Tumor hypoxia and radiotherapy: A major driver of resistance even for novel radiotherapy modalities

Hypoxia in solid tumors is an important predictor of poor clinical outcome to radiotherapy. Both physicochemical and biological processes contribute to a reduced sensitivity of hypoxic tumor cells to ionizing radiation and hypoxia-related treatment resistances. A conventional low-dose fractionated radiotherapy regimen exploits iterative reoxygenation in between the individual fractions, nevertheless tumor hypoxia still remains a major hurdle for successful treatment outcome. The technological advances achieved in image guidance and highly conformal dose delivery make it nowadays possible to prescribe larger doses to the tumor as part of single high-dose or hypofractionated radiotherapy, while keeping an acceptable level of normal tissue complication in the co-irradiated organs at risk. However, we insufficiently understand the impact of tumor hypoxia to single high-doses of RT and hypofractionated RT. So-called FLASH radiotherapy, which delivers ionizing radiation at ultrahigh dose rates (> 40 Gy/sec), has recently emerged as an important breakthrough in the radiotherapy field to reduce normal tissue toxicity compared to irradiation at conventional dose rates (few Gy/min). Not surprisingly, oxygen consumption and tumor hypoxia also seem to play an intriguing role for FLASH radiotherapy. Here we will discuss the role of tumor hypoxia for radiotherapy in general and in the context of novel radiotherapy treatment approaches.