Simultaneous dose and dose rate optimization for clinical FLASH proton radiotherapy

项目摘要 超高剂量率的照射，即闪光放射治疗，可以显著降低正常组织的毒性 同时保持肿瘤反应(所谓的闪光效应)，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这一潜在的益处 对于普通癌症患者，闪光放射治疗的有效性有待进一步验证。 临床试验。 到目前为止，唯一商业上可用的系统可以提供普通- 目的临床闪光放射治疗是一种质子模式，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)，只优化剂量和效果 不能直接优化剂量率或闪光效果。质子闪光放射治疗临床缺少的前提条件 Trials是一种兼容的治疗计划方法，具有闪存优化能力。 这项临床闪光放射治疗的关键创新和使能技术是同类项目中的第一项 通过SDDRO的闪存优化引擎，最近被PTCOG 59认可为Michael Goitein 最佳物理学摘要奖，以表彰其对Flash-RT的创新和影响(Gao等人，2021)。尽我们最大努力 据了解，SDDRO是唯一可以优化闪光剂量率和剂量的方法。我们的 针对肺病患者的初步工作(Gao Et Al 2020)表明，与IMPT相比，SDDRO 大大提高了闪光剂量率覆盖范围(为了具有闪光效果，以减少正常- 组织毒性)，同时保持剂量覆盖范围，例如增加靶区周围体积 接受≥40Gy/S由~40%降至至少98%，肺体积由~30%/≥/S降至~80%， 它发生在高剂量和高不确定性的地点，具有高风险的辐射诱导毒性。是这样的 在低分馏的情况下，改善闪光覆盖对于减少正常组织毒性尤为关键 Flash-RT的性质。 鉴于我们创新的SDDRO、IBA质子机具有超高剂量率能力，学术-工业 与IBA、闪光放射生物学和剂量学专业知识合作，我们在开发 具有闪存优化能力的新型SDDRO方法，目前无法获得和迫切需要 对于临床Flash-RT，包括(1)具有逼真Flash模型的通用SDDRO方法、机器 特性和传输机制(传输光束、共形能量滤光器或接头)；(2) 将SDDRO方法转换到我们的IBA系统中，进行端到端验证和验证的闪光剂量测量。 该项目的完成将使SDDRO方法具有闪存优化能力，即 目前无法获得和迫切需要临床闪光RT，并为闪光动物研究奠定了基础 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.