Although several rare congenital syndromes are associated with hypersensitivity to radiotherapy, the extent to which genetic factors modulate the radiosensitivity of cells from “normal” individuals is largely unknown. Some evidence exists that fibroblasts from apparently normal patients who sustained unusually severe radiation reactions are more radiosensitive in vitro than cells from patients treated similarly whose reactions were not excessive. Other data show that tumor cells from cancers that recur after radiotherapy are on average less radiosensitive in vitro than cells from tumors that are cured. Finally, there are fragmentary clinical data suggesting that a correlation may exist between the severity of normal tissue reactions to radiotherapy in a given patient and the probability of tumor control. All of these data are consistent with the hypothesis that genetic factors modulate the radiosensitivity of both normal and neoplastic cells from patient to patient. If this hypothesis is true, development of assays precise enough to identify patients who are significantly more or less radiosensitive than average would allow radiation doses to be titrated according to individual radiosensitivity with an improvement of the therapeutic ratio for all patients.

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Serum concentrations of cisplatin (CDDP) and acute complications were studied in patients treated for head and neck cancer by radiotherapy combined with daily administration of low doses of CDDP (5mg/m² or 6mg/body) at Osaka University Hospital between March 1988 and December 1989. Serum concentrations of total-CDDP (6 patients) and free-CDDP (2 patients) were studied in cases injected intravenously with 5mg/m² daily. Total-CDDP determined just before daily administration of CDDP was increased gradually (0.35 to 0.64μEg/ml by the 7th day;0.42 to 0.91μEg/ml by the 14th day and 0.60 to 0.82μEg/ml by the 20 or 21st day) and still observed in the serum for more than two weeks after cessation of the chemotherapy. Serum concentrations of free-CDDP were about 0.35μEg/ml at 5 minutes and 0.15μEg/ml at 30 minutes after the intravenous injection of CDDP. Incidence of the acute complications more severe than grade 2 were nausea and vomiting: 4/52 (8%), leukopenia: 11/52 (21%) and thrombocytopenia: 4/52 (8%): Incidence of myelosuppression (leukopenia and/or thrombocytopenia) was 11/26 (42%) when the total dose of CDDP exceeded 120mg;and 3/26 (12%) when it was less than 120 mg. Transient renal dysfunction (increase of serum creatinine) of grade 1 was seen in only 3 patients.

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Bromodeoxyuridine (BUdR), a nonradioactive thymidine analogue, is taken up by cells in S-phase, and the ratio of BUd R-positive nuclei to the total number of cells counted is defined as the labeling index (LI). We analyzed BUd R LIs and the clinical course of 47 cerebral glioblastomas in adults; 26 at initial surgery, 13 after completion of radiation therapy, and 8 at clinical recurrence. LIs at initial treatment had a range of 3.9-17.4%(mean 8.2%). Patients with Lis of less than 5% had a median recurrence-free period (RFP) of 15 months, whereas the median RFP of patients with LIs exceeding 5% was 6 months. Median survival times were 36 months and 16 months, respectively. These differences in RFP and survival time were both statistically significant. Histologically, lebelled cells were seen more frequently around capillaries with endothelial proliferation than around capillaries without endothelial proliferation. After radiation therapy, the mean LI fell to 3.8% with higher radiation doses, and the lowest LI, less than 0.1%, was obtained in cases treated with a 70Gy dose. Statistically significant differences in the survival of patients and time to recurrence were observed between groups with LIs of more than 5% and less than 1%. LI was inversely correlated with survival time on a logarithmic scale. Tumor cells with swollen cytoplasm or pyknotic nuclei around the occluded vessels were hardly positive for BUd R staining, whereas surviving tumor cells around patent capillaries showed LIs of 2-5% or more. In 8 cases of recurrent glioblastoma after radiation therapy, 4 showed LIs of less than 0.2% and the other 4 showed LIs of more than 4%. In the 4 cases with LIs of less than 0.2%, most of the tumor showed coagulation necrosis with scattered swollen gemistocytic cells. From these observations, it is suggested that cells around vessels with endothelial proliferation are more sensitive to radiation therapy, and that patients with lower LIs after radiation therapy have better prognoses. At least a dose of 70Gy by external irradiation would be needed to obtain the lowerst LI of less than 0.1%.

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The number of patients who receive radiotherapy for carcinoma of the endometrium with or without surgery has gradually increased in recent years at the Department of Radiation Therapy, The Center for Adult Diseases, Osaka (CADO), since the incidence of endometrial carcinoma has increased greatly over the past 15 years according to the Osaka Prefectural Cancer Registry. In this paper we describe technical improvements in high dose-rate intracavitary radiotherapy against endometrial carcinoma during the past 12 years. Of 67 endometrial cancer patients who received radiotherapy from 1977 through 1988, 13 medically or technically inoperable patients underwent definitive high dose-rate intracavitary radiotherapy with or without external beam radiotherapy. These patients can be divided into three groups according to the type of applicator employed. For patients in group A, a soft polyethylene tandem tube and colpostat were used with a source arrangement similar to that of the Manchester rule for endometrial carcinoma. Our newly designed metallic CADO-EI type and CADO-EII type endometrial applicators were used for patients in groups B and C, respectively. CADO-EII type endometrial applicator resulted in a sufficient isodose curve against endometrial carcinoma. Among patients of advanced age, severe intercurrent disease or advanced disease were selected for treatment, only four of these patients survived for more than three years. However, there is no doubt that high dose-rate intracavitary radiotherapy for carcinoma of the endometrium results in the possibility of long-term survival, since 7 of 8 patients with T la carcinoma could be controlled as to intrapelvic lesions.

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From 1971 to 1984, 96 patients with oropharyngeal squamous cell carcinoma received megavoltage radiotherapy with several dose fractionation schedules. All patients were treated on four times per week schedules. The daily doses were distributed between 2.5Gy to 3.45Gy according to the treatment period. The actuarial five year survival rate of all cases was 32 percent. The local control rate of primary site of 71 eligible patients was 37 percent. Log-log time-dose scattergrams to correlate the probability of local control with dose showed that the slope of an iso-effective curve between 4 and 7 weeks might be 0.38 for T_1-3 lesions. When one assumed the 50 percent local control iso-effective curve was linear-quadratic, the “α/β ratio” was approximately 1.8, which was quite lower than expected. However, the “α/β ratio” of severe late complication was suggested to be still lower than that of tumor control.

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Between 1971 and 1988, thirty-one patients were treated with radiation for confirmed or suspected intracranial germinoma. From 1971 to 1978, thirteen patients received 20-50 Gy/13f-28f in the primary tumor site. The field sizes ranged from 4×5 cm to 9×13cm, but were mostly 8×8cm. After 1979, eighteen patients were treated with a total dose of 50 Gy/28 f over 6 weeks, 30 Gy/18 f over 4.5 weeks, delivered to the whole brain, and 20Gy/10 f over 2.5 weeks to the primary tumor site. The overall 5-and 10-year survival rates of the 31 cases in which radiotherapy was completed were 93.0% and 84.3%. The survival rates of patients treated with only regional irradiation were 84.6% at 5 years and 76.9% at 10 years. On the other hand the survival rates of patients treated with whole brain irradiation was 100% at 5 years. Intracranial relapse occurred in four patients whose treatment was limited to primary tumor site and/or tumor dose was less than 40 Gy over 5 weeks. Prophylactic spinal irradiation was undertaken in 10 patients. Prophylactic irradiation of the spinal axis (20 Gy in 2.5 weeks) was carried out in patients exhibiting abnormal cerebrospinal fluid (CSF): positive cytology for tumor cells, or increased protein and cell-count levels. In a 15-year-old patient who had not been treated despite positive CSF findings, lumbar spinal relapse occurred after 2.5 years. Except for this case there were no spinal metastases regardless of radiotherapy. On the basis of our results, we recommend whole-brain irradiation to 30Gy over 4.5 weeks plus a boost of 20Gy over 2.5 weeks to the primary site and prophylactic spinal irradiation for patients exhibiting abnormal CSF.

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Whole body irradiation of mice was performed with a set of single 2mm wide thin fan slit beams of electrons from a 45 MeV linear accelerator to investigate the effects of inhomogeneous irradiation on normal tissue. Beam intervals were adjusted to 0 mm, 1mm, 2mm, 3mm, and 4mm creating an inhomogeneous field, while the anesthesized mice were moved by a remote control device. The effect was analysed in terms of the LD_50/30 relation to the beam intervals. Dosimetries were carried out using TLD rods and FCR imaging plates. Doses were indicated at the center of the slit beam on the surface of the acrylate phantom, irradiated by only a single slit beam. LD_50/30 was 9.3Gy for a 0mm wide beam interval, 11.3Gy for 1mm, 15.0Gy for 2mm, 26.3Gy for 3mm, and 29.8Gy for 4mm. The relation between LD_50/30 (Ld) and relative volume (Rv=a ratio of beam width/(beam width+beam interval)) was expressed by the following equation:
Ld=8.21×Rv^-1.12.
The exponent value was-1.12. The results suggest that the product of LD_50/30 and relative volume is nearly constant, and LD_50/30 depends almost entirely on the integral dose received by a mouse, independent of the beam interval.

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Preoperative radiotherapy or thermoradiotherapy was administered to 72 patients with invasive T1-4N0M0 bladder cancer (UICC classification 1987). Between October 1980 and October 1983, 20 patients were treated by preoperative radiotherapy with a regimen of 2Gy per fraction and 5 fractions per week to a total dose of 40Gy (TDF=66, Group 1). Between April 1984 and March 1989, 24 patients were treated preoperatively by radiotherapy following a schedule of 4Gy per fraction and 3 fractions per week to a total dose of 24Gy (TDF=53, Group 2). Another 28 patients were treated with the same radiotherapy regimen as group 2 combined with hyperthermia (Group 3). Regional hyperthermia was administered for 35-60 minutes immediately after irradiation, and was given in 2 sessions per week for a total of 4 sessions using an 8MHz RF capacitive heating device. Group 3 was divided into group 3 (High), in which the average temperature (Tav) inside the urinary bladder was above 41.5°, and group 3 (Low) with Tav below 41.5° C. Group 3 (High) experienced significantly more down-staging and tumor degeneration than group 2 or group 3 (Low). The patients of group 3 (High) also had a better local control rate and survival time, although the differences were not significant. Complications associated with hyperthermia were mostly pain during treatment and were not serious. The results indicate that thermoradiotherapy is effective as preoperative treatment for invasive bladder cancer.

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