Bringing Capacity for Theranostic Dosimetry Planning to the Nuclear Medicine Clinic

摘要 体内给药靶向放射性核素治疗(TRT)，使用放射性标记分子传递细胞毒 肿瘤放射治疗已成功应用于多种癌症的治疗。尽管结果很有希望，但仍有很多 改善TRT的持久反应和存活率的空间。TRT非常适合于 治疗的无声学方法，因为在开始治疗周期之前进行发射成像可以 用于预测将被释放的吸收剂量(ADS)。因此，治疗所需的活动 在将关键器官毒性保持在可接受的水平的同时对肿瘤的影响可以个性化地计划 基础。虽然精确的治疗计划通常用于外照射，但在TRT中， 在不考虑投放广告的情况下，采用固定或基于体重的活动来处理仍然是 护理的标准。剂量学引导TRT个人化的主要障碍是缺乏剂量学工具 对于临床环境来说是有效的，但也是实用的。为了改善这种情况，目标是开发、验证 并为临床提供了一个平台，用于患者特定剂量学驱动的治疗计划，适用于 临床应用，可适应各种TRT。拟议的系统将集成SPECT/CT成像工具箱 基于端到端测试的体素级别剂量测量(目标1)，用于减少成像负担的有效协议 与患者特定剂量学(AIM 2)相关，包含临床因素的稳健剂量-结果模型 和作为协变量的成像生物标记物(目标2)，以及临床医生可以用来计划的交互式用户界面 该疗法考虑了剂量学和临床因素以及由此产生的疗效/毒性权衡(目标3)。这个 系统集成了将利用最新进展(如基于学习的技术)开发的新组件 用于低计数SPECT重建和高效图像分割的方法建立在我们现有的基础上 包括先前开发的快速蒙特卡罗剂量学代码。与行业合作伙伴的合作 在翻译创新的医学图像分析工具方面的记录将有助于确保临床翻译 系统。为了证明开发的工具的能力，患者研究将集中在177Lu DOTATE 神经内分泌肿瘤的治疗。这种最近批准的治疗方法分四个周期进行，固定的 活动，尽管有一个独特的机会来进行基于SPECT成像的病变/器官剂量测量 每个周期都要计划下一个周期。该系统可用于其他放射性核素和靶向治疗。 可以从基于SPECT/CT成像的计划中受益的代理，例如使用177Lu PSMA进行放射配基治疗 用于前列腺癌和阿尔法排放物的新兴疗法。拟议的系统集成了以下方面的改编 过去由两个团队开发的工具和新工具为最终用户带来了有效的新能力 计划TRT，在一个平台内方便地执行所有数据处理。这将产生重大的积极影响 影响，因为个性化剂量学指导的TRT方法可能会显著提高疗效，同时 保持低毒性，与目前任意的“一刀切”的方法相比。

Abstract Internally administered targeted radionuclide therapy (TRT) with radio-labeled molecules that deliver cytotoxic radiation to tumor has been successfully used to treat multiple cancers. Despite promising results, there is much room to improve the durable response and survival rates achieved with TRT. TRT is ideally suited for the theranostic approach to treatment because emission imaging performed before initiating a treatment cycle can be used to predict the absorbed doses (ADs) that will be delivered. Thus, the activity needed for a therapeutic effect on tumor while keeping critical organ toxicities at an acceptable level can be planned on an individualized basis. While precise treatment planning is routinely used in external beam radiotherapy, in TRT however, treatment with fixed or weight-based activities without consideration of delivered ADs continues to be the standard of care. The main barrier to dosimetry guided personalization of TRT is the lack of dosimetry tools that are valid yet practical for the clinic environment. To improve this situation the objective is to develop, validate and bring to the clinic a platform for patient-specific dosimetry-driven treatment planning that is practical for clinical use and adaptable to various TRTs. The proposed system will integrate a toolbox for SPECT/CT imaging based voxel-level dosimetry with end-to-end testing (Aim 1), validated protocols for reducing the imaging burden associated with patient specific dosimetry (Aim 2), robust dose – outcome models that include clinical factors and imaging biomarkers as covariates (Aim 2), and an interactive user interface that the clinician can use to plan the therapy considering dosimetric and clinical factors and the resulting efficacy/toxicity trade-off (Aim 3). The system integrates new components that will be developed exploiting recent advances such as learning-based methods for low-count SPECT reconstruction and efficient image segmentation atop our existing foundation that includes a previously developed fast Monte Carlo dosimetry code. The collaboration with an industry partner with a track record in translating innovative tools for medical image analysis will help ensure clinical translation of the system. To demonstrate the capacity of the tools developed, patient studies will focus on 177Lu DOTATATE treatment of neuroendocrine tumors. This recently approved therapy is administered in four cycles with fixed activity although there is a unique opportunity to perform SPECT imaging-based lesion/organ dosimetry after each cycle to plan the next cycle. The system can be adapted to therapies with other radionuclides and targeting agents that can benefit from SPECT/CT imaging based planning such as radioligand therapy with 177Lu PSMA for prostate cancer and emerging therapies with alpha emitters. The proposed system integrates adaptations of tools developed in the past by both teams and new tools to bring a new capacity to the end user to effectively plan TRT with all data handling conveniently performed within one platform. This will have a significant positive impact because a personalized dosimetry guided approach to TRT is likely to substantially improve efficacy while maintaining low toxicity, compared with the current arbitrary ‘one dose fits all’ approach.