Simultaneous dose and dose rate optimization for clinical FLASH proton radiotherapy

项目摘要 超高剂量率辐照，即FLASH-RT，可显著降低正常组织的毒性 同时保持肿瘤反应（所谓的FLASH效应），与常规照射相比， 剂量率（CONV-RT）。尽管许多临床前和一些临床研究证明了潜在的益处， 对于FLASH-RT，FLASH-RT对一般癌症患者的有效性将通过以下方法进一步验证： 临床试验 到目前为止，唯一的商用系统，可以提供超高剂量率所需的一般- 目的临床FLASH-RT是质子模式，如我们的IBA系统。然而，最先进的 治疗计划方法，即，强度调制质子治疗（IMPT），只优化剂量， 不直接优化剂量率或FLASH效应。质子FLASH-RT临床缺少的先决条件 试验是一种兼容的治疗计划方法，具有FLASH优化功能。 该项目中用于临床FLASH-RT的关键创新和使能技术是同类产品中的第一个 通过SDDRO的闪存优化引擎，最近被PTCOG 59评为Michael Goitein 物理学最佳摘要奖，以表彰其对FLASH-RT的创新和影响（Gao et al 2021）。据我们所 SDDRO是唯一一种可以优化FLASH剂量率和剂量的方法。我们 针对肺部患者的初步研究（Gao et al 2020）表明，与IMPT相比，SDDRO 大大提高了闪光剂量率的覆盖范围（为了有闪光效果，以减少正常的， 组织毒性），同时保持剂量覆盖，例如，靶周围体积增大 接受≥ 40 Gy/s的剂量从~40%到至少98%，接受≥ 40 Gy/s的肺体积从~30%到~ 80%， 这发生在高剂量和高度不确定的地点，具有高风险的辐射诱发毒性。等 提高FLASH的覆盖率对于减少低分割的正常组织毒性尤其重要 FLASH-RT的性质 鉴于我们创新的SDDRO，具有超高剂量率能力的IBA质子机， 与IBA，FLASH放射生物学和剂量学专业知识的合作伙伴关系，我们处于独特的地位， 具有闪存优化功能的新型SDDRO方法，目前尚不具备，且急需使用 对于临床FLASH-RT，包括（1）具有真实FLASH模型的一般SDDRO方法，机器 特性和输送机制（传输光束、适形能量过滤器或接头）;（2） 将SDDRO方法转化为IBA系统，并进行端到端验证和经验证的FLASH剂量测定。 该项目的完成将使新的SDDRO方法具有闪存优化功能， 目前还没有，迫切需要用于临床FLASH-RT，并为FLASH动物研究奠定基础 和临床试验。

Project Summary The irradiation at ultra-high dose rates, namely FLASH-RT, can substantially reduce normal-tissue toxicities while maintaining tumor response (so-called the FLASH effect), compared with the irradiation at conventional dose rates (CONV-RT). Although many preclinical and some clinical studies demonstrated the potential benefit of FLASH-RT, the effectiveness of FLASH-RT for general cancer patients is to be further validated through clinical trials. By far the only commercially available system that can deliver ultra-high dose rates needed for general- purpose clinical FLASH-RT is the proton modality, such as our IBA system. However, the state-of-the-art treatment planning method, i.e., intensity modulated proton therapy (IMPT), only optimizes the dose and does not directly optimize the dose rate or the FLASH effect. A missing prerequisite for proton FLASH-RT clinical trials is a compatible treatment planning method with FLASH optimization capability. The key innovation and enabling technology in this project for clinical FLASH-RT is the first-of-its-kind FLASH optimization engine via SDDRO, which was recently recognized by PTCOG 59 as the Michael Goitein Best Abstract Award in Physics for its innovation and impact for FLASH-RT (Gao et al 2021). To the best of our knowledge, SDDRO is the only method that can optimize the FLASH dose rate as well as the dose. Our preliminary work (Gao et al 2020) for lung patients has demonstrated that, compared with IMPT, SDDRO substantially improved the FLASH-dose-rate coverage (in order to have the FLASH effect for reducing normal- tissue toxicities) while preserving the dose coverage, e.g., increasing of the target-surrounding volume receiving ≥40Gy/s from ~40% to at least 98%, and the lung volume receiving ≥40Gy/s from ~30% to ~80%, which occurred at high-dose and high-uncertainty locations with high-risk radiation-induced toxicities. Such improved FLASH coverage is especially critical for reducing normal tissue toxicities given the hypofractionation nature of FLASH-RT. Given our innovative SDDRO, IBA proton machine with ultra-high-dose-rate capability, academic-industrial partnership with IBA, FLASH radiobiology and dosimetry expertise, we are uniquely positioned to develop novel SDDRO methods with FLASH optimization capability that is currently unavailable and urgently needed for clinical FLASH-RT, including (1) general SDDRO methods with realistic FLASH models, machine characteristics, and delivery mechanisms (transmission beams, conformal energy filters, or joint); (2) translation of SDDRO methods into our IBA system, with end-to-end validation and verified FLASH dosimetry. The completion of this project will render novel SDDRO methods with FLASH optimization capability that is currently unavailable and urgently needed for clinical FLASH-RT, and set the stage for FLASH animal studies and clinical trials.