Use of heating rate and specific absorption rate in the hyperthermia clinic

The specific absorption rate (SAR), which is the mass-normalized rate of energy absorption by a biological body, has been used by hyperthermia researchers to characterize energy deposition and heating patterns in tissues and in biological models. Before thermal diffusion and blood flow alter the temperature distribution, energy deposition and heating rate (HR) are related by constants. Therefore SAR is usually calculated from the initial rate of temperature rise measured during heating. SAR is an appropriate parameter for theoretical calculations or electric field measurement in tissue. However, the ultimate parameter in hyperthermia is temperature. Instead of computing the temperature rise from SAR (W/kg) and specific heat (kcal/kg.degree C) which were originally obtained from temperature measurements, it is simpler and more convenient to use HR (degree C/W-min) directly, especially when heterogeneous tissues are involved. The advantages of using HR instead of SAR in hyperthermia clinics are discussed.     

Use of heating rate and specific absorption rate in the hyperthermia clinic

The specific absorption rate (SAR), which is the mass-normalized rate of energy absorption by a biological body, has been used by hyperthermia researchers to characterize energy deposition and heating patterns in tissues and in biological models. Before thermal diffusion and blood flow alter the temperature distribution, energy deposition and heating rate (HR) are related by constants. Therefore SAR is usually calculated from the initial rate of temperature rise measured during heating. SAR is an appropriate parameter for theoretical calculations or electric field measurement in tissue. However, the ultimate parameter in hyperthermia is temperature. Instead of computing the temperature rise from SAR (W/kg) and specific heat (kcal/kg. °C) which were originally obtained from temperature measurements, it is simpler and more convenient to use HR (°C/W-min) directly, especially when heterogeneous tissues are involved. The advantages of using HR instead of SAR in hyperthermia clinics are discussed.     

Effects of local hyperthermia on the tissue levels and toxicity of three radiosensitizers in mice.

The toxicity of the radiosensitizers misonidazole (MISO), demethylmisonidazole (DEMISO) and pimonidazole (PIM) in mice can be affected differently when combined with local hyperthermia at 43 degrees C for 30 min. At a dose of 1 mg/g, only MISO plus heat resulted in 50% lethality in animals over a period of 7 days post-treatment, whereas 100% survival was observed in the case of DEMISO and PIM. The enhanced lethality may be associated with the production of toxic intermediates of MISO. Heat did not affect the levels of DEMISO in the tissues studied (plasma, brain and tumour), whereas those of PIM were markedly lowered in tumour but not affected in brain for up to 4 h after combined treatment. MISO was found to be decreased in the tumour at all times but affected differently in brain after 1 and 2 h, initially decreasing and then increasing significantly. In all cases the treatment sequence, i.e. sensitizer plus heat or vice-versa, did not affect the rate of survival. At a dose of 2 mg/g, DEMISO plus heat was found to be more toxic when DEMISO was given first (25% survival) compared to 58% on reversal. However, the levels of DEMISO in the tissues were not affected by heat. Thus, it would appear that there is no correlation between parent drug levels measured in plasma, tumour or brain and hyperthermia-induced drug lethality.     

An in-vivo experimental study of temperature elevations in animal tissue during magnetic nanoparticle hyperthermia

In magnetic nanoparticle hyperthermia in cancer treatment, the local blood perfusion rate and the amount of nanofluid delivered to the target region are important factors determining the temperature distribution in tissue. In this study, we evaluate the effects of these factors on the heating pattern and temperature elevations in the muscle tissue of rat hind limbs induced by intramuscular injections of magnetic nanoparticles during in vivo experiments. Temperature distribution in the vicinity of the injection site is measured inside the rat limb after the nanoparticle hyperthermia. The measured temperature elevations at the injection site are 3.5° ± 1.8°C and 6.02° ± 0.8°C above the measured body temperature, when the injection amount is 0.1 cc and 0.2 cc, respectively. The full width of half maximum (FWHM) of the temperature elevation, an index of heat transfer in the radial direction from the injection site is found to be approximately 31 mm for both injection amounts. The temperature measurements, together with the measured blood perfusion rate, ambient air temperature, and limb geometry, are used as inputs into an inverse heat transfer analysis for evaluation of the specific absorption rate (SAR) by the nanoparticles. It has been shown that the nanoparticles are more concentrated in the vicinity of the injection site when the injection amount is bigger. The current in vivo experimental studies have demonstrated the feasibility of elevating the tissue temperature above 43°C under the experimental protocol and equipment used in this study.     

Optimization of power deposition and the rate of heating of tissue during RF capacitive hyperthermia

The toxicity of the radiosensitizers misonidazole (MISO), demethylmisonidazole (DEMISO) and pimonidazole (PIM) in mice can be affected differently when combined with local hyperthermia at 43°C for 30 min. At a dose of 1 mg/g, only MISO plus heat resulted in 50% lethality in animals over a period of 7 days post-treatment, whereas 100% survival was observed in the case of DEMISO and PIM. The enhanced lethality may be associated with the production of toxic intermediates of MISO. Heat did not affect the levels of DEMISO in the tissues studied (plasma, brain and tumour), whereas those of PIM were markedly lowered in tumour but not affected in brain for up to 4 h after combined treatment. MISO was found to be decreased in the tumour at all times but affected differently in brain after 1 and 2 h. initially decreasing and then increasing significantly. In all cases the treatment sequence, i.e. sensitizer plus heat or vice-versa, did not affect the rate of survival. At a dose of 2 mg/g, DEMISO plus heat was found to be more toxic when DEMISO was given first (25% survival) compared to 58% on reversal. However, the levels of DEMISO in the tissues were not affected by heat. Thus, it would appear that there is no correlation between parent drug levels measured in plasma, tumour or brain and hyperthermia-induced drug lethality.     

Specific absorption rate steering by patient positioning in the 'Coaxial TEM' system: phantom investigation

Cylindrical and elliptical homogenous phantoms were used to investigate, both theoretically and experimentally, the effect of phantom positioning on the specific absorption rate (SAR) distribution of the 'Coaxial TEM' system. Theoretical predictions indicated that the maximum of the SAR distribution was stationary around the central axis of the applicator system, irrespective of the position of the phantom. Therefore the maximum SAR can be located at different phantom sites as required. Although two-dimensional models give a qualitative insight in the phenomena studied, they lack quantitive agreement. The steering capacity has been confirmed experimentally and is now clinically applied by positioning the tumour mass according to these insights.     

Clinical experiences with local microwave hyperthermia

At the Claire Zellerbach Saroni Tumor Institute, Mount Zion Hospital and Medical Center, 38 patients who failed definitive radiotherapy and chemotherapy were treated with 915 megahertz and 2450 megahertz microwave hyperthermia to observe normal tissue tolerance and therapeutic responses. Superficial and measurable lesions were selected. Thirty-seven courses were given with radiation and eleven courses were given alone. When hyperthermia was combined with radiation, complete clinical regression occurred in 41 % ($\text{15}\text{37}$) of patients and partial regression in 37% ($\text{14}\text{37}$); however with hyperthermia alone, complete regression occurred in 18% ($\text{2}\text{11}$) of patients and partial regression in 18 % ($\text{2}\text{11}$). Thus, moderate local tumor hyperthermia (42.5°C) following low dose irradiation (1800–2700 rad) has resulted in significant responses in recurrent tumors in previously irradiated areas. The maximum temperature achieved during a course of treatment appeared to correlate with tumor responses. Also a relationship existed between radiation dose and tumor response. There was no relationship between radiation dose and thermal side effects. Thermal dosimetry remained an outstanding problem for clinical hyperthermia, in part because of inadequacy of heat delivery and measurement systems, and in part because of patient variations in terms of tolerance to beat and tumor physiological changes with fractions of hyperthermia. Side effects of thermal blistering and burns were correlated with maximum temperatures attained during heat treatments. They were tolerable by patients, and can be decreased by appropriate skin cooling in some patients. Further protocol studies are needed to determine the optimal temperature/radiation dosage, treatment schedules and sequences, and treatment techniques.     

Increased tumour response of a murine fibrosarcoma to low temperature hyperthermia and low dose rate brachytherapy

The present animal tumour study was carried out to determine the effectiveness of low temperature hyperthermia combined with low dose rate radiation based on the cell culture studies of our laboratory and others that demonstrated a significant radiosensitization obtained by low temperature hyperthermia and low dose rate radiation. Well-oxygenated murine fibrosarcoma Meth-A tumours growing in Balb/c mice were treated with heat (41d`C tumour temperature) by immersion of the tumour-bearing leg in a waterbath concurrently with low dose rate radiation. Radiation was delivered using <sup>192</sup>Ir interstitial implantation at absolute dose rates of 0.416–0.542 Gy/h. The effect of heat alone on tumour growth and normal tissue was minimal. Tumour growth delay following 30 Gy radiation was 4.9 days. Significant delay in tumour growth was observed with the addition of low temperature hyperthermia delivered concurrently. Enhancement in radiation response was seen with increasing duration of heat treatment; tumour growth delays were 9.5 days following 4h heat (41d`C) treatment and 16 days following 6 h treatment. Three sessions of fractionated hyperthermia 4 h/day during the course of low dose-rate radiation significantly delayed tumour growth to 18.6 days. The results indicate that fractionated heat treatment in conjunction with low dose rate radiation has potential for improving tumour response without adversely affecting normal tissue reaction. This in vivo study represents an extension of the cell culture data and provides further radiobiological basis for the combined use of low temperature hyperthermia and low dose rate radiation.     

An assessment of local hyperthermia in clinical practice

A total of 116 small superficial tumours have been treated by radiation alone, hyperthermia alone, or radiation and hyperthermia combined in a Phase I/II study. Most tumours were metastases or local recurrences of adenocarcinoma of breast but other histologies were involved including melanoma. Hyperthermia was delivered predominantly by microwaves, but radiofrequency and ultrasound methods were also used. Rigorous thermal dosimetry, based on measurements from invasive multipoint thermocouple arrays, has shown that 58 per cent of hyperthermal treatments reached a minimum dose within tumour equivalent to 20 min at 43 degrees C (minEq43); 24 per cent reached at least 60 minEq43. Minima of 20 minEq43 were achieved successfully on every intended occasion in a quarter of the 75 tumours heated, and on one/two occasions in 39; unfortunately, this minimum threshold was not reached at any point monitored at any hyperthermia session in 17(23 per cent) tumours. Tumours that received radiation and effective hyperthermia were more likely to disappear completely (CR rate 86 per cent) than those that were irradiated but inadequately heated (CR rate 35 per cent) (P less than 0.001) or were treated by the same doses of radiation alone (CR rate 35 per cent) (P less than 0.05). This improvement with hyperthermia became more apparent with suboptimal radiation doses. A small but measurable growth delay was imposed by heat alone with a poor complete response rate (11 per cent). The real-time use of a thermal dose unit in clinical practice facilitates hyperthermal treatment comparisons and provides an important parameter for checking the technical performance of a heat delivery system. The results of this study emphasizes the need for improvements in intratumour temperature distribution, in order to establish minimum threshold temperatures to enhance tumour response rates.     

Functional state of body systems in local hyperthermia

The bioelectrical activity of the cerebral cortex, cardiovascular system status, cell-mediated immunity and peripheral blood parameters were studied in 208 cases of head and neck cancer who received local pneumo- and ultra-high frequency hyperthermia in combination with chemoradiation treatment. Local hyperthermia was found to produce no untoward side-effects.     

Blood flow in human tumors during local hyperthermia

The response of tumor blood flow during local hyperthermia was studied at 40 different points in 15 superficial human tumors. Hyperthermia was administered for 60 minutes by use of 915 MHz microwaves. Blood flow was determined from the rate of thermal clearance by use of the bioheat equation. The rate of thermal clearance was sampled at 10-15 minutes intervals by turning the applied power off for 30 seconds. A correction was made for thermal conduction from orthogonal profiles of the tumor temperature. No measurements were made during the first 10-15 minutes of heating. The response of tumor blood flow was found to be independent of temperature in the range of 40-44 degrees C. The mean blood flow rate increased 10-15% between 15 and 30 minutes, but remained nearly constant thereafter. The coefficient of variation in this pattern is 15-20%. No evidence of a sharp reduction in flow was observed. Furthermore, the mean temperature elevation, net forward power, and rate of thermal conduction all remained nearly constant with time, providing further evidence of stability in the blood flow rate. Data obtained in one tumor suggest that a reduction in flow may occur at temperatures above 44 degrees C. The mean blood flow rates obtained in this study range from 0-34 ml/100g/min with an average value of 15 ml/100g/min.     

Treatment of a solid tumor by local simultaneous hyperthermia and ionizing radiation: Dependence on temperature and dose

Studies in this laboratory have shown that the application of local combined simultaneous heat and X-rays significantly increased local tumor control and cure in mice bearing an SV-40 fibrosarcoma in the limb and in humans bearing metastatic or locally recurrent tumors.The present studies were carried out in order to investigate the relations involved in the radiosensitization of tumor tissues with different local heating temperatures and different doses of ionizing radiation.(BALB/C × C57BL/6)F1 mice, bearing an SV-40 fibrosarcoma in the limb, were exposed to (a) local X-rays alone (500–800 rads); (b) local hyperthermia alone (hot air temperatures 45°C, 50°C, 55°C); duration of heat treatment 15, 30 and 45 min), and (c) simultaneous heat and radiation in various combinations of (a) and (b). Hyperthermia was achieved by means of hot air. Heating and X-irradiation were administered separately or simultaneously once, or twice after a 7-day interval.The results confirm our previous conclusions that although the SV-40 tumor is both poorly thermosensitive and radioresistant, the synergistic effect of heat and irradiation is striking. The tumor response to the combined simultaneous treatment indicates that the radiation enhancement effect depends upon the local heating temperature and duration, and upon the X-ray dose. It is apparent from these data that the combined simultaneous treatment has a synergistic effect on neoplastic tissues and has important implications in radiation therapy of human cancer.     

Catheter induced temperature artifacts in ultrasound hyperthermia

Temperature artifacts were evaluated at 72 different sensor locations in 10 different tumour sites heated by use of planar ultrasound transducers operated at 1 and 3 MHz. Thermometry was carried out by single-and multisensor thermocouple probes inserted into 19-and 16-gauge polyurethane catheters, respectively. Nearly all catheters were oriented approximately perpendicular to the ultrasound beam. The artifacts were determined by backward extrapolation of the thermal decay 30–60 s after the power was turned off. The effective blood flow and specific absorption rate (SAR) at the sensor locations were determined from the rate of decay and the steady-state temperature. The sample mean steady-state temperature, effective blood flow, and SAR were 41.4°C, 17.5 ml/100 g/min, and 46.3 W/kg, respectively. The most frequent artifact was in the range 0–0.2°C and the mean artifact was 0.6°C. Less than 15% of the artifacts were above 1°C. The magnitude of the artifact correlates with the SAR of ultrasonic power, the effective blood flow rate, and the steady-state temperature. These results indicate that the artifact produced at 1 MHz by a multisensor, Teflon-sheathed thermocouple inserted into a 16-gauge polyurethane catheter is 1.7±0.4 degrees at an SAR of 100 W/kg.     

Catheter induced temperature artifacts in ultrasound hyperthermia

Temperature artifacts were evaluated at 72 different sensor locations in 10 different tumour sites heated by use of planar ultrasound transducers operated at 1 and 3 MHz. Thermometry was carried out by single- and multisensor thermocouple probes inserted into 19- and 16-gauge polyurethane catheters, respectively. Nearly all catheters were oriented approximately perpendicular to the ultrasound beam. The artifacts were determined by backward extrapolation of the thermal decay 30-60s after the power was turned off. The effective blood flow and specific absorption rate (SAR) at the sensor locations were determined from the rate of decay and the steady-state temperature. The sample mean steady-state temperature, effective blood flow, and SAR were 41.4 degrees C, 17.5 ml/100 g/min, and 46.3 W/kg, respectively. The most frequent artifact was in the range 0-0.2 degrees C and the mean artifact was 0.6 degrees C. Less than 15% of the artifacts were above 1 degree C. The magnitude of the artifact correlates with the SAR of ultrasonic power, the effective blood flow rate, and the steady-state temperature. These results indicate that the artifact produced at 1 MHz by a multisensor, Teflon-sheathed thermocouple inserted into a 16-gauge polyurethane catheter is 1.7 +/- 0.4 degrees at an SAR of 100 W/kg.