Laboratory of Radiation Oncology/DO/Radio-Oncology/CHUV, Lausanne University Hospital and University of Lausanne, Switzerland.
Department of Radiation Oncology, University of California, Irvine, California.
Clin Cancer Res. 2021 Feb 1;27(3):775-784. doi: 10.1158/1078-0432.CCR-20-0894. Epub 2020 Oct 15.
Recent data have shown that single-fraction irradiation delivered to the whole brain in less than tenths of a second using FLASH radiotherapy (FLASH-RT), does not elicit neurocognitive deficits in mice. This observation has important clinical implications for the management of invasive and treatment-resistant brain tumors that involves relatively large irradiation volumes with high cytotoxic doses.
Therefore, we aimed at simultaneously investigating the antitumor efficacy and neuroprotective benefits of FLASH-RT 1-month after exposure, using a well-characterized murine orthotopic glioblastoma model. As fractionated regimens of radiotherapy are the standard of care for glioblastoma treatment, we incorporated dose fractionation to simultaneously validate the neuroprotective effects and optimized tumor treatments with FLASH-RT.
The capability of FLASH-RT to minimize the induction of radiation-induced brain toxicities has been attributed to the reduction of reactive oxygen species, casting some concern that this might translate to a possible loss of antitumor efficacy. Our study shows that FLASH and CONV-RT are isoefficient in delaying glioblastoma growth for all tested regimens. Furthermore, only FLASH-RT was found to significantly spare radiation-induced cognitive deficits in learning and memory in tumor-bearing animals after the delivery of large neurotoxic single dose or hypofractionated regimens.
The present results show that FLASH-RT delivered with hypofractionated regimens is able to spare the normal brain from radiation-induced toxicities without compromising tumor cure. This exciting capability provides an initial framework for future clinical applications of FLASH-RT..
最近的数据表明，使用 FLASH 放射治疗（FLASH-RT）在不到十分之一秒的时间内对整个大脑进行单次照射，不会在小鼠中引起神经认知缺陷。这一观察结果对管理侵袭性和治疗抵抗性脑肿瘤具有重要的临床意义，因为这些肿瘤需要用高细胞毒性剂量对相对较大的照射体积进行治疗。
因此，我们旨在使用一种经过充分特征描述的小鼠原位神经胶质瘤模型，在暴露后 1 个月，同时研究 FLASH-RT 的抗肿瘤疗效和神经保护作用。由于分割放疗方案是神经胶质瘤治疗的标准，我们将剂量分割纳入其中，以同时验证 FLASH-RT 的神经保护作用和优化肿瘤治疗。
FLASH-RT 减少放射性脑毒性诱导的能力归因于活性氧的减少，这引起了人们对其可能导致抗肿瘤疗效丧失的担忧。我们的研究表明，FLASH 和 CONV-RT 在所有测试方案中都具有相同的能力来延缓神经胶质瘤的生长。此外，只有在给予大神经毒性单次剂量或低分割方案后，FLASH-RT 才被发现能显著减轻荷瘤动物的学习和记忆中的辐射诱导认知缺陷。
本研究结果表明，低分割方案的 FLASH-RT 能够在不影响肿瘤治愈的情况下，使正常大脑免受辐射诱导的毒性。这一令人兴奋的能力为 FLASH-RT 的未来临床应用提供了初步框架。
