X-rays and electrons produced by the Linear accelerator (Linacs) are widely used clinically and thus play a primary role in RT. Both X-rays and electrons are forms of low-LET radiation. The primary treatment method used for RT is high energy radiation, and approximately 70% of the biological effect of the high energy RT on the tumor is considered to be caused by the indirect effect of the hydroxyl radical (OH radical) that is generated from water (reviewed in Fujita et al., 2019). The OH radicals play a major role in radiation-induced cell damage and induces apoptotic cell death by activating the proapoptotic pathways. Oxidation, which causes the radical reaction, is indispensable for cancer treatment, but oxygen-deficiency (hypoxic tumors) causes a decrease the anti-tumor effect of RT, and the drop in the radical reaction is one of the reasons for low local efficacy.

Hypoxia occurs to some degree in most solid tumors as a result of several factors, including the rapid growth rate of cancer cells and the highly disorganized/inefficient vasculature (Hammond et al., 2014).

Hypoxia conferred resistance to radiation damage of a wide range of cells and tissues (reviewed in Brown, 1999). Figure 1 shows the difference in radiation sensitivity between the aerobic and hypoxic cells.

Figure 1. The difference in radiation sensitivity between the aerobic and hypoxic cells

Figure 2 shows oxygen distribution in a lymph node metastasis of a head and neck tumor and in the surrounding normal s.c. tissue. The normal tissue shows a typical Gaussian distribution of oxygen tensions with a median between 40 and 60 mmHg, and no values less than 10 mmHg. Tumors, on the other hand, invariably show a distribution with much lower oxygen tension. The one shown in Figure 2 is typical in the sense that in many series of human tumors at different sites, roughly half the tumors have a median value of less than 10 mmHg, and half have a median greater than this. This median of 10 mmHg is also significant in that this is the point at which radiation resistance starts to develop with full resistance at values of less than approximately 0.5 mmHg. Thus, the tumor shown in Figure 2 would be expected to have regions with cells at greater radiation resistance than those in adjacent normal tissues.