**2.2. Targeting complications**

The large heating energy heats up the healthy surrounding as well, see Figure 10. The blood-flow will be enhanced, the nutrients supply will be higher and the result is the opposite of our aim. The situation becomes even worse by continuing the high-energy heating: the high blood-flow helps the dissemination [147], [148], [149] and could gain the metastases: Figure 11. With this, we can definitely worsen the survival and the quality of life of the patient. This problem gained the official policy in many oncological departments: avoid application of hyperthermia in oncotherapies.

Local Hyperthermia in Oncology – To Choose or not to Choose? 17

y = 42.599x-0.4089 R2 = 0.9943

mechanisms, which tries to reestablish the local homeostatic equilibrium by intensified blood-flow. The blood is on body temperature and this way it is an effective cooling media. This is the reason why huge energy is necessary to compensate the heat-loss of the tumor,

A typical capacitive coupling solution pumps enormous energy, [150]. The rise of temperature, applying 1200 W energy after 45 min, was 4.8 oC but the reached focus differs with about 1 oC only from its untargeted neighborhood. In case of radiative applications the situation is the same. The temperature elevation in the tumor after 57 min was 4.2 oC; reached by as high power as 1300 W [151]. The overall heating obviously shows unwanted hot-spots. The elapsed time smears the relatively focused temperature. The temperature increase in the tumor was 4.2 oC on average, while in the surrounding muscle it was only 3.8 oC [151]. Is this the focus we expected? (Note, a standard speedy electric tea kettle uses 1300 W to boil a cup of water within a couple of minutes. The increase of the temperature for the ~ 0.3 liter water is ~75 ºC. We apply, in these cases, the same power reaching a temperature

Further problems occur by a huge surface energy-density pumping high energy dose in depth. Due to the huge thermal load on the skin, more and more sophisticated methods have been/are being developed to cool the skin and to avoid its burn. A new technical race

The maximal surface power density could be 1 W/cm2 (10 kW/m2), for ~ 42 min, (see Figure

started: cooling the surface together with the increase of the incident power.

**Figure 12.** Threshold of surface blisters by power density through the dermal layers

Threshold of blisters

In general, the injury level (threshold of blisters) depends on the full integral of the heatflux, consequently, a longer treatment-time has lower power limit of use and for example, the 60 min treatment allows maximum 0.5 W/cm2 without surface toxicity. Cooling is applied in most of the technical solutions to avoid the surface burn from overheating, see

0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 **Power density [W/cm2]**

**12**. [152]), which is a definite limit of the energy intake.

and keeps the tumor temperature actually higher than its healthy environment.

increase ~7 ºC during 60 minutes).

**Time of heat exposing [min]**

Figure 13.

**Figure 10.** The real situation heats up the surroundings, the local heating does not remain locally focused

**Figure 11.** The large heated volume is not controlled from the focus, and makes the malignant dissemination possible by the high blood-flow in the healthy surroundings

It is plausible: the temperature spreads to the neighboring volumes independently of how precise the focus of the energy is. The energy can be focused, but the temperature seek is to be equalized and the focused energy-intake will heat up the tissue out of the focus too. This process is very rapid anyway in such good heat-conduction material as the living tissue. The cooling becomes even more emphasized, considering the physiological feedback mechanisms, which tries to reestablish the local homeostatic equilibrium by intensified blood-flow. The blood is on body temperature and this way it is an effective cooling media. This is the reason why huge energy is necessary to compensate the heat-loss of the tumor, and keeps the tumor temperature actually higher than its healthy environment.

16 Hyperthermia

focused

**2.2. Targeting complications** 

avoid application of hyperthermia in oncotherapies.

The large heating energy heats up the healthy surrounding as well, see Figure 10. The blood-flow will be enhanced, the nutrients supply will be higher and the result is the opposite of our aim. The situation becomes even worse by continuing the high-energy heating: the high blood-flow helps the dissemination [147], [148], [149] and could gain the metastases: Figure 11. With this, we can definitely worsen the survival and the quality of life of the patient. This problem gained the official policy in many oncological departments:

**Figure 10.** The real situation heats up the surroundings, the local heating does not remain locally

**Figure 11.** The large heated volume is not controlled from the focus, and makes the malignant

It is plausible: the temperature spreads to the neighboring volumes independently of how precise the focus of the energy is. The energy can be focused, but the temperature seek is to be equalized and the focused energy-intake will heat up the tissue out of the focus too. This process is very rapid anyway in such good heat-conduction material as the living tissue. The cooling becomes even more emphasized, considering the physiological feedback

dissemination possible by the high blood-flow in the healthy surroundings

A typical capacitive coupling solution pumps enormous energy, [150]. The rise of temperature, applying 1200 W energy after 45 min, was 4.8 oC but the reached focus differs with about 1 oC only from its untargeted neighborhood. In case of radiative applications the situation is the same. The temperature elevation in the tumor after 57 min was 4.2 oC; reached by as high power as 1300 W [151]. The overall heating obviously shows unwanted hot-spots. The elapsed time smears the relatively focused temperature. The temperature increase in the tumor was 4.2 oC on average, while in the surrounding muscle it was only 3.8 oC [151]. Is this the focus we expected? (Note, a standard speedy electric tea kettle uses 1300 W to boil a cup of water within a couple of minutes. The increase of the temperature for the ~ 0.3 liter water is ~75 ºC. We apply, in these cases, the same power reaching a temperature increase ~7 ºC during 60 minutes).

Further problems occur by a huge surface energy-density pumping high energy dose in depth. Due to the huge thermal load on the skin, more and more sophisticated methods have been/are being developed to cool the skin and to avoid its burn. A new technical race started: cooling the surface together with the increase of the incident power.

The maximal surface power density could be 1 W/cm2 (10 kW/m2), for ~ 42 min, (see Figure **12**. [152]), which is a definite limit of the energy intake.

**Figure 12.** Threshold of surface blisters by power density through the dermal layers

In general, the injury level (threshold of blisters) depends on the full integral of the heatflux, consequently, a longer treatment-time has lower power limit of use and for example, the 60 min treatment allows maximum 0.5 W/cm2 without surface toxicity. Cooling is applied in most of the technical solutions to avoid the surface burn from overheating, see Figure 13.

Local Hyperthermia in Oncology – To Choose or not to Choose? 19

40-45 oC. The local maximal temperature in most cases depends more on the patient than on the incident power. At the end, the origin of the heat-flow will not exceed the 1 W/cm2 on average. The higher isolation will absorb more energy, and so we need more cooling for safety and so on, see Figure 16. It is a positive feedback regulation, requesting enormous

**Figure 15.** The blood-perfusion changes the conductivity and the relative permittivity as well

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.1

Conductivity [S/m] Relative permittivity

Conductivity (S/m)

Relative permittivity

Blood perfusion (ratio)

**Water-bolus Water-bolus** Physiologically regulated larger isolation layer High drop of field

High drop of field burns the subcutaneous layer under the electrode

Intensive cooling continues

**Electric parameters of the skin, depending on the blood-perfusion**

d e ve pe e b y

Regulated temperature No intensive cooling

> Physiologically regulated good heat- and electric conduction (optimized for low drop of field)

1

10

100

**Figure 16.** The physiologically regulated optimum is necessary for energy control. The large cooling grows the physiological reaction, creates a layer of isolation, which accelerates the dangerous surface

Regulated optimum Overcooled surface Positive feedback <sup>→</sup> burn

Further complication in the control is the value of blood-flow, which is temperature dependent. The physiologic effects connected with the blood-flow are considered to be

The cooling energy is indefinite. The applied definite heating is modified with this energyfactor, making the really applied energy immeasurable. The hyperthermia dose must be the physically correct, accepted specific-energy absorption rate in J/kg, as we do it in the case of ionizing radiation too. The dosing in this case requests other, deep-inside measurement for indication of the process: the temperature as the character of the really absorbed energy. However, it is again problematic from a technical point of view: in fact, the absorbed energy

important and it is studied in details, [154], [155], [156], [157], [158].

**Water-bolus** Intensive cooling

energies.

overheating by positive feedback

**Figure 13.** The incident power can overcome the threshold of blisters (a). Appropriate surface cooling is introduced to avoid this burn (b)

The surface cooling has a double effect: it cools down the surface taking away the surface energy to avoid the burn and to keep the heat-sensors (which are located in the near-surface subcutaneous area) of the body in the pleasant range of feeling.

However, the surface cooling creates serious problems too:

It makes the control of the energy intake ambiguous, no precise dose can be measured by the forwarded power. When the forwarded dose is 100 W, the cooling is 50W and the intensive cooling of the blood circulation on the surface is 30W and then maximum 20W can be absorbed in the target (see Figure 14.).

**Figure 14.** The forwarded power and the cooling power work oppositely. No idea about the real power pumped into the body

The high energy loss in the surface area is mainly due to the adipose layers, which are good electric- and heat-isolators [153]. Their isolation ability depends on their thickness, and it is controlled by the blood perfusion. When we cool down the surface, the homeostatic control will increase the isolating layer (see Figure 15.) by reducing the blood-flow in the area.

There is a misleading competition on the power, which is applied for local hyperthermia. The subcutane adipose tissue is an electric- and heat-flow blockade, and its conductivity decides the current transport at a fixed power transmission. The applied voltage depends on the contact area and on the applied frequency as well. The available devices for local heating range from 150W to 2000W and, in fact, the local temperature in the tumor ranges between 40-45 oC. The local maximal temperature in most cases depends more on the patient than on the incident power. At the end, the origin of the heat-flow will not exceed the 1 W/cm2 on average. The higher isolation will absorb more energy, and so we need more cooling for safety and so on, see Figure 16. It is a positive feedback regulation, requesting enormous energies.

18 Hyperthermia

introduced to avoid this burn (b)

**Figure 13.** The incident power can overcome the threshold of blisters (a). Appropriate surface cooling is

The surface cooling has a double effect: it cools down the surface taking away the surface energy to avoid the burn and to keep the heat-sensors (which are located in the near-surface

It makes the control of the energy intake ambiguous, no precise dose can be measured by the forwarded power. When the forwarded dose is 100 W, the cooling is 50W and the intensive cooling of the blood circulation on the surface is 30W and then maximum 20W can

**Figure 14.** The forwarded power and the cooling power work oppositely. No idea about the real power

The high energy loss in the surface area is mainly due to the adipose layers, which are good electric- and heat-isolators [153]. Their isolation ability depends on their thickness, and it is controlled by the blood perfusion. When we cool down the surface, the homeostatic control will increase the isolating layer (see Figure 15.) by reducing the blood-flow in the area.

There is a misleading competition on the power, which is applied for local hyperthermia. The subcutane adipose tissue is an electric- and heat-flow blockade, and its conductivity decides the current transport at a fixed power transmission. The applied voltage depends on the contact area and on the applied frequency as well. The available devices for local heating range from 150W to 2000W and, in fact, the local temperature in the tumor ranges between

subcutaneous area) of the body in the pleasant range of feeling.

However, the surface cooling creates serious problems too:

be absorbed in the target (see Figure 14.).

pumped into the body

**Figure 15.** The blood-perfusion changes the conductivity and the relative permittivity as well

**Figure 16.** The physiologically regulated optimum is necessary for energy control. The large cooling grows the physiological reaction, creates a layer of isolation, which accelerates the dangerous surface overheating by positive feedback

Further complication in the control is the value of blood-flow, which is temperature dependent. The physiologic effects connected with the blood-flow are considered to be important and it is studied in details, [154], [155], [156], [157], [158].

The cooling energy is indefinite. The applied definite heating is modified with this energyfactor, making the really applied energy immeasurable. The hyperthermia dose must be the physically correct, accepted specific-energy absorption rate in J/kg, as we do it in the case of ionizing radiation too. The dosing in this case requests other, deep-inside measurement for indication of the process: the temperature as the character of the really absorbed energy. However, it is again problematic from a technical point of view: in fact, the absorbed energy

distribution and the gained temperature are very different [159]. The reason is simple: provide the same energy to identical volume but the blood-flow is different in every case so it will result in different temperature. The physiology modifies the temperature! It is not possible to match the specific absorption rate (SAR) and the developed temperature.

Local Hyperthermia in Oncology – To Choose or not to Choose? 21

liberates large energy in a short time, and only a small fraction of this could be applied beneficially, most of the energy is radiated, conducted or lost in various other ways. One of the largest losses is the heat-exchange by the high temperature, which somehow has to be used again (e.g. intercooler, turbo). The latest solution, however, is the set of microscopic explosions, promoting the chemical reactions individually by a membrane control (i.e. fuel cell solution) and using the energy step-by-step as a sum of the micro-reactions. The relatively low efficacy combusting engines are intended to be replaced by the fuel-cell energy-sources combined with electric motors, which are based on the membrane regulated

In fact, life "invented" the controlled energy-liberation by micro-processes, blocking the sudden, explosion-like energy liberation, driving the processes small subsequent energyconversion steps instead. In the living objects the energy is liberated gradually in a "ladder"

**Figure 18.** The difference between macro- and micro-liberation of energy. The latter is much more

heats up the environment, having only 10% efficacy.

The applied power and its efficacy are usually not connected. Good examples can be found in our everyday life, in systems like the standard light bulbs and the energy safe ones using a fraction of the power for the same light*;* or the various power-consumptions of cars, having equal performance, or the various fuel consumption of them having the same engine-power. The incandescent bulb creates light by high-temperature filament, which

Fluorescent technology solves this task more smartly: it makes the energy-liberation selective where the effect radiates light only (see Figure 19.). Fluorescent particles turn the UV from mercury excitation to visible light. The full process has approx. 45% efficacy.

The LED technology is even more effective, because no intermediate mercury-plasma is used, direct annihilation of the electrons and electron-holes emit the light with over 90%

efficient.

efficacy! (see Figure 20*.)*

microscopic reactions of gases. (Mostly hydrogen and oxygen gases are in use.)

of multistep processes, and this is also moderated by surface reactions.

The measurement of the power is missing, due to the fact that cooling is immeasurable and has a modifying effect on the temperature. This makes the temperature measurement in the target important, as this is the only parameter which gives us some idea about the absorbed energy, (see Figure 17.). This (generally invasive, measurement) makes it possible to have orienting value of the absorbed power in general, and sometimes it is important for safety to avoid the unwanted hot spots as well. For the successful energy dose control we have to know the energy taken away by the cooling. This underlines the importance of the control of the surface cooling triggered by the actual physiological conditions in the subcutaneous capillary bed.

**Figure 17.** The control of both the energies together with the physiological parameters make oncothermia safe and effective

The full unsuccessful temperature focusing together with the intensive cooling process in conventional hyperthermia is, borrowing the words from Shakespeare, "much ado about nothing".

Dr. Storm a recognised specialist of hyperthermia formulated **[**78**]** a general opinion: "The mistakes made by the hyperthermia community may serve as lessons, not to be repeated by investigators in other novel fields of cancer treatment."
