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

4 Hyperthermia

scars.

 rheumy, gout,

arthritis,

pain-management,

muscle spasms,

some allergies,

 rhinitis, common cold, pediatric ear diseases, wound healing,

[44], [45], [46], [47], [48], [49].

some dermatological disorders,

 supportive therapies in sport, some gynecological disorders,

 Increased metabolic rate of contracted joints using heat and stretch techniques, Need of stretching during and/or immediately following the treatment,

Heat increases the extensibility of fibrous tissues such as tendons, joint capsules and

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

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],

Alterations of collagen properties, allowing it to elongate,

 Increased ATP activity (assisting wound regeneration), Psycho-feedback (pleasant sensing) [positive placebo effect],

Ability to control the chronic infection by increasing the circulation,

Increased rate of phagocytosis,

It was applied for many various diseases like:

supporting the general rehabilitation process.

paralytica" to Julius Wagner-Jauregg, (1857-1940, Austria).

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 deep heating without skin injury.

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

**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 Figure **3**.)

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 inflammation-inducing toxins.

The oldest whole body heating was the contact method, immersing the patient into the hot bath, but due to its numerous disadvantages of this method, it is rarely in use any more. Mainly two direct methods are available in the modern medicine to make systemic hyperthermia. The less frequently used is the extracorporeal (the blood is heated outside the body), or the intracorporeal (the blood is heated in-situ in the body). In most cases the capillary bed of the subcutane area is heated by conductive (e.g. hot-bath) or radiative (e.g. infrared) way, using extra-corporal blood-heating. This method takes out the blood from the continuous flow by a definite arterial outlet and the outside heated hot blood is pumped back to the patient.

Local Hyperthermia in Oncology – To Choose or not to Choose? 7

**Figure 4.** Various main methods of the whole-body heating: (a) steam, (b) water, (c) electromagnetic

important factor for patients with weak immune-system.

[71], or by capacitive [72], [73], [74] technical solutions.

methods make the heat-therapies different, (see Figure 7.).

mechanisms in the organism.

When the whole body is systemically heated, it has a strict physiological limit: 42 ºC in humans. The thermal distribution till this level is homogeneous and well controllable. No hot-spots exist, no question arises about the isotherms; the physiologically extreme temperature can be fixed all over the body. Suppressing the risk; a decreased treatment temperature (moderate WBH/whole-body fever-range thermal-therapy) is also applied. The application of lower temperatures for longer time period (fever-therapy, or mildhyperthermia) also showed surprisingly good efficacy for whole-body hyperthermia treatments [61], [62], [63], [64]. The whole body hyperthermia and even its fever-range versions mean effective immune support, [65], [66], [67], [68], which might be a very

The local/regional hyperthermia has also large categories (see Figure **5**.) and various technical choices (see Figure 6.). The widely applied technical solutions were available only after the discovery of the electromagnetic heating. The electromagnetic waves can penetrate deeply into the body. Dominantly, the local/regional systems work by radiative [69], [70],

Both heating categories form large groups of treating options having special subcategories, which are involved in different physiological actions and support different reaction

Technically, a huge variety of heating can be applied by heat therapies. Its energyproduction, its selectivity, locality, kind of energy-delivery, invasivity control, frequency of the electromagnetic waves, as well as their medical applications and combination with other

radiation

**Figure 3.** Categories of whole-body hyperthermia

The whole-body heating could be solved in various ways, like steam, water or radiation heating (see Figure 4.). There are other possibilities as well (e.g. wax heating, hot-air heating, etc.) but the limited possible heat-flux and the poor technical realizations hinder these solutions. By all of these whole-body heating forms the patient's safety has to be seriously considered. These are based on the blood-heating in the subcutaneous capillary bed, and the physiological reactions (vasodilatation and sweating) work well against the huge heat-flux into the body. The long heating time is also challenging (over an hour) moving the body away from the healthy homeostasis. The heat-flux through the skin is limited by the heat injuries (~1 W/cm2 is the limit) so the contact heating with steam and water has definite problems. The radiation heating can be solved by special infrared wave (Infrared A) which penetrates deeper (~1-2 mm) into the subcutaneous layer, and can manage higher energyflux without burn injuries. The method has many early descriptions [51], [52], [53], [54]; but the dominant systemic hyperthermia method is based on the infra-red radiation by multireflecting filtering [55], [56] or by water-filtering [57], [58], [59], [60].

back to the patient.

**Figure 3.** Categories of whole-body hyperthermia

The oldest whole body heating was the contact method, immersing the patient into the hot bath, but due to its numerous disadvantages of this method, it is rarely in use any more. Mainly two direct methods are available in the modern medicine to make systemic hyperthermia. The less frequently used is the extracorporeal (the blood is heated outside the body), or the intracorporeal (the blood is heated in-situ in the body). In most cases the capillary bed of the subcutane area is heated by conductive (e.g. hot-bath) or radiative (e.g. infrared) way, using extra-corporal blood-heating. This method takes out the blood from the continuous flow by a definite arterial outlet and the outside heated hot blood is pumped

The whole-body heating could be solved in various ways, like steam, water or radiation heating (see Figure 4.). There are other possibilities as well (e.g. wax heating, hot-air heating, etc.) but the limited possible heat-flux and the poor technical realizations hinder these solutions. By all of these whole-body heating forms the patient's safety has to be seriously considered. These are based on the blood-heating in the subcutaneous capillary bed, and the physiological reactions (vasodilatation and sweating) work well against the huge heat-flux into the body. The long heating time is also challenging (over an hour) moving the body away from the healthy homeostasis. The heat-flux through the skin is limited by the heat injuries (~1 W/cm2 is the limit) so the contact heating with steam and water has definite problems. The radiation heating can be solved by special infrared wave (Infrared A) which penetrates deeper (~1-2 mm) into the subcutaneous layer, and can manage higher energyflux without burn injuries. The method has many early descriptions [51], [52], [53], [54]; but the dominant systemic hyperthermia method is based on the infra-red radiation by multi-

reflecting filtering [55], [56] or by water-filtering [57], [58], [59], [60].

**Figure 4.** Various main methods of the whole-body heating: (a) steam, (b) water, (c) electromagnetic radiation

When the whole body is systemically heated, it has a strict physiological limit: 42 ºC in humans. The thermal distribution till this level is homogeneous and well controllable. No hot-spots exist, no question arises about the isotherms; the physiologically extreme temperature can be fixed all over the body. Suppressing the risk; a decreased treatment temperature (moderate WBH/whole-body fever-range thermal-therapy) is also applied. The application of lower temperatures for longer time period (fever-therapy, or mildhyperthermia) also showed surprisingly good efficacy for whole-body hyperthermia treatments [61], [62], [63], [64]. The whole body hyperthermia and even its fever-range versions mean effective immune support, [65], [66], [67], [68], which might be a very important factor for patients with weak immune-system.

The local/regional hyperthermia has also large categories (see Figure **5**.) and various technical choices (see Figure 6.). The widely applied technical solutions were available only after the discovery of the electromagnetic heating. The electromagnetic waves can penetrate deeply into the body. Dominantly, the local/regional systems work by radiative [69], [70], [71], or by capacitive [72], [73], [74] technical solutions.

Both heating categories form large groups of treating options having special subcategories, which are involved in different physiological actions and support different reaction mechanisms in the organism.

Technically, a huge variety of heating can be applied by heat therapies. Its energyproduction, its selectivity, locality, kind of energy-delivery, invasivity control, frequency of the electromagnetic waves, as well as their medical applications and combination with other methods make the heat-therapies different, (see Figure 7.).

Local Hyperthermia in Oncology – To Choose or not to Choose? 9

**Combination**

**locality** local regional systemic

**with** chemo-therapy radio-therapy surgery gene-therapy hormone therapy supportive therapy

and its gradients (non-homogeneities) are the driving forces of the dynamic processes in case of microscopic (non-homogeneous) heating. The average temperature does not inform us

> **Clinical applications** superficial intracavitational deep-seated whole-body

**technical notes** control regulation preparation sheelding

**Figure 7.** Categories of the possible hyperthermia methods. A few hundred of healing processes have

**hyperthermia**

**Delivery kind** conduction convection radiation bioactive

**Figure 8.** The average temperature cannot characterize the thermodynamic situation. The internal temperature differences can serve as driving forces of various processes on the same average

been introduced

temperature of the system

about the distribution of the real energy-absorption (see Figure **8**.).

**frequency** not applied Hz-region kHz region MHz region GHz region THz region

**Energy production** contact methods chemical biological mechanical electromagnetic

> **invasivity** invasive semi-invasive

non-invasive **selectivity**

artificial focus self-selective not selective

**Figure 5.** Categories of local heat-treatments

**Figure 6.** Main technical solutions of local heating: (a) contact heat, (b) deep-heating, (c) radiative heating, (d) immersing a part of the body in hot water

These combinations involve more than a hundred solutions of hyperthermia used as treatment, which make the therapy indefinite in its applications. This emphasizes the reason why the present review tries to summarize the main categories.

The thermodynamic situation, and in consequence of the physiological effects of the systemic and local/regional heating modalities are entirely different. There is a definite difference between the temperature of the blood and the inter-capillary volume in the microscopic structure of the target: the blood-arteries are hot-sources in case of systemic treatment, they deliver the heat. However, in case of local/regional hyperthermia it is entirely the opposite: the blood is relatively cold (remaining on unchanged body temperature), the arteries are heat-sinks which are cooling the tumor down, in fact, these work against the local heating.

One question automatically arises: when the heat, the energy-flow has a central role in hyperthermia, then what does the temperature do in the living systems?

The temperature as the average of kinetic energy in the system has a double role in the control of the heat-absorption. It characterizes the heat-absorption, when the heating is homogeneous, and its gradients (non-homogeneities) are the driving forces of the dynamic processes in case of microscopic (non-homogeneous) heating. The average temperature does not inform us about the distribution of the real energy-absorption (see Figure **8**.).

8 Hyperthermia

**Figure 5.** Categories of local heat-treatments

heating, (d) immersing a part of the body in hot water

work against the local heating.

why the present review tries to summarize the main categories.

**Figure 6.** Main technical solutions of local heating: (a) contact heat, (b) deep-heating, (c) radiative

These combinations involve more than a hundred solutions of hyperthermia used as treatment, which make the therapy indefinite in its applications. This emphasizes the reason

The thermodynamic situation, and in consequence of the physiological effects of the systemic and local/regional heating modalities are entirely different. There is a definite difference between the temperature of the blood and the inter-capillary volume in the microscopic structure of the target: the blood-arteries are hot-sources in case of systemic treatment, they deliver the heat. However, in case of local/regional hyperthermia it is entirely the opposite: the blood is relatively cold (remaining on unchanged body temperature), the arteries are heat-sinks which are cooling the tumor down, in fact, these

One question automatically arises: when the heat, the energy-flow has a central role in

The temperature as the average of kinetic energy in the system has a double role in the control of the heat-absorption. It characterizes the heat-absorption, when the heating is homogeneous,

hyperthermia, then what does the temperature do in the living systems?

**Figure 7.** Categories of the possible hyperthermia methods. A few hundred of healing processes have been introduced

**Figure 8.** The average temperature cannot characterize the thermodynamic situation. The internal temperature differences can serve as driving forces of various processes on the same average temperature of the system

Herewith we do not discuss the extreme temperature facilities in local treatments, the ablative techniques with high temperature (heat-ablation, [75]) or low-temperature (cryoablation, [76]).

Local Hyperthermia in Oncology – To Choose or not to Choose? 11

Indeed, there are many factors showing the validity of this assumption, but the breakthrough to accept the method widely hasn't been reached in the long historic period. The appropriate temperature selectively administered in the tumor still cannot be reached.

What happened to hyperthermia and what is its current status in cancer treatment? [78];

Many of the researchers evaluating the capabilities of oncological hyperthermia share the opinion expressed in the editorial comment of the European Journal of Cancer in 2001: the biological effects are impressive, but physically the heat delivery is problematic. The hectic results are repulsive for the medical community. The opinion, to blame the "physics" (means technical insufficiency) for inadequate treatments is general in the field of oncological hyperthermia, formulated the following statement: "The biology is with us, the physics are against us [82]. In the latest oncological hyperthermia consensus meeting the physics was less problematic. However, in accordance with the many complex physiological effects, a modification was proposed: "The biology and the physics are with us, but the

The most problematic issues have always been technical: how to heat in depth, locally focused, being selective for malignant cells, and the other side: how to control it and how to measure the efficacy of the treatment? Even when the local treatment is focused well, the temperature by its way tends to be equalized; the focus is extended by time, due to the very effective heat-exchanger – the blood-stream. The heated tumor strongly exchanges its heat with its healthy surrounding, extending the focus gradually and increasing the local blood-

1. The heating focus is growing, it is not correct any more, so the healthy tissue is also

2. The distributed spots of the tumour (local metastases) can be covered only by on

3. The natural movements of the patients (i.e. due to the breathing) cannot be followed by

4. The blood-flow is increased locally, supplying the tumor with nutrients (first of all with

5. The intensive tumor-metabolism produces high level of lactic acid in the volume, which lowers the pH and forces the blood to buffer it. The blood starts to shift to alkaline and

average, covering the area completely with the intermediate healthy parts,

glucose) and the higher temperature gains the local metabolic rate as well,

Is the community of radiation oncologist ready for clinical hyperthermia? [77];

Should interstitial thermometry be used for deep hyperthermia? [80];

This fact forms a lot of questions in the published literature:

 If we can't define the quality, can we assure it? [81]; Is there a future for hyperthermia in cancer treatment? [82]; What is against the acceptance of hyperthermia? [83];

Is heating the patient a promising approach? [86];

flow. This unwanted effect has some problematic consequences:

Where there's smoke, is there fire? [79];

Prostate cancer: hot, but hot enough? [85];

Hyperthermia: has its time come? [87].

Progress in hyperthermia? [84];

physiology is against us" [88].

heated up,

the focus,
