Dose Heterogeneity Reduces Radiation Oxygen Dependence in Both Tumor and Healthy Tissues: The Case of Proton Minibeam Radiation Therapy.

PURPOSE: Proton minibeam radiation therapy (pMBRT) is an innovative delivery technique characterized by spatially modulated radiation. It was shown to increase the therapeutic index in preclinical glioma models by reducing toxicities while maintaining or even increasing tumor control. Moreover, pMBRT leads to differential immunomodulatory effects. Both dosimetry and radiobiology diverge from classical concepts. We hypothesize that the distinct mechanisms and characteristics of pMBRT could reduce the oxygen dependence of radiation tissue response.

METHODS AND MATERIALS: To address this question, in this study, glioblastoma-bearing and naïve animals were irradiated with different oxygen supplementation concentrations with a single fraction of pMBRT or conventional proton therapy (CPT) at an average dose of 25 Gy. The differential effects of blood oxygenation were assessed by analyzing immune response, survival capability, and histopathological changes in brain and bone tissues. The tumor's hypoxic nature was confirmed by hypoxia inducible factor-1α staining before irradiation.

RESULTS

Our results revealed no significant influence of oxygen supplementation on survival outcomes or immune infiltration after pMBRT. These findings contrast with CPT, where oxygen supplementation was detrimental to immune infiltration but improved survival probability. Also, no significant brain or bone tissue alterations have been observed after pMBRT, regardless of blood oxygenation levels during irradiation. These differences highlight the distinct radiobiological effects of pMBRT and its potential to bypass the classical oxygen dependency observed in CPT and conventional radiation therapy.

CONCLUSIONS

The distinct radiobiological effects of pMBRT have the potential to bypass the classical oxygen dependency. Thus, pMBRT could be beneficial for the treatment of hypoxic tumors.