It is well known that molecular oxygen is a product of the radiolysis of water with high-linear energy transfer (LET) radiation, which is distinct from low-LET radiation wherein O₂ radiolytic yield is negligible. Since O₂ is a powerful radiosensitizer, this fact is of practical relevance in cancer therapy with energetic heavy ions, such as carbon ions. It has recently been discovered that large doses of ionizing radiation delivered to tumors at very high dose rates (i.e., in a few milliseconds) have remarkable benefits in sparing healthy tissue while preserving anti-tumor activity compared to radiotherapy delivered at conventional, lower dose rates. This new method is called “FLASH radiotherapy” and has been tested using low-LET radiation (i.e., electrons and photons) in various pre-clinical studies and recently in a human patient. Although the exact mechanism(s) underlying FLASH are still unclear, it has been suggested that radiation delivered at high dose rates spares normal tissue via oxygen depletion. In addition, heavy-ion radiation achieves tumor control with reduced normal tissue toxicity due to its favorable physical depth-dose profile and increased radiobiological effectiveness in the Bragg peak region. To date, however, biological research with energetic heavy ions delivered at ultra-high dose rates has not been performed and it is not known whether heavy ions are suitable for FLASH radiotherapy. Here we present the additive or even synergistic advantages of integrating the FLASH dose rates into carbon-ion therapy. These benefits result from the ability of heavy ions at high LET to generate an oxygenated microenvironment around their track due to the occurrence of multiple (mainly double) ionization of water. This oxygen is abundant immediately in the tumor region where the LET of the carbon ions is very high, near the end of the carbon-ion path (i.e., in the Bragg peak region). In contrast, in the “plateau” region of the depth-dose distribution of ions (i.e., in the normal tissue region), in which the LET is significantly lower, this generation of molecular oxygen is insignificant. Under FLASH irradiation, it is shown that this early generation of O₂ extends evenly over the entire irradiated tumor volume, with concentrations estimated to be several orders of magnitude higher than the oxygen levels present in hypoxic tumor cells. Theoretically, these results indicate that FLASH radiotherapy using carbon ions would have a markedly improved therapeutic ratio with greater toxicity in the tumor due to the generation of oxygen at the spread-out Bragg peak.

众所周知，分子氧是水与高线性能量转移（LET）辐射的水解产物，不同于低LET辐射，其中O _2的辐射分解率可忽略不计。由于O ₂是一种强大的放射增敏剂，这一事实在使用高能重离子（例如碳离子）的癌症治疗中具有实际意义。最近发现，与以传统的较低剂量率递送的放射疗法相比，以非常高的剂量率（即几毫秒）递送给肿瘤的大剂量电离辐射在节省健康组织的同时，在保留抗肿瘤活性的同时具有显着的益处。 。这种新方法称为“ FLASH放射疗法”，并已在各种临床前研究以及最近在人类患者中使用低LET辐射（即电子和光子）进行了测试。尽管仍不清楚FLASH的确切机制，但已建议以高剂量率递送的辐射可通过耗氧来节省正常组织。此外，重离子辐射由于其良好的物理深度-剂量分布以及在布拉格峰区域的放射生物学有效性提高而实现了对肿瘤的控制，同时降低了正常组织的毒性。然而，迄今为止，尚未进行以超高剂量率递送高能重离子的生物学研究，并且尚不清楚重离子是否适合于FLASH放射疗法。在这里，我们介绍了将FLASH剂量率整合到碳离子治疗中的累加甚至协同优势。这些好处归因于高LET下重离子在水的轨迹周围产生多次（主要是两次）电离的能力，从而在其轨道周围产生氧化的微环境。该氧立即在碳离子路径的末端附近（即碳离子路径的末端）非常高的肿瘤区域富集（即 ，在布拉格峰区域）。相反，在离子的深度剂量分布的“高原”区域（即在正常组织区域）（其中LET显着较低），这种分子氧的产生是微不足道的。在FLASH照射下，表明这种早期的O₂均匀地分布在整个被照射的肿瘤体积上，其浓度估计比缺氧肿瘤细胞中的氧气含量高几个数量级。从理论上讲，这些结果表明，由于在扩散的布拉格峰处产生了氧气，使用碳离子的FLASH放射疗法将具有显着改善的治疗率，并且在肿瘤中具有更大的毒性。