[in Japanese]

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The Japanese Society of Hypperthermia Oncology conducted a nation-wide survey of the present situation of local hyperthermia in Japan as of December 1992. We could receive responses to this survey from 119 institutions out of 156 institutions where hyperthermic equipment was installed.
We explain the result of survey concerning the following 7 items :
1) Hyperthermia in Japan : As of December 1991, the Ministry of Health and Welfare of Japan approved 10 models of hyperthermia equipment, and the number of installed equipment is 185. There are 47 units of microwave heating equipment, representing 25.4%. There are three kinds of RF capacitive heating equipment. They represent 61.6% of the total.
2) Theatment schedule : The time required for one session ranged from 40 to 60 minutes. The numbers of sessions per one course of treatment were 5, 6, or 10.
3) Heating techiques : Difficulties encountered in local hyperthermia was surveyed. In average, these items were mentioned in the decreasing order of difficulty as follows : (1) To obtain effective heating. (2) To alleviate pains experenced by patients. (3) To measure exact temperatures. (4), To have sufficient manpower.
4) Thermometry : In case of microwave heating and BSD-1000, temperatures were measured for 80% or more of total cases of both shallow-seated tumors and deep-seated tumors. On the contrary, in case of RF capacitive heating, temperatures were measured often for shallow-seated tumors. Temperature were not measured often for deep-seated tumors.
5) Hyperthermia treatment : Until December 1991, 8872 patients were treated at 104 institutions. 21 % of them are superficial tumors, 22.6 % of them are shallow-seated tumors, 56.2% of them are deep-seated tumors. On other hand, 12.5% of them are heated by microwave heating. 63.2% of them are heated by RF capacitive heating.
6) Hyperthermia treatment classification : We have analyzed the breakdown of combination therapy applied to 4916 cases treated for the recent 4 years. Hyperthermia alone represents 5.3%; thermoradiotherapy, 57.5%, thermochemotherapy, 22.6%; and thermochemoradiotherapy, 14.4%.
7) Indication of thermomadiotherapy and evaluation of thermochemotherapy : Thermoradiotherapy is most widely applied, and their indications have been clarified. Thermoradiotherapy is performed at the 70% of the total institutions surveyed, and the therapeutic efficacy is expected.

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In the period from November 1984 until May 1993 hyperthermia was applied to seven patients with local recurrences of rectal cancer. For the heating we used a BSD made BSD-1000 for five patients and an Omron made HEH-500C for two patients. Hyperthermia was performed on the average 8.7 times (range : 3-18) for each patient for 60 minutes each. All patients underwent combined radiotherapy and received a mean radiation dose of 45 Gy (range : 9-60 Gy). Five patients underwent heating within 1 hour after irradiation and two patients simultaneously with the irradiation. Five patients underwent combined chemotherapy and two patients immunotherapy. Before the treatment all patients had painful lesions, but pain decreased posttherapeutically in six patients. Performance status improved in two patients. High carcinoembryonic antigen levels prior to the therapy in five patients decreased in all cases after treatment. Posttherapeutical computed tomograms revealed only minor response or no changes. After the treatment four patients died of exacerbations of recurrent tumors and two patients of distant metastases. The 50 % survival time after initiation of the treatment was 24 months. Hyperthermia combined with radiotherapy, chemotherapy and or immunotherapy was useful for the alleviation of pain in patients who developed local recurrence after surgery and could be expected to improve survival after recurrences.

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To study the change of blood coagulation in rabbits under whole body heating, many parameters concerning blood coagulation were measured periodically after heating. Normal rabbits were heated at 30, 37, 40 or 45°C, respectively. Blood sample were obtained after heating (preheating, 0, 1, 3 and 24hrs) and were examined coagulation parameters (APTT, PT, clotting and fibrinolitic factors, platelets and fibrin monomer). APTT was prolonged significantly, clotting factors (prothrombin, Factor X) and fibrinolytic factor (plasminogen) were decresed from 0 to 3hrs after heating. A fall in platelets was apparent and continued during the 24hrs after heating. Fibrin monomer was detected at 3 and 24hrs after heating at 45°C.
From these results, it was concluded that rabbits receiving whole body heating showed DIC like complications.

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A bolus for hyperthermic oncology, that emanates infra red rays has been developed and tested for superficial malignant tumors. In addition to reduce edge effect, emanated infra red rays contributes to heating in the superficial region against cooling with water boluses. Favorable heat distribution was confirmed in a huge chest wall reccurence of breast cancer. The present bolus is useful in hyperthermia for superficial tumors.

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The Japanese Society of Hyperthermia conducted a multicenter trial to study the effect of thermochemotherapy for gastrointestinal cancer. Ninety patients, including 33 patients with gastric cancer, 30 patients with large bowel cancer and 27 patients with pancreatic cancer, received thermochemotherapy. The effects on shrinkage of tumor size, life span, performance status and quality of life were compared with the results of matched patients who received chemotherapy alone. Auti-tumor response was observed in 45 %, 16 % and 30% of patients with gastric, large bowel and pancreatic cancer by thermochemotherapy, respectively. These figures in the chemotherapy groups were 23 %, 7% and 7% (p < 0.04 between the thermochemotherapy and chemotherapy groups in gastric cancer and pancreatic cancer). In the thermochemotherapy group, 50% of patients survived for 6, 10 and 7 months in gastric, large bowel and pancreatic cancer, respectively. In the chemotherapy group, these figures were 5, 5 and 2 months (P < 0.0001 between the two groups in large bowel cancer and pancreatic cancer). Performance status was improved in 44 %, and cancer pain was relieved in 75 % of patients received thermochemotherapy. There was no serious side effect in hyperthermia treatment, and thermochemotherapy was well-tolerable by patients. Thus, thermochemotherapy is a powerful tool for cancer treatment by exerting not only anti-tumor effects but also improvement in performance status, cancer pain and quality of life.

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Amilorid, 3, 5-diamino-6-chloro-N- (diaminomethylene) pyrazinecarboxamide, and its derivative MH-12-43, N-amidino-3-amino-6-chloro-5- (N-ethylisopropylamino) pyrazinecarboxamide, were studied for cytotoxicity, thermosensitivity and changes of intracellular pH (pH_i) in Ehrlich ascites tumor cells (EAT cells). Similar cytotoxicities were observed in MH-12-43 at lower concentrations than amiloride. After treatment with 0.5 mM amiloride or 0.05 mM MH-12-43 at 37°C for 120 min, no decrease in survival rate were shown. The effects of hyperthermia at 42°C were enhanced by amiloride and MH-12-43, and the more decrease in suvival rate with 0.05 mM MH-12-43 was observed rather than that with 0.5 mM amiloride from hyperthermia at 42°C. The treatment of 0.5 mM amiloride or 0.05 mM MH-12-43 reduced pH_i at 37°C, while the more reduction was observed by the treatment at 42°C. The reduction of pH_i by 0.05 mM MH-12-43 was more substantial than that of 0.5 mM amiloride at 42°C. These suggest that the enhancement in the hyperthermic effects by amiloride or MH-12-43 may be due in part to a decrease in pH_i.

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The effect of thermochemotherapy was evaluated through in vivo experiments using radiofrequency (RF) hyperthermia and Mitomycin C (MMC). Male Donryu rats were implanted Yoshida sarcoma to their legs. At about 500mm³ of tumor size, rats were given 42°C or 43°C RF heating with or without intraperitoneal 1mg/kg of MMC (n =10 in each group). The tumor size was measured during 5 days after the treatment. MMC concentration in tumor tissues was compared between the heated and unheated tumor in the same rat after thermochemotherapy. An inhibitory effect on tumor growth was significantly enhanced by combination treatment of MMC and hyperthermia at 43°C compared with the group treated by MMC administration alone or hyperthermia alone. The area under the curve representing the MMC concentration in the tumor was about 1.6 times higher on the heated side than that on the unheated side. Thus, the increase of MMC concentration in the tumor tissues appears to cause the synergistic inhibitory effect on tumor growth by combination of MMC administration and hyperthermia.

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Temperature sensitive liposome-encapsulated MMC (liposome MMC) was developed to increase the efficacy of thermochemotherapy. Ascitic Yoshida sarcoma cells were implanted to male Donryu rats. When tumors grew about 500 mm³ in volume, the rats were treated with varying intravenous dosages of a liposome and native form of MMC to compare the effects between the two forms. Then, rats with tumor were treated with hyperthermia at 42°C and intravenous 0.5 mg/kg of liposome MMC or native MMC. Marked inhibition of tumor growth was observed in the growp treated by liposome MMC compared with native MMC when combined with hyperthermia. The intratumor MMC concentration was about 4.2 times higher by the area under the curve in the treatment by liposome MMC and hyperthermia than the treatment by native MMC and hyperthermia. This increase in the intratumor MMC concentration may have caused the enhancement of inhibitory effects on tumor growth. Thus, temperature sensitive liposome-encapsulated MMC is a good drug delivery form to increase the efficacy of thermochemotherapy.

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