Biophysical modes of ultrasound are classified as follows : 1) thermal effects, 2) cavitational effects, 3) the other nonthermal and noncavitational effects. There have been three approaches to cancer therapy with ultrasound : studies have sought to measure the effects of ultrasound alone on tumors, ultrasound in combination with radiotherapy, and ultrasound in combination with chemotherapy.
In this paper we will review and discuss the implications of the nonthermal effects of ultrasound when ultrasound is combined with heat, ionizing radiation, and chemotherapeutic agents, on the basis of the current reports related to ultrasonic cancer therapy and the biological effects of ultrasound.

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Combined modality of local hyperthermia and chemotherapy has been clinically applied based on in vitro enhancing antiproliferation of chemotherapeutic drugs to cancer cells by heating. The combined modality of whole body hyperthermia and chemotherapy may be capable of completely eliminnating cancer cells from the host, if there is drug highly specific to cancer, but such drug was not found yet. Therefore, complete cure of cancer mainly depends on anticancer immune system of the host. During whole body hyperthermia, the body has to be kept at the temperature to enhance the host immunity, especially the temperature for activation of neutrophils and monocytes. Recently, cytokine therapy as well as activation of monocytes, temperature-dependently enhances antiproliferation of cancer cells until elevating 39 °C. The combined modaltiy of hyperthermia and immunotherapy remains to find a difference in heating temperature from that of hyperthermia and chemotherapy.

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Heating effects induced by extremely low frequency (ELF) pulse magnetic fields have been investigated with relation to an application to local hyperthermia. The pulse generator used in this experiment has been already registered as a Japanese patent number 1394207. The generator permits the pulse direct current to flow through the coil rapidly. Generating the pulse magnetic field is achieved by discharging the capacitor. Discharge of the capacitor is accomplished by triggering on the thyristor (SCR). Two types of coils for magnetic exposure are provided. One is an air-core coil with 40 turns, the other is a transrectal applicator with bar-shaped ferrite core coil. The peak-current to flow the air-core coil and the transrectal applicator coil were 110A and 300A respectively, at a frequency of 8Hz. Using an air-core coil under a condition to be isolated completely from temporo-facial area in rabbits, the ELF pulse magnetic force applied to the parotid glands of the rabbits for 30 minutes. Thirty minutes after the magnetic exposure, the mean temperature of the parotid glands was increased by 7.3°C, and up to 45.5°C, reached finally an equilibrium temperature (n=5). The heating effect in this experiment must be the inductitve heating for thermoelectric current generated by the ELF pulse magnetic field. In the same manner, after inserting a transrectal applicator into the rectum, the transrectal pulse magnetic exposure was initiated. Thirty minutes after the magnetic exposure, the mean temperature of the rectovesical pouch in rabbits was raised by 6.9 °C, and up to 44.6 °C, reached an equilibrium temperature (n=5). In case of transrectal magnetic exposure, not all heating effects are coming from inductive heating, an influence of its own self-heating of the applicator must be also considered. However, it is no problem practically in applying the transrectal local hyperthermia to clinical region. It is concluded that the ELF pulse magnetic heating can be used enough for practical application in local hyperthermia.

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Animals were 8 week-old C3H/He mice derived charles-Riber Co., Ltd. A spontaneous fibrosarcoma in the C3H/He mouse, FSIIa were used throughout. Single-cell suspensions were prepared by trypsinization and the number of viable tumor cells was counted by the trypan blue exclusion method. Approximately 1x10⁵ unstained cells in 5 μl of a single cell suspension were transplanted into the right footpad. Hyperthermia was given in a water bath where a desire temperature ±0.1 °C was maitained by a constant temperature circulator. Each animal was kept in an individual holder with a short arm where the animal leg was gently taped. Animal holders were placed on a achlyl plate which had holes through which animal legs were immersed into the water bath.
Human recombinant TNF (Asahikasei Industrial Co., Ltd.) were used. TNF were administered intratumorally just before the hyperthermia treatment. Tumor response was examined by tumor growth time analysis. Tumors were treated when they reached an average diameter of 8 mm. Three diameters of the tumor, a, b and c, were measured at least 3 times a week and the tumor volume was calculated by πx a xb xc/6. The TG time was obtained on a graph. Six to 8 mice were used in each dose.
Dose of TNF do not influenced to tumor growth curve.
Greater growth tumor inhibition was obtained after TNF 1000 unit + Heat (44 °C, 10 min) than TNF 1000 unit + RT 10 Gy.
Thermal sensitizing effects of TNF was remarkable in higher temperature.

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We propose a model for lethal thermal effects on cells. Thermotolerance is also included. Three steps in the process to cellular inactivation are hypothesized. 1) A group of lethally affected atoms in a cell sometimes gains a great amount of kinetic energy due to thermal fluctuation which causes damage to the target itself. 2) The cell is inactivated when the target is damaged once or several times. However, 3) the damage is repaired in a certain period after the cell receives it. This is called the damage repair time. The damage repair time depends on temperature and period of heating. The surviving fractions of cells were calculated as functions of temperature and heating period using the above model. The resulting survivng fraction curves showed the induction of thermotolerance.

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The efficacy of thermochemotherapy was examined by using solid Yoshida Sarcoma implanted on the feet of rats. Water bath treatment was applied for heating. With heat treatment alone, 42-44°C induced significantly tumor growth suppression. At 45°C, the tumor size was reduced significantly. Treatment with MMC alone reduced significant tumor growth. 42°C or 43°C heating combined with 1 mg/kg MMC induced complete tumor regression which was not obtained through heating alone or chemotherapy with MMC alone.
Histopathologically, central necrosis, fibrinous thrombus and obliteration of the blood vessels were observed on the 5th day after heating at 42°C and over. Severe necrotic changes such as coagulating necrosis of the deep seated striated muscle were observed with 45°C heating on the 5th day. A small number of viable tumor cells remained surrounding the necrotic lesion on the 5th day after treatment with 1 mg/kg MMC alone, however, necrotic or degenerative tumor cells with pyknosis of the nuclei were found strikingly.
The histopathological findings with thermochemotherapy showed remarkable changes such as complete tumor necrosis as compared with either heating alone or MMC alone.
The efficacy of thermochemotherapy was synergistic.

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The applicability of a 430MHz microwave (MW) hyperthermia system (HTS-100) using an electric field converging (lens) applicator was evaluated. Thirty-two tumors with a maximum tumor depth of less than 7cm (16 chest wall tumors, 7 abdominal and pelvic tumors, 6 extremity tumors, and 3 head and neck tumors) were treated with HTS-100 for a total of 104 sessions in conjunction with irradiation or chemotherapy. In 91 (88%) of the 104 sessions, intratumor temperature exceeded 42 °C for more than 20 min. The average tumor temperature was 42.8 °C, 43.5 °C, 42.1 °C, and 42.7 °C for chest wall, abdominal and pelvic, extremity, and head and neck tumors, respectively; similarly 87%, 90%, 66%, and 78% of monitored intratumor points exceeded 41 °C. A lens applicator heating system increased the penetration depth of MW, and tumor temperature of 41 °C at 5cm from the surface was easily achieved with a four -aperture lens applicator. Of the 31 evaluable tumors, 14 tumors exhibited complete response (CR), 11 partial response (PR) and 6 no response (NR). These results suggest that the lens applicator heating system is useful for heating localized subsurface tumors with a maximum tumor depth of 5-6cm.

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