First Demonstration of the FLASH Effect With Ultrahigh Dose-Rate High-Energy X-Rays

Abstract

Purpose/Objective(s)Ultrahigh dose-rate (FLASH) radiotherapy has attracted immense attention because of its tumor control efficiency and healthy tissue protection during preclinical experiments with electrons, kilo-voltage X-rays, and protons. Using high-energy X-rays (HEXs) in FLASH is advantageous owing to its deep penetration, small divergence, and cost-effectiveness. We did this experiment to find out whether PARTER (platform for advanced radiotherapy research) platform built on CTFEL (Chengdu THz Free Electron Laser facility) can trigger FLASH effect.Materials/MethodsSubcutaneous tumor-bearing mice and healthy mice were treated with sham, FLASH, and conventional (CONV) radiotherapy respectively to observe the tumor control and normal tissue damage under different radiation conditions. With a high-current and high-energy superconducting linear accelerator, FLASH with a good dose rate and high penetration was achieved. Breast cancers artificially induced in BAL b/c mice were efficiently controlled, and normal tissues surrounding the thorax/abdomen in C57BL/6 mice were protected from radiation with HEX-FLASH (HEX with FLASH). Theoretical analyses of cellular responses following HEX-FLASH irradiation were performed to interpret the experimental results and design further experiments.ResultsHEX-FLASH was implemented using the superconducting LINAC with the maximum mean dose rate up to over 1000 Gy/s. Tumor-bearing mice experiment showed a good result on tumor control (F = 25.14, P < 0.0001) and significantly different in survival curves (P < 0.005) among the three groups. In the thorax-irradiated healthy mice experiment, there was a statistically significant difference (P = 0.038) in survival among the three groups. The hazard ratio (HR) was 0.19, 95% confidence intervals (CIs) was 0.035–1.010, and P was 0.0486 between the FLASH and CONV groups; therefore, the risk of death decreased by 81% in the FLASH group compared with that in the CONV group. Although the survival time of healthy mice irradiated on abdomen in the FLASH group was undoubtedly higher (62.5 % of mice were still alive when we stopped observation) than that in the CONV group (7 days), the difference in survival between the two groups was not statistically significant (HR 0.369; 95% CI 0.113–1.202; P = 0.0735). Despite this, the survival trend of mice treated with HEX-FLASH radiotherapy was better. We demonstrated theoretical cellular response analysis of the FLASH effect based on the ROD hypothesis and it showed consistent radioprotective effects in normal cells under FLASH irradiation.ConclusionThis study highlights the generation of HEX-FLASH for the first time and its potential in future clinical applications. Ultrahigh dose-rate (FLASH) radiotherapy has attracted immense attention because of its tumor control efficiency and healthy tissue protection during preclinical experiments with electrons, kilo-voltage X-rays, and protons. Using high-energy X-rays (HEXs) in FLASH is advantageous owing to its deep penetration, small divergence, and cost-effectiveness. We did this experiment to find out whether PARTER (platform for advanced radiotherapy research) platform built on CTFEL (Chengdu THz Free Electron Laser facility) can trigger FLASH effect. Subcutaneous tumor-bearing mice and healthy mice were treated with sham, FLASH, and conventional (CONV) radiotherapy respectively to observe the tumor control and normal tissue damage under different radiation conditions. With a high-current and high-energy superconducting linear accelerator, FLASH with a good dose rate and high penetration was achieved. Breast cancers artificially induced in BAL b/c mice were efficiently controlled, and normal tissues surrounding the thorax/abdomen in C57BL/6 mice were protected from radiation with HEX-FLASH (HEX with FLASH). Theoretical analyses of cellular responses following HEX-FLASH irradiation were performed to interpret the experimental results and design further experiments. HEX-FLASH was implemented using the superconducting LINAC with the maximum mean dose rate up to over 1000 Gy/s. Tumor-bearing mice experiment showed a good result on tumor control (F = 25.14, P < 0.0001) and significantly different in survival curves (P < 0.005) among the three groups. In the thorax-irradiated healthy mice experiment, there was a statistically significant difference (P = 0.038) in survival among the three groups. The hazard ratio (HR) was 0.19, 95% confidence intervals (CIs) was 0.035–1.010, and P was 0.0486 between the FLASH and CONV groups; therefore, the risk of death decreased by 81% in the FLASH group compared with that in the CONV group. Although the survival time of healthy mice irradiated on abdomen in the FLASH group was undoubtedly higher (62.5 % of mice were still alive when we stopped observation) than that in the CONV group (7 days), the difference in survival between the two groups was not statistically significant (HR 0.369; 95% CI 0.113–1.202; P = 0.0735). Despite this, the survival trend of mice treated with HEX-FLASH radiotherapy was better. We demonstrated theoretical cellular response analysis of the FLASH effect based on the ROD hypothesis and it showed consistent radioprotective effects in normal cells under FLASH irradiation. This study highlights the generation of HEX-FLASH for the first time and its potential in future clinical applications.