Purpose: To review the relationships between volume irradiated, total dose of radiotherapy, and normal tissue complication probabilities.
Methods and Materials: Two types of tissue structure in organs are distinguished. Critical Volume organs, where the Functional Sub-Units (such as nephrons in kidney or alveoli in lung) operate in parallel, do not show any complications until a critical proportion of the organ has been destroyed, about 70% in human kidneys. Critical Element organs, on the other hand, where Functional Sub-Units are arranged in series, like links of a chain (spinal cord, long peripheral nerves, ureter, GI tract when its whole circumference is irradiated), show loss of function if only one Functional Sub-Unit is destroyed. Functional Sub-Units may each have from 104 to 109 cells in different tissues; and this uncertainty gives rise to a wide range of possible responses. We are still learning.
Results: Although both types of tissue give rise to sigmoid dose-response curves, their changes with volume irradiated are very different. Typical examples are illustrated by recently published curves of complication probability versus partial volume irradiated at constant dose; and also by curves of probability versus total dose for different volumes irradiated. Basic diagrams and the formulae that have been developed to obtain them are explained step by step in the Appendix.
Conclusions: For Critical Volume (parallel) organs, the important factor is the proportion of the organ which can be destroyed without loss of organ function. For Critical Element (series) organs, the three factors are the number and radiosensitivity of the cells in the Functional Sub-Units, and then the number of FSUs in the volume irradiated. For late complications in general, their incidence can be reduced by using doses-per-fraction closer to 1 than to 2 Gy.

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From clinical experience, osteosarcomas and malignant melanomas are generally considered to be radioresistant. To explain this impression, the responses to radiation of 7 osteosarcomas and 6 melanomas were analyzed by in vitro coloy-forming assay and compared with those of 8 human fibroblasts. The values of Do, the surving fraction after 2 Gy (SF2), and the mean inactivation dose of all osteosarcomas and 5 malignant melanomas in log-phase culture were significantly higher than those of fibroblasts. One malignant melanoma (P-39: Do=74 cGy, Dq=85 cGy) was very sensitive; sirilar to fibroblasts. P-39 cells had low capacity for PLD (potentially lethal damage) repair and also low efficiency for DNA double strand break repair in comparison to other radioresistant malignant melanomas (G-361: Do=145 cGy, Dq= 249 cGy).
With reference to the molecular basis for radiation resistance, it has been proposed that ras, myc, and/or raf oncogenes may be involved. Comparing G-361 and P-39 melanomas, we found no difference in the expression of ras, c-myc and c-raf, and no evidence of mutations in c-ras at codons 12, 13, or 61. We conclude that, whereas the repair of PLD may be a principal reason for the radiation resistance of melanomas, this property would apply only to those tumors whose cells are inherently resistant and, therefore, cells in which the involved sector of PLD is large.

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Tumor size, which is readily measurable in clinical situations, is one of the most important predictors of radiation response for tumors of a specified histological type. We propose in this paper a simple model that defines the tumor radioresistance in terms of tumor control dose (TCD) relative to tumor volume, assuming that the number of target cells is proportional to the power function of tumor volume. In the model the TCD increases linearly with increasing logarithm of tumor volume, with a slope proportional to the effective Do of the target cells. The model was applied to the analysis of radioresistance of 169 cervical lymph node-metastases from head and neck cancers. Unsing the logistic multivariate regression equation, the TCD was expressed as a function of tumor volume. Result indicated that the lymph node-metastases become progeressively radioresistant with increasing tumor volume. This was strongly suggested to be caused by progressive increase in the radioresistance of the target cells.

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A method of making ⁶⁰Co γ-ray primary and scatter dose spread arrays in water is described. The primary dose spread array is made using forward and backward primary dose spread equations (h₁ and h₂) where both equations contain a laterally spread primary dose equation (G), made from measured dose data in a cork phantom. The scatter dose spread array is made using dierential scatter-maximum ratio (dSMR) and differential backscatter factor (dBSF) equations (k₁ and k₂), where both equations are made to be continuous on the boundary. Primary and scatter dose calculations are performed along the beam axis in layered cork heterogeneous phantoms. It is found, even for ⁶⁰Co γ-rays, that when a small tumor in a lung is irradiated with a field that just surrounds the tumor, the beam entrance surface and lateral side of the tumor may obtain no therapeutic dose, because of loss of longitudinal and lateral electronic equilibrium, and when a large tumor in a lung is irradiated with a field just surrounding the tumor, the lateral side of the tumor may obtain no therapeutic dose due to loss of lateral electronic equilibrium.

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We retrospectively studied 97 patients with stage III-IV cervical cancer treated by radical radiotherapy to clarify the radiotherapeutic parameters that influenced pelvic recurrence. The diseases were staged as III in 75 patients and IV in 22. The patients were treated by whole pelvis irradiation and split field irradiation to the parametrial tissue followed by high dose-rate intracavitary irradiation. The actuarial 5-year pelvic recurrence rate was 27%. Multivariate analyses by the proportional hazard method showed significant positive correlations between pelvic recurrence and the duration of external irradiation, or the total duration of both the external and intracavitary irradiation. The other radiotherapeutic parameters were not related to pelvic recurrence. There was a marked inverse correlation between patient age and pelvic recurrence. T-stage was also a pretreatment factor affecting pelvic recurrence.

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The effects of radiation on the thyroid were investigated in 102 patients treated by radiation therapy to the neck. All patients had radiation ports which included the thyroid gland. Serum TSH levels were elevated in 41 cases and the cumulative elevation rate was 52.1% in 5 years. The high frequency of elevated serum TSH levels observed in patients whose thyroid glands were included within the radiation fields (74.1%) was statistically significant compared to those whose thyroid glands were only partially included (23.4%). Among the patients whose entire thyroid glands were included within the radiation field, combination with chemotherapy increased the frequency of elevated serum TSH levels, but the increase was not statistically significant. Among 36 laryngeal cancer patients treated by only radiation therapy through a portal encompassing part of the thyroid, 4 (14%) were found to have elevated serum TSH levels. We advocate routine monitoring of thyroid functions after radiation therapy to the neck.

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The results of a retrospective analysis of 84 patients with nasopharyngeal carcinoma are reported. From 1972 to 1982, 55 patients were treated with radical radiotherapy [RT] alone (treatment 1). From 1983 to 1989, 29 patients received four to six courses of adjuvant chemotherapy [CT] of CMU regimen (cyclophosphamide, methotrexate and UFT, a 5-FU analog) after radical RT (treatment 2). The actuarial 5-year survival rates of treatments 1 and 2 were 30.9% and 44.4%, respectively. There was statistically significant difference in survival curves of treatments 1 and 2 with a p-value less than.05 by the logrank test. The total failure rates of treatments 1 and 2 were estimated to be 73% and 59%, respectively, indicating that addition of CT does not lead to remarkable improvement in tumor control. The median times to progression were 7 months in treatment 1 and 13 months in treatment 2. In conclusion, the combined CT of CMU regimen with RT achieved significantly better 5-year survival, with the improvement mainly attributable to a later relapse time compared to 55 historical controls that received RT alone.

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We conducted a prospective randomized study to determine whether or not Etoposide (Et), applied concomitantly with radiation, would be more effective in reducing the tumor sizes of non-small cell lung cancer than radiation alone. Radiation was administered in doses of 1.5-2.0 Gy/day, 5 times a week with targets of a total of 40 Gy or more. Et was administered daily in oral doses of 25mg/day every day, but 1hour before radiation on the relevant designated days. The effectiveness of radiation alone was similar in both adenocarcinoma and epidermoid carcinoma. Combined with Et, there was no difference from radiation alone in adenocarcinoma, but a significant difference was evident in epidermoid carcinoma. The number of patients in whom tumors were decreased to less than 50% of the initial sizes by 60 Gy was 16/23 (69.6%) in the concomitant therapy group. In the radiation alone group this rate was 11/29 (37.9%). This difference is statistically significant (0.02<P<0.03). In terms of tumor size, effects were seen only is the sub-group with tumor sizes of 3.1-5cm.

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