Therapeutic synergism of hyperthermia-cis-platinum in a mouse tumor model.

A small-animal model was developed as a guide to whole-body hyperthermia in cancer patiens. Anesthetized DBA/2 mice were secured to a platform, and their hindlimbs were immersed in a 42.3 degrees C water bath for 30-60 minutes. Hindlimb hyperthermia reulted in steady-state rectal and femoral bone marrow and muscle temperatures of 42 degrees C and upper extremity muscle and esophagus temperatures of 41 degrees C. With this hyper thermia technique, the mouse spleen colony assay could be used to quantitate the lethality of hyperthermia and/or cis-dichloro-diammineplatinum(II) (cis-platinum) on clonogenic bone marrow and leukemia cells. Hyperthermia prior to cis-platinum administration increased cis-platinum inhibition of leukemia colony formation as much as 2 logs; however, antileukemia synergism ws greatest when cis-platinum administration immediately preceded hyperthermia and no evidence existd of synergism against normal bone marrow colonies. Correlative in vivo drug uptake studies showed a marked increase in leukemia cell uptake of 195mPt-cis-platinum at elevated temperatures, which suggested a potential mechanism for the apparent antileukemia synergism of cis-platinum and heat.

Will thermometric tomography become practical for hyperthermia treatment monitoring?

Thermal tomography refers to the acquisition of detailed thermal information throughout a slice of the subject. Experimental temperature information of this nature to be obtained experimentally using some form of scanning mechanism is usually implied by the term, noninvasive thermometry. Desirable specifications for such a system are presented, and the degree to which the proposed methods are likely to achieve these are reviewed. Four major issues that must be resolved for any system to be useful clinically are: (a) will the system interfere with coupling the heating source to the patient and will the physician or technologist have access as well; (b) will its noise rejection be sufficient to operate in the presence of strong electromagnetic or ultrasonic heating fields; (c) will the spatial, temporal, and thermal resolution be sufficient to record important variations during treatments; and (d) will the parameter sensed be a function only of temperature or will it change as a consequence of physiological variations or therapeutic effects? It is concluded that noninvasive temperature scanning is unlikely to have a significant effect on thermal therapy for many years. Conversely, invasive thermometry coupled with numerical modeling is well along the way to becoming clinically useful.

Applications of bioheat transfer simulations in hyperthermia.

The applications of mathematical simulations of tissue temperature distributions in hyperthermia treatments are discussed in terms of four areas, comparative, prospective, concurrent, and retrospective thermal dosimetry. These four aspects of thermal dosimetry cover the range of hyperthermia applications of interest to clinicians, from comparative evaluation of competitive heating modalities to individual treatment planning, through feedback control during a treatment and, finally, to posttreatment therapy evaluation. Mathematical simulations of hyperthermia treatments can play a significant role in each of these areas.

Status and future developments in the physical aspects of hyperthermia.

The state of hyperthermia physics is reviewed. Major changes affecting the field are: (a) it is becoming far more sophisticated than just a few years ago, now that experts from many engineering and physical specialties are involved; (b) the ubiquitous computer is central to developments in data acquisition and analysis, treatment control, device comparison, treatment planning, and thermal dosimetry; and (c) entrepreneurial firms are arising to produce clinically engineered equipment. University and other research centers can concentrate their efforts on investigating new technologies up to the development of physical prototypes; they need no longer spend time on constructing complete clinical systems. At present, regional heating systems are unable to reliably induce therapeutic temperatures throughout the entire tumor volume. Interstitial techniques are able to accomplish this and so may make the greatest clinical impact in the near future. Invasive thermometry coupled with computerized data acquisition systems and numerical models appears to be a very promising approach to detailed thermal dosimetry. The tools for performing good clinical trials of hyperthermia are gradually becoming available.

Scalp hypothermia: a comparison of ice packs and the Kold Kap in the prevention of doxorubicin-induced alopecia.

Two methods of scalp hypothermia were compared in preventing alopecia, a side effect of doxorubicin chemotherapy that has a significant psychologic impact on the patient. Thirty-three patients received scalp ice packs consisting of crushed ice in plastic bags. Twenty-nine patients received Kold Kap, a device that produces chilling via an endothermic reaction. Scalp hypothermia was applied for 5-10 min before the doxorubicin bolus and left in place for 30-40 min afterward. The percent of hair loss was rated at each visit and photographs were used to further quantitate any hair loss. Sixty-three percent of Kold Kap and 56% of ice pack patients had good or better protection and did not require wigs. Excellent protection (less than 25% loss) was provided for 51% of Kold Kap and 33% of ice pack patients. Similar protection was provided to Kold Kap patients regardless of dose, while ice pack patients received significantly better protection if their doxorubicin doses were less than 50 mg. Scalp hypothermia is an effective method of preventing doxorubicin-induced alopecia.

Uniform regional heating of the lower trunk: numerical evaluation of tumor temperature distributions.

The temperature distributions in deep seated tumors resulting from uniform heating of the abdominal and pelvic regions of the trunk are predicted from a one dimensional numerical solution of the bio-heat transfer equation. The effect of tumor size and location are investigated for two tumor perfusion models: uniform perfusion and a concentric annulus perfusion model. Tumor temperature distributions are considered acceptable if the range of temperatures in the tumor lie between 42 degrees C and 60 degrees C. This range of tumor temperatures is defined as Tave +/- 2 sigma where sigma is the population standard deviation of tumor temperatures from the average computed at the nodal points in the finite difference array. To simulate practical clinical restrictions, muscle and fat temperatures are not allowed to exceed 44 degrees C, significant portions of the viscera are not allowed to exceed 42 degrees C, and the total absorbed power required to maintain steady state cannot exceed two kilowatts. Over 100 possible cases are presented in a compact form. From this study it appears that heating systems with power deposition patterns approximately uniform are promising for heating deep-seated tumors. Small, detectable tumors (approximately 2 cm in size) are adequately heated for a wider range of conditions than are larger tumors. Excessively high temperatures in deep-seated, normal tissue could be a significant limitation for this technique.

Magnetic induction heating of tissue: numerical evaluation of tumor temperature distributions.

A one dimensional (radial) numerical model based on the bioheat transfer equation has been developed and applied to the abdomen and pelvis heated by a concentric magnetic induction electrode. This model consists of four normal tissue regions: viscera, muscle, fat and skin. Each region is assigned thermal properties characteristic of that region and power deposition values consistent with those for this mode of heating. Tumors of 2, 4 and 7 cm thicknesses are positioned in five different radial locations ranging from the central axis to the skin surface. Two blood perfusion models of the tumor are considered: the uniformly perfused model and an annular model. Tumor temperature distributions are considered acceptable if the average tumor temperature plus and minus two standard deviations lie between 42 degrees C and 60 degrees C. To stimulate practical clinical restrictions, muscle and fat temperatures are not allowed to exceed 44 degrees C, significant portions of the viscera (except for a 1 cm thick band) are not allowed to exceed 42 degrees C, and the total absorbed power required to maintain steady state cannot exceed one kilowatt. Over 100 possible cases are presented in a compact form. A conclusion drawn from this study is that with few exceptions, only small tumors in the muscle annulus are heated adequately with this modality. Large tumors will have significant unheated portions if the specified limitations are not exceeded. While this heating modality can raise the necrotic core of a tumor to high temperatures, it cannot adequately heat well perfused regions of a deep seated tumor. These conclusions are borne out clinically and are discussed in a companion paper.

Fast and efficient computer modeling of ferromagnetic seed arrays of arbitrary orientation for hyperthermia treatment planning.

PURPOSE: Effective hyperthermia treatment planning requires an ability to predict temperatures quickly and accurately from an arbitrary distribution of power. Our purpose was to design such a fast executing computer code, MGARRAY, to compute steady-state temperatures from ferromagnetic seed heating, allowing seeds to have arbitrary orientations and to be curved to permit more realistic modeling of clinical situations. We further required flexibility for the tissue domain, allowing inhomogeneity with respect to thermal conductivity and blood perfusion, as well as an arbitrary shaped boundary. METHODS AND MATERIALS: MGARRAY uses multigrid methods and a finite volume discretization to solve the Pennes bioheat transfer equation in three dimensions. We used MGARRAY to compare temperature distributions that result from an array of straight, parallel seeds and from an array of seeds that were curved and tilted randomly by 13 degrees. RESULTS: On a personal workstation the Central Processing Unit (CPU) time of MGARRAY was under 4 min. We found that the median temperature in a predetermined target volume was approximately 0.8 degrees C higher in the straight array than in the curved array. At specific locations within the target volume temperature differed by approximately 0.5-0.9 degrees C, but could differ by up to several degrees, depending on proximity to a seed and the level of blood perfusion. CONCLUSION: These differences can impact on retrospective analyses whereby temperatures at a few locations are used to infer the overall temperature field and blood perfusion levels. The flexibility and computational speed of MGARRAY could potentially lead to a substantial improvement in both retrospective and prospective hyperthermia treatment planning.

Treatment planning of template-guided stereotaxic brain implants.

We have initiated a Phase I clinical trial of interstitial hyperthermia induced with inductively heated ferromagnetic implants in combination with Ir-192 implants for glioblastomas and anaplastic astrocytomas of the brain. For speed and accuracy of the implant procedure, and to control the radiation and thermal dose, a stereotaxic frame is used to position a template. We have modified the Brown-Roberts-Wells frame to be used with a variety of templates which we designed. On the morning of the implant procedure, a CT scan is done, and a CT-based treatment plan is then completed before the patient goes to the operating room. We also describe the CT-based treatment planning system developed to accommodate the template-guided implant and illustrate its clinical use.

Obtaining local SAR and blood perfusion data from temperature measurements: steady state and transient techniques compared.

A series of analyses and experiments was performed to determine the extent that SAR and blood perfusion information can be extracted from steady state temperature values and from transient temperature measurements following a step change in applied power. Multiple local temperature measurements were made in canine thighs heated by 2450 MHZ microwaves to evaluate two parameters: the local absorbed power in the tissue, and the local "effective blood perfusion." The theoretical bases for these calculations are presented in order to identify their underlying assumptions and to obtain a unified basis for comparison of the various calculation methods used by previous investigators. From energy balance considerations it can be shown that the local absorbed power can be obtained from either the rate of increase of temperature following a step increase in power, or from the rate of decrease in temperature immediately following a step decrease in power. These theoretical observations are verified experimentally by comparing the SAR results at fixed positions in canine thighs as calculated from both increasing and decreasing power steps. For decreasing power steps, the resulting decreasing temperature curves can also be used to calculate an effective blood perfusion rate if thermal conduction is included. Alternatively, this same effective blood perfusion rate can be calculated from steady state data. (These two approaches have been used by previous investigators to determine "blood perfusion" values. We have added the modifier "effective" to specifically denote the presence of thermal conduction effects in such perfusion calculations.) From our experimental results and theoretical calculations it appears that differences between the predictions of the two calculation methods arise from changing thermal conduction values during the cooling period of the thermal clearance method. The steady state calculation approach is easier to apply than the washout method, but it requires the additional knowledge of the local SAR value. It is important to realize that effective blood perfusion values calculated using thermal techniques are subject to large errors under conditions where thermal conduction is important, unless this conduction is explicitLy included in the calculation. Such effective blood perfusion values should not be quantitatively compared to values calculated from non-thermal techniques that are not affected by thermal conduction. Unless such conduction effects are known to be negligible, effective perfusion values are only qualitative indicators of the presence of changes in blood perfusion.

Clinical hyperthermia with a new device: the current sheet applicator.

PURPOSE: The current sheet applicator (CSA) is a newly developed microwave hyperthermia device. Advantages over commercial microwave applicators include its small size and high ratio of heating area to physical aperture area. These physical characteristics make the CSA excellent for heating constricted areas and allow the use of arrays of CSAs over large surfaces. This study examines the clinical efficacy of the CSA for heating superficial malignant tumors. METHODS AND MATERIALS: From December 1989 through October 1991, 19 patients with recurrent or metastatic superficial malignant tumors were treated once or twice weekly to 30 hyperthermia fields using one to four CSAs. Each field received from one to four hyperthermia treatments for a total of 74 treatments. The treatment objective was to elevate the tumor temperature to a minimum of 42.5 degrees C for 30 min (2 patients) or 60 min (17 patients). Intratumor temperatures were measured with percutaneous fiberoptic thermometry probes. All patients received concurrent fractionated radiation therapy with total dose ranging from 20 to 65 Gy (median 46 Gy). Seventeen of the 30 fields had been previously irradiated to a median dose of 50 Gy. RESULTS: Mean values for the maximum temperature, average temperature, and minimum temperature were 43.6 degrees C +/- 1.0, 42.2 degrees C +/- 1.4, and 41.0 degrees C +/- 1.5, respectively. Mean values for T50 and T90 were 42.2 degrees C +/- 1.1 and 41.0 degrees C +/- 1.3, respectively. The overall response rate for all assessable fields was 96%. Only Only three responding tumors have progressed with a median follow-up period of 6 months. Treatment related morbidity was generally mild and self-limited. CONCLUSION: The CSA is a promising new microwave hyperthermia device capable of heating superficial tumors to therapeutic temperatures. When used in combination with radiotherapy, response rates are excellent without excessive toxicity.

Interstitial thermoradiotherapy: thermal dosimetry and clinical results.

From August 1977 to August 1986, 72 patients with advanced primary or recurrent cancers were treated using interstitial thermoradiotherapy. Sites treated included the pelvis in 49 patients, the head and neck in 15, and other sites in six. Median tumor volume was 52 cm3, and all but nine patients had received prior irradiation. In 69 patients, hollow stainless steel catheters were implanted and used as electrodes with a 0.5 MHz radiofrequency (RF) generator, whereas in three patients, standard plastic Henschke tubes were used with a commercially available interstitial microwave (MW) system operating at 915 MHz. Most patients were heated intraoperatively for 30 minutes, aiming for a minimum measured intratumoral temperature (Tmin) of 42 degrees C. The implant was occasionally preceded by external irradiation, and after hyperthermia, the catheters were afterloaded with 192Ir for brachytherapy. Tmin exceeded 42 degrees, 42.5 degrees, 43 degrees, and 44 degrees in 25, 16, 12, and 3, respectively, of 70 patients with temperature data available, and the probability of successful heating was independent of tumor volume or site. Twenty-five of 69 (36%) evaluable patients achieved a complete response (CR). Probability of CR demonstrated a significant univariate dependence upon Tmin, radiation dose, site treated, and tumor volume, but multivariate analysis showed only three significant predictor variables: tumor volume, radiation dose, and Tmin. The probability of a CR ranged from 95% for patients with small tumors receiving high doses of radiation and adequate heat, to 5% for patients with large tumors receiving low radiation doses and less than adequate heat. Of 25 patients with CR, 10 relapsed; median response duration was less than 18 months, depended marginally upon disease site, and was independent of Tmin, radiation dose, and tumor volume. Seventeen patients sustained a complication, of which nine were severe enough to require hospitalization or surgery. All severe complications occurred in patients with pelvic tumors. The probability of a complication of any severity had a significant univariate association with maximum intratumoral temperature (Tmax) and tumor size. We conclude that interstitial thermoradiotherapy offers the promise of heating large tumors in locations where externally applied hyperthermia has not been successful.

Interstitial thermoradiotherapy of brain tumors: preliminary results of a phase I clinical trial.

A Phase I clinical trial has been initiated to determine the feasibility, tolerance, and toxicity of interstitial thermoradiotherapy in the treatment of high-grade supratentorial brain gliomas. Hyperthermia was delivered by means of thermally-regulating ferromagnetic implants afterloaded into stereotactically placed plastic catheters. Heat treatments were given immediately before interstitial irradiation; in addition, five patients received a second heat treatment at the completion of brachytherapy. The desired target temperature for the 60-minute hyperthermia session was between 42 degrees C and 45 degrees C. Following hyperthermia, the catheters were afterloaded with Ir-192, which delivered a variable radiation dose of 14-50 Gy depending on the clinical situation. Interstitial irradiation was supplemented with external beam radiotherapy (40-41.4 Gy) in patients with previously untreated tumors. A total of 14 patients (4 males, 10 females) have been treated to date on this protocol. Eleven of the patients had a diagnosis of glioblastoma multiforme, whereas three had anaplastic astrocytoma. The mean implant volume was 61.5 cm3 (range: 9-119 cm3); the median number of interstitial treatment catheters implanted was 19 (range: 7-33). Continuous temperature monitoring was performed by means of multisensor thermocouple probes inserted in the center as well as in the periphery of the tumor. Of the 175 monitored intratumoral points, 83 (47%) had time-averaged mean temperatures of greater than 42 degrees C, and only 12 sensors (7%) exceeded a temperature of 45 degrees C. Among the 19 heat treatments attempted, there have been four minor acute toxicities, all of which resolved with conservative medical management and one major complication resulting in the demise of a patient. These preliminary results indicate that ferromagnetic implants offer a promising new approach to treating brain tumors with hyperthermia.

Hyperthermia by magnetic induction: experimental and theoretical results for coaxial coil pairs.

High-frequency magnetic induction for producing elevated temperatures in human tumors can be accomplished with several electrode arrangements. We describe the physical characteristics of a coaxial pair of electrodes or current loops placed on either side of the body. This electrode arrangement can improve the depth of power deposition within the body relative to that obtained with an electrode circumferentially encircling the body or a single surface applicator ("pancake coil"). We report results of measured and calculated magnetic field distributions and power density distributions obtained with a coaxial pair. The effect of varying load geometry upon the power density distribution was shown to be significant in several static phantom experiments. Electrode geometry was also important, as shown by calculations of power deposition as a function of electrode diameter in a simple model of body tissue conductivities. The power density was found to diminish at given depths as the electrode diameter decreased. Finally, values of magnetic fields were measured during treatment of human subjects with a coaxial electrode pair and were found to vary significantly from subject to subject. This resulted from variation in the geometry and electrical characteristics of tissues among subjects, and indicates the difficulty of formulating a standard accurate model for use with this magnetic induction technique.

Comparative evaluation of hyperthermia heating modalities. I. Numerical analysis of thermal dosimetry bracketing cases.

A method for comparing the relative abilities of different hyperthermia heating modalities to properly heat tumors has been developed using solutions of the bio-heat transfer equation. A single measure, the range of absorbed powers that gives acceptable tissue temperature distributions, is used to characterize the ability of a given heating technique to heat a given tumor. An acceptable tissue temperature distribution is one for which (a) the temperatures in the coolest regions of the tumor are above a minimum therapeutic value, (b) the temperatures in the hottest regions of the tumor do not exceed a maximum clinically acceptable value, and (c) the normal tissue temperatures do not exceed maximum clinically acceptable levels. This measure can be interpreted directly in clinical terms as the range of power settings on the power indicator of a heating device for which acceptable tumor heatings will occur. This paper describes the basis of the method and investigates the role of tumor blood perfusion patterns in determining the size of the acceptable power range. Three tumor perfusion patterns are investigated: uniform tumor perfusion, a concentric annulli perfusion model in which the tumor consists of a necrotic core surrounded by two concentric layers of increased perfusion, and a random perfusion distribution model. The results show that, in general, the uniform and annular perfusion models serve as bracketing case patterns. That is, they give acceptable power range values that are upper and lower limits of the acceptable power ranges obtained for the random perfusion patterns. The method is applied to heating patterns that simulate those obtained from a variety of different available heating techniques, and it is found to be valid for all cases studied. The role of normal tissue limiting conditions is also investigated.

Comparative evaluation of hyperthermia heating modalities. II. Application of the acceptable power range technique.

The acceptable power range technique previously described in a companion paper [R. B. Roemer, T. C. Cetas, J. R. Oleson, S. Halac, and A. Y. Matloubieh, Radiat. Res. 100, 450-472 (1984)] is applied to two heating modalities to demonstrate its application to simulated clinical situations. Comparisons of the abilities of the different modalities to heat given tumors are made using the relative sizes of the acceptable power ranges obtained for each modality. Similar comparisons are also possible for determining the efficacy of physiological manipulations and adjustments in power deposition patterns for a given heating modality. Predictions of the ability of modalities and configurations to properly heat tumors are made using the bracketing nature of the uniform and annular tumor perfusion models. These comparisons and predictions are possible because a single measure of the ability of any heating technique to heat an arbitrary tumor in any location is utilized (the size of the acceptable power range). While relatively simple models are presently utilized, this approach can be extended to take into account a host of physical and biological conditions that model the patient-device interaction to an arbitrarily high degree of detail. These refinements will be based on extended clinical and experimental data, particularly as tumor and normal tissue blood perfusion characteristics either become better known in general cases or can be specified for each real tumor. The applications of this approach should be far-reaching and complementary to clinical hyperthermia, especially as further model refinements are incorporated. Additional data are presented which reinforce the bracketing nature of the uniform and annular tumor perfusion models presented in the companion paper.

Thermometry considerations in localized hyperthermia.

The introduction of local hyperthermia as a method of cancer therapy implies the necessity of quantitative measurements of the thermal dose. Our intention is to describe the nature of the problem, both physically and physiologically, with illustrations drawn from thermographic measurements in phantoms and in animals. The characteristics of a thermometry calibration facility are described. Some measurement problems associated with conventional thermometer probes are mentioned and several new thermometers which were developed for use in the electromagnetic fields are reviewed. We present some of the concepts that will guide the development of noninvasive thermometry. Systemic hyperthermia is not considered. We recommend that other reviews specifically directed toward localized hyperthermia be prepared on the methods of heating and on thermal physiological problems.

Three-dimensional simulations of ferromagnetic implant hyperthermia.

A general three-dimensional planning program has been developed for hyperthermia treatments for cancer. In this study, the program is used to analyze the three-dimensional temperature distributions generated by interstitial ferromagnetic implants. An empirical power absorption formula developed by Haider for thermally self-regulating nickel-silicon ferromagnetic seeds has been used to calculate the seed power absorption as a function of seed temperature. By properly choosing the seed type (Curie point of seeds), and by using appropriate seed spacing, this heating modality can generate desirable three-dimensional temperature distributions for many different situations over a fairly large range of blood perfusion values. Detailed information regarding the choice of the Curie points of the seeds and the seed spacing for certain blood perfusions is also given as a quantitative guide for treatment planning.

Power absorption and temperature control of multi-filament palladium-nickel thermoseeds for interstitial hyperthermia.

In interstitial hyperthermia using ferromagnetic seeds, multi-filament seeds have gained interest because of a more effective power absorption than solid seeds. Palladium-nickel (PdNi) seeds composed of filaments with diameters in the range from 0.1 to 1.0 mm (maximally 90 filaments) have been investigated to find the conditions for optimal power absorption and temperature control. Magnetic and calorimetric experiments have shown that a decreasing filament radius results in a more effective power absorption. The power absorption approaches a common asymptote for high field intensities at all filament diameters. This asymptotic behaviour can be understood as a consequence of the approach of saturation magnetization of PdNi. The sharpness of the transition at the Curie temperature, which is a measure for the quality of temperature control, improves as the magnetic field strength increases, but it is limited by the asymptote of the power absorption. When the asymptote has been reached the quality of temperature regulation of a seed can only be improved by increasing the amount of PdNi, e.g. by increasing the number of filaments. Calculations of the power absorption, using the generally applied theory based on a linear relation between the magnetization of PdNi and the magnetic field strength, do not correspond quantitatively with experimental results for seeds having an induction number smaller than the 'optimal value' of 2.5. For these seeds the measured heat production is larger than the calculated one.

Use of Gaussian beam model in predicting SAR distributions from current sheet applicators.

The Gaussian beam model is shown to be a good predictor of SAR distributions due to current sheet applicators (CSAs). It is fast, efficient and adaptable. SAR distributions from a single applicator and from simple arrays of CSAs in homogeneous and layered lossy media are computed at 434 and 450 MHz at CPU times of less than 60 s. The good agreement between theory and experiment justifies the use of the Gaussian beam model to predict SAR distributions from CSAs.