Jeffrey Hand

Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: Results from five randomized controlled trials

PURPOSE Claims for the value of hyperthermia as an adjunct to radiotherapy in the treatment of cancer have mostly been based on small Phase I or II trials. To test the benefit of this form of treatment, randomized Phase III trials were needed. METHODS AND MATERIALS Five randomized trials addressing this question were started between 1988 and 1991. In these trials, patients were eligible if they had advanced primary or recurrent breast cancer, and local radiotherapy was indicated in preference to surgery. In addition, heating of the lesions and treatment with a prescribed (re)irradiation schedule had to be feasible and informed consent was obtained. The primary endpoint of all trials was local complete response. Slow recruitment led to a decision to collaborate and combine the trial results in one analysis, and report them simultaneously in one publication. Interim analyses were carried out and the trials were closed to recruitment when a previously agreed statistically significant difference in complete response rate was observed in the two larger trials. RESULTS We report on pretreatment characteristics, the treatments received, the local response observed, duration of response, time to local failure, distant progression and survival, and treatment toxicity of the 306 patients randomized. The overall CR rate for RT alone was 41% and for the combined treatment arm was 59%, giving, after stratification by trial, an odds ratio of 2.3. Not all trials demonstrated an advantage for the combined treatment, although the 95% confidence intervals of the different trials all contain the pooled odds ratio. The greatest effect was observed in patients with recurrent lesions in previously irradiated areas, where further irradiation was limited to low doses. CONCLUSION The combined result of the five trials has demonstrated the efficacy of hyperthermia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of these encouraging results is that hyperthermia appears to have an important role in the clinical management of this disease, and there should be no doubt that further studies of the use of hyperthermia are warranted.

Relationship between thermal dose and outcome in thermoradiotherapy treatments for superficial recurrences of breast cancer: Data from a phase III trial

PURPOSE The objective of this study was to determine whether the thermal dose delivered during hyperthermia treatments and other thermal factors correlate with outcome after combined radiation and hyperthermia of breast carcinoma recurrences. Data were from the combined hyperthermia and radiation treatment arms of four Phase III trials, which when pooled together, demonstrated a positive effect of hyperthermia. METHODS AND MATERIALS Four Phase III trials addressing the question of whether hyperthermia could improve the local response of superficial recurrent breast cancer to radiation therapy were combined into a single analysis. Thermal dosimetry data were collected from 120 of the 148 breast cancer recurrence patients who received hyperthermia. The data were analyzed for correlations between thermal parameters as well as important clinical parameters and outcome (complete response rate, local disease free survival, time to local failure, and overall survival). RESULTS Five thermal parameters were tested, all associated with the low regions of the measured temperature distributions. Max(TDmin) and Sum(TDmin) were associated with complete response where TDmin is the minimum thermal dose measured by any of the tumor temperature sensors during a treatment: Max(TDmin) is the maximum of TDmin over a series of treatments. Using a categorical relationship with a cutoff of 10 min for Sum(TDmin), the complete response rate was 77% for Sum(TDmin) > 10 min and 43% for Sum(TDmin) < or = 10 min (p = 0.022, adjusted for study center and significant clinical factors). The overall complete response rate for hyperthermia and radiation was 61% compared to 41% for radiation alone. Either Max(TDmin) or Sum(TDmin) were also associated with local disease free survival, time to local failure and overall survival. CONCLUSIONS An earlier report of this trial demonstrated a significant benefit when hyperthermia was added to radiation in the treatment of breast cancer recurrences. The analysis of thermal factors demonstrates that parameters representative of the low end of the measured temperature distributions are associated with initial complete response rate, local disease-free survival, time to local failure and overall survival.

Numerical Modeling of Temperature Distributions within the Neonatal Head

Introduction of hypothermia therapy as a neuroprotection therapy after hypoxia-ischemia in newborn infants requires appraisal of cooling methods. In this numerical study thermal simulations were performed to test the hypothesis that cooling of the surface of the cranium by the application of a cooling bonnet significantly reduces deep brain temperature and produces a temperature differential between the deep brain and the body core. A realistic three-dimensional (3-D) computer model of infant head anatomy was used, derived from magnetic resonance data from a newborn infant. Temperature distributions were calculated using the Pennes heatsink model. The cooling bonnet was at a constant temperature of 10°C. When modeling head cooling only, a constant body core temperature of 37°C was imposed. The computed result showed no significant cooling of the deep brain regions, only the very superficial regions of the brain are cooled to temperatures of 33–34°C. Poor efficacy of head cooling was still found after a considerable increase in the modeled thermal conductivities of the skin and skull, or after a decrease in perfusion. The results for the heatsink thermal model of the infant head were confirmed by comparison of results computed for a scaled down adult head, using both the heatsink description and a discrete vessel thermal model with both anatomy and vasculature obtained from MR data. The results indicate that significant reduction in brain temperature will only be achieved if the infants core temperature is lowered.

Modelling the interaction of electromagnetic fields (10 MHz–10 GHz) with the human body: methods and applications

Numerical modelling of the interaction between electromagnetic fields (EMFs) and the dielectrically inhomogeneous human body provides a unique way of assessing the resulting spatial distributions of internal electric fields, currents and rate of energy deposition. Knowledge of these parameters is of importance in understanding such interactions and is a prerequisite when assessing EMF exposure or when assessing or optimizing therapeutic or diagnostic medical applications that employ EMFs. In this review, computational methods that provide this information through full time-dependent solutions of Maxwells equations are summarized briefly. This is followed by an overview of safety- and medical-related applications where modelling has contributed significantly to development and understanding of the techniques involved. In particular, applications in the areas of mobile communications, magnetic resonance imaging, hyperthermal therapy and microwave radiometry are highlighted. Finally, examples of modelling the potentially new medical applications of recent technologies such as ultra-wideband microwaves are discussed.

Heating techniques in hyperthermia

During the last decade there has been great interest in the use of hyperthermia in cancer therapy. The reasons why elevated temperatures, either alone or together with radiotherapy or chemotherapy, may prove useful have been the subjects of several recent reviews (Connor et al., 1977; Field and Bleehen, 1979).* Clinical applications of hyperthermia fall into two broad categories—whole-body and localized hyperthermia. During whole-body hyperthermia, which has been used on patients with advanced and widespread malignancies, core temperature is maintained at 41.8–42°C for a few hours. This appears to be the range of maximum tolerated temperatures; the organs which limit such treatment are the liver, which may be relatively sensitive to thermal damage, and the heart. Methods of inducing whole-body hyperthermia include the use of wax baths (Pettigrew et al., 1974), hot air cabinets (Pomp, 1978), water blankets (Barlogie et al., 1979) and space suits (Bull et al., 1979). Common features of these methods are the...

Observation by MR imaging of in vivo temperature changes induced by radio frequency hyperthermia.

Volunteers have undergone radio frequency hyperthermia in a magnetic resonance (MR) imaging system to investigate which of several possible MR parameters would be most convenient and sensitive to use to observe in vivo temperature changes. Measurements were made for T1, T2, and perfusion and diffusion variations, although the number of sequences needed at each temperature meant that the number of data points obtainable was limited. However, in the temperature range studied (around 28-42 degrees C), changes in both T1 and the diffusion coefficient were observed that agreed quite well with those predicted theoretically (respectively around 1.3%/degrees C and 2.4/degrees C).

Numerical study of RF exposure and the resulting temperature rise in the foetus during a magnetic resonance procedure

Numerical simulations of specific absorption rate (SAR) and temperature changes in a 26-week pregnant woman model within typical birdcage body coils as used in 1.5 T and 3 T MRI scanners are described. Spatial distributions of SAR and the resulting spatial and temporal changes in temperature are determined using a finite difference time domain method and a finite difference bio-heat transfer solver that accounts for discrete vessels. Heat transfer from foetus to placenta via the umbilical vein and arteries as well as that across the foetal skin/amniotic fluid/uterine wall boundaries is modelled. Results suggest that for procedures compliant with IEC normal mode conditions (maternal whole-body averaged SAR(MWB) < or = 2 W kg(-1) (continuous or time-averaged over 6 min)), whole foetal SAR, local foetal SAR(10 g) and average foetal temperature are within international safety limits. For continuous RF exposure at SAR(MWB) = 2 W kg(-1) over periods of 7.5 min or longer, a maximum local foetal temperature >38 degrees C may occur. However, assessment of the risk posed by such maximum temperatures predicted in a static model is difficult because of frequent foetal movement. Results also confirm that when SAR(MWB) = 2 W kg(-1), some local SAR(10g) values in the mothers trunk and extremities exceed recommended limits.

A theoretical assessment of the relative performance of spherical phased arrays for ultrasound surgery

Computer modeling of spherical-section phased arrays for ultrasound surgery (tissue ablation) is described. The influence on performance of the number of circular elements (68 to 1024), their diameter (2.5 to 10 mm), frequency (1 to 2 MHz), and degree of sparseness in the array is investigated for elements distributed randomly or in square, annular, and hexagonal patterns on a spherical shell (radius of curvature, 120 mm). Criteria for evaluating the quality of the intensity distributions obtained when focusing the arrays both on and away from their center of curvature, and in both single focus and simultaneous multiple foci modes, are proposed. Of the arrays studied, the most favorable performance, for both modes, is predicted for 256 5-mm diameter, randomly distributed elements. For the single focus mode, this performed better than regular arrays of 255 to 1024 elements and, for the case of nine simultaneous foci produced on a coplanar 3/spl times/3 grid with 4-mm spacing, better than square, hexagonal, or annular distributed arrays with a comparable number of elements. Randomization improved performance by suppressing grating lobes significantly. For single focus mode, a several-fold decrease in the number of elements could be made without degrading the quality of the intensity distribution.

Monitoring of deep brain temperature in infants using multi-frequency microwave radiometry and thermal modelling

In this study we present a design for a multi-frequency microwave radiometer aimed at prolonged monitoring of deep brain temperature in newborn infants and suitable for use during hypothermic neural rescue therapy. We identify appropriate hardware to measure brightness temperature and evaluate the accuracy of the measurements. We describe a method to estimate the tissue temperature distribution from measured brightness temperatures which uses the results of numerical simulations of the tissue temperature as well as the propagation of the microwaves in a realistic detailed three-dimensional infant head model. The temperature retrieval method is then used to evaluate how the statistical fluctuations in the measured brightness temperatures limit the confidence interval for the estimated temperature: for an 18 degrees C temperature differential between cooled surface and deep brain we found a standard error in the estimated central brain temperature of 0.75 degrees C. Evaluation of the systematic errors arising from inaccuracies in model parameters showed that realistic deviations in tissue parameters have little impact compared to uncertainty in the thickness of the bolus between the receiving antenna and the infants head or in the skull thickness. This highlights the need to pay particular attention to these latter parameters in future practical implementation of the technique.

Focusing of high-intensity ultrasound through the rib cage using a therapeutic random phased array.

A method for focusing high-intensity ultrasound (HIFU) through a rib cage that aims to minimize heating of the ribs while maintaining high intensities at the focus (or foci) was proposed and tested theoretically and experimentally. Two approaches, one based on geometric acoustics and the other accounting for diffraction effects associated with propagation through the rib cage, were investigated theoretically for idealized source conditions. It is shown that for an idealized radiator, the diffraction approach provides a 23% gain in peak intensity and results in significantly less power losses on the ribs (1% vs. 7.5% of the irradiated power) compared with the geometric one. A 2-D 1-MHz phased array with 254 randomly distributed elements, tissue-mimicking phantoms and samples of porcine rib cages are used in experiments; the geometric approach is used to configure how the array is driven. Intensity distributions are measured in the plane of the ribs and in the focal plane using an infrared camera. Theoretical and experimental results show that it is possible to provide adequate focusing through the ribs without overheating them for a single focus and several foci, including steering at +/- 10-15 mm off and +/- 20 mm along the array axis. Focus splitting caused by the periodic spatial structure of ribs is demonstrated both in simulations and experiments; the parameters of splitting are quantified. The ability to produce thermal lesions with a split focal pattern in ex vivo porcine tissue placed beyond the rib phantom is also demonstrated. The results suggest that the method is potentially useful for clinical applications of HIFU, for which the rib cage lies between the transducer(s) and the targeted tissue.