Historical Review of the Role of Indirect Cell Death in High-Dose Per Fraction Radiation Therapy.

Purpose: This study aims to elaborate and further establish that indirect cell death secondary to vascular injury and stimulation of antitumor immunity plays a role in the tumor response to high-dose per fraction radiation therapy. Methods and Materials: We reviewed literature available from the National Library of Medicine on the indirect death of tumor cells caused by high-dose per fraction irradiation in experimental tumors and human tumors. We then examined the implications of indirect/additional cell death in applying the LQ (Linear Quadratic) model for high-dose per fraction radiation therapy of human tumors. Results: We found that numerous preclinical and clinical studies reported over the last 100 years clearly indicated that high-dose per fraction radiation therapy induces indirect tumor cell death by causing vascular damage and stimulating the immune system to varying degrees. On the other hand, a handful of studies have been reported that failed to observe significant indirect tumor cell death after high-dose per fraction irradiation. The LQ and associated models may be applicable to certain clinical situations, yet the inherent flaw of the LQ model overestimating cell death as the fraction dose increases is likely accommodated by the additional amount of indirect tumor cell death that occurs at these higher doses. Furthermore, the indirect effects of immune system stimulation are not accounted for by the LQ or other models. Conclusions: Indirect tumor cell death due to tumor vascular injury from radiation exposure has been observed over the last ∼100 years. Vascular damage as well as stimulation of antitumor immunity contribute significantly to the response of tumors to many, if not all, high-dose per fraction radiation therapy regimens.