Reoxygenation of tumors during fractionated radiotherapy.

Abstract

The work on dose-response of mammalian cells in tissue culture under oxygenated and under anoxic conditions led to calculations of the dose required to cure human tumors. It was immediately apparent that much larger doses would be needed than are used clinically. The conclusion was that anoxic portions of these tumors must become oxygenated during the course of a therapy series. Several aspects of reoxygenation invite investigation. Is a time ever reached when all of the anoxic cells have become oxygenated? Does the size or spacing of the fractions have any influence on the degree to which reoxygenation takes place? A method of examining these questions was suggested by an experiment reported over a year ago. Spontaneous mammary adenocarcinomas in C3H mice were treated with 1,000 R twice a week while the mice breathed air or carbogen. The tumors were measured at the time of each treatment by fitting them to graduated holes in stiff paper. These measurements are plotted on semi-log paper in Figure 1 and show that the tumors shrank faster in carbogen. All details of the treatments were identical except for the atmosphere in which the mice were treated. Therefore the gas must be responsible for the difference in the rate of shrinking. Because of vascular dilatation and increased respiratory rate the carbogen carried more oxygen to the tumors, some anoxic cells were oxygenated, and the tumors were more radiosensitive, responded more to each treatment, and decreased more rapidly in size. Thus, the rate of shrinking is a measure of the degree of oxygenation of the tumors. Furthermore, as shown in Figure 2, when the therapy series was begun in air, then changed to carbogen, the rate of decrease in size accelerated after this change was made. Again anoxic cells were oxygenated and the tumors were more radiosensitive. If none of the cells remaining at the time of the change had been hypoxic, the carbogen could not have increased the oxygenation of the tumor and it would have continued to shrink at the same rate. The presence of hypoxic cells, then, can be detected by more rapid shrinking of the tumor in response to carbogen. As a base line for evaluation, the tumors were first treated in air throughout the series. The results of this part of the experiment seemed interesting enough in themselves to report at this time. As can be seen in Figure 3, tumors treated seven days a week with 400 R, and to a lesser degree those treated with 500 R, shrank faster and faster as the series was delivered. In contrast, those treated with 1,000 R shrank at the same rate throughout the series. This is interpreted as showing that tumors treated with 400 or 500 R fractions improve their oxygenation to such a degree that they become more radiosensitive during the series. While tumors treated with large fractions of 1,000 R, on the other hand, also improve the oxygenation of their hypoxic components between treatments, they never do so to such an extent that the radiosensitivity of the tumor as a whole is increased.