Session Item

Preclinical studies indicate a normal tissue sparing effect using ultra-high dose rate (FLASH) radiation with comparable tumor response. This differential response is promising in order to obtain improved clinical outcome. We have previously conducted an in vivo study validating the effect of PBS proton FLASH on acute skin toxicity, and demonstrated that a 44-58% higher dose was needed to obtain the same biological response when using proton FLASH. The aim of the present study was to use the same model to investigate the biological effect of introducing short pauses in the dose delivery, emulating a clinical situation with FLASH delivery with multiple treatment fields.

The right hind limbs of non-anaesthetized CDF1 mice were irradiated in the entrance plateau of a scanning proton pencil beam. The delivered fields were 2cm x 3cm to ensure a homogeneous dose across the whole mouse leg. The irradiation dose was 39.3Gy using field dose rates of 60Gy/s for FLASH and 0.4Gy/s for conventional delivery (CONV). The FLASH dose was given either as a single delivery or split into 2, 3, 4 or 6 identical deliveries with 2 minutes pauses between each delivery. For example, splitting into 2 deliveries meant 19.65Gy followed by a pause of 2 minutes followed by 19.65Gy with the same field (100% overlap of the fields). The CONV dose was given in either 1 or 6 deliveries with 2 minutes pauses. 9-11 mice were included in each treatment group. The endpoints were different levels of skin toxicity within 25 days post irradiation. Statistical significance between FLASH and CONV groups (for 1 and 6 deliveries) were calculated with Fisher´s exact test.

For CONV, all mice displayed skin toxicity at all levels when irradiated with 39.9Gy in one delivery, and that was unaltered by splitting the dose into 6 deliveries (Fig 1). For FLASH, delivering the dose unsplit revealed comparable outcome to previously published data with no animals displaying moderate or severe damage (score 2.5-3, Fig 1). The reduced toxicity for FLASH with 1 delivery relative to CONV was significant for score 2.0 (p <0.001), score 2.5 (p <0.0001) and score 3.0 (p <0.0001). Splitting the FLASH dose into 2 deliveries reduced the FLASH effect, but the normal tissue sparing effect was still observed comparing to CONV. For 3 or more deliveries, the FLASH effect was almost abolished for lower grades of acute toxicity. With 6 deliveries, the toxicity for FLASH relative to CONV was not significant for any of the scores (p>2 – p>0.99).

Splitting the total dose into more deliveries with 2 minutes in between reduced the observed normal tissue sparing of FLASH compared to a single delivery. Clinically this can have an impact for regions where two or more FLASH fields overlap within same treatment session. It should be taken into consideration for FLASH treatment planning and design of clinical trials.