Development of wearable technology to enable therapy personalization of 177Lu DOTATATE for neuroendocrine tumors

对于转移性、生长抑素受体2(SSTR2)阳性的神经内分泌肿瘤(NETS)患者， 使用177 Lu-DOTATE的靶向治疗极大地提高了无进展生存率(PFS)，如 Netter-1试验。177Lu-1治疗20个月时PFS为65.2%(95%CI，50.0-76.8)。 在接受60毫克长链奥曲肽的对照组中，单用DOTATE的比例为10.8%(95%CI，3.5-23.0)。 每4周出院一次。既然177Lu-DOTATE已经获得FDA的批准，它很可能会成为标准 对有症状的净患者和有转移扩散的患者的护理。然而，FDA的包装说明 呼吁患者接受四次7.4GBq的治疗，无论其大小、体重、性别或患者的健康状况如何。 传统上，靶向放射性核素治疗是根据主要危险器官的剂量进行个性化的。 标准化治疗与个性化医疗的理想背道而驰，并将导致非最优 为许多患者提供治疗性剂量。177Lu(6.65)器官剂量估算的传统方法 半衰期)需要3-4次纵向成像周期，持续时间约7天。这是昂贵的，利用一个 耗费大量临床资源，给患者带来负担。该项目的目标是实现精确的 个性化的177Lu-DOTATE器官剂量测定，无需连续成像会议(注：主要 ~98%接受177Lu-DOTATE治疗的患者的OAR是肾脏)。我们将通过以下方式实现这一目标 开发廉价、可穿戴的监控技术，以便通过以下方式进行定量测量 病人在家中。这将支持对单个危险器官(OAR)的准确估计， 为每个治疗阶段提供准确的器官剂量测定，从而使医生能够单独定制 基于个性化器官剂量信息的治疗数量。在目标1中测量的方法 来自可穿戴的、低成本的个性化家庭剂量测量(PHD)腰带的个人器官剂量信息将被 使用蒙特卡罗模拟工具开发。在目标2中，一个器官特定剂量的原型PHD带 估计将是捏造的。皮带将由6-15个小型光谱计数探测器和称重组成 &lt；750克，具体取决于皮带中安装的探测器数量。它的设计将是轻便的 重量，形状适合，并将具有对齐功能，以实现一致的日常佩戴/定位 将安全带系在病人的内脏上。这条腰带将进一步配备电子设备，可以 获取、存储数据并通过Wi-Fi发送到安全的网站，以进行近乎实时的数据监控。在目标3中，一个 使用简化方案(即，一个)比较单个器官剂量估算的小型试点研究 输液后24小时SPECT/CT和PHD腰带测量加上家中7-21 PHD腰带测量) 对比3个时间点(即，1、4和7天)的临床SPECT/CT成像(即，许多情况下遵循的标准方案 非美国国家)将进行。在本项目结束时，创建和利用博士带的方法将 已经过测试和验证，博士带将准备好在早期临床试验中进行评估。

For patients with metastatic, somatostatin-receptor-2 (SSTR2) positive neuroendocrine tumors (NETs), targeted therapy using 177Lu-DOTATATE greatly increases progression-free survival (PFS), as shown in the NETTER-1 trial. PFS at month 20 was 65.2% (95% CI, 50.0 - 76.8) for midgut NETs treated with 177Lu- DOTATATE alone compared to 10.8% (95% CI, 3.5 - 23.0) in a control group receiving 60 mg octreotide long- acting release every 4 weeks. Now that 177Lu-DOTATATE has FDA approval it likely will become the standard of care for symptomatic NET patients and those with metastatic spread. However, FDA package instructions call for patients to receive four 7.4 GBq treatments, regardless of size, weight, gender or patient health status. Traditionally, targeted radionuclide therapies are personalized based upon dose to the main organs at risk. Standardized therapy is counter to the ideals of personalized medicine and will lead to non-optimum therapeutic dosing for many patients. Traditional methods for organ dosimetry estimation for 177Lu (i.e., 6.65 day half-life) require 3-4 longitudinal imaging sessions spread out over ~7 days. This is expensive, utilizes a lot of clinic resources and is burdensome to the patient. The goal of this project is to enable precise individualized 177Lu-DOTATATE organ dosimetry without requiring serial imaging sessions (note: the main OAR for ~98% of patients receiving 177Lu-DOTATATE therapy is the kidneys). We will accomplish this by developing inexpensive, wearable monitoring technology to allow quantitative measurements to be made by the patient at home. This will support accurate estimation of the washout from individual organs at risk (OAR), enabling accurate organ dosimetry for each treatment session thereby allowing physicians to individually tailor the number of treatments based upon personalized organ dosimetry information. In Aim 1 methods to measure individual organ dose information from a wearable, low cost, personalized home dosimetry (PHD) belt will be developed using Monte Carlo simulation tools. In Aim 2, a prototype PHD belt for organ specific dose estimation will be fabricated. The belt will consist of 6-15 small, spectrographic counting detectors and weigh <750 grams depending upon the number of detectors incorporated into the belt. It will be designed to be light weight, form fitting and will have alignment features to enable consistent day to day wearing/positioning of the belt with respect to the patient’s internal organs. The belt will further be equipped with electronics that can acquire, store and send the data via Wi-Fi to a secure web-site for near real time data monitoring. In Aim 3, a small pilot study to compare individual organ dosimetry estimates using a streamlined protocol (i.e., one SPECT/CT and PHD belt measurement at 24 hr post infusion plus 7-21 PHD belt at home measurements) versus 3-time point (i.e., 1, 4 and 7 day) in-clinic SPECT/CT imaging (i.e., standard protocol followed in many non-US countries) will be conducted. At the end of this project, methods to create and utilize a PHD belt will have been tested and validated and the PHD belt will be ready for evaluation in an early phase clinical trial.