Danish Centre for Particle Therapy, Aarhus University Hospital, Denmark; Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark.
Danish Centre for Particle Therapy, Aarhus University Hospital, Denmark.
Radiother Oncol. 2022 Oct;175:178-184. doi: 10.1016/j.radonc.2022.05.014. Epub 2022 May 17.
Preclinical studies indicate a normal tissue sparing effect when ultra-high dose rate (FLASH) radiation is used, while tumor response is maintained. This differential response has promising perspectives for improved clinical outcome. This study investigates tumor control and normal tissue toxicity of pencil beam scanning (PBS) proton FLASH in a mouse model.
Tumor bearing hind limbs of non-anaesthetized CDF1 mice were irradiated in a single fraction with a PBS proton beam using either conventional (CONV) dose rate (0.33-0.63 Gy/s field dose rate, 244 MeV) or FLASH (71-89 Gy/s field dose rate, 250 MeV). 162 mice with a C3H mouse mammary carcinoma subcutaneously implanted in the foot were irradiated with physical doses of 40-60 Gy (8-14 mice per dose point). The endpoints were tumor control (TC) assessed as no recurrent tumor at 90 days after treatment, the level of acute moist desquamation (MD) to the skin of the foot within 25 days post irradiation, and radiation induced fibrosis (RIF) within 24 weeks post irradiation.
TCD (dose for 50% tumor control) was similar for CONV and FLASH with values (and 95% confidence intervals) of 49.1 (47.0-51.4) Gy for CONV and 51.3 (48.6-54.2) Gy for FLASH. RIF analysis was restricted to mice with tumor control. Both endpoints showed distinct normal tissue sparing effect of proton FLASH with MDD (dose for 50% of mice displaying moist desquamation) of <40.1 Gy for CONV and 52.3 (50.0-54.6) Gy for FLASH, (dose modifying factor at least 1.3) and FD (dose for 50% of mice displaying fibrosis) of 48.6 (43.2-50.8) Gy for CONV and 55.6 (52.5-60.1) Gy for FLASH (dose modifying factor of 1.14).
FLASH had the same tumor control as CONV, but reduced normal tissue damage assessed as acute skin damage and radiation induced fibrosis.
临床前研究表明，超高速率（FLASH）放射时正常组织具有保护作用，而肿瘤反应得以维持。这种差异反应为改善临床结果提供了有前景的思路。本研究在小鼠模型中研究了笔束扫描（PBS）质子 FLASH 的肿瘤控制和正常组织毒性。
在单次照射中，使用 PBS 质子束以常规（CONV）剂量率（0.33-0.63 Gy/s 场剂量率，244 MeV）或 FLASH（71-89 Gy/s 场剂量率，250 MeV）对未麻醉的 CDF1 小鼠的荷瘤后肢进行照射。将 162 只皮下植入 C3H 小鼠乳腺肿瘤的小鼠用 40-60 Gy 的物理剂量照射（每个剂量点 8-14 只小鼠）。终点是肿瘤控制（TC），定义为治疗后 90 天无复发性肿瘤；照射后 25 天内足部皮肤的急性湿性脱皮（MD）水平；照射后 24 周内的放射性纤维化（RIF）。
CONV 和 FLASH 的 TCD（肿瘤控制剂量）相似，分别为 49.1（47.0-51.4）Gy 和 51.3（48.6-54.2）Gy。RIF 分析仅限于肿瘤控制的小鼠。两个终点均显示质子 FLASH 具有明显的正常组织保护作用，CONV 的 MDD（出现湿性脱皮的 50%小鼠的剂量）为<40.1 Gy，FLASH 的 MDD 为 52.3（50.0-54.6）Gy（剂量修正因子至少为 1.3），FD（出现纤维化的 50%小鼠的剂量）为 48.6（43.2-50.8）Gy 对于 CONV 和 55.6（52.5-60.1）Gy 对于 FLASH（剂量修正因子为 1.14）。
FLASH 的肿瘤控制与 CONV 相同，但急性皮肤损伤和放射性纤维化的正常组织损伤减少。
