Purpose: Previous studies using FLASH radiotherapy (RT) in mice showed a marked increase of the differential effect between normal tissue and tumors. To stimulate clinical transfer, we evaluated whether this effect could also occur in higher mammals.Experimental Design: Pig skin was used to investigate a potential difference in toxicity between irradiation delivered at an ultrahigh dose rate called “FLASH-RT” and irradiation delivered at a conventional dose rate called “Conv-RT.” A clinical, phase I, single-dose escalation trial (25–41 Gy) was performed in 6 cat patients with locally advanced T2/T3N0M0 squamous cell carcinoma of the nasal planum to determine the maximal tolerated dose and progression-free survival (PFS) of single-dose FLASH-RT.Results: Using, respectively, depilation and fibronecrosis as acute and late endpoints, a protective effect of FLASH-RT was observed (≥20% dose-equivalent difference vs. Conv-RT). Three cats experienced no acute toxicity, whereas 3 exhibited moderate/mild transient mucositis, and all cats had depilation. With a median follow-up of 13.5 months, the PFS at 16 months was 84%.Conclusions: Our results confirmed the potential advantage of FLASH-RT and provide a strong rationale for further evaluating FLASH-RT in human patients.See related commentary by Harrington, p. 3

Significance: Ultra-high dose-rate (≥100 Gy⋅s ⁻¹ ) irradiation, termed FLASH radiotherapy, affords some remarkable (if not unexpected) normal tissue sparing in the irradiated brain when compared with conventional dose rates (0.07–0.1 Gy⋅s ⁻¹ ) used in clinical practice. Radiation-induced neurocognitive deficits, persistent neuroinflammation, and the structural degradation of mature neurons, typical of conventional dose-rate exposures, were resolved significantly in a preclinical mouse model exposed to FLASH radiotherapy. These benefits persisted over a 6-mon postirradiation interval and were caused, in part, by a mechanism involving reduced reactive oxygen species. Since normal tissue injury during and following radiotherapy dictates the maximum tolerated dose, the capability to ameliorate these adverse side effects holds significant promise for improving therapeutic outcome for cancer survivors worldwide.

Radiotherapy is a cornerstone of both curative and palliative cancer care. However, radiotherapy is severely limited by radiation-induced toxicities. If these toxicities could be reduced, a greater dose of radiation could be given therefore facilitating a better tumor response. Initial pre-clinical studies have shown that irradiation at dose rates far exceeding those currently used in clinical contexts reduce radiation-induced toxicities whilst maintaining an equivalent tumor response. This is known as the FLASH effect. To date, a single patient has been subjected to FLASH radiotherapy for the treatment of subcutaneous T-cell lymphoma resulting in complete response and minimal toxicities. The mechanism responsible for reduced tissue toxicity following FLASH radiotherapy is yet to be elucidated, but the most prominent hypothesis so far proposed is that acute oxygen depletion occurs within the irradiated tissue. This review examines the tissue response to FLASH radiotherapy, critically evaluates the evidence supporting hypotheses surrounding the biological basis of the FLASH effect, and considers the potential for FLASH radiotherapy to be translated into clinical contexts.

Objective: Recent in vivo results have shown prominent tissue sparing effect of radiotherapy with ultra-high dose rates (FLASH) compared to conventional dose rates (CONV). Oxygen depletion has been proposed as the underlying mechanism, but in vitro data to support this have been lacking. The aim of the current study was to compare FLASH to CONV irradiation under different oxygen concentrations in vitro. Methods: Prostate cancer cells were irradiated at different oxygen concentrations (relative partial pressure ranging between 1.6 and 20%) with a 10 MeV electron beam at a dose rate of either 600 Gy/s (FLASH) or 14 Gy/min (CONV), using a modified clinical linear accelerator. We evaluated the surviving fraction of cells using clonogenic assays after irradiation with doses ranging from 0 to 25 Gy. Results: Under normoxic conditions, no differences between FLASH and CONV irradiation were found. For hypoxic cells (1.6%), the radiation response was similar up to a dose of about 5–10 Gy, above which increased survival was shown for FLASH compared to CONV irradiation. The increased survival was shown to be significant at 18 Gy, and the effect was shown to depend on oxygen concentration. Conclusion: The in vitro FLASH effect depends on oxygen concentration. Further studies to characterize and optimize the use of FLASH in order to widen the therapeutic window are indicated. Advances in knowledge: This paper shows in vitro evidence for the role of oxygen concentration underlying the difference between FLASH and CONV irradiation.