Thomas C. Cetas

Clinical hyperthermia: Results of a phase I trial employing hyperthermia alone or in combination with external beam or interstitial radiotherapy

Forty‐three patients with advanced, locally accessible neoplasms were treated in a Phase I clinical trial employing hyperthermia alone or hyperthermia combined with either high‐dose‐rate external beam or low‐dose‐rate interstitial radiotherapy (interstitial thermoradiotherapy). All patients had failed previous conventional therapeutic attempts, including various combinations of surgery, chemotherapy and radiation therapy. Many had received tolerance or near tolerance levels of prior radiation that restricted dose prescriptions in this trial to subcurative values. A number of tumors with different histologies were treated, including squamous cell carcinoma (14), adenocarcinoma (14), melanoma (8), malignant fibrous histiocytoma (2), and sarcoma (5). The response evaluation criteria used included no response (NR— less than 50% decrease in tumor volume), partial response (PR—50% ≤ tumor volume reduction < 100%) and complete response (CR—complete tumor disappearance). For all tumor types, hyperthermia therapy alone resulted in a total response rate of 45% (27% PR, 18% CR). Hyperthermia combined with high‐dose‐rate external beam radiotherapy yielded a total response rate of 80% (53% PR, 27% CR). Seventeen patients treated with interstitial thermoradiotherapy displayed a 100% total response rate (29% PR, 71% CR). By tumor histologies for all treatment groups, total response rates have ranged from 50 to 79% for all types except melanoma, which has shown a 100% (8/8) response rate to date. Response durations have varied from one to 24 months. Twelve of the 43 patients remain alive; three have no evidence of disease (NED) while nine have either stable local disease or are NED in the treated volumes but have metastatic disease. Complications have been minimal and have included one third‐degree burn and three second‐degree burns from fringing RF fields, one vaginal‐rectal fistula, a superficial focal soft tissue necrosis, and some minor blistering. The results of this Phase I trial demonstrate that hyperthermia alone or combined with radiation can be safely applied in the treatment of malignant disease. Most importantly, the data suggest that hyperthermia, especially when combined with interstitial thermoradiotherapy, can yield remarkable results in the eradication of local cancers.

Magnetic Induction Heating of Ferromagnetic Implants for Inducing Localized Hyperthermia in Deep-Seated Tumors

A variable frequency magnetic induction heating system has been developed for localized hyperthermic treatment of deep-seated tumors via power deposition into arrays of 1-2 mm diameter ferromagnetic cylindrical implants. The frequency dependence of implant heating compared to that induced directly into tissues indicates use of frequencies below 4 MHz. Above 10 MHz, tissues are heated directly from the induced eddy currents. Thermographic analyses of temperature distributions induced in tissues equivalent phantom models and in exposed animal tissues in vivo have been performed for several implant materials and array configurations. Results of the thermal dosimetry show that the majority of tissue contained within multiimplant arrays can be heated such that the temperature rises to 55-70 percent of the implant temperature differential. The resulting tissue temperature distribution is dependent on local blood flow and array characteristics, but not significantly on tissue electrical properties. Operating the system at 1.9. MHz, we demonstrate that it is possible to raise an implanted volume to therapeutic temperatures safely, in less than 10 min, with little increase in temperature outside the array boundaries.

Observations on the Use of Ferromagnetic Implants for Inducing Hyperthermia

Magnetic induction heating of ferromagnetic implants can be used to produce highly localized hyperthermia in deep seated tumors. We discuss the physical parameters which characterize this method and give illustrations from initial clinical investigations in animals. The physical parameters studied include magnetic field strength, frequency, load size, field uniformity, coil designs, and the heating potential of implant materials and configurations. Calculations consistent with our experimental results predict a maximum heating frequency of the order of 500 kHz for large cross-sectional loads, such as the human abdomen, and 1.9 MHz for smaller loads, such as the human brain. An experlhnental technique is introduced for accurate quantitative evaluation of the heating potentials of ferromagnetic materials in a gelled phantom medium. These data are analyzed in terms of heating efficiency per unit implant length (¿L), which is itself a function of implant length, diameter, annealed state, and orientation with respect to the magnetic field. A spiral sheet coil design is described and recommendations are given for proper E-Field shielding of induction coils for clinical applications. A brief discussion of techniques of implanting the ferromagnetic materials is also given. Finally, several in vivo animal studies are presented to illustrate the use of the technique for treating tumors in pelvis, thorax, oral-pharynx, and brain.

RTOG quality assurance guidelines for clinical trials using hyperthermia.

M. W. DEWHIRST, D.V.M., PH.D.,* T. L. PHILLIPS, M.D.,+ T. V. SAMULSKI, PH.D.,+ P. STAUFFER, MSEE,? P. SHRIVASTAVA, PH.D.,+ B. PALIWAL, PH.D.,+ T. PAJAK, PH.D.,+ M. GILLIM, PH.D.,+ M. SAPOZINK, M.D., PH.D.,+ R. MYERSON, M.D., PH.D.,+ F. M. WATERMAN, PH.D.,+ S. A. SAPARETO, PH.D.,+ P. CORRY, PH.D.,+ T. C. CETAS, PH.D.,+ D. B. LEEPER, PH.D.,+ P. FESSENDEN, PH.D.,+ D. KAPP, M.D., PH.D.,+ J. R. OLESON, M.D., PH.D.+ AND B. EMAMI, M.D.*

A scanned, focused, multiple transducer ultrasonic system for localized hyperthermia treatments

A commercial diagnostic ultrasound scanner (Octoson) was modified for performing hyperthermia treatments. The temperature elevations were induced in tissues by four large, focused ultrasonic transducers whose common focal zone was scanned along a computer controlled path as determined from B-scan images. The system is described and the results of preliminary tests demonstrating some of its capabilities are given. Extensive tests with canine thighs and kidneys were performed. The blood flow to the kidneys was controllable, and thus tumours having different blood perfusion rates could be simulated. The results showed that the system is capable of inducing a local temperature maximum deep in tissues (up to 10 cm was tested) and that tissues with high perfusion rates could be heated.

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.

Treatment of malignant gliomas with interstitial irradiation and hyperthermia

A Phase I study of interstitial thermoradiotherapy for high-grade supratentorial gliomas has been completed. The objective of this trial was to test the feasibility and toxicity of hyperthermia induced by ferromagnetic implants in the treatment of intracranial tumors. The patient population consisted of 16 males and 12 females, with a median age of 44 years and a median Karnofsky score of 90. Nine patients had anaplastic astrocytoma while 19 had glioblastoma multiforme. Twenty two patients were treated at the time of their initial diagnosis with a course of external beam radiotherapy (median dose 48.4 Gy) followed by an interstitial implant with Ir-192 (median dose 32.7 Gy). Six patients with recurrent tumors received only an interstitial implant (median dose 40 Gy). Median implant volume for all patients was 55.8 cc and median number of treatment catheters implanted per tumor was eighteen. A 60-minute hyperthermia treatment was given through these catheters just before and right after completion of brachytherapy. Time-averaged temperatures of all treatments were computed for sensors located within the core of (> 5 mm from edge of implant), and at the periphery of the implant (outer 5 mm). The percentage of sensors achieving an average temperature > 42 degrees C was 61% and 35%, respectively. Hyperthermia was generally well tolerated; however, there have been 11 minor toxicities, which resolved with conservative management, and one episode of massive edema resulting in the death of a patient. In addition, there were three major complications associated with the surgical implantation of the catheters. Preliminary survival analysis shows that 16 of the 28 patients have died, with a median survival of 20.6 months from diagnosis. We conclude that interstitial hyperthermia of brain tumors with ferromagnetic implants is feasible and carries significant but acceptable morbidity given the extremely poor prognosis of this patient population.

Current sheet applicator arrays for superficial hyperthermia of chestwall lesions

The current sheet applicator is an electromagnetic heating device whose size may be chosen virtually independent of frequency even though practical limitations may restrict it to VHF and UHF bands. In this paper we investigate absorbed power distributions in muscle tissue from current sheet applicators when used as elements of a planar array intended for superficial hyperthermic treatment of tumours. Advantages offered by current sheet applicators for tissue heating include compact size, a linear polarization of the induced electric field and relatively large heating area. It is shown that the effective field produced by a pair of these elements is continuous regardless of whether the common edges of the elements are perpendicular or parallel to the direction of impressed current. The feasibility of customizing the shape and size of the field is also illustrated. The absorbed power distribution patterns due to a coherently driven array operating around 434 MHz is relatively insensitive to phase variations of about 20 degrees but is sensitive to relative power level variations as low as 10%. Mutual coupling between array elements may be reduced to acceptable levels by incorporating suitable spacing between them. It is also demonstrated that there is good agreement between measurements of absorbed power distributions and predictions using the Gaussian beam model.

Numerical Simulation of Magnetic Induction Heating of Tumors with Ferromagnetic Seed Implants

Calculations based on the bioheat transfer equation have been carried out to determine the temperature distributions to be expected from the use of inductively heated ferromagnetic implants to heat deep-seated tumors. Two types of ferromagnetic implants are considered: constant power seeds, for example, those constructed from Type 430 stainless steel; and constant temperature seeds which pass through a Curie transition to the nonmagnetic state at a specified temperature. The temperature distributions are studied as a function of the size of the implant array, its geometrical relationship to the tumor, the density of implants within the array, and the blood perfusion characteristics of the tumor and its surrounding normal tissue. Two tumor models are considered: a uniformly perfused model which is indistinguishable from the surrounding normal tissue, and an annular perfusion model with a necrotic core surrounded by intermediately and highly perfused shells. Temperature distributions are considered acceptable if the minimum temperature in the tumor is greater than 42°C and the maximum temperature does not exceed a maximum allowable value (either 48 or 60°C). The results of over 200 combinations of the above parameters are presented in a compact format. General conclusions drawn are that the tumor should lie entirely within the implanted array if the tumor periphery is to be heated adequately, and that the constant temperature seeds, which are self-regulating in temperature, give better tumor temperature distributions.

Institutional reports: Clinical evaluation of hyperthermia equipment: The University of Arizona Institutional Report for the NCI Hyperthermia Equipment Evaluation Contract

Two-hundred and fifteen independent sites in 203 patients were treated with hyperthermia at the University of Arizona from 10/81 through 3/86 under the auspices of this contract. In the head and neck, a site dominated by superficial tumors, air-coupled and water-coupled microwave applicators yielded the best results. Similarly in the thorax, also dominated by superficial tumors, water-coupled microwave applicators were best. In the abdomen and pelvis, sites dominated by deep tumors, only interstitial radiofrequency (RF) heating, an invasive technique useful only in selected cases, was capable of consistently producing therapeutic temperatures. Toxicity appeared to be site-related, and treatment discomfort was especially common in abdominal and pelvic sites. In conclusion, while superficial sites were readily heated using propagative electromagnetic devices, these devices were ineffective and poorly tolerated at deeper sites. Effective deep hyperthermia was best produced with interstitial techniques, and further development of these techniques using RF electrodes, implantable microwave antennas and thermoregulating ferromagnetic seeds, as well as scanned, focussed-ultrasound techniques, holds promise for effective heating of deep visceral sites.