Département de Médecine Nucléaire et de Radiobiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Canada.
Rutgers Biomedical and Health Sciences, New Jersey Medical School, Department of Radiology, Newark, New Jersey.
Radiat Res. 2020 Dec 1;194(6):587-593. doi: 10.1667/RADE-19-00015.1.
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,分子氧是具有高线性能量转移(LET)辐射的水辐射分解的产物,这与低 LET 辐射明显不同,后者的 O2 辐射分解产率可以忽略不计。由于 O2 是一种强大的放射增敏剂,因此对于使用诸如碳离子等高能重离子进行癌症治疗,这一事实具有实际意义。最近发现,以非常高的剂量率(即几毫秒内)向肿瘤递送大剂量的电离辐射,与以常规的低剂量率进行的放射治疗相比,在保护健康组织的同时保留抗肿瘤活性方面具有显著的益处。这种新方法称为“FLASH 放射治疗”,已在各种临床前研究中使用低 LET 辐射(即电子和光子)进行了测试,并最近在人类患者中进行了测试。尽管 FLASH 的确切机制尚不清楚,但有人认为,以高剂量率递送的辐射通过耗氧来保护正常组织。此外,由于其有利的物理深度剂量分布和布拉格峰区域内增加的放射生物学效应,重离子辐射可实现肿瘤控制,同时减少正常组织毒性。然而,迄今为止,尚未进行高能重离子以超高剂量率递送的生物学研究,也不知道重离子是否适合 FLASH 放射治疗。在这里,我们提出了将 FLASH 剂量率整合到碳离子治疗中的附加甚至协同优势。这些好处源自重离子在高 LET 下由于水的多次(主要是双)电离而在其轨迹周围产生含氧微环境的能力。这种氧在碳离子 LET 非常高的肿瘤区域中立即大量存在,就在碳离子路径的末端(即布拉格峰区域)。相比之下,在离子深度剂量分布的“平台”区域(即正常组织区域)中,这种分子氧的产生微不足道。在 FLASH 照射下,结果表明,这种早期产生的 O2 均匀地扩展到整个受照射的肿瘤体积中,浓度估计比缺氧肿瘤细胞中存在的氧水平高几个数量级。从理论上讲,这些结果表明,由于在扩展的布拉格峰处产生氧,使用碳离子进行 FLASH 放射治疗将具有明显改善的治疗比,并且肿瘤中的毒性更大。