized that malignant and infectious diseases can be successfully treated by raising the body temperature. The first known oncotherapy by heat was made by an Egyptian priest/physician, Imhotep, in the 5th century BC. He exposed the tumors to "natural heat" (fever) before surgically removing them, which was in fact the very first

the consequences of the unwanted high body temperature.

**Figure 1.** Main categories of hyperthermia

**Disease**  caused by various functional irregularities or by accidental whole-body heating

religious beliefs and philosophical focus.

**1.2. Medical history of hyperthermia in oncology** 

simple as traditions interpret it.

temperature.

immune approach as well.


Increased metabolic rate of contracted joints using heat and stretch techniques,

Local Hyperthermia in Oncology – To Choose or not to Choose? 5

As it was shown before, there are two, basically different hyperthermia processes: the systemic (heats the complete body, whole-body treatment), and the local/regional heating (heats only a part of the organism). The two basic kinds of the heating methods also differ in their physiological limitations: the systemic treatment, of course, modifies the entire physiology of the organism, and that could limit the applied energy-absorption and bodytemperature. There is a possibility to absorb energy in large volume equally or having a layer-by-layer changing front (heat-diffusion, heat-flow flux) depending on the penetration depth of the actually applied energy. Nevertheless, the old direct heating methods (hot solids or liquids in the area or in the nearest body cavity) were not effective enough for local

Thermodynamically the systemic and local/regional treatments differ by their energy-intake. The whole body treatment is based on the blood-heating (mostly heats up the subcutaneous capillary bed, or heats the mainstream of the blood directly with extracorporeal heater), while the local hyperthermia is definitely a tissue heating approach. This difference drastically divides the two methods from thermal point of view. In whole body treatment the blood is a heating media, it delivers the heat to the tumor and heats it up; while in local treatment, the blood remains on body temperature during the local heating, so it is a cooling

**Figure 2.** Opposite thermodynamic mechanisms of whole-body, systemic (a) and local (b) heating methods. The blood-heated tumor in whole body treatment reaches thermal equilibrium after a certain time, while the local treatment is always in non-equilibrium state, because the body temperature is lower than the heated tissue, creating intensive heat-flow from the target to the neighborhood.

The systemic (whole-body) treatment uses the blood-circulation to heat-up the body. (see

The artificially elevated body-temperature is the source of heating in fever inducing methods. Fever inducing can be solved with various drugs [50], as well as with special

**1.3. Heating methods – local and systemic** 

media (heat-sink) for the locally heated tumor, (see Figure **3**).

deep heating without skin injury.

Figure **3**.)

inflammation-inducing toxins.


It was applied for many various diseases like:


A Nobel Prize was also granted for hyperthermia in Physiology & Medicine in 1927 "for his discovery of the therapeutic value of malaria inoculation in the treatment of dementia paralytica" to Julius Wagner-Jauregg, (1857-1940, Austria).

The application of heat in oncology has been restarted with huge intensity. Among the first modern curative applications in oncology, Busch [12] and Coley [13] were successful at the end of the 19th century with artificial fever generated by infection and toxins, respectively. These systemic applications were soon followed by local and regional heating by Westermark F. [14], Westermark N. [15], and Overgaard K. [16]. The leading German surgeon at that time, Bauer KH's opinion in his monograph "Das Krebsproblem" about the oncologic hyperthermia is typical: "All of these methods impress the patient very much; they do not impress their cancer at all." However, very early, in 1912, a controlled Phase II clinical study was published, 100 patients showing the benefit of the thermo-radiation therapy [17]. Tremendous number of publications were prepared in the first quarter of the 20th century, expecting fantastic development in the topic, [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], [49].
