**2. Malignant diseases – To heat or not to heat?**

The popular terms "*heat-dose*", "*temperature-gain*", "*thermal dose*", "*energy-intake*", "*energy-dose*" may have different definitions in various individuals who use them. Our first task is to clarify the differences between these (in popular literature many times used as synonyms) terms.

Nevertheless, the temperature is not heat, not even energy. Temperature, in this sense, is a hypothetical value of the average energy. Particles have various energies and it could happen no any individual particle has such definite energy as the average (the temperature) indicates.The temperature is an average; we can define it only on a large number of participating units (particles). The average energy of the various particles at normal human body temperature (ideal thermodynamic model) is ~ 2.5 kJ/mol. This relatively large energy is embedded and blocked in the actual system. (It is so large, that if it could be liberated within one second, the obtained power would be 2.5 kW/mol.) This average thermal energy limits the internal bonds and interactions, because any lower energy bond will be destroyed by this thermal background. This internal energy could make abrupt changes by such chemical reactions, by which activation energy is smaller (or equal) than the actual thermal average energy. The weakest bonds in life are the hydrogen-bridges, having 18 kJ/mol in ice [89] and ranging 3-30 kJ/mol in various compounds in living objects [90].

Pumping heat into a system can increase its temperature. The result of heating is not a definite temperature. The resulting temperature always greatly depends on how the heat is consumed in the system, and how the system transfers this energy to its environment. Pumping the same energy into identical volumes, but having different surfaces, the temperature increase will be definitely different, because the volume is differently cooled down by the environmental conditions. Furthermore, the heat can make structural or other rearrangement in the material, it could be transformed into work without temperature increase of the system. For example: melting the ice absorbs energy without temperature increase, still it is completely transformed into liquid. The heat, which is pumped in to the system at this phase transition does not increase the temperature; its energy is used completely to change the structure of the material from solid to liquid.

Other clear example is the Sun radiation to the Earth. A huge part of the energy of the Sun's radiation is converted to the meteorology (like wind or rain), their mechanical effects (like waves in the ocean, like distortion of the rocks). The Sun's energy is the solely energy-source of the life processes, and this energy of the Sun makes our oil reserves, allowing us to use this energy for various applications in our everyday life. So the simple electromagnetic radiation (the spectrum of the Sun) is converted to the various kinds of energies in the Earth. Only a fraction of the radiation is realized as heat and rising temperature.

Other simple example is the human energy-intake: a female adult eats ~1600 kcal/day. When she takes more energy a day, it will not change her body temperature at all. However, when she gets this energy from radiation, she will starve, despite of the fact that she gets more energy than she could take from nutrients.

When there are so serious differences between the heat and temperature, why do we confuse them? The main reason is: we fix our attention to simple situations when we heat such materials which distribute the energy immediately all over the system, making thermal equilibrium without internal work (reactions, dilatation, etc.) in the system. In such cases, of course, all the heat energy increases the internal energy of the system, and so it is distributed in it, and proportionally increases its temperature.

When we fix our attention to such systems, like heating water in its liquid form, the applied heat and temperature are strictly proportional in a certain interval (when the water is definitely liquid). However, we have a problem even in this simple system. When a phasetransition occurs, we lose this proportionality completely. At the/a study of hyperthermia in living systems, we have to well distinguish the overall energy, the heat energy and the temperature (which is not energy) from each other.

"The use of thermodynamics in biology has a long history rich in confusion." [91]. The main complication is the fact that life cannot be studied isolated from its environment, and so the energetically open system could lead to numerous uncertainties, leading sometimes to mystification as well.

### **2.1. The heating paradigm**

12 Hyperthermia

mechanism,

complicated,

control of the treatment process,

with its ability to create carcinogens in situ.

**2. Malignant diseases – To heat or not to heat?** 

the alkaline blood delivers more oxygen to the volume, by positive feedback

8. Enlarging the sphere having certain temperature gradients increases the area of the

9. The growing heated volume is uncontrolled, the vigilance of the process becomes

10. The incident energy might burn the skin, so surface cooling is necessary. The heat-sink of the surface decreases the incident power, but its quantity has no measurable parameters. This is the reason why only the temperature in the target will orientate the

11. The necessary temperature measurement is mostly invasive, which could cause many complications, including inflammation, bleeding, infection, dissemination of the cells, etc. 12. The microwave heating might do harm not only by its unwanted hot-spots, but also

These technical challenges are definitely complex, and can make the actual hyperthermia treatment uncontrolled. This branch of problems could be the reason for some controversial results and the weak acceptance of the conventional hyperthermia among medical experts.

The popular terms "*heat-dose*", "*temperature-gain*", "*thermal dose*", "*energy-intake*", "*energy-dose*" may have different definitions in various individuals who use them. Our first task is to clarify the differences between these (in popular literature many times used as synonyms) terms.

Nevertheless, the temperature is not heat, not even energy. Temperature, in this sense, is a hypothetical value of the average energy. Particles have various energies and it could happen no any individual particle has such definite energy as the average (the temperature) indicates.The temperature is an average; we can define it only on a large number of participating units (particles). The average energy of the various particles at normal human body temperature (ideal thermodynamic model) is ~ 2.5 kJ/mol. This relatively large energy is embedded and blocked in the actual system. (It is so large, that if it could be liberated within one second, the obtained power would be 2.5 kW/mol.) This average thermal energy limits the internal bonds and interactions, because any lower energy bond will be destroyed by this thermal background. This internal energy could make abrupt changes by such chemical reactions, by which activation energy is smaller (or equal) than the actual thermal average energy. The weakest bonds in life are the hydrogen-bridges, having 18 kJ/mol in ice

Pumping heat into a system can increase its temperature. The result of heating is not a definite temperature. The resulting temperature always greatly depends on how the heat is consumed in the system, and how the system transfers this energy to its environment.

[89] and ranging 3-30 kJ/mol in various compounds in living objects [90].

6. The intensive blood-flow has a risk of the further disseminations and metastases, 7. The heat flow to the surroundings can damage the healthy neighbourhood,

injury current which supports the cell-proliferation,

The idea of the local heating effect to burn-out the energy sources of the malignancy has dominated the hyperthermia applications from the time of Hippocrates. Its operation measured by modern methods [92], shows definite decrease of ATP and increase of lactic

acid in tumors after hyperthermia treatment. The ATP depletion makes a heavy ionicimbalance in cells [93]. Furthermore, the increased temperature can slow down or even arrest DNA replication, [94], [95].

Local Hyperthermia in Oncology – To Choose or not to Choose? 15

[118]. Furthermore, hyperthermia acts in G0 phase of cell-division which makes the action of

For radiotherapies, the increased microcirculation sensitizes the effect of ionizing radiation [119]. The primarily applied heat can enhance the effect of ionizing radiation because of the higher oxygen concentration in the area. Furthermore, the most efficient action of hyperthermia is in S-phase [120], which well completes the weak effect of radiotherapy in this phase of the cell-cycle. The heat-induced decrease of the DNA-dependent proteinkinase (DNA-PK), [121] is also a radio-sensitizer. Sensitizing the classical ionizing-radiation by hyperthermia has been well-known [122], [123] for a long time, and different review articles have summarized this knowledge [124], [125], [126], [127]. The advantage of combining heat-treatment with the classical ionizing-radiation is unambiguous, [128], [129], [84], the synergy between the methods is well known [130], [122] and successfully applied

Hyperthermia has also been found to have pronounced advantages for surgical interventions. Through hyperthermia induced inhibition of angiogenesis and heat entrapment, the outline of the tumor often becomes pronounced and the size of the tumor often shrinks, making previously dangerous operations possible [133]. The feasibility of the preoperative application for locally advanced rectal cancer is well shown in a Phase II clinical trial [134]. Postoperative application of hyperthermia has also been thought to prevent relapses and metastatic processes [132]. Intraoperative radiofrequency ablation [135]

The combination of hyperthermia with gene-therapy also looks very promising, as shown by the successful combination of hyperthermia with HSP-promoter mediated gene therapy in cases of patients with advanced breast cancer [137]. Hyperthermia improved the results of the HSP-promoter gene therapy by inducing local HSP production and by enhancing the local rate of release from liposome [138]; it was also helpful in the double suicide gene transfer into prostate carcinoma cells [139]. It was proven that this combination therapy was highly selective for mammary carcinoma cells. Also the heat-induced gene expression could

Combination with hormone therapies is also a vivid method, applied for prostate [141]; and in melanoma treatment **[**112**]**. Enzyme-therapy [142], photodynamic therapy [143], gene therapy [144], immune- [145] and other supportive-therapies [146] are used in combination

 All these factors position hyperthermia to one of the most effective treatments in oncology. Since these are mostly temperature dependent effects, an accelerated race has been started for the rising temperature and providing the highest available thermal support for the conventional therapies. Most of the applied electromagnetic techniques started to gain their power over 1 kW, providing powerful radiative, capacitive and

magnetic effects to increase the temperature in depth in the targeted tissue.

and local hyperthermia [136] have also been used to improve surgical outcomes.

be an excellent tool in the targeted cancer gene therapy [140].

conventional therapies possible on these cells too.

[131], [132], [106].

with hyperthermia.

Higher tissue temperature stimulates the immune system **[**94] with observed increase in natural killer cell activity [96]. Moreover, the elevated temperature distributes tumorspecific antigens on the surface of various tumor cells [97] and assists in their secretion into the extracellular fluid [98], triggering the immune reactions against the malignant cell [94].

Hyperthermia has shown significant pain-reduction during treatments [99]. This makes this method excellent to improve the quality of the patient's life and it can be applied as palliative treatment when the curative solution does not work.

Multiple effects can be counted by homogeneous heating the living organisms completely or locally. One of the decisional factors is the vasodilatation. The induced vasodilation increases:


These induce the following actions:


The chemo-drugs are delivered to the tumor by the blood-stream. Higher local temperature increases the microcirculation in the heated volume, [100], [101], [102], [103], [104], [105], [106], [107], [108], [109]; and with this it enhances the efficacy of the conventional chemotherapies [110]. The synergy between heat-treatment and many of the chemotherapies is well-established [111], [112].

Further support is that the hot drug is more reactive [113], providing excellent possibility to synergy, which is even more effective when we consider the accelerated drug metabolism and gained pharmacokinetic parameters. The thermo-chemotherapy results in a better therapeutic effect and it increases the target specificity as well as it reduces the systemic side effects [114], [115]. In some cases the low-dose chemotherapy could be used [116], [117] with the hyperthermia promotion, it is also applied in low-dose metronomic chemo-regulation, [118]. Furthermore, hyperthermia acts in G0 phase of cell-division which makes the action of conventional therapies possible on these cells too.

14 Hyperthermia

increases:

Blood flow

 Capillary filtration Capillary pressure Oxygen perfusion

These induce the following actions:

higher local temperature),

pathways, etc.),

well-established [111], [112].

arrest DNA replication, [94], [95].

acid in tumors after hyperthermia treatment. The ATP depletion makes a heavy ionicimbalance in cells [93]. Furthermore, the increased temperature can slow down or even

Higher tissue temperature stimulates the immune system **[**94] with observed increase in natural killer cell activity [96]. Moreover, the elevated temperature distributes tumorspecific antigens on the surface of various tumor cells [97] and assists in their secretion into the extracellular fluid [98], triggering the immune reactions against the malignant cell [94].

Hyperthermia has shown significant pain-reduction during treatments [99]. This makes this method excellent to improve the quality of the patient's life and it can be applied as

Multiple effects can be counted by homogeneous heating the living organisms completely or locally. One of the decisional factors is the vasodilatation. The induced vasodilation

Increases drug-delivery in the volume, when the drug is administered systemically,

Increases the metabolic activity in the volume (higher quantity of nutrition, oxygen and

Increases the field-dependent effects, (membrane excitation, activation of signal

The chemo-drugs are delivered to the tumor by the blood-stream. Higher local temperature increases the microcirculation in the heated volume, [100], [101], [102], [103], [104], [105], [106], [107], [108], [109]; and with this it enhances the efficacy of the conventional chemotherapies [110]. The synergy between heat-treatment and many of the chemotherapies is

Further support is that the hot drug is more reactive [113], providing excellent possibility to synergy, which is even more effective when we consider the accelerated drug metabolism and gained pharmacokinetic parameters. The thermo-chemotherapy results in a better therapeutic effect and it increases the target specificity as well as it reduces the systemic side effects [114], [115]. In some cases the low-dose chemotherapy could be used [116], [117] with the hyperthermia promotion, it is also applied in low-dose metronomic chemo-regulation,

Increases the micro vascular perfusion (circulation), nutrients, and phagocytes.

palliative treatment when the curative solution does not work.

Increases fibroblastic activity and capillary growth,

Increases the nutrition concentration in the volume,

Increases the effects on the blood-structure in the volume,

Increases the oxygenation in the volume,

For radiotherapies, the increased microcirculation sensitizes the effect of ionizing radiation [119]. The primarily applied heat can enhance the effect of ionizing radiation because of the higher oxygen concentration in the area. Furthermore, the most efficient action of hyperthermia is in S-phase [120], which well completes the weak effect of radiotherapy in this phase of the cell-cycle. The heat-induced decrease of the DNA-dependent proteinkinase (DNA-PK), [121] is also a radio-sensitizer. Sensitizing the classical ionizing-radiation by hyperthermia has been well-known [122], [123] for a long time, and different review articles have summarized this knowledge [124], [125], [126], [127]. The advantage of combining heat-treatment with the classical ionizing-radiation is unambiguous, [128], [129], [84], the synergy between the methods is well known [130], [122] and successfully applied [131], [132], [106].

Hyperthermia has also been found to have pronounced advantages for surgical interventions. Through hyperthermia induced inhibition of angiogenesis and heat entrapment, the outline of the tumor often becomes pronounced and the size of the tumor often shrinks, making previously dangerous operations possible [133]. The feasibility of the preoperative application for locally advanced rectal cancer is well shown in a Phase II clinical trial [134]. Postoperative application of hyperthermia has also been thought to prevent relapses and metastatic processes [132]. Intraoperative radiofrequency ablation [135] and local hyperthermia [136] have also been used to improve surgical outcomes.

The combination of hyperthermia with gene-therapy also looks very promising, as shown by the successful combination of hyperthermia with HSP-promoter mediated gene therapy in cases of patients with advanced breast cancer [137]. Hyperthermia improved the results of the HSP-promoter gene therapy by inducing local HSP production and by enhancing the local rate of release from liposome [138]; it was also helpful in the double suicide gene transfer into prostate carcinoma cells [139]. It was proven that this combination therapy was highly selective for mammary carcinoma cells. Also the heat-induced gene expression could be an excellent tool in the targeted cancer gene therapy [140].

Combination with hormone therapies is also a vivid method, applied for prostate [141]; and in melanoma treatment **[**112**]**. Enzyme-therapy [142], photodynamic therapy [143], gene therapy [144], immune- [145] and other supportive-therapies [146] are used in combination with hyperthermia.

 All these factors position hyperthermia to one of the most effective treatments in oncology. Since these are mostly temperature dependent effects, an accelerated race has been started for the rising temperature and providing the highest available thermal support for the conventional therapies. Most of the applied electromagnetic techniques started to gain their power over 1 kW, providing powerful radiative, capacitive and magnetic effects to increase the temperature in depth in the targeted tissue.
