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.     

Specific absorption rate and tissue temperature in local hyperthermia

Specific absorption rate (SAR) and tissue temperature were measured for a total of 83 treatments in 33 patients who received local hyperthermia treatment for cancer. The patients were grouped into three categories according to tumor size. Hyperthermia was induced by 13.56 MHz electromagnetic energy applied using capacitive coupling. A method is described for evaluating SAR from the tissue temperature traces at any time in the treatment when a step change is made in applied power. The method is possible only if the temperature traces are free from interference and the total power delivered to the patient is monitored. Mean values of SAR ranged from 4.6 to 89 W kg-1 depending on the treatment site. Satisfactory heating was achieved for superficial tumors, with temperatures greater than 42 degrees C being recorded in 69% of treatments. For axillary nodes only 4% of treatments exceeded 42 degrees C. For cervix tumors an idealized tumor model was used to estimate tumor temperature from the temperature and SAR measured in the adjacent normal tissue. From the model it appears necessary either to raise the systemic temperature to 40 degrees C or to increase the SAR by at least a factor of 4 to obtain a temperature of 42 degrees C in a typical tumor. Measurements of SAR and temperature are essential for feedback control of computer models which, in principle, could provide a complete distribution of temperature during a hyperthermia treatment. Furthermore, measured SAR provides a direct comparison of the power deposition from different treatment machines in a clinical environment. The data presented form a basis for comparison with the clinical use of other heating systems.     

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.     

The modification of specific absorption rates in interstitial microwave hyperthermia via tissue-equivalent material bolus

Patterns of specific absorption rates generated by interstitial, microwave antenna arrays must be experimentally ascertained and quantified to facilitate their clinical incorporation. Phantom studies involved the use of four single-gap, coaxial antennas oriented in a 2 cm square array. These dipoles were driven in phase by a microwave generator at a frequency of 915 MHz. The inherent limitations in modifying the specific absorption rate patterns were addressed with the addition of bolus to the phantom. These additions of Guy's muscle tissue-equivalent material were made either proximal or distal to the phantom proper. Experiments conducted in the presence and absence of tissue-equivalent material bolus showed the ability to achieve broader bands of 50% power deposition in certain bolus conditions. These heating patterns were sufficiently reproducible and predictable to warrant clinical application of the bolus addition. A through-and-through method of catheter implantation allowed for bolus addition when deemed necessary. Treatments with veterinary and human patients using the bolus method to modify heating patterns yielded augmented patterns of power deposition. The effective length of the antennas that would radiate efficiently was essentially broadened via introduction of a microwave-interacting medium. As a result of the tissue equivalent material's ability to absorb microwave power, it was necessary to interpose minimally-interactive styrofoam spacers to limit heat transfer effects at the tissue-bolus interfaces.     

A comparison of the heating characteristics of capacitive and radiative superficial hyperthermia

Background: Superficial hyperthermia is applied in combination with radiotherapy for e.g. melanoma and recurrent breast cancer, using both capacitive and radiative systems. In this paper, numerical simulations are applied to address the question which technique yields the most favourable heating characteristics.

Methods: A 434?MHz contact flexible microstrip applicator (CFMA type 4H, size 19.6?×?19.6?cm²) and a capacitive system consisting of two circular electrodes with diameter 15 and 25?cm were modelled. The water bolus of the CFMA was filled with deionised water and for capacitive heating both saline and deionised water were modelled. Specific absorption rate (SAR) and temperature simulations were performed for a perfused muscle-equivalent phantom and phantoms with a 1?cm thick superficial fat layer, assuming cylindrical target regions. Subsequently, a real patient model with a chest wall recurrence was studied with the target assumed to have muscle-like properties, fat properties or heterogeneous properties as derived from the CT Hounsfield Units.

Results: Phantom simulations showed that high SAR peaks occur around the bolus edges with capacitive heating. Power absorption below the fat layer is substantially higher for radiative heating and unless the target region is limited to the fat layer, radiative heating yields better target coverage in terms of SAR and temperature. Patient simulations showed that the T₉₀ for radiative heating was 0.4–1.1?°C higher compared with capacitive heating.

Conclusions: Radiative heating yields more favourable SAR and temperature distributions for superficial tumours, compared with capacitive heating, especially within heterogeneous tissues. Higher tumour temperatures are achieved without occurrence of treatment limiting hot spots.     

Variability of heating patterns in animals by magnetic induction hyperthermia

In a test of electromagnetic induction hyperthermia to deep viscera of a live dog model, we found that heating was not uniform to any depth, but was quite variable. In general, there was a thermal gradient between peripheral and central portions of the transposed spleen of about 1 degree C. Though heat generation within the abdomen was not uniform, its temperature pattern in the alive animal resulted in significant heating of that part of the organ that had been surgically placed at the center of the animal. This heating could not be explained by perfusion with regionally heated core blood. Our results indicate that extensive investigations in living systems and complex dynamic phantoms will be necessary before individual patient response can be predicted.     

Radiofrequency hyperthermia: the design of coil transducers for local heating

Simple and complex coils have been designed and built for use as radiofrequency transducers for local and regional hyperthermia. The heating from such coils is produced by currents generated in the dielectric by the electromagnetic field radiated from the coil elements. The heating rate profile, as a function of phantom depth, is dependent upon the size and geometry of the coil, its proximity to the dielectric, and the transducer current. Since the fields of simple pancake coils are inhomogeneous, either complex geometries or some method of smoothing is required. A simple solution is to move the coil over the region to be heated or to use multiple applicators. However, many satisfactory heating patterns have been derived for stationary coils designed to heat well-defined subcutaneous volumes to a depth of 3-5 cm. Thermometry studies in static saline-gelatin phantoms demonstrate extensive heating ranges and flexibility since the coils couple with the dielectric through air.     

Mitigation of eddy current heating during magnetic nanoparticle hyperthermia therapy

Background: Magnetic nanoparticle hyperthermia therapy is a promising technology for cancer treatment, involving delivering magnetic nanoparticles (MNPs) into tumours then activating them using an alternating magnetic field (AMF). The system produces not only a magnetic field, but also an electric field which penetrates normal tissue and induces eddy currents, resulting in unwanted heating of normal tissues. Magnitude of the eddy current depends, in part, on the AMF source and the size of the tissue exposed to the field. The majority of in vivo MNP hyperthermia therapy studies have been performed in small animals, which, due to the spatial distribution of the AMF relative to the size of the animals, do not reveal the potential toxicity of eddy current heating in larger tissues. This has posed a non-trivial challenge for researchers attempting to scale up to clinically relevant volumes of tissue. There is a relative dearth of studies focused on decreasing the maximum temperature resulting from eddy current heating to increase therapeutic ratio.

Methods: This paper presents two simple, clinically applicable techniques for decreasing maximum temperature induced by eddy currents. Computational and experimental results are presented to understand the underlying physics of eddy currents induced in conducting, biological tissues and leverage these insights to mitigate eddy current heating during MNP hyperthermia therapy.

Results: Phantom studies show that the displacement and motion techniques reduce maximum temperature due to eddy currents by 74% and 19% in simulation, and by 77% and 33% experimentally.

Conclusion: Further study is required to optimise these methods for particular scenarios; however, these results suggest larger volumes of tissue could be treated, and/or higher field strengths and frequencies could be used to attain increased MNP heating when these eddy current mitigation techniques are employed.     

Interstitial hyperthermia of experimental brain tumor using implant heating system

Summary New experimental system of induction hyperthermia for brain tumor using ferromagnetic implant with low Curie point has been developed. The metal implant is cylindrical needle and made of Fe-Pt alloy with low Curie point suitable for hyperthermia (50–60°C). Induction coil and generator which produce maximum power of 200 W and variable frequency of 100–500 kHz, yielding magnetic power of 16.7 Oe, have been developed.Interstitial hyperthermia was made on rat brain tumor model (T9 gliosarcoma) by this system. Significant effects of single hyperthermia (45°C for 30 minutes) were observed by the extension of life span and morphological changes of the tumor.     

A multiple RF heating system for experimental hyperthermia in small animals

A versatile system is described for locally heating a number of mouse tumours simultaneously using RF capacitive coupling. The system is designed around a single RF power amplifier supplying a number of heating jigs via an efficient isolated power splitter. It is primarily intended for use at 13.56 and 27.12 MHz, but can operate from 2-30 MHz and could be modified for use at other frequencies. Microthermocouples are used for monitoring the intra-tissue temperature quasi-continuously, by making temperature measurements every 220 ms within 20 ms periods during which the RF power is turned off to all the jigs. This method avoids any artefacts in the temperature measurement which are associated with electromagnetic interference. Thermostatic regulation of tissue temperature is provided by on-off control of the average power supplied independently to each heating jig.     

Sensitization to hyperthermia induced in a normal tissue by step-down heating

The effect of step-down heating was investigated in the skin of the CDF1 mouse foot. Step-down heating was induced with a 44.7 degrees C/10 min pretreatment followed by a test treatment at a lower temperature for variable time. Step-up heating, that is, a test treatment followed by a 44.7 degrees C/10 min treatment, and single heating were used as controls. The normal tissue reaction was scored at five levels of damage (from slight redness and oedema to loss of a toe or greater reaction), and the heating time to induce each level in 50% of the animals, RD50, was used as the endpoint. The effect of step-down heating was quantified by the step-down ratio, calculated as the ratio of test heating times to obtain the endpoint. A significant reduction of the RD50 was seen at all score levels when the 44.7 degrees C/10 min was given in a step-down heating schedule, and the effect increased with decreasing test treatment temperature. In contrast, the heat sensitivity was only marginally influenced by step-up heating. An analysis of the time-temperature relationship demonstrated a log-linear relationship between temperature and RD50 for single heating in the range 42.2-44.7 degrees C and for step-down heating in the range 41.7-44.7 degrees C. The curve for step-down heating showed a lesser slope indicating a decrease of the activation energy. The kinetics of the SDH effect were investigated by inserting an interval between a primary 44.7 degrees C/10 min treatment and a test treatment performed at 42.2 degrees C. The effect of step-down heating was maximal with no interval between the priming treatment and the test treatment. As the interval was increased to 1.5 hr the step-down sensitization disappeared, and with even longer intervals thermotolerance developed. From a clinical point of view, the present data indicate that step-down heating may increase the extent of both reversible and irreversible heat damage in the normal tissue.     

Clinical evaluation of hyperthermia with radiofrequency capacitive heating in combination with radiotherapy

Clinical studies of radiofrequency (RF) hyperthermia combined with radiotherapy have been applied on the superficial bulky tumors and deep-seated tumors. Some improvement during the local heating was achieved by applying the small pad and/or the overlay bolus onto the skin surface underlain by subcutaneous fatty tissue. The condition of effective heating on tumors had shown to have a tendency to lead a good response regarding reduction rates in a tumor size. However, for the clinical evaluation, we have considered that it should be suitable to apply such findings as one showing the necrotic degenerative changes on computed tomograms in addition to the evaluation guide on the local response.     

Rapid heating: Critical theoretical assessment of thermal gradients found in hyperthermia treatments

There is increasing evidence that many hyperthermia failures are closely related to the large variability of temperatures found in the treatment field. These are linked to thermal gradients near the treatment boundary, vascular perfusion differences, localized cooling, and poor distribution of energy deposition in the tissues. One way of reducing the temperature gradients is to replace traditional heating treatments of 30–60 min by a rapid heating technique, in which the treatment time is a few seconds combined with higher treatment temperatures. The purpose of this paper is to model potential advantages of using various rapid heating protocols, and to compare them with traditional treatments. Theoretical models (in agreement with clinical treatments) suggest that traditional hyperthermia treatments often do not produce the necessary temperature homogeneity needed to kill the last malignant cells in the tumour due to cooler regions in the field. The simulations presented in this paper suggest that much shorter treatment times (1–10 s) should give significant improvements in the treatment field for both the temperature homogeneity and equivalent thermal doses.     

Rapid heating: critical theoretical assessment of thermal gradients found in hyperthermia treatments

There is increasing evidence that many hyperthermia failures are closely related to the large variability of temperatures found in the treatment field. These are linked to thermal gradients near the treatment boundary, vascular perfusion differences, localized cooling, and poor distribution of energy deposition in the tissues. One way of reducing the temperature gradients is to replace traditional heating treatments of 30-60 min by a rapid heating technique, in which the treatment time is a few seconds combined with higher treatment temperatures. The purpose of this paper is to model potential advantages of using various rapid heating protocols, and to compare them with traditional treatments. Theoretical models (in agreement with clinical treatments) suggest that traditional hyperthermia treatments often do not produce the necessary temperature homogeneity needed to kill the last malignant cells in the tumour due to cooler regions in the field. The simulations presented in this paper suggest that much shorter treatment times (1-10 s) should give significant improvements in the treatment field for both the temperature homogeneity and equivalent thermal doses.     

An edge-element based finite element model of microwave heating in hyperthermia: method and verification

Hyperthermia has been shown to improve local tumour control of superficial and deep seated lesions when combined with radiotherapy. There remains difficulty in heating larger tumours with conventional applicators, but this is being addressed by several new applicator designs. This paper presents a new numerical model of microwave heating which is designed to aid in the development of new applicators for superficial heating. The model is based on a finite element method which utilises vector valued basis functions instead of the more conventional scalar valued basis functions. These basis functions were chosen since they are inherently suited for the solution of Maxwell's equations due to their vector nature. The model was successfully verified against an analytic solution to the Mie scattering problem as well as against previously published measurements of heating from a modified water bolus attached to a conventional waveguide applicator. An accompanying paper describes an application of this model to the design optimization of this modified bolus.     

Use of LAK-cells and systemic chemotherapy with hyperthermia in the management of chemo-resistant tumors

Tentative results of LAK-cell and whole-body hyperthermia (WBH) were evaluated in 19 children with advanced chemorefractory tumors. LAK-cells were obtained by extracorporeal incubation of peripheral blood lymphocytes: a germ-cell rhabdomyosarcoma was detected in 4, Askin's tumor--2--2, renal cell carcinoma--2 and miscellaneous--7. Autologous LAK-cells were infused twice: on completion of WBH as body temperature fell to as low as (+) 40 deg. C and on day after WBH. The latter was well tolerated. Complete or partial response to thermochemobiotherapy was reported in 8 patients. Overall 5-year survival was 43% (median follow-up--12.6 months).     

The relationship between heating time and temperature: its relevance to clinical hyperthermia

It is well known that for a given level of damage to either cells in vitro or tissues in situ the relationship between temperature and time of application undergoes a transition in the range 42-43 degrees C and that above this temperature a change of 1 degree C is equivalent to a change in heating time by a factor of two. The present study has concentrated on establishing the relationship between time and temperature over a wide range. The investigation is in two parts, i.e. a review of the literature and an experimental study in which the endpoint used was necrosis in the tail of the baby rat. The aim is to provide information which might help solve a major clinical problem, namely the lack of a satisfactory means of relating treatments given with different temperatures for different lengths of time. The difficulty arises because there is no satisfactory definition of heat dose, in this context. The results confirm the relationship given above for temperatures above the transition. However, below the transition a change of 1 degree C is equivalent to a change in heating time by a factor of six. It is suggested that these relationships provide a means of monitoring a treatment in which the temperature does not remain constant and may vary within a heated volume. The method may also be used to compare treatments from different centres. An indication of the considerable uncertainties of the procedure is given.(ABSTRACT TRUNCATED AT 250 WORDS)     

Determination of continuous atracurium infusion rate in dogs undergoing whole-body hyperthermia

Infusion rates for atracurium were calculated from multiple bolus injection data for normothermic (38 degrees C; n = 4) and hyperthermic (42 degrees C; n = 14) dogs anesthetized with thiopental and oxymorphone while undergoing whole-body hyperthermia treatment. The calculated infusion rate for atracurium at 38 degrees C was 6.2 +/- 0.3 micrograms/kg/min and the calculated infusion rate at 42 degrees C was 8.5 +/- 0.4 micrograms/kg/min. Infusion of atracurium at the calculated infusion rate of 8.5 micrograms/kg/min produced an estimated 90-100% neuromuscular blockade during heating from 38-42 degrees C and at 42 degrees C. Following discontinuation of the infusion and cooling to 38 degrees C, neuromuscular function returned to normal within 20 min with no evidence of recurarization. Atracurium infusion rates appear to be linear and related to body temperature from 26-42 degrees C. Clinically useful neuromuscular blockade in dogs may be obtained during whole-body hyperthermia by utilizing the 42 degrees C atracurium infusion rate throughout the 38-42 degrees C heating phase.     

An edge-element based finite element model of microwave heating in hyperthermia: method and verification.

Hyperthermia has been shown to improve local tumour control of superficial and deep seated lesions when combined with radiotherapy. There remains difficulty in heating larger tumours with conventional applicators, but this is being addressed by several new applicator designs. This paper presents a new numerical model of microwave heating which is designed to aid in the development of new applicators for superficial heating. The model is based on a finite element method which utilises vector valued basis functions instead of the more conventional scalar valued basis functions. These basis functions were chosen since they are inherently suited for the solution of Maxwell's equations due to their vector nature. The model was successfully verified against an analytic solution to the Mie scattering problem as well as against previously published measurements of heating from a modified water bolus attached to a conventional waveguide applicator. An accompanying paper describes an application of this model to the design optimization of this modified bolus.