Imaging Based Dosimetry for Individualized Internal Emitter Therapy

基于成像的剂量测定，用于个体化内部发射器治疗

• 批准号: 8463525
• 负责人: YUNI K DEWARAJA
• 金额: $ 43.04万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463525
• 关键词: 3-Dimensional; Accounting; Affect; Antibodies; Biological Factors; Biological Markers; Biology; Bone Marrow; Bone Marrow Neoplasms; Clinical; Clinical Research; Coupling; Data; Dose; Dose-Limiting; FLT3 gene; Funding; Future; Goals; Heterogeneity; I131 isotope; Image; Immunoassay; Immunohistochemistry; Kidney; Knowledge; Label; Life; Malignant Neoplasms; Marrow; Measures; Methodology; Methods; Mission; Modeling; Modification; Monoclonal Antibodies; Non-Hodgkin' s Lymphoma; Organ; Outcome; Patient Selection; Patients; Phase II Clinical Trials; Physicians; Public Health; Radiation; Radiation Tolerance; Radioimmunotherapy; Radioisotopes; Radiolabeled; Radionuclide therapy; Refractory; Regression Analysis; Research; Testing; Toxic effect; Treatment Efficacy; Variant; Work; abstracting; base; burden of illness; clinical care; cold agglutinins; conventional therapy; design; disability; dosimetry; improved; innovation; novel therapeutics; predictive modeling; public health relevance; radiation absorbed dose; radiotracer; reconstruction; response; single photon emission computed tomography; therapy outcome; tool; tositumomab; treatment planning; tumor

DESCRIPTION (provided by applicant): Imaging based dosimetry for individualized internal emitter therapy Summary/Abstract The current standard practice for internal emitter therapy rarely involves pre-treatment planning to optimize the radiation absorbed dose to the tumor while avoiding critical organ (typically bone marrow) toxicity. This is in stark contrast to planning for external beam therapy where precise absorbed dose calculations to tumor and surrounding organs are now mandatory. Such therapy optimization has not been used in therapies such as radioimmunotherapy (RIT) primarily because accurate internal emitter dose estimation is relatively difficult and because clinical studies thus far have failed to show a consistent relationship between radiation absorbed dose and effect. These past studies typically relied on suboptimal methods of dose estimation and/or did not account for biologic factors that are also expected to affect outcome. The long-term goal is clinical implementation of effective individualized treatment planning for radionuclide therapies such as I-131 tositumomab RIT in non- Hodgkin's lymphoma (NHL). The objective in the present application is to develop accurate imaging based methods for tumor and bone marrow dosimetry and to develop predictive models for tumor response and bone marrow toxicity incorporating key dosimetric factors as well as biologic factors, such as differential proliferation, radiosensitivity and sensitivity to the unlabeled antibody, that will be determined by biomarker studies. The central hypothesis is that integrating dosimetry and biology will enable better prediction of RIT outcome than is obtained with the strictly dosimetric measures commonly used. The hypothesis will be tested in refractory NHL patients undergoing I-131 RIT in standard clinical care and in frontline patients on a phase II clinical trial. To accomplish the objective of this application the following specific aims will be pursued: 1) Develop SPECT reconstruction methods that utilize CT-image information (without needing explicit segmentation of target boundaries) to more accurately estimate the 3-D activity distribution in targets, because dose heterogeneity impacts the effect of the therapy; 2) Develop imaging based bone marrow dosimetry coupling SPECT/CT with Monte Carlo radiation transport and accounting for variations in marrow composition as determined by quantitative CT; 3) Using patient data develop a multivariate regression model for predicting therapy outcome (response, toxicity) based on dosimetric factors and biologic factors from biomarker studies (e.g., Ki-67, p53 and FLT3-L from immunohistochemistry/immunoassay); and 4) Develop a mechanistic model (with and without modification for low dose hyper-radiosensitivity) to determine the equivalent biologic effect for predicting therapy outcome. The proposed work is innovative because unlike past studies focusing purely on dosimetry this work combines dosimetric factors with biologic factors to arrive at the optimal model for individualized treatment planning. The contribution is highly significant because once the methodologies and predictive models for treatment optimization are established, they will be used in the future by physicians for patient selection and to tailor RIT on a patient-by-patient basis to considerably improve the efficacy of the treatment.

描述（由申请人提供）：基于成像的剂量法，用于个性化内部发射机治疗摘要/摘要内部发射机治疗的当前标准实践很少涉及预处理计划，以优化对肿瘤吸收的辐射剂量，同时避免临界器官（通常是骨髓）毒性。这与计划外束治疗的计划形成鲜明对比，在外部束治疗中，对肿瘤和周围器官的精确吸收剂量计算是必须的。这种疗法优化尚未用于诸如放射免疫疗法（RIT）之类的疗法中，主要是因为准确的内部发射极剂量估计相对困难，并且由于迄今为止临床研究未能显示出吸收剂量和作用之间的疗程一致的关系。这些过去的研究通常依赖于剂量估计的次优方法和/或不考虑也有望影响预后的生物学因素。长期目标是针对非霍奇金淋巴瘤（NHL）中的放射性核素疗法（例如I-131 tositumomab RIT）进行有效的个性化治疗计划。本应用的目的是开发基于肿瘤和骨髓剂量测定法的准确成像方法，并开发用于肿瘤反应和骨髓毒性的预测模型，这些模型融合了关键的剂量学因素以及生物学因素，例如差异增殖，鉴定性增殖，放射性敏感性和对无贴抗抗体抗体抗体的敏感性，以确定生物标记研究。中心假设是，综合剂量法和生物学将比普遍使用的严格剂量计测量获得更好的RIT结果预测。该假设将在标准临床护理中I-131 RIT的难治性NHL患者和II期临床试验中的前线患者中进行检验。为了实现本应用的目标，将追求以下特定目标：1）开发使用CT图像信息（无需明确的目标边界分割）的SPECT重建方法，以更准确地估算目标中的3-D活动分布，因为剂量异质性会影响治疗效果； 2）开发基于成像的骨髓剂量测定偶联SPECT/CT与蒙特卡洛辐射传输，并考虑通过定量CT确定的骨髓组成的变化； 3）使用患者数据开发了一种基于生物标志物研究的剂量学因素和生物学因素（例如，来自免疫组织/免疫组织/免疫分析的Ki-67，p53和FLT3-L）的多元回归模型来预测治疗结果（反应，毒性）； 4）开发一种机械模型（低剂量过度敏感性的机械模型），以确定预测治疗结果的等效生物学效应。拟议的工作具有创新性，因为与过去的研究纯粹针对剂量法不同，这项工作将剂量学因素与生物学因素结合在一起，以达到个性化治疗计划的最佳模型。该贡献非常重要，因为一旦建立了治疗优化的方法和预测模型，将来医生将使用它们用于患者选择，并逐个患者量身定制RIT，以大大提高治疗的功效。