Improved cellular automata model shows that indirect apoptotic cell death due to vascular damage enhances the local control of tumors by single fraction high-dose irradiation.

We investigated the effects of indirect apoptotic cell death due to vascular damage on tumor response to a single large dose with an improved two-dimensional cellular automata model. The tumor growth was simulated by considering the oxygen and nutrients supplied to the tumor through the blood vessels. The cell damage processes were modeled by taking account of the direct cell death and the indirect death due to the radiation-induced vascular damages. The radiation increased the permeation of oxygen and nutrients through the blood vessel or caused the breakdown of the vasculature. The amount of oxygen in cancer cells affected the response of cancer cells to radiation and the tumor growth rate after irradiation. The lack of oxygen led to the apoptotic death of cancer cells. We calculated the tumor control probability (TCP) at different radiation doses, the probability of apoptotic death, the threshold of the oxygen level for indirect apoptotic death, the average oxygen level in cancer cells and the vessel survival probability after radiation damage. Due to the vessel damage, indirect cell death led to a 4% increase in TCP for the dose ranging from 15 Gy to 20 Gy. TCP increased with increasing the probability of apoptotic death and the threshold of the oxygen level for indirect apoptotic death due to increased apoptotic death. The variation of TCP as a function of the average oxygen level exhibited the minimum at the average oxygen level of 2.7%. The apoptosis increased as the average oxygen level decreased, leading to an increasing TCP. On the other hand, the direct radiation damage increased, and the apoptosis decreased for higher average oxygen level, resulting in a higher TCP. We showed by modeling the radiation damage of blood vessels in a 2D CA simulation that the indirect apoptotic death of cancer cells, caused by the reduction of the oxygen level due to vascular damage after high dose irradiation, increased TCP.