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Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice

Pulsed, ultrahigh dose-rate irradiation is safer than standard radiotherapy for the treatment of lung cancer and selectively spares normal tissue. Safer Radiation for the Lung Radiation is used to treat a variety of tumor types, including lung cancer. Unfortunately, radiation-induced damage to the surrounding healthy lung is a major problem, which can cause long-term complications and limits the amount of radiation that can be safely delivered to the tumor. Favaudon et al. now present a technology called FLASH, which allows the delivery of pulsed, ultrahigh dose-rate irradiation, which causes less damage to the healthy lung than conventional radiotherapy in mouse models. The authors confirmed that FLASH is effective against tumor cells but causes little damage to normal tissue. These results suggest that FLASH radiation may be a viable option for treating lung tumors, although this will need to be confirmed in human patients. In vitro studies suggested that sub-millisecond pulses of radiation elicit less genomic instability than continuous, protracted irradiation at the same total dose. To determine the potential of ultrahigh dose-rate irradiation in radiotherapy, we investigated lung fibrogenesis in C57BL/6J mice exposed either to short pulses (≤500 ms) of radiation delivered at ultrahigh dose rate (≥40 Gy/s, FLASH) or to conventional dose-rate irradiation (≤0.03 Gy/s, CONV) in single doses. The growth of human HBCx-12A and HEp-2 tumor xenografts in nude mice and syngeneic TC-1 Luc+ orthotopic lung tumors in C57BL/6J mice was monitored under similar radiation conditions. CONV (15 Gy) triggered lung fibrosis associated with activation of the TGF-β (transforming growth factor–β) cascade, whereas no complications developed after doses of FLASH below 20 Gy for more than 36 weeks after irradiation. FLASH irradiation also spared normal smooth muscle and epithelial cells from acute radiation-induced apoptosis, which could be reinduced by administration of systemic TNF-α (tumor necrosis factor–α) before irradiation. In contrast, FLASH was as efficient as CONV in the repression of tumor growth. Together, these results suggest that FLASH radiotherapy might allow complete eradication of lung tumors and reduce the occurrence and severity of early and late complications affecting normal tissue.