Radiobiology of Stereotactic Ablative Radiation Therapy

Stereotactic ablative radiotherapy (SABR) not only directly kills tumor cells through DNA damage but also causes indirect cell deaths via destruction of vascular networks in the tumors. Growing evidence demonstrates that the indirect tumor cell death secondary to the vascular damage accounts for the high efficacy of SABR in causing local control of tumors. Unfortunately, the radiation-induced vascular damages and the resultant increases in tumor hypoxia upregulate HIF-1α expression in the tumors, which in turn promotes the survival and proliferation of the residual hypoxic tumor cells leading to recurrence and metastasis. High-dose radiation per fraction has been shown to cause massive release of tumor antigens and cytokines and promotes the downstream immune pathways leading to immunogenic killing of target tumor cells. On the other hand, the upregulation of HIF-1α in the intratumor microenvironment invokes wide array of immunosuppressive reactions, thereby counterbalancing the aforementioned radiation-induced increases in the antitumor immune responses. Therefore, at present, the contribution of antitumor immunity to the outcome of SABR is still obscure. Nevertheless, boosting the antitumor immunity with immunotherapy may improve the efficacy of SABR. The roles of 5Rs in SABR are dependent on the radiation dose delivered to the tumors and HIF-1α expression due to vascular damage. The repopulation of tumor cells is greatly affected by revascularization mediated by HIF-1α. The reoxygenation rate of hypoxic ells is directly dependent on the radiation dose, with increasing radiation dose causing faster reoxygenation. Extremely high-dose radiation completely halts the cell cycle progression leading to interphase cell death. LQ model cannot precisely predict the outcome of SABR treatment.