Indirect Tumor Cell Death After High-Dose Hypofractionated Irradiation: Implications for Stereotactic Body Radiation Therapy and Stereotactic Radiation Surgery

Abstract

Summary In experimental mouse tumors, high-dose irradiation in a single fraction caused progressive increase in tumor cell death in 2 to 5 days. Such delayed tumor cell deaths appeared to be due to radiation-induced deterioration of intratumor microenvironment characterized by profound reduction of blood perfusion and increase in hypoxia. Similar secondary and indirect cell death may play an important role in clinical stereotactic body radiation therapy and stereotactic radiation surgery. Purpose The purpose of this study was to reveal the biological mechanisms underlying stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS). Methods and Materials FSaII fibrosarcomas grown subcutaneously in the hind limbs of C3H mice were irradiated with 10 to 30 Gy of X rays in a single fraction, and the clonogenic cell survival was determined with in vivo—in vitro excision assay immediately or 2 to 5 days after irradiation. The effects of radiation on the intratumor microenvironment were studied using immunohistochemical methods. Results After cells were irradiated with 15 or 20 Gy, cell survival in FSaII tumors declined for 2 to 3 days and began to recover thereafter in some but not all tumors. After irradiation with 30 Gy, cell survival declined continuously for 5 days. Cell survival in some tumors 5 days after 20 to 30 Gy irradiation was 2 to 3 logs less than that immediately after irradiation. Irradiation with 20 Gy markedly reduced blood perfusion, upregulated HIF-1α, and increased carbonic anhydrase-9 expression, indicating that irradiation increased tumor hypoxia. In addition, expression of VEGF also increased in the tumor tissue after 20 Gy irradiation, probably due to the increase in HIF-1α activity. Conclusions Irradiation of FSaII tumors with 15 to 30 Gy in a single dose caused dose-dependent secondary cell death, most likely by causing vascular damage accompanied by deterioration of intratumor microenvironment. Such indirect tumor cell death may play a crucial role in the control of human tumors with SBRT and SRS.

The changing paradigm of tumour response to irradiation

“…[59][60][61] Recent studies have suggested that this may be an important factor in the response of tumours to SBRT. 62 These observations are consistent with the concept that acutely hypoxic cells and/or the larger number of cells that are partially resistant to irradiation due to being at intermediate oxygen levels in tumours may in fact represent a more important population of cells relevant to tumour control effected by standard fractionated radiation therapy rather than the most hypoxic cell populations. 63 However, despite the overwhelming data that many tumours contain hypoxic cells and the findings that levels of hypoxia in various tumour types are predictive of treatment outcome, approaches to addressing this issue in radiation therapy treatment of patients have had only limited success.…”

Developing oxygen-enhanced magnetic resonance imaging as a prognostic biomarker of radiation response

“…A significant increase in tumor oxygenation was observed by 19 F MRI in Dunning prostate AT1 tumors up to 10 hours after 20 Gy irradiation [50] and by EPR in RIF-1 tumors, 72–120 hours after 20 Gy [24]. Meanwhile, a recent study in FSaII tumors demonstrated secondary cell death, based on clonogenic survival assays 2–5 days, after 20 Gy, attributed to by vascular damage, which was accompanied by a significant increase in hypoxic markers [55]. As levels of hypoxia and response are expected to vary with radiation dose, tumor type, host species and method of anesthesia the need for further investigations is obvious.…”

The radiosurgery fractionation quandary: single fraction or hypofractionation?

“…[8][9][10] Some argue that the linear-quadratic model provides an adequate representation of the doseresponse relationship at high doses and that observed clinical outcomes are entirely consistent with the predictions of this model. [11][12][13] Others assert that radiobiologic mechanisms, such as profound vascular damage 14,15 and antigen expression, different from classic DNA damage, are evoked above a threshold dose of [8][9][10][11][12] Gy and that the high levels of tumor control observed in radiosurgery reflect this "new radiobiology" and enhanced dose-response 13,[16][17][18] Fig. 2).…”