Heating characteristics of the TRIPAS hyperthermia system for deep seated malignancy.

A deep heating hyperthermia device TRIPAS (a triapplicator system) consisting of three independent, dielectrically loaded horn applicators operating in phase at 300 MHz was investigated. The heating characteristics produced by this hyperthermia system were analyzed by means of thermochromic liquid-crystal cards and a modified CDRH (Center for Devices and Regulatory Health) elliptical phantom. Both homogenous and inhomogeneous phantoms were used, simulating high and low permittivity tissues (muscle and lung). These equivalent tissues were made of polyacrylamide gel. The semiquantitative heating pattern analysis showed a central heating of 1/3 of maximum heating at a depth of 10 cm in both homogenous (muscle) and heterogenous (muscle/fat) phantoms. Also more uniform temperature/SAR distributions were generated in muscle equivalent material than those in lung.

TRIPAS: a triapplicator system with relocatable 'hot spot' at tissue depth.

Solving the problem of heat focusing and standardization of the clinical application of hyperthermia requires a mathematical prediction model. The model should include the medium constitutive parameter, and be able to predict positioning of the microwave applicators to optimize treatment planning and provide for reproducible treatment set-up. We present a configuration of 3 applicators subtended by an equilateral triangle in order to target and relocate a 'hot spot' for improved treatment of deep tumors. A simple geometric analysis is illustrated. The microwave beam absorption profile, from the three power sources, was obtained from phantom studies depicting the radiative heat pattern for the triapplicator system (TRIPAS). A complex mathematical model was developed to demonstrate interaction of the beams in the medium. It was observed empirically that under coherent propagation in the near field electromagnetic (EM) waves tend to add at the center, while varying the propagation axial focal length caused a relocation of the summing focal points. Mathematical prediction correlated very well with the phantom studies. SAR values above 100 W/kg were achieved at 12.5 cm phantom depth, creating a relocatable 'hot spot' at the concentric foci of the 3 air cooled horn microwave applicators operating at 300 MHz.

Microwave hyperthermia as an adjunct to radiation therapy: summary experience of 256 multifraction treatment cases.

Results in 256 cases of malignant disease treated by multifraction combination hyperthermia-radiation therapy under the supervision of one physician are presented. The overall response rate was 94% including a 62% complete response. Complications specifically ascribed to hyperthermia were minor, and most side effects of combined treatment were radiation dose related. Tumor response was somewhat better for chest wall recurrence (72% CR) and for adenocarcinoma in general (64% CR), but no significant dependence on tumor site or type was found. Most patients were treated with low dose external radiation with hyperthermia given by air cooled microwave applicators or intracavitary antennae operating at 915 or 300 MHz, and some by interstitial microwave antennae plus 192 Ir. Results appeared to be independent of the microwave source employed. Response did depend on radiation dose: complete response rate with 4000 rad was 65%, and with 2000 rad was 42%.

Changes in tumor tissue oxygenation during microwave hyperthermia: clinical relevance.

As previously described (Bicher 1981) TpO2 and blood flow increase in tumor as temperature increases until 41 degrees C and decrease thereafter (microcirculation "breaking point"). In the present clinical study using O2 microelectrodes this response was reproduced in over 54 treatment sessions. However, it was found that as treatment progresses (patients are treated for one hour 10 times, twice weekly, and concomitantly receive 4000 rads of ionizing radiation) the initial increase of blood flow and TpO2 is reduced and there is immediate decrease in tissue oxygenation. A correlation between microvascular tumor physiological changes and tumor treatment responses is being developed.

Loss of vascular fibrinolytic activity following irradiation of the liver--an aspect of late radiation damage.

The vascular fibrinolytic activity, known to originate from the endothelium, was studied histochemically by fibrinolysis autography in liver samples from beagles exposed to radiation treatment. Eighteen to thirty months prior to sacrifice, six dogs received X irradiation (4600 rad in 5 weeks) and three dogs received X irradiation plus aspirin (1 g/kg). Two dogs served as untreated controls. Control livers showed extensive fibrinolytic activity related to large and small vascular structures. The vascular fibrinolytic activity had been lost from all vessels except the major portal branches in five irradiated livers and was severely diminished in three. One irradiated liver appeared to possess normal fibrinolytic activity.

Impact of microcirculation and physiologic considerations on clinical hyperthermia.

Changes in tumor tissue oxygenation and acidity were determined using ultramicroelectrodes, and presented in histogram fashion. The effect of Hyperthermia and HpD phototherapy were tested. It was found that both modalities affect tumor microcirculation, causing a marked drop in oxygen availability. Tissue pH is decreased by Hyperthermia, but not by phototherapy. These effects are long lasting at least for 24 hours after treatment.

Changes in tissue oxygenation and acidity induced by localized microwave hyperthermia and hematoporphyrin phototherapy, an update.

Changes in tumor tissue oxygenation and acidity were determined using ultramicroelectrodes, and presented in histogram fashion. The effect of Hyperthermia and Hpd photo-therapy were tested. It was found that both modalities affect tumor microcirculation, causing a marked drop in oxygen availability. Tissue pH is decreased by Hyperthermia, but not by phototherapy. These effects are long lasting, at least for 24 hours after treatment.

Identification of viable regions in "in vitro" spheroidal tumors: a mathematical investigation.

In the treatment of solid tumors by hyperthermia, a major question is how to obtain an a priori knowledge of which tumors can be effectively treated with this modality. The key question is; given a solid tumor, what parameters in the various regions of the tumor, need to be measured so that a tumor-tissue model can provide a meaningful real time simulation of the hyperthermic treatment. This paper addresses the former question as a mathematical investigation, and the latter as a consequence of the former.

Computer modeling of tumor hyperthermia (a dynamic lumped parameter model).

The thermal behavior of normal and neoplastic tissue is modeled by a set of coupled ordinary differential equations. The equations lump the tissue and tumor into individual compartments, so that the equations are time dependent. These equations represent an initial step in the development of a comprehensive model which may be used in studying the dynamics and control of the system under normo- and hyperthermic conditions.

Results of a phase I/II clinical trial of fractionated hyperthermia in combination with low dose ionizing radiation.

This paper addresses, in part, the current status of hyperthermia as a new clinical modality and reports the results of a large, prospective clinical trial employing microwave hyperthermia in combination with low doses of ionizing radiation. In the protocol employed, each treated area received 8 hyperthermia treatments of 1.5 hour combined with 1600 rad over a total period of 5 weeks. Patients were heated with microwaves of 915 or 300 MHz employing external applicators or internal intracavitary antennas. The results of this fractionation scheme are encouraging since in 121 fields that were treated completely according to protocol and were available for follow-up for at least 2 months, complete responses were observed in 65% of all cases, partial response in 30% and no response in only 5%. It is also important to note that toxicity was minimal throughout the study.

Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma.

Severe disturbances in microcirculation during advanced phases of tumor growth lead to restrictions of convective and diffusive transport. In addition, an inhomogeneous distribution of transport conditions develops, resulting in insufficient and heterogeneous substrate supply and an inadequate drainage of wastes. Polarographic measurements of the local tissue oxygen tension (PO2) using gold microelectrodes reveal that very low PO2 values are prevalent in C3H mouse mammary carcinomas. The tissue PO2 frequency distributions are shifted to low PO2 values and limited in variability. The mean PO2 value is 7 mm Hg. The median is 4 mm Hg, the modal class being 0 to 5 mm Hg. Within different microareas of the same tumor, pronounced heterogeneities exist. Due to an elevated rate of lactic acid production and its subsequent inadequate removal, a severe tissue acidosis is evidenced in malignant tumors. For C3H mouse mammary carcinomas, most of the measured pH values are in the range of 6.4 to 7.1, the modal class being 6.7 to 6.8 (mean pH, 6.73; median pH, 6.75). Within different microareas of the same tumor, clear heterogeneities in the pH distribution do occur. Very low pH values (5.8 to 6.3) have been observed in large ulcerated tumors. In extensively necrotic areas, pH values even higher than the arterial pH could be detected.

Radiation sensitivity modification by chemotherapeutic agents.

Three chemotherapeutic agents, chlorambucil, mustargen, and BCNU-409962, being investigated for their possible clinical use in conjunction with radiation therapy have been shown in vitro to dramatically affect the characteristics of standard radiation survival curves (in V79 cells and spheroids). The agent mustargen, at a concentration of 0.25 microgram/ml administered 1 hour prior to 9-MeV-electron exposure, had a significant effect in reducing D0. The 165-rad D0 observed in control curves was reduced to 105 rads in the presence of drug. One hour preincubation with BCNU (prior to radiation exposure) at a concentration of 3.0 microgram/ml was found to dramatically reduce the initial shoulder region with n number values for drug curves approximately one-half those seen for controls. No effect is seen when chlorambucil is combined with radiation in exponential or confluent cultures but an enhancement ratio of 1.8 is found when intact spheroids are pretreated with this drug.

A system for determining the pharmacology of indirect radiation sensitizer drugs on multicellular spheroids.

We have characterized some of the physiology of multicellular spheroids of different sizes grown from Chinese hamster lung fibroblast (V79) cells. Among the parameters studied were oxygen tension distributions within the spheroid. This was achieved using ultramicroelectrodes with tip diameters of 1-5 mu and a perfusion system whereby environmental conditions such as flow, temperature, and chemical makeup of the milieu could be measured and controlled. Plateau pO2 values of less than 10 mm Hg were consistently obtained from spheroids under various conditions. We were able to modify these distributions by use of indirect radiation sensitizer drugs such as mechlorethamine HCl (mustargen) at nontoxic doses. We have also made determinations of the inhibitory capacities of several other drugs on the respiration rate of constituent cells of multicellular spheroids in single-cell suspensions. We have concluded that there are indeed hypoxic cells in spheroids whose radioresistance may be modified by essentially nontoxic levels of indirect radiosensitizer drugs and that the system described shows great promise for screening agents which may modify radiation response.