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The authors describe a case of a sweat gland carcinoma that underwent complete remission after treatment with radiotherapy and hyperthermia. This sweat gland carcinoma had been thought to be unamenable to any therapeutic treatment. Based on this result, the authors feel that radiotherapy combined with hyperthermia may be effective for the treatment of a sweat gland carcinoma.

Non-randomized clinical trials of thermoradiotherapy for breast cancer and carcinoma of the urinary bladder were reported. Thermoradiotherapy was useful for breast cancer treatment in term of (1) increased local control for locally advanced tumors and (2) possibility of reducing dose of irradiation for recurrent tumors following radiotherapy. Tumor response to thermoradiotherapy was dependent on tumor volume and maximum or minimum tumor temperature. Thermoradiotherapy was also effective as a preoperative-treatment for urinary bladder cancer. The incidence of down-staging and degeneration of tumors was significantly higher in thermoradiotherapy than in radiotherapy. These effects were temperature dependent. Patients with T 3-4 NOMO or Grade 3 tumors treated with thermoradiotherapy showed a tendency of increased survival compared with those treated with radiotherapy alone.

The results of clinical trials of hypoxic cell radiosensitizers were reviewed in order to clarify the present status and problems in this field. Most trials failed to show an effectiveness of the combination, however, some ENT tumors and bladder cancers were improved in local tumor responses and survivals. A selection of the patients suitable for the combination and development of simple method for the selection are indispensable. SERs necessary for clinical radiotherapy are considered to be larger than 1.2 at 2 Gy fraction level. Present hypoxic cell radiosensitizers have no significant effects on alpha values. Since radiation responses at low radiation dose ranges are dominated by alpha values, the chemicals having an effects on alpha values have to be developed.

It is believed that anemia is an important prognostic factor in the case of cancer patients treated by radiation therapy. One possible explanation for this is tumor oxygenation. With respect to tumor oxygenation, the arterial oxygen content (CaO2) may be more direct indicator than hemoglobin (Hb) level. Fourty-two patients with squamous cell lung cancer treated solely by irradiation were reviewed. It was found that CaO2 was more important than the Hb level in determining a tumor response to radiation therapy. This is considered as important indirect evidence of the existence of hypoxic fractions of cells in human tumors.

Bone metastasis from a thyroid papillary cancer of a 59-year-old woman had been successfully treated with radiotherapy (6,000 rad) and iodine-131 (120 mCi). One year later, the patient developed leukocytosis (maximum 143,000/mm3) and hypercalcemia (16.0 mg/dl). A colony stimulating factor (CSF) was detectable in her plasma, and nude mice that had been given metastatic tissues similarly developed leukocytosis and hypercalcemia. Leukocytosis and hypercalcemia seemed to have been caused by the CSF produced in the bone metastasized tissues of this thyroid cancer.

Hypoxic fractions (HF) and reoxygenation of various murine tumors were studies using a paired survival assay. All irradiations were given to whole-body of mice without anesthesia or physical restraint, both of which can increase HF artificially. HF's of 4 different tumors of 1 cm in diameter were between 4.5% and 14%. Thus, variation of HF due to tumor type was quite small. HF was roughly correlated with tumor size and proportion of necrotic areas. Reoxygenation was examined in two tumor systems, and it occurred rapidly (within 1 hr after radiation) in one tumor but rather slowly in another.

Recent developments in the evaluation methods for hypoxic cell sensitizers were reported with emphasis on the following 3 points. (1) A new sensitizer-screening system consisting of the EMT 6 single cell, spheroid, and solid tumor was proposed by us and was found to be a useful, sophisticated system. (2) In the in vivo experiments, irradiation conditions for mice and the drug dose level influenced the hypoxic fraction of tumors significantly. Investigators must always take these facts into consideration when doing in vivo experiments. (3) Three new compounds recently developed in Japan proved to be superior to misonidazole.

Fluorine modification of nitroazoles has been characterized as a useful method of molecular design of hypoxic cell sensitizers. In vitro sensitizing activities were correlated to the promotion efficiency of radiolytic hydroxylation of thymine to thymine glycol and to the one-electron reduction potential of a variety of fluorinated and non-fluorinated nitroazole derivatives. The absolute activity of sensitizers, which was evaluated from the enhancement ratio in vivo (SERvivo) and the tumor affinity, showed a linear relationship with the in vitro sensitizing activity. The sensitizer dose required to achieve an SERvivo of 1.5 decreased as the tumor affinity became greater. The fluorine modification of nitroazole sensitizers could enhance both the absolute activity and the tumor affinity.

Results of radiotherapy for 164 supratentorial malignant gliomas were analyzed based on recent histological subclassification into glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA). Patients with AA had a better prognosis than those with GBM. The 5-year survival rate was 1% for GBM and 16% for AA. The size of radiation field did not influence survival significantly, and whole brain radiation appeared of no benefit. Survival time prolonged with an increase of radiation dose between 45 Gy and 72 Gy. The optimal radiotherapy for the disease is discussed.

To determine effects of surgical treatments on the quality and duration of survival following tumor recurrence and to analyze prognostic factors that may affect the outcome, we have reviewed our experience with reoperations for 43 patients having recurrence with malignant histologic findings among 188 cases of supratentorial glioblastoma multiforme (GM), anaplastic astrocytoma (AA) and low-grade astrocytoma (LGA) (27 of 77 patients with GM, and 16 of 42 patients with AA) since introduction of computed tomography (CT) in May, 1976. Using CT and/or more recent magnetic resonance imaging (MRI), the regrowth patterns of tumor recurrence were examined with aspect of local extension, non-contiguous or remote metastatic invasion, and tumor cell dissemination through cerebrospinal fluid. MRI can provide more significant informations on the selection for reoperation in terms of recognition of the developmental features. In most of the patients who underwent reoperations at recurrence, surgically accessible components of the lesion were shown to cause neurological deficits as a result of compression rather than infiltration of functionally important areas. Reoperations thus might be achieved with acceptable mortality and morbidity. In contrast, patients with tumors in inaccessible areas of the central nervous system received additional chemotherapy and/or interferon administration. Indications for re-irradiation of the recurrence is also discussed.

Clinical and basic studies in hypoxic cell radiosensitizers and potentially lethal damage (PLD) repair inhibitors were reviewed. Most clinical trails on misonidazole (MISO) show that the toxicity of MISO is a major reason for failure in the trials and an adequate selection of tumors is needed for the success. Phase III studies on SR-2508 and RO 03-8799, less toxic and more effective sensitizers, are in progress. AK-2123 and RK-28 developed in Japan are drugs with similar clinical applicability of MISO. Thiol depletion of tumors is one of the way to increase the radiosensitization. The measurement of intercapillary distance on histopathological microslide is a valuable method to select the tumors containing much hypoxic cell fractions. Stable and effective chemicals as MISO in hypoxic cell sensitization must be developed to investigate the clinical applicability of PLD repair inhibitors.

The correlation between cell survival curve and dose response curve of MN frequency following irradiations was studied using cytokinesis-block method. Both dose response curves were analyzed by linear quadratic model, i.e. SF = exp (- alpha D - beta D2) and MN frequency = aD + bD2 + c. A good correlation between alpha/beta and a/b ratios was observed in repeated paired experiments (gamma = 0.97). When the cells were treated with BUdR, alpha-type radiosensitizer, a value in dose response curve of MN frequency increased but b value did not. In 10 renal cell carcinomas, the linear correlations between cell surviving fractions and MN frequencies were observed. When radioresponses of 5 esophageal cancer cell lines were evaluated with MN assay, wide range of a/b ratios was found. These data present that MN frequency assay using CB method is available as a tool of rapid assay of radiosensitivity of cells.