Now hyperthermia is widely used to treat clinical malignancies. In this articles, the history, the principle, the techniques and the clinical results of hyperthermia treatment were reviewed, and prospects of it were also mentioned. At present, methods of deep heating have to be improved, the possibility of non-invasive thermometry has to be considered, heat sensitivity needs to be defined and a practical concept of thermal dose has to be worked out. The recent wide clinical use of hyperthermia will no doubt lead to well-defined clinical trials which will bring with them important biological answers to hyperthermia-related problems. The design of large multicenter randomised clinical trial is therefore encouraged in order to evaluate the effects of hyperthermia for primary treatment of a malignancy as well as supplementary studies on metastatic and/or recurrent malignancy. The clinical results of combination of hyperthermia and irradiation for the patients with carcinoma of the esophagus are also presented herein.

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A synergistic increase in the cytotoxic effects of recombinant human tumor necrosis factor (TNF) and hyperthermia was demonstrated both in vitro and in vivo. The cytotoxicity of TNF against L-M cells in incubation for 12 h at 38.5 and 40°C based on the concentration necessary for 50% cytotoxicity was, respectively, 125 and more than 500 times as high as in similar incubation at 37°C. And, it was also shown to be ralated to an accelerated turnover rate of TNF receptor complex under elevated temperatures rather than to changes in number of cell receptors or binding strength.
As observed 18 days after implantation of Meth-A fibrosarcoma cells in mice, single i. v. administration of TNF at 1, 000 units/mouse resulted in complete cures in five mice when performed in combination with hyperthermia (40°C), whereas TNF alone in the same dose resulted in 27.1% inhibition of tumor growth and hyperthermia alone had no appreciable effect on tumor growth. The i. v. administration of TNF three times at 100 or 300 units/mouse together with hyperthermia (40°C) resulted in 41.2 and 89.0% tumor growth inhibition, respectively ; similar administration without hyperthermia appeared to have little or no appreciable effect on tumor growth.
A clearly synergistic inhibition of metastatic tumor growth by combined administration of TNF (300 units) and hyperthermia (40°C, 30 min) was also observed in BALB/c mice previously given injections of 1 × 10⁶ Meth-A (F₁₅) cells/mouse via tail vein, neither of which alone resulted in significant inhibition.
The results suggest that combination therapy including TNF and hyperthermia may be of value in the treatment of malignancy in human patients.

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We present a newly type applicator using a re-entrant resonant cavity for deep and concentrated hyperthermia. In this system, a human body is placed between the gap of the re-entrant resonant cavity, and is heated by standing wave electromagnetic fields.
From the results of computer simulations using a three layers disk phantom, that is, fat-muscle-fat model, it is shown that the deep and local tumor may be heated effectively without generating any hotspot or edge effects as in the case of RF capacitive heating method.

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Various type of 25 refractory tumors (16 : shallow-seated tumors, 9 : deep-seated tumors) were treated with radiotherapy and RF capacitive heating using HEH-500. Heating state, acute toxity and clinical result were analysed as follows.
Mean maximum intratumor temperature over 42°C and 41-42°C could be obtained in 9 (36%) and 8 (32%) respectively. Bulky shallow-seated tumors in the flat portion were capable of getting good heating state. But the temperatures of deep-seated tumors in the pelvis and lung could not be reached 42°C. In the rugged portions such as neck, supraclavicular region and chest wall after radical mastectomy, heatings tend to be unstable due to complaining of hot spot. The frequency of painful hot spot which was the cause of power limiting factor decreased from 81% to 41% by using large water bolus. Acute toxicity occured in 15 cases (12 : burns, 3 : subcutaneous indurations). There were no serious complications. Tumor response was evaluated by tumor shrinkage and complete responses were observed in 28% (7/ 25), partial responses in 40% (10/25) and no responses in 32% (8/25). Therefore the heating device (HEH -500) is thus suitable for heating of shallow-seated bulky tumors. It is considered that further improvement of applicators and boluses and increasing power of machine are necessary in order to heat deepseated tumors and other various site of tumors properly.

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The effects of general anesthesia on changes in temperature of the tissue heated in hyperthermic treatment were investigated in 9 rabbits. The thermosensitive tissue of the preoptic area and anterior hypothalamus (PO/AH) was locally heated by Argon Laser irradiation guided with glass fiber (0.4 mm in diameter). After local heating of PO/AH at 45 mW for 10 min under unanesthesia, PO/AH was locally heated at 45, 63, 90, 125 mW for 10 min under anesthesia with sodium pentobarbital (2.5 mg/kg/hr i.v.) in each rabbit. The heat loss responses of increase in ear skin temperature (Tea') by vasodilatation and increase in respiratory rate (RR) for evaporative heat loss were induced by local heating of PO/AH, and temperatures of the rectum (Tre) and brain (Tbr) at 10 mm apart from the irradiated center decreased following these heat loss responses in unanesthetic condition. But under anesthesia, unchanging Tre and increase in Tbr were observed because of no heat loss responses induced by local heating of PO/AH. Under unanesthesia, changes in Tea', RR, Tre and Tbr at 45 mW were +5.48 ± 0.57 °C, +56 ± 9min^-1, -0.33 ± 0.04 °C and -0.47 ± 0.08 °C, respectively. Under anesthesia, the changes in Tea', RR, Tre and Tbr at 45 mW were +0.22 ± 0.19 °C, +8 ± 2 min^-1, +0.01 ± 0.03 °C and +0.17 ± 0.06 °C, respectively. Furthermore, changes in Tea', RR, Tre and Tbr at 63, 90 and 125 mW were -0.45±0.25 °C, +12±2 min^-1, -0.02±0.03 °C and +0.19±0.04 °C, respectively. In cases of all values obtained under anesthesia, there were significant differences to compare with each value under unanesthesia.
Heat loss responses are likely to be induced in hyperthermic treatment, and these responses act on decreasing of core temperature. This phenomenon is obvious disadvantage to hyperthermic treatment under unanesthesia. One disadvantage is that the excess heat energy should be supplied to keep the temperature of the target tissue at the effective level. And the other is that the tissue temperature is variable depending on change in temperature of circulating blood as well as change in blood flow of the tissue. Inhibiting heat loss responses of thermoregulation with anesthesia is significantly effective in hyperthermic treatment. But the greatest attention should be paied to the temperature of heated tissue and heat load in the time course of hyperthermic treatment, since the unpredictable tissue damage might be caused by excess heating in consequence of inhibited physiological functions under anesthesia.

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The 915 MHz microwave hyperthermia system Clini-therm Mark IX was introduced in Hokkaido university hospital in September 1986 and 33 patients were treated using this system until july 1987. Hyperthermia was given once or twice weekly for 60 minutes at 43 °C using direct contact applicators. In most of the cases hyperthermia was combined with radiation therapy. Other combined therapies were chemotherapy and I-131 therapy.
The materials evaluated were 18 patients who had more than 6 fractions of hyperthermia, more than 3 months' follow-up period and were combined with irradiation. Tumor volume response were : CR= 28%, PRa=39%, PRb=11%, NC=22%.
In analysis of intratumoral temperature, the tumor edge temperature and the uniformity of heating were correlated with the tumor response, which suggests the minimum intratumoral temperature is important for the evaluation of hyperthermic effect to the tumors.On the other hand the maximum intratumoral temperature appeared to be correlated with heat-induced toxicities.

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A new type of applicator for microwave local hyperthermia, which can penetrate the electromagnetic energy deeper in lossy dielectric medium than a conventional waveguide applicator, has been developed. This applicator, which consists of an integrated waveguide array, whose aperture size is 212mm × 80mm is operated at 430MHz. A water bag is attached on the aperture to perform the body surface cooling. Furthermore, the applicator can be filled with water as a dielectric material, and it becomes compact in size and the impedance matching to the directly contacted is improved. This applicator has the movable metallic plates, which are set inside the applicator, to control the phase of the electromagnetic field in the aperture and it can control the heating pattern and change the depth of the tissues within the hyperthermic temperature. The radiated field distributions of this applicator were measured in a saline solution, and it was confirmed that the temperature distribution in hyperthermic range was performed in to the dobule portion comparing the heating by a conventional waveguide applicator. The results of the theoretical analysis and heating experiments with phantom model show that the maximum depth of heating by this newly developed applicator is approximately 60mm below the surface.

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In hyperthermia, it has been required to develop a microwave heating system which can heat locally on a superficial tumor and a little-deep seated tumor. For this purpose, the authers have developed a microwave heating system (HTS-100) which can heat a little-deep seated tumor with a lens applicator. This system consists of five parts, a microwave power unit, a surface cooling unit, a temperature measurement unit, a control unit and an arm structure for an applicator. Furthermore it has been a compact and very useful system with considered important points as reliability, safety and easy operation in clinical use. It is also equipped all functions desired in microwave hyperthermia therapy, so that it will work well in clinical use not only for animal experiments.

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For hyperthermic treatment of superficial and protrudent malignant tumors on bodies by using RF capacitive heating, we attempted at new type applicator. The trial appliance is what two 10 cm square electrodes make a right angle. Experiment of this applicator resulted that the highest temperature was recognized in the center of the right triangle which was consisted by the electrodes. This applicator was used for a patient who had a recurrent maxillary carcinoma on her face, and heating was remarkably performed. The effect of treatment, however, was not able to be investigated becase of her death by lung metastasis. Although using of this applicator is just the beginning, the right angle type applicator may become very useful for the hyperthermic treatment by RF capacitive heating of malignant tumors which exist on head, neck, external genitals and extremities.

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