FLASH irradiation, an emerging cancer treatment that delivers radiation at ultrahigh dose rates, has been shown to significantly reduce acute skin toxicity in laboratory mice compared with conventional radiotherapy. Having demonstrated this effect using proton-based FLASH treatments, researchers from Aarhus University in Denmark have now repeated their investigations using electron-based FLASH (eFLASH).
Reporting their findings in Radiotherapy and Oncology, the researchers note a “remarkable similarity” between eFLASH and proton FLASH with respect to acute skin sparing.
Principal investigator Brita Singers Sørensen and colleagues quantified the dose–response modification of eFLASH irradiation for acute skin toxicity and late fibrotic toxicity in mice, using similar experimental designs to those previously employed for their proton FLASH study. This enabled the researchers to make direct quantitative comparisons of acute skin response between electrons and protons. They also compared the effectiveness of the two modalities to determine whether radiobiological differences were observed.
Over four months, the team examined 197 female mice across five irradiation experiments. After being weighed, earmarked and given an ID number, each mouse was randomized to receive either eFLASH irradiation (average dose rate of 233 Gy/s) or conventional electron radiotherapy (average dose rate of 0.162 Gy/s) at various doses.
For the treatment, two unanaesthetized mice (one from each group) were restrained in a jig with their right legs placed in a water bath and irradiated by a horizontal 16 MeV electron beam. The animals were placed on opposite sides of the field centre and irradiated simultaneously, with their legs at a 3.2 cm water-equivalent depth, corresponding to the dose maximum.
The researchers used a diamond detector to measure the absolute dose at the target position in the water bath and assumed that the mouse foot target received the same dose. The resulting foot doses were 19.2–57.6 Gy for eFLASH treatments and 19.4–43.7 Gy for conventional radiotherapy, chosen to cover the entire range of acute skin response.
FLASH confers skin protection
To evaluate the animals’ response to irradiation, the researchers assessed acute skin damage daily from seven to 28 days post-irradiation using an established assay. They weighed the mice weekly, and one of three observers blinded to previous grades and treatment regimens assessed skin toxicity. Photographs were taken whenever possible. Skin damage was also graded using an automated deep-learning model, generating a dose–response curve independent of observer assessments.
The researchers also assessed radiation-induced fibrosis in the leg joint, biweekly from weeks nine to 52 post-irradiation. They defined radiation-induced fibrosis as a permanent reduction of leg extensibility by 75% or more in the irradiated leg compared with the untreated left leg.
To assess the tissue-sparing effect of eFLASH, the researchers used dose–response curves to derive TD50 – the toxic dose eliciting a skin response in 50% of mice. They then determined a dose modification factor (DMF), defined as the ratio of eFLASH TD50 to conventional TD50. A DMF larger than one suggests that eFLASH reduces toxicity.
The eFLASH treatments had a DMF of 1.45–1.54 – in other words, a 45–54% higher dose was needed to cause comparable skin toxicity to that caused by conventional radiotherapy. “The DMF indicated a considerable acute skin sparing effect of eFLASH irradiation,” the team explain. Radiation-induced fibrosis was also reduced using eFLASH, with a DMF of 1.15.
For DMF-based equivalent doses, the development of skin toxicity over time was similar for eFLASH and conventional treatments, throughout the dose groups. This supports the hypothesis that eFLASH modifies the dose–response rather than causing a changed biological mechanism. The team also suggests that the difference in DMF seen for fibrotic response and acute skin damage suggests that FLASH sparing depends on tissue type and might be specific to acute and late-responding tissue.
Similar skin damage between electrons and protons
Sørensen and colleagues compared their findings to previous studies of normal-tissue damage from proton irradiation, both in the entrance plateau and using the spread-out Bragg peak (SOBP). DMF values for electrons (1.45–1.54) were similar to those of transmission protons (1.44–1.50) and slightly higher than for SOBP protons (1.35–1.40). “Despite dose rate and pulse structure differences, the response to electron irradiation showed substantial similarity to transmission and SOBP damage,” they write.
Although the average eFLASH dose rate (233 Gy/s) was higher than that of the proton studies (80 and 60 Gy/s), it did not appear to influence the biological response. This supports the hypothesis that beyond a certain dose rate threshold, the tissue-sparing effect of FLASH does not increase notably.
The researchers point out that previous studies also found biological similarities in the FLASH effect for electrons and protons, with this latest work adding data on similar comparable and quantifiable effects. They add, however, that “based on the data of this study alone, we cannot say that the biological response is identical, nor that the electron and proton irradiation elicit the same biological mechanisms for DNA damage and repair. This data only suggests a similar biological response in the skin.”
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