Localized hyperthermia and radiation in cancer therapy

Clinical researches in hyperthermia have recently expanded rapidly with the increase in our knowledge of the biological effects of heat on experimental systems. This article provides background information on the biological rationale and current status of technologies concerning thermometry and heating equipment for the application of hyperthermia to human cancer treatment. Much data has been accumulated recently in hyperthermia treatment with and without radiation to superficial tumours which are refractory to conventional treatments. In this paper the treatment results published recently have been surveyed. The complete responses of tumours treated by heat alone are in the range of 15 per cent as opposed to approximately 60 per cent for the combination of heat plus radiation. Clinical results so far published have demonstrated that local control is consistently better in the lesions treated with radiation plus heat than with radiation alone. The morbidity related to heat therapy is within tolerable limits. Several articles on the clinical results of deep-seated tumours treated by hyperthermia are reviewed. Problems to be solved in the application of heat to cancer therapy are discussed.     

Ultrasound Doppler as an Imaging Modality for Selection of Murine 4T1 Breast Tumors for Combination Radiofrequency Hyperthermia and Chemotherapy

Noninvasive radiofrequency-induced (RF) hyperthermia has been shown to increase the perfusion of chemotherapeutics and nanomaterials through cancer tissue in ectopic and orthotopic murine tumor models. Additionally, mild hyperthermia (37°C-45°C) has previously shown a synergistic anticancer effect when used with standard-of-care chemotherapeutics such as gemcitabine and Abraxane. However, RF hyperthermia treatment schedules remain unoptimized, and the mechanisms of action of hyperthermia and how they change when treating various tumor phenotypes are poorly understood. Therefore, pretreatment screening of tumor phenotypes to identify key tumors that are predicted to respond more favorably to hyperthermia will provide useful mechanistic data and may improve therapeutic outcomes. Herein, we identify key biophysical tumor characteristics in order to predict the outcome of combinational RF and chemotherapy treatment. We demonstrate that ultrasound imaging using Doppler mode can be utilized to predict the response of combinational RF and chemotherapeutic therapy in a murine 4T1 breast cancer model.     

Tissue temperature feedback control of power: the key to successful ablation

Multiple ablation technologies are used to treat atrial fibrillation during cardiac operations. All such ablation technologies use locally induced temperature extremes (>50°C or <-20°C) to kill tissue and create a lesion pattern in the atria which blocks activation pathways that initiate and sustain atrial fibrillation. The technologies used to heat tissue have included radiofrequency (RF), microwave, high-intensity focused ultrasound, and infrared laser. RF accounts for more than 95% of the heating-based ablation technology used by cardiac surgeons. Energy delivery with RF is easier to control than with some other technologies, the heating produced by the energy source is well understood, and manufacturing costs are not excessive. Whichever heating technology is used, control of energy delivery is required to ensure both safe and effective heating of the targeted tissue. All targeted tissue needs to be heated above 50°C to achieve cell death. However, the targeted tissue should not be heated above 100°C, as this can cause perforation due to a steam pop. In addition, adjacent noncardiac tissues must not be damaged during the ablation procedure. The best method to achieve this control uses direct measurement of tissue temperature, because the tissue temperature defines both the safe and effective limits for the ablative process.     

Simultaneous measurements of local tissue temperature and blood perfusion rate in the canine prostate during radio frequency thermal therapy

Local tissue temperature and blood perfusion rate were measured simultaneously to study thermoregulation in the canine prostate during transurethral radio-frequency (RF) thermal therapy. Thermistor bead microprobes measured interstitial temperatures and a thermal clearance method measured the prostatic blood perfusion rate under both normal and hyperthermic conditions. Increase in local tissue temperature induced by the RF heating increased blood perfusion throughout the entirety of most prostates. The onset of the initial increase in blood perfusion was sometimes triggered by a temporal temperature gradient at low tissue temperatures. When tissue temperature was higher than 41°C, however, the magnitude and the spatial gradient of temperature may play significant roles. It was found that the temperature elevation in response to the RF heating was closely coupled with local blood flow. The resulting decrease in or stabilization of tissue temperature suggested that blood flow might act as a negative feedback of tissue temperature in a closed control system. Results from this experiment provide insights into the regulation of local perfusion under hyperthermia. The information is important for accurate predictions of temperature during transurethral RF thermal therapy.     

Evaluation of the effectiveness of transurethral radio frequency hyperthermia in the canine prostate: temperature distribution analysis

The heating pattern of a transurethral radio frequency (RF) applicator and its induced steady-state temperature field in the prostate during transurethral hyperthermia treatment were investigated in this study. The specific absorption rate (SAR) of the electromagnetic energy was first quantified in a tissue-equivalent gel phantom. It was used in conjunction with the Pennes bioheat transfer equation to model the steady-state temperature field in prostate during the treatment. Theoretical predictions were compared to in vivo temperature measurements in the canine prostate and good agreement was found to validate the model. The prostatic tissue temperature rise and its relation to the effect of blood perfusion were analyzed. Blood perfusion is found to be an important factor for removal of heat especially at the higher RF heating level. To achieve a temperature above 44 degrees C within 10 percent of the prostatic tissue volume, the minimum RF power required ranges from 5.5 W to 36.4 W depending on the local blood perfusion rate (omega = 0.2-1.5 ml/gm/min). The corresponding histological results from the treatment suggest that to obtain better treatment results, either higher RF power level or longer treatment time (> 180 minutes) is necessary. This is consistent with the predictions from the theoretical model developed in this study.     

Study of thermal effects of ultrasound stimulation on fracture healing

Low intensity ultrasound stimulation has been used as a strategy to promote fracture healing. This study investigated the mechanism of ultrasound stimulation in enhancing fracture healing. Forty-five adult New Zealand White rabbits were divided into control, microwave treated, and ultrasound stimulation groups. After anesthesia, transverse osteotomy was created at midportion of the fibula bone. Intravital staining followed by fluorescence microscopic examination of new bone formation in the osteotomy site and biomechanical tests on torsional stiffness of the osteotomy site were performed. The difference between each examination was evaluated and analyzed. After ultrasound stimulation, new bone formation in the osteotomy site of the stimulated limb was 23.1-35.8% faster than that of the sham treated limb; the torsional stiffness of the stimulated limb was 44.4-80.0% higher than that of the sham treated limb. In the group of microwave hyperthermia treatment, the new bone formation was higher than that of the sham treated limb, but the difference was not statistically significant. The difference in torsional stiffness between the microwave hyperthermia treated limbs and the sham treated limb was not quite statistically significant. We demonstrated that low intensity ultrasound stimulation could increase the new bone formation and torsional stiffness. These effects probably are not mediated via hyperthermia.     

Enhancement of DMBA induced mammary tumours by intermittent whole body hyperthermia (42 degrees C)

Wistar Female rats bearing DMBA induced mammary tumours were subjected to whole body hyperthermia 42 degrees C dry heat exposure for 15 minutes daily for 6 weeks. The control group was maintained at a room temperature of 25 degrees C. Hyperthermia induced significant growth stimulation of breast tumour compared to the controls. Plasma estradiol was slightly decreased while total T4 and TSH values remained unchanged in heat stressed rats. Plasma prolactin was significantly increased together with enhanced synthetic activity of pituitary prolactin cells. It is concluded that heat acting as stressor accelerates breast tumor growth, probably by influencing synthesis of prolactin. Therefore the hormone dependency of tumours should be considered before hyperthermia is used as an anticancer modality.     

Spatial and Temporal Control of Hyperthermia Using Real Time Ultrasonic Thermal Strain Imaging with Motion Compensation,Phantom Study

Mild hyperthermia has been successfully employed to induce reversible physiological changes that can directly treat cancer and enhance local drug delivery. In this approach, temperature monitoring is essential to avoid undesirable biological effects that result from thermal damage. For thermal therapies, Magnetic Resonance Imaging (MRI) has been employed to control real-time Focused Ultrasound (FUS) therapies. However, combined ultrasound imaging and therapy systems offer the benefits of simple, low-cost devices that can be broadly applied. To facilitate such technology, ultrasound thermometry has potential to reliably monitor temperature. Control of mild hyperthermia was previously achieved using a proportional-integral-derivative (PID) controller based on thermocouple measurements. Despite accurate temporal control of heating, this method is limited by the single position at which the temperature is measured. Ultrasound thermometry techniques based on exploiting the thermal dependence of acoustic parameters (such as longitudinal velocity) can be extended to create thermal maps and allow an accurate monitoring of temperature with good spatial resolution. However, in vivo applications of this technique have not been fully developed due to the high sensitivity to tissue motion. Here, we propose a motion compensation method based on the acquisition of multiple reference frames prior to treatment. The technique was tested in the presence of 2-D and 3-D physiological-scale motion and was found to provide effective real-time temperature monitoring. PID control of mild hyperthermia in presence of motion was then tested with ultrasound thermometry as feedback and temperature was maintained within 0.3°C of the requested value.     

Intraocular tumours

Intraocular tumours may be benign or malignant. The latter are more numerous, and endanger not only vision but life as well. Two of them deserve special attention: melanoma malignum oculi in adults and retinoblastoma in children. Melanoma malignum may arise from all three areas of the uvea: the iris, the ciliary body and the choroid. The more malignant growths are those which are situated closer to the posterior pole. Histologically the epitheloid cell-type of melanoma is more malignant than those containing only spindle cells. Their treatment depends on the size: in the case of large tumours enucleation is required, while for the smaller ones, radiation therapy can be applied. Retinoblastoma is most common in children of 1-2 years of age. It has familial and sporadic forms. Sixty-seven percent of the inherited-type cases are bilateral. An early symptom in small children is strabismus. A white tissue mass growing into the vitreous is seen on the fundus. A diagnostic feature that can be detected by ultrasound examination is calcification. The tumour may also present intracranially, therefore CT of the skull should be performed in each case. Histologically the tumour contains malignant neuroepithelial cells, which may form a rosette. In the case of large tumours the treatment is enucleation; in bilateral processes the bulbus with the larger mass is removed and the other eye is treated with radiation therapy. In both cases chemotherapy is used according to a prescribed schedule. Metastases to the eye occur most frequently from carcinomas of the breast, lungs or gastrointestinal tract. These are treated with radiotherapy, chemotherapy and hormone therapy. Primary intraocular lymphoma often occurs bilaterally, and may be accompanied by primary lymphoma of the central nervous system (CNS). Some benign tumours are found by chance on routine eye examinations, others due to subjective and objective symptoms.     

Predicting effects of blood flow rate and size of vessels in a vasculature on hyperthermia treatments using computer simulation

Background

Pennes Bio Heat Transfer Equation (PBHTE) has been widely used to approximate the overall temperature distribution in tissue using a perfusion parameter term in the equation during hyperthermia treatment. In the similar modeling, effective thermal conductivity (K_eff) model uses thermal conductivity as a parameter to predict temperatures. However the equations do not describe the thermal contribution of blood vessels. A countercurrent vascular network model which represents a more fundamental approach to modeling temperatures in tissue than do the generally used approximate equations such as the Pennes BHTE or effective thermal conductivity equations was presented in 1996. This type of model is capable of calculating the blood temperature in vessels and describing a vasculature in the tissue regions.

Methods

In this paper, a countercurrent blood vessel network (CBVN) model for calculating tissue temperatures has been developed for studying hyperthermia cancer treatment. We use a systematic approach to reveal the impact of a vasculature of blood vessels against a single vessel which most studies have presented. A vasculature illustrates branching vessels at the periphery of the tumor volume. The general trends present in this vascular model are similar to those shown for physiological systems in Green and Whitmore. The 3-D temperature distributions are obtained by solving the conduction equation in the tissue and the convective energy equation with specified Nusselt number in the vessels.

Results

This paper investigates effects of size of blood vessels in the CBVN model on total absorbed power in the treated region and blood flow rates (or perfusion rate) in the CBVN on temperature distributions during hyperthermia cancer treatment. Also, the same optimized power distribution during hyperthermia treatment is used to illustrate the differences between PBHTE and CBVN models. K_eff (effective thermal conductivity model) delivers the same difference as compared to the CBVN model. The optimization used here is adjusting power based on the local temperature in the treated region in an attempt to reach the ideal therapeutic temperature of 43°C. The scheme can be used (or adapted) in a non-invasive power supply application such as high-intensity focused ultrasound (HIFU). Results show that, for low perfusion rates in CBVN model vessels, impacts on tissue temperature becomes insignificant. Uniform temperature in the treated region is obtained.

Conclusion

Therefore, any method that could decrease or prevent blood flow rates into the tumorous region is recommended as a pre-process to hyperthermia cancer treatment. Second, the size of vessels in vasculatures does not significantly affect on total power consumption during hyperthermia therapy when the total blood flow rate is constant. It is about 0.8% decreasing in total optimized absorbed power in the heated region as γ (the ratio of diameters of successive vessel generations) increases from 0.6 to 0.7, or from 0.7 to 0.8, or from 0.8 to 0.9. Last, in hyperthermia treatments, when the heated region consists of thermally significant vessels, much of absorbed power is required to heat the region and (provided that finer spatial power deposition exists) to heat vessels which could lead to higher blood temperatures than tissue temperatures when modeled them using PBHTE.     

Numerical study of the effect of ultrasound frequency on temperature distribution in layered tissue

The high intensity focused ultrasound (HIFU) technology can produce therapeutic benefits in deep-seated tissues of interest, selectively and noninvasively. In order to control the treatment process, it is important to recognize the heat generation in biological tissue and the parameters that have an effect on temperature rising. This study investigates the influence of frequency and source intensity on temperature distribution during high-intensity focused ultrasound (HIFU). A nonlinear full wave equation model is simulated to compute the pressure field. Additionally, the absorbed coefficient of tissue is added to the nonlinear equations to simulate accurately the wave propagation in tissue with high absorbed coefficient. In addition, temperature distribution was solved by the Pennes bio-heat equation. Conclusively, frequencies in the range of 1–1.5 MHz are prescribed to have maximum heat absorption in the focal region.     

Thirty-five years in bioelectromagnetics research

For 35 years, I have been involved in various bioelectromagnetics research projects including acute and long-term radiofrequency (RF) bioeffects studies, dosimetry, exposure systems, MRI safety, cancer studies involving hyperthermia and electrochemical treatment, development of RF exposure and measurement standards, and product compliance. My first study demonstrated that effects on isolated nerve and muscle preparations were due to thermal effects of RF exposure. The recording of cochlear microphonics in animals shows the mechanical nature of the microwave auditory effect. In 1992, we published the results of a large-scale lifetime study in which 100 rats were sham-exposed and 100 rats were exposed for 21 h/day for 25 months to a pulsed RF signal. In dosimetry studies, human models were employed as well as many animal species including mice, rats, rabbits, monkeys, and birds of many sizes. Cancer hyperthermia studies demonstrated that knowledge of temperature distribution was crucial for successful treatment. Research on electrochemical treatment of tumors with direct current involved cellular, animal, and clinical studies. Over the past few decades, there has been rather extensive investigation of the public health impact of RF exposure. In my opinion, future research in bioelectromagnetics should place greater emphasis on medical applications.     

Dependence of synergism of the combined effect of ultrasound and hyperthermia upon intensity of ultrasound

The inactivation of wild-type yeast Saccharomyces cerevisiae was studied after simultaneous treatment with ultrasound and hyperthermia. A temperature range was established within which ultrasound and hyperthermia exert a synergistic action. The effect was shown to depend on ultrasound intensity and the temperature at which the treatment takes place. The temperature range enhancing the ultrasound effect shifted forward higher temperature with increasing ultrasound intensity. For every intensity value, an optimal temperature exists at which the synergetic effect is maximum. The biophysical interpretation of the results obtained is based on the assumption that synergism is due to an additional lethal damage, which arises from the interaction of some sub-lesions induced by both agents. These sublesions are considered non-lethal if the agents are applied separately.     

Bone destruction by breast tumours

In 1975 we reported preliminary evidence that normal human breast tissue and benign breast tumours contain and synthesise little PG- like material, whereas malignant breast tumours contain significantly more. Those tumours synthesising most PG were associated with spread to bone (1), possibly because some PGs are potent bone resorbing agents (2,3). Our further data re-inforce the correlation between tumour PG levels and the incidence of bone metastases.     

The effects of some physical factors on the production of hyperthermia by ultrasound in neoplastic tissues

Summary A one-dimensional and a three-dimensional computer model have been built in order to study the importance of blood flow and ultrasonic absorption in tissues during local hyperthermia. The decreased blood flow in the interior of certain tumours and possibly the increased ultrasonic absorption of the malignant tissue in some cases may cause selectively higher temperatures inside the tumours though the heat input is the same as in the surrounding tissues. Also, the vasodilation of blood vessels in normal tissues as a response to heat causes a therapeutically useful temperature difference. These blood flow differences can lead to enhanced effects during sonication to produce hyperthermia in the tumour. The inhomogenity of blood flow in the tumour causes a non-uniform temperature distribution leaving the well-perfused cells in the advancing front at a much lower temperature than the cells in the necrotic centre. Thus, the combination of local hyperthermia with radio-and chemotherapy seems to offer the most attractive means of destroying malignant tissue.     

Treatment of superficial cancerous tumors by hyperthermia induced by ultrasonics or microwaves

Results of treating superficial human cancerous tumors by ultrasound (1-3 MHz) or microwave (434 MHz) hyperthermia, alone or combined with radiotherapy or chemotherapy are presented according to the heating method. The comparison of in vivo thermal distributions obtained at depth with these two techniques could partially explain their different therapeutic efficiency.     

Local tumor hyperthermia using a computer-controlled microwave system

A minicomputer-based system was designed to control the microwave (2.45-GHz) power to four local hyperthermia applicators. Errors in temperature measurement, due to electromagnetic field interactions with small thermocouple probes, are minimized by sampling the temperature only when the microwave power is off. The programmable controller can regulate the temperature in tumors in 0.1 °C increments from 30 to 60 °C. This technique reduces temperature differences throughout the tumor at steady state to less than 0.4 °C and prevents skin burns.     

Chemotherapy and Radiofrequency-Induced Mild Hyperthermia Combined Treatment of Orthotopic Pancreatic Ductal Adenocarcinoma Xenografts

Patients with pancreatic ductal adenocarcinomas (PDAC) have one of the poorest survival rates of all cancers. The main reason for this is related to the unique tumor stroma and poor vascularization of PDAC. As a consequence, chemotherapeutic drugs, such as nab-paclitaxel and gemcitabine, cannot efficiently penetrate into the tumor tissue. Non-invasive radiofrequency (RF) mild hyperthermia treatment was proposed as a synergistic therapy to enhance drug uptake into the tumor by increasing tumor vascular inflow and perfusion, thus, increasing the effect of chemotherapy. RF-induced hyperthermia is a safer and non-invasive technique of tumor heating compared to conventional contact heating procedures. In this study, we investigated the short- and long-term effects (~20 days and 65 days, respectively) of combination chemotherapy and RF hyperthermia in an orthotopic PDAC model in mice. The benefit of nab-paclitaxel and gemcitabine treatment was confirmed in mice; however, the effect of treatment was statistically insignificant in comparison to saline treated mice during long-term observation. The benefit of RF was minimal in the short-term and completely insignificant during long-term observation.     

Design and performance of a high speed driver circuit for PIN diode switches used in microwave hyperthermia

In many cancer treatment facilities where hyperthermia treatments are performed, there is a need to split a single channel microwave source into multiple, individually controllable channels. In the application reported here, microwave power is alternately switched between active and passive elements for each channel. The active element is either a microwave antenna inside a catheter in tumour tissue or a planar spiral applicator placed superficially, the total power to each channel being pulse width modulated from 1 to 99% of a 1 s duty cycle. The system is computer controlled and is capable of dividing and controlling power to 12 channels. PIN diode switch assemblies control the flow of power in each channel but they must be switched within a few microseconds to avoid failure at the high power levels used in the clinic. A high speed circuit was fabricated and tested to drive each PIN diode switch; the PIN diode switches are turned on in 1.5 μs and off in 3.0 μs, which meets the specifications for hot switching. The increase in speed over the former driver system is a factor of 5.1 for the on cycle and 1.5 × 10⁵ for the off cycle and the maximum power tested in each channel was 80 W for 1 h at random duty cycles between 1 and 99%. The circuit was also tested with 40 W of power at duty cycles of 1, 50 and 99% for 1 h each; no failures or performance decrements were observed. The 12 channel circuit driver has been used for six months of clinical treatments without failure.     

铁磁热籽加温治疗肿瘤的研究

热疗治疗肿瘤是应用各种致热源的热效应,将肿瘤加热至有效治疗温度范围并维持一定时间,以杀灭肿瘤细胞的一种方法。本文探讨了用于加温治疗肿瘤的铁磁热籽在治疗时的加热原理和自控温机制。与目前几种加温方式和测温方式的相比,得出铁磁热籽在肿瘤治疗中利用感应加温有效的克服了其它加温方式的缺点,并且利用居里点效应实现了自控温。因此,有着诱人的前景。