Optimizing Carbon Ion Therapy for Pediatric CNS Tumors

总结 原发性中枢神经系统（CNS）肿瘤是儿童中最常见的实体肿瘤， 儿童癌症相关死亡的原因。因此，迫切需要确定新的治疗方法。 其中一个进步是碳离子放射治疗（CIRT）。然而，尽管治疗了2万名2岁以上的病人， 几十年来，由于担心使用这种方式治疗儿童脑肿瘤， 正常组织会受到无法弥补的伤害这种恐惧是许多问题的结果， 关于量化CIRT的相对生物学有效性（RBE）的能力尚未回答。一个重要 由带电粒子传递的物理剂量的属性是电离密度，其随粒子电荷而变化 和速度。电离密度通常用线性能量传递（LET）来描述，定义为 由于与电子的相互作用，带电粒子在每单位距离内所损失的平均能量𝑑𝐸𝑑𝑙𝑑𝑙 在物质上。对于带电粒子，剂量和LET在粒子的终端几毫米上急剧增加。 粒子停止时的原始布拉格峰一个主要的不确定性是从剂量和LET到生物效应的比例， 其在肿瘤和正常组织内以复杂的方式变化。计算剂量和RBE模型 在毫米尺度上模拟剂量、能量和LET谱以及粒子碎片谱的变化， 患者解剖结构，并将这些物理特性与生物学数据联系起来，这些生物学数据通常由体外克隆形成测定。 存活测定。一个关键的知识缺口是在临床上对高LET辐射的真实体内组织反应。 相关的生物测定。不确定性是巨大的， 在临床实践中可能是灾难性的。因此，RBE值需要根据 最大可能的准确性。我们的中心假设是，碳离子放射治疗的优化将 允许改善儿童脑肿瘤的治疗结果，具有等同或更低的神经功能 与X射线治疗相比，两个具体的目标将被用来测试的假设。目标1将 系统地量化了小儿脑啮齿动物模型中CIRT正常组织毒性的RBE， 功能和病理终点，在可变剂量和LET，与X射线治疗相比。目标2将测试 工作假设，高LET碳离子在控制儿童高级别胶质瘤方面比 常规辐射。因此，这项工作的总体目标是研究正常的脑毒性，认知， 在儿科患者相关临床前模型中的副作用、继发性癌症风险和抗肿瘤疗效， 为将该模式推进到临床实践提供了良好的基础。我们将回答这个问题， 碳离子疗法在历史上对放射抵抗性癌症显示出巨大的潜力， 有望改善儿童高级别胶质瘤患者的治疗窗口。此外，我们将 贡献有关治疗风险和神经毒性副作用的基础新知识， 放射治疗的小儿中枢神经系统肿瘤。

SUMMARY Primary central nervous system (CNS) tumors are the most common solid tumors in children and the leading cause of childhood-cancer-related deaths. Thus, there is an urgent need to identify novel therapeutic treatments. One such advancement is carbon-ion radiation therapy (CIRT). Yet, despite treating 20,000 patients over 2 decades, there is a significant reluctance to use this modality to treat pediatric brain tumors because of a fear that normal tissue would be irreparably harmed. This fear is a consequence of the many questions that are unanswered regarding the ability to quantify the relative biologic effectiveness (RBE) of CIRT. An important attribute of the physical dose delivered by charged particles is ionization density, which varies with particle charge and velocity. Ionization density is frequently described in terms of linear energy transfer (LET), defined as the mean energy lost 𝑑𝐸∆/𝑑𝑙 by a charged particle per unit distance 𝑑𝑙 traversed due to interactions with electrons in matter. For charged particles, the dose and LET increase dramatically over the terminal few millimeters of the pristine Bragg peak as the particle halts. A major uncertainty is the scaling from dose and LET to biological effect, which varies within tumors and normal tissues in a complex manner. The computational dose and RBE models simulate on a millimeter-scale the variation of dose, energy and LET spectra, and particle fragment spectra within the patient anatomy and link these physical properties to biologic data, often determined from in vitro clonogenic survival assays. A critical gap in knowledge is the true in vivo tissue response to high-LET radiation in clinically relevant biological assays. The uncertainty is enormous and the impact of incorrect assignment of an RBE value to a given voxel can be catastrophic in clinical practice. Therefore, RBE values need to be determined with the greatest possible accuracy. Our central hypothesis is that optimization of carbon-ion radiation therapy will allow for improved curative outcomes for pediatric brain tumors, with equivalent or lower neurologic toxicity compared to x-ray therapy. Two specific aims will be used to test the hypothesis. Aim 1 will systematically quantify the RBE of CIRT normal-tissue toxicity in a rodent model of pediatric brain, for various functional and pathologic endpoints, at variable dose and LET, compared to x-ray therapy. Aim 2 will test the working hypothesis that high-LET carbon ions are more effective in controlling pediatric high-grade glioma than conventional radiation. Thus, the overall objective of this work is to investigate the normal brain toxicity, cognitive side effects, second cancer risks, and anti-tumor efficacy in preclinical models relevant for pediatric patients, providing a sound foundation for advancing this modality into clinical practice. We will answer the question as to whether carbon-ion therapy, which shows immense potential for historically radioresistant cancers, can be expected to improve the therapeutic window for pediatric high-grade glioma patients. Furthermore, we will contribute fundamental new knowledge regarding treatment risks and neurotoxic side effects relevant for all pediatric CNS tumors treated with radiation.