Ultra-high dose rate carbon-ion irradiation does not preferentially spare normal tissue in the gastrointestinal tract

Increasing evidence of the great normal tissue sparing effect in ultra-high dose-rate (UHDR) irradiation points to the potential for improving the therapeutic ratio. However, limited accumulation of data still prevents further understanding of the normal tissue sparing effect mechanism and its subsequent clinical translation.

This study aimed to be the first to provide in vivo data for intestinal toxicity in UHDR carbon-ion irradiation.

The abdominal part of eight week old C3H/HeSlc female mice was locally irradiated at an entrance region of 400-MeV/u monoenergetic carbon-ion beams either with a conventional dose rate (CONV) or UHDR. The CONV and UHDR irradiations had mean dose rates (MDRs) of ∼0.3 Gy/s and ∼96 Gy/s, respectively. Multiple dose levels (12-18 Gy) were used under the dedicated dosimetry system for UHDR irradiation. Acute intestinal toxicity was evaluated by monitoring the survival of 96 irradiated mice for 30 days post-irradiation. To investigate the influence of dose rate on intestinal crypts, CONV, and UHDR irradiations were conducted for an additional six mice for each. These mice were autopsied 6 or 84 h after irradiation along with two non-irradiated mice and their immunohistochemically stained intestines were used to count the apoptotic cells in crypts or regenerating crypts.

Survival fractions of mice were comparable for both dose rates. At the sub-lethal dose, 14 Gy, normal tissue complication probabilities (NTCPs) for the endpoint of survival were 0.78 and 0.89 for CONV and UHDR irradiations, respectively. The 13 Gy dose resulted in NTCP of 0.11 for both dose rates. Doses leading to 50% NTCP were 13.6 and 13.5 Gy for CONV and UHDR irradiations, respectively, which produced a dose modifying factor of 1.008. The percentages of apoptotic crypts at 6 h post-irradiation were 36% for CONV and 34% for UHDR irradiations, showing a small difference (p = 0.782). The percentages of remaining crypts at 84 h post-irradiation were 7.9% for CONV and 5.8% for UHDR irradiations (p = 0.214), indicating a slightly worse result for UHDR irradiation, albeit without statistical significance.

The intestinal toxicity in UHDR carbon-ion irradiation was investigated for the first time. UHDR carbon-ion irradiation did not produce a substantial sparing effect for intestinal toxicity at least under the beam conditions tested here, i.e., a 400-MeV/u carbon-ion beam at an MDR of ∼96 Gy/s. Additional experiments with different endpoints and beam conditions are mandatory to assess the potential of FLASH carbon-ion therapy.