Physical and Photobiological Basics of wIRA-Hyperthermia

Abstract

Information regarding physical and photobiological basics of wIRA-HT has been derived under in vivo conditions in piglets and human tissues. Since wIRA fits into the optical window of tissues, direct conversion of absorbed radiation into heat (T >39 °C) has been proven up to tissue depths of 26 mm. Tissue heating cannot sufficiently be characterized by the specification of the radiant exposure (dose) due to its dependence on the thermal impact of irradiance and exposure time and on heat dissipation and metabolic heat production. If irradiations of identical doses are used, resulting tissue hyperthermia levels are the higher, the shorter the exposure time and the higher the irradiance. To comply with the ESHO criteria, incident wIRA irradiances should exceed ≈ 110 mWcm⁻² (IR-A). At higher irradiances, steady-state temperatures (SST) ≥ 39 °C have been observed to tissue depths >20 mm in piglets and up to 26 mm in humans. SST values ≥40 °C have been measured up to tissue depths >20 mm (piglets) and up to 16 mm (humans), and SSTs ≥41 °C up to 16 mm (piglets) and up to 8 mm (humans). Post-heating temperature decay times limit optimal intervals between hyperthermia (HT) and subsequent radiotherapy (RT) sessions to periods ≤5 min.

1 Introduction

Derived from the primary idea to simulate living tissue heating, as experienced by solar infrared radiation at the surface of our planet, hyperthermia using water-filtered infrared A radiation (wIRA) has been established as a potent method in physical therapy and radiation oncology (see [1,2,3,4,5,6,7,8,9,10,11] and respective chapters in this book). wIRA-hyperthermia (wIRA-HT) is based on tissue heating induced by absorption of water-filtered infrared A radiation by chromophores (mainly water molecules). However, kinetics of heating and resulting heating states depend on several physical and photobiological processes, and on physiological/regulatory responses. These processes interact with each other and should be considered to ensure appropriate hyperthermia levels that are required for special indications.

This article aims to extent and update previous publications on physical and photobiological basics of wIRA-hyperthermia [12, 15] with a special focus on optical interactions of wIRA with tissues, thermal field formation during irradiation within tissues, and the kinetics of temperature decay after completion of wIRA exposure.

The following items will be discussed in more detail: (a) effects of irradiance, exposure time, thermoregulation, and individual responses upon heating, (b) needs for adequate dosage and documentation of wIRA exposures due to the non-applicability of the Bunsen–Roscoe law of reciprocity upon tissue heating, (c) evidence of direct conversion of absorbed wIRA irradiation into heat, as assessed by comparison of depth profiles of wIRA penetration and of heating rates, (d) vertical temperature profiles and their dependence on irradiance and individual thermoregulation, and (e) effects of irradiance on tissue heating with respect to the quality assurance criteria of the European Society of Hyperthermic Oncology (ESHO) for adequate heating.

Analyses of the thermal field formation within the tissue have been based on invasive temperature measurements in piglets that had been in vivo irradiated with wIRA using different irradiances [16], supplemented by data derived from analogous measurements in human abdominal wall and breast cancer [17, 18]. Optical interaction data have been derived from measurements on healthy volunteers of different skin color and are discussed using model calculations [19, 20].

2 wIRA: Infrared Radiation That Fits into the Optical Window of Tissues

From the optical point of view, human tissues can be considered as turbid media. When optical radiation penetrates the skin, subcutis/fat layer, and muscle, its propagation is characterized by multiple scattering and absorption. Both processes depend on the wavelength. Scatterers with small diameters—as compared to the wavelength—cause isotropic (Rayleigh) scattering. Small diameter scatterers include membranes, striations in collagen fibrils and muscle fibers, and macromolecular aggregates with diameters between about 10 nm and 100 nm. However, the greater the diameter of scatterers, the more the scattering passes into forward direction (Mie scattering). Scatterers of the latter type are lysosomes, vesicles, mitochondria, and nuclei having diameters between about 100 nm and 10 μm. Moreover, each interface within the tissue causes scattering if the relative refraction indexes of both media differ. Similarly, fluctuations of the dielectric constant and of density may contribute to scattering. As a consequence, the multiple scattering that appears prolongs the retention time of radiation in the tissue and results mainly in forward propagation of short-wavelength infrared radiation, in deep penetration and transmission, and in backscattering within the tissue and diffuse reflectance (remission) (see Fig. 3.1).

Fig. 3.1

Schematic overview of interactions between optical radiation and skin. Processes of interaction are reflection at the surface, refraction of subsurface irradiance, multiple scattering and backscattering, and absorption by chromophores ([14], ©Thieme Gruppe). Layer depths are approximate values for human skin (epidermis and dermis). Individual thicknesses of skin may deviate. Measured values for Caucasians ranged from 0.5 to 2.0 mm with mean values between 0.8 and 1.5 mm [21]. The proportion of the epidermis within the dermis is approx. 4% for Caucasians and up to 8% for Asians [21]. In piglets, thicknesses of skin and fat layer are up to 5 mm each [16]

According to the first law of photobiology (Grotthuss–Draper law), only absorption of radiation (by chromophores) causes photochemical and photophysical effects within tissues. The most important chromophore of human soft tissues is intra- and extracellular water (average water content ≈70–80%). However, as shown in Fig. 3.2, the absorption coefficient of water in the visible spectral range is small. It increases with wavelength up to a factor of about 15 within the range of IR-A, but up to 10⁴ for wavelengths above 1400 nm. This causes strong absorption of mid- and long-wavelength infrared radiation (IR-B and IR-C) within the subsurface layer of the skin and defines the long-wavelength edge of the optical window (see Fig. 3.3). The short-wavelength edge of the optical window is mainly defined by absorption of radiation according to the contents of hemoglobin and melanin, and by increasing influence of scattering with decreasing wavelengths (Figs. 3.2 and 3.3).

Fig. 3.2

The spectral absorption coefficient (μ_a, left ordinate) of melanosomes, oxyhemoglobin, deoxyhemoglobin, lipids (25% fat), and water, and the reduced spectral scattering coefficient of skin (μ’_s, right ordinate) as a function of wavelength ([14], ©Thieme Gruppe)

Fig. 3.3

Relative spectral absorbance in fair skin (curve 1a, blue) and in black skin (curve 1b, green) compared to the relative spectral irradiance of a wIRA-radiator (type Hydrosun 750, Hydrosun Medizintechnik, Müllheim, Germany, curve 2, red) as a function of wavelength. Relative spectral absorbance data were calculated from in vivo measurements of spectral transmittance at the ear lobes and of spectral remittance at the forearms of volunteers with fair or black skin. Individual thickness of both ear lobes: 2.4 mm [19]. The wIRA-radiator was equipped with a water filter of 7 mm thickness and with a cutoff filter (type: RG 780/3, Schott, Mainz, Germany)

Presuming values for relative spectral absorbance ≤0.5, the optical window ranges from about 600 nm in fair skin and about 750 nm in black skin to about 1300 nm. Curve 2 in Fig. 3.3 shows that the spectrum of the wIRA radiator matches the optical window of tissues. It shows minima where spectral absorbance shows maxima, and it is limited to the spectral range inside of the optical window.

3 Optical Effects of Interaction Between wIRA and Tissues

3.1 Spectral Transmittance and Remittance of wIRA (In vivo Data)

Spectra of transmittance and remittance measured in vivo show characteristic local minima (Fig. 3.4a, b, curves 1a, 1b). These characteristic curves are caused by absorption of radiation within the absorption bands of water (maxima at about 970, 1197, and 1400 nm), of lipids (maxima at about 932 and 1212 nm), of hemoglobin (maxima at about 573 and 758 nm), and of cytochrome-c (maximum at about 840 nm) and can be used for optically based diagnostics. However, since intra- and extracellular water is the main absorbent of infrared radiation in the tissue, the basic concept of wIRA relies on the extracorporeal attenuation of infrared radiation within the spectral absorption bands of water by using a water filter, which minimizes the spectral distribution within these absorption bands and outside of the spectral range of IR-A [13].

Fig. 3.4

Relative spectral transmittance (a) and relative spectral diffuse remittance (b) assessed in vivo in fair skin (curve 1a, blue) and in black skin (curve 1b, green) compared to relative spectral irradiance of a wIRA-radiator (type Hydrosun 750, Hydrosun Medizintechnik, Müllheim, Germany, curve 2, red) as a function of wavelength. Spectral transmittance data were measured in the ear lobes, and spectral remittance in the forearms of volunteers with fair and black skin. Individual thickness of both ear lobes: 2.4 mm [19]. Arrows show local minima due to absorption by hemoglobin (573 nm, 758 nm), cytochrome-c (840 nm), lipids (932 nm, 1212 nm), water (970 nm, 1197 nm, and 1400 nm), and local maxima (1082 nm and 1268 nm). The wIRA-radiator was equipped with a water filter of 7 mm thickness and with a cut-off filter (type: RG 780/3, Schott, Mainz, Germany)

Thus, wIRA entering the skin shows a similar spectral distribution as compared to the spectra of transmittance and remittance within the spectral range of IR-A (Fig. 3.4a, b, curves 1a, 1b, and 2). This allows for (a) direct transformation of absorbed energy into heat in deeper tissue layers and (b) reduced heating in the upper tissue layers by absorption of radiation within the absorption bands of water, as compared to unfiltered IR-A (for detailed data, see [19]).

The transmittance of ear lobes (individual thickness: 2.4 mm) is exemplified in Fig. 3.4a: the maximum appears at a wavelength of about 1082 nm with values of 30.0% (fair skin, curve 1a) and approximately 23.4% (black skin, curve 1b), whereas within the total IR-A range, mean values range from 19.4% (fair skin) to 15.3% (black skin).

Weak absorption enabling deeper penetration into the tissue is correlated with a high loss of incident radiation due to backscattering and remission. This results in maximum remittances of 62.4% (fair skin) and 56.5% (black skin) at a wavelength of about 1082 nm and in mean values of 45.4% (fair skin) and 44.0% (black skin) within the total IR-A range (Fig. 3.4b, curves 1a, 1b).

It is apparent that the effect of absorption by melanin in black skin upon spectral remittance and spectral transmittance within the IR-A range is small. In contrast, mean transmittances (shown in Fig. 3.4a) shift from 13.0% (fair skin) to 5.3% (black skin) and remittances (shown in Fig. 3.4b) from 45.9% (fair skin) to 19.2% (black skin) in the visible range.

3.2 Penetration of wIRA into Tissues

Penetration of wIRA into tissues was calculated using a model based on Monte Carlo simulation, which assumes fair, bloodless, plane-parallel oriented skin, and vertical homogeneous distribution of scatterers and chromophores within the tissue [19, 20].

Results depicted in Fig. 3.5 show that incident irradiance (= 100%) decreased to about 53.6% at the immediate subsurface of the skin, indicating a loss of incident irradiance of about 46.4% due to diffuse remission. This calculated value is in very good accordance with the remittance of 45.4% measured in vivo for fair skin using wIRA-exposure (see Fig. 3.4b, curve 1a). Calculated transmittance at a tissue depth of 2.4 mm is about 23.5%, a value that differs from the in vivo measurement (see Fig. 3.4a, curve 1a) by about 20% and is within the ranges of error for the measurement and model calculation.

Fig. 3.5

Relative irradiance of wIRA as a function of tissue depth in fair skin and underlying tissues (subcutis and muscle). Incident irradiance of 100% at skin surface decreased to about 53.6% at the immediate subsurface level due to relative remittance of about 46.4%. Calculated data [20]

Considering the 20% margin of error for the model calculation and in vivo conditions, approximated levels of relative irradiances of wIRA in fair skin and underlying tissues (subcutis and muscle) are 36.8% (1/e) at a depth of 2.3 mm, 10% at 5 mm, 1% at 16 mm, and 0.1% at 28.5 mm.

It is noteworthy to mention that the slope of the curve in Fig. 3.5 transitions from a steep to shallow decline with increasing depth at a depth of about 5 mm. This is the result of decomposition of the incident wIRA spectrum with depth due to spectral selective absorption by chromophores (as shown in Fig. 3.2) and in favor of spectral parts where absorption is small.

4 Thermal Field Formation in Superficial Tissues During wIRA-Hyperthermia

In vivo data reported in this chapter are derived from wIRA-skin exposures of the upper thighs of anesthetized piglets (body weight: 15–20 kg) [16]. To exclude superposing effects of convective or conductive heating upon skin and tissue temperature, wIRA-treatments were performed in a closed room with constant air temperature of 22–24 °C, without airflow, and with humidity monitoring turned on.

4.1 Individual Responses to wIRA-Skin Exposures

The thermal state of tissues during wIRA-heating depends not only on spectrum, irradiance, and exposure time, but - according to Pennes’ Bioheat equation - also on additional factors such as individual local blood flow, heat conductivity of tissues, and metabolic heat production [20, 22].

This is exemplified in Fig. 3.6 by comparing two identically exposed piglets. Probably due to its higher body core temperature of 39 °C (resulting in decreased vertical temperature gradients in the tissue and in decreased convective heat transport by increased blood flow due to its higher body temperature), piglet p2 was unable to effectively thermoregulate and, thus, showed a continuous increase in temperature during the exposure up to a tissue depth of 10 mm, exceeding 45 °C at a tissue depth of 4 mm after 35 min wIRA-irradiation was consequently stopped. In contrast, piglet p3 initially showed a physiological body core temperature of 37.8 °C. P3 achieved a thermal steady state due to rapidly activated thermoregulation and approximately constant temperatures (up to 43.5 °C) within the upper tissue layers after ≈15 min of wIRA-exposure. Further activation of thermoregulation was started after ≈40 min of exposure to decrease the temperature level.

Fig. 3.6

Temperature at skin surface (1) and at tissue depths of 4 mm (2), 10 mm (3), and 20 mm (4) as a function of treatment time during wIRA-skin exposure of two piglets (p2 and p3) in vivo (a: p3, blue lines, b: p2, red lines). Irradiance used: 126.5 mW cm⁻² (IR-A)

4.2 Effects of Irradiance, Exposure Time, and Thermoregulation Upon Heating

During the first 1–2 min of exposure, tissue temperature increases approximately proportionally with exposure time and as a function of irradiance and tissue depth (as shown in Fig.3.6). This is caused by a delayed onset of heat dissipation and thermoregulation and allows for the calculation of heating rates as a crucial measure of heating effectiveness (see Sect. 3.4.3).

Data in Fig. 3.7 A show that after the onset of thermoregulation, i.e., 2–5 min after onset of exposure, irradiance affects the extent of regulatory processes in different ways. Using the smallest irradiance, only moderate regulation is evident resulting in a continuous increase in tissue temperature (curve 3). In contrast, the two higher irradiances caused adequate thermoregulatory responses resulting in a balance between heat input and heat dissipation, i.e., in a thermal steady state (curves 1 and 2).

Fig. 3.7

Mean values and standard deviations of skin surface temperatures as a function of exposure time (a) and of dose (b) calculated according to Eq. (3.1). Skin exposures were performed with wIRA using IR-A irradiances of 126.5 mW cm⁻² (1, diamonds, four piglets), 103.2 mW cm⁻² (2, triangles, four piglets), and 85.0 mW cm⁻² (3, dots, three piglets)

Note: Limitations in thermoregulation may result in tissue overheating (as discussed above for piglet p2 in Sect. 3.4.1). Therefore, febrile patients and patients with inadequate convective (i.e., blood flow-mediated) heat transfer due to certain peripheral vascular pathologies should be excluded from wIRA-treatment if continuous control/monitoring of skin surface temperatures using thermography is not ensured.

Radiant exposure (dose) H_wIRA is calculated according to

$$ {\mathrm{H}}_{\mathrm{wIRA}}={\mathrm{E}}_{\mathrm{wIRA}}\cdot \varDelta t $$

(3.1)

where E_wIRA denotes the irradiance of wIRA, and Δt denotes the exposure time.

Data in Fig.3.7b show that identical doses result in different levels of tissue hyperthermia. They are inversely related to the exposure time and correlate directly with irradiances. Thus, tissue heating cannot be adequately characterized by specifying the radiant exposure (dose) due to its dependence on the thermal impact determined by irradiance and exposure time and, additionally, by heat dissipation and metabolic heat production. For this reason, the Bunsen–Roscoe law of reciprocity is not applicable in tissue heating and reported data should specify both irradiance and exposure time, instead of the dose only [20].

4.3 Effective Tissue Heating by Direct wIRA Absorption and Heat Conduction

To prove effectiveness of wIRA-heating within tissues, vertical profiles of relative heating rates and of relative temperature rises in piglets were compared to the profile of relative wIRA-irradiance (Fig. 3.8a, b).

Fig. 3.8

Relative heating rates assessed in piglets after 1 min of wIRA-exposure (a), and relative temperature rises during wIRA skin exposure after achieving thermal steady states (b) in comparison with relative wIRA-irradiance (0, broken line) and as a function of tissue depth. Piglets were exposed to wIRA-irradiances (IR-A) of 126.5 mW cm⁻² (1, red diamonds), 103.2 mW cm⁻² (2, green triangles), and 85.0 mW cm⁻² (3, blue dots)

Heating rates were calculated using the temperature increase in the tissue (δT) as a function of tissue depth (d) during the first minute of exposure (δt = 1 min) and before onset of thermoregulation according to:

$$ HR\left(\mathrm{d}\right)=\delta T\left(\mathrm{d}\right)/\delta t. $$

(3.2)

In contrast, temperature rise data were related to the conditions after achieving thermal steady states.

To compare depth profiles, relative wIRA-irradiance data within the tissue were normalized to the value at the skin surface, and relative heating rates and relative temperature rises were related to the respective mean values at the skin surface of piglets exposed to 126.5 mW cm⁻² (IR-A).

According to Fig. 3.8a, relative heating rates measured at tissue depths of 5–20 mm comparably decrease with depth as compared to the decrease of wIRA-irradiance. This verifies, for the first time by experimental data, that (a) direct conversion of absorbed energy of wIRA into heat occurs significantly in the total depth range observed and (b) absorption of wIRA initially is the only source of heating.

In the skin of piglets (tissue depths of 0–5 mm), the heating rate shows a smaller decrease with depth as compared to the decrease in wIRA-irradiance. This is due to a (a) rapid induction of both, conductive (by molecular vibrations) and convective (via blood flowing through U-shaped capillary loops in the papillary and subpapillary layers, thus locally heated by direct radiation absorption), centripetally oriented heat flow, which also contributes to tissue heating in addition to the heating by absorption of radiation and to a (b) heat loss at the skin surface by increased radiant exitance to the environment.

In contrast, after achieving the thermal steady state, relative temperature increments only marginally decreased with depth, as compared to the decrease in relative wIRA-irradiance (Fig. 3.8b). This is caused by the balance between heat input (by wIRA absorption and conductive/convective heat transport from upper to deeper tissue layers) and heat dissipation due to thermoregulatory responses (mainly by an increase in blood flow resulting in convective heating of the body core and by conductive heat transport into deeper tissue layers). Evidence for this interpretation is based on the increased body core temperatures of piglets after skin exposure to wIRA (see [16], Table 3.1).

Table 3.1 Mean tissue depth with therapeutically relevant temperature ranges during wIRA-HT after achieving thermal steady states. Means assessed in piglets in vivo exposed to different irradiances and in the abdominal wall of healthy volunteers exposed to wIRA (135 mW cm⁻², IR-A) [16, 23]. Note that skin thickness is different in humans and piglets. Skin thickness is ≈ 5 mm in piglets [16]. In humans, the thickness of the skin (epidermis + dermis) of the abdominal wall and lumbar region ranges from 2 to 2.5 mm [21]

4.4 Vertical Temperature Profiles After Achieving Thermal Steady States

Tissue temperatures in piglets show maxima in the skin at a depth of ≈ 4 mm. These increase skin surface temperatures up to 2 K in individual cases and to about 0.7 K on average, and these ranged from 43.6 °C for 126.5 mW cm⁻² to 42.6 °C for 85 mW cm⁻² (Fig. 3.9). Similarly, tissue temperatures assessed in the abdominal wall and the lumbar region of healthy volunteers exceeded skin surface temperatures by about 0.6 K at a depth of 1 mm (see Fig. 3.2 [23]).

Fig. 3.9

Mean values and standard deviations of tissue temperatures as a function of tissue depth after achieving a thermal steady state in piglets exposed to wIRA using irradiances of 126.5 mW cm⁻² (1, red diamonds), 103.2 mW cm⁻² (2, green triangles), and 85.0 mW cm⁻² (3, blue dots). Comparison with respective tissue temperatures before heat exposure (0, black squares) [16]

In piglets, these maxima result from heat accumulation in the transition region skin/subcutaneous fat layer due to decreased conductive heat transport into deeper tissue layers when heat passes the fat layer [16], and might, under certain circumstances result in side effects due to overheating of tissues [24].

In both, fat layer and skeletal musculature temperatures continuously decrease with tissue depth. Based on data shown in Fig. 3.9 (and in Fig. 1, presented in Piazena et al. [23]), Table 3.1 provides mean tissue depths with therapeutically relevant temperature levels.

4.5 Choice of Irradiance for Adequate wIRA-Hyperthermia in Oncology

Heating rate, as defined in Eq. (3.2), is considered a crucial parameter for characterizing and documenting the performance of heat applicators used in hyperthermia [25].

For adequate/appropriate performance, the guidelines of the European Society of Hyperthermic Oncology (ESHO) require values of HR ≥1 K min⁻¹ at a tissue depth of 5 mm for applicators used for superficial heating [25].

As shown in Fig. 3.10, heating rates increase with irradiance and decrease with tissue depth. In piglets, the quality criterion of ESHO is not fulfilled at heating rates using wIRA-irradiances of 85.0 mW cm⁻² and of 103.2 mW cm⁻². In contrast, adequate heating rates are reached in piglets exposed to 126.5 mW cm⁻² and using 146.2 mW cm⁻² for human abdominal wall and breast cancer [26].

Fig. 3.10

Heating rates assessed in vivo as a function of tissue depth in the upper thigh of piglets exposed to wIRA using IR-A irradiances of 126.5 mW cm⁻² (curve 1, red diamonds), 103.2 mW cm⁻² (curve 2, green triangles), and 85.0 mW cm⁻² (curve 3, blue dots). Data are mean values and standard deviations (curve fits using polynomial regression). Results are compared to published data from preliminary in vivo measurements in human abdominal wall (pink stars, [17]) and in recurrent breast cancer (black squares, [18]) during wIRA skin exposure using 146.2 mW cm⁻² (IR-A) [26]

Further data analysis yields an approximately linear increase in mean heating rates with rising irradiances. This results in mean heating rates ≥1 K min⁻¹ at 5 mm for wIRA-irradiances ≥110 mW cm⁻² (Fig. 3.11).

Fig. 3.11

Mean heating rates assessed in piglets and in human tissues in vivo at a tissue depth of 5 mm as a function of wIRA-irradiance. Piglets: upper thigh (interpolated data from measurements at a depth of 4 mm and 7 mm, dots). Human tissues: abdominal wall (star) and recurrent breast cancer (square). Linear regression of data

Figure 3.10 depicts substantial individual variability of HR data, and thus, wIRA-irradiances of 135–150 mW cm⁻² (IR-A) are currently recommended for wIRA-hyperthermia in the clinical setting to ensure compliance with the quality assurance criteria of ESHO for appropriate heating of patients and to limit the risk of side effects due to overheating. Compliance of wIRA-hyperthermia with temperature rises requested by ESHO for adequate heating has been proven under in vivo conditions after achieving thermal steady state in piglets irradiated with a wIRA-irradiance of 126.5 mW cm⁻² (IR-A) and in human abdominal wall exposed to 146.2 mW cm⁻² [26]. Results are provided in Table 3.2, which presents additional data of specific absorption rate (SAR), which is closely related to heating rate by

$$ SAR={\mathrm{c}}_{\mathrm{p}}\cdot HR. $$

(3.3)

(Data of specific heat capacity: c_p = 3.662 Ws g⁻¹ K⁻¹ for skin, c_p = 2.387 Ws g⁻¹ K⁻¹ for fat, c_p = 3.639 Ws g⁻¹ K⁻¹ for muscle tissue, and c_p = 3.852 Ws g⁻¹ K⁻¹ for tumor tissue [26]). (Eq. 3.3 should be restricted as first estimation of SAR, neglecting the effect of skin blood flow and refers to more accurate models, such as Pennes’ Bioheat equation [22].)

Table 3.2 Summary of in vivo data from superficial tissues of piglets and in humans during wIRA-irradiation with reference to parameters for adequate heating [25]. Tissues investigated: skin/subcutis of the upper thigh (piglets), abdominal wall (humans [17]), and recurrent breast cancers (humans [18])

4.6 Post-Heating Temperature Decay Times to Ensure Effective Hyperthermia Levels During Subsequent Radiotherapy

Radiotherapy immediately following hyperthermia (a potent radiosensitizer) must be performed at post-heating temperature levels >39 °C.

Figure 3.12 shows the time periods for post-heating temperature decays to reach effective hyperthermia levels of 39–42 °C. Measurements were performed in anesthetized piglets exposed to an irradiance of 126 mW cm⁻² (IR-A), i.e., exposed to an irradiance of therapeutic relevance and in accordance with the quality standards of ESHO for appropriate hyperthermia (see Sect. 3.4.5). The shortest times for decays to reach 42 °C were about 1.5 min at the skin surface and approximately 4.5 min at a tissue depth of 8 mm. The longest times for decays to reach 39 °C were about 8 min at the skin surface and 20 min at a tissue depth of 20 mm. The respective mean post-heating decay times for the temperature to reach 40 °C were ≈ 4.5 min and ≈ 11 min. Standard deviations in Fig. 3.12 indicate significant deviations from these mean values in individual cases.

Fig. 3.12

Post-heating temperature decay times to reach effective hyperthermia levels of 39 °C (curve 1, red diamonds), 40 °C (curve 2, blue triangles), 41 °C (curve 3, green dots) and 42 °C (curve 4, black squares) as a function of tissue depth. Means and standard deviations were calculated for anesthetized piglets in vivo upon completion of wIRA skin exposure using an irradiance of 126.5 mW cm⁻² (IR-A)

Thus, in radio-oncological (HT-RT) settings, it is strongly recommended/mandatory that, to ensure effective hyperthermia levels (39–42 °C) when following wIRA-HT treatment with radiotherapy (RT), the heated region should be covered with a thermo-isolating blanket between the two treatments (time interval ≤5 min).

5 Conclusions

Using irradiances >110 mW cm⁻² for wIRA-hyperthermia (wIRA-HT) has been proven to comply with the quality standards of ESHO for appropriate tissue heating under in vivo conditions.

By adjusting the spectrum to the optical window of tissues, wIRA skin exposures allow effective tissue heating (T >39 °C) up to 26 mm in humans (abdominal wall). Direct conversion of absorbed radiation into heat is supplemented by secondarily induced conductive and convective heat transport from upper to deeper tissue layers.

Tissue heating using wIRA should be specified by irradiance and exposure time as wIRA-hyperthermia cannot be sufficiently characterized by the radiant exposure (dose). This is due to heat dissipation by conductive and convective heat transport of individual, different kinetics, and limitations in transport capacity within the tissue. Thus, similar doses result in different heating states if applied irradiances are different, and the Bunsen–Roscoe law of reciprocity cannot be applied to describe dosages in schedules of hyperthermia.

The use of hyperthermia in oncology (combined with radiotherapy, chemotherapy, anticancer immunotherapy, or combinations thereof) and in physical therapy should not only consider relevant hyperthermia levels of tissues needed at target depths as shown in Table 3.1 (see also Fig. 3.9 for piglets and Fig. 2 shown for humans by Piazena et al. [23]), but also heating-up times needed to achieve steady state of the target temperature (see Fig. 1, Piazena et al. [23]).

Post-heating temperature decay times (as exemplified for anesthetized piglets in Fig. 3.12) limit eligible intervals between hyperthermia and subsequent radiotherapy to periods ≤5 min to ensure effective hyperthermia levels.

In vivo data from piglets (Fig. 3.9) indicate temperatures within the tissue up to 2 K higher than those measured on the skin surface. This information may be used to protect tissues from overheating and harmful skin effects by controlling skin surface temperature during wIRA-hyperthermia [16]. In humans, comparable temperature increments upon wIRA-exposure have not so far been observed.