A Novel Dose Calculation Method for Targeted Radionuclide Therapy

描述（由申请人提供）：由于发现了更好的肿瘤生物标志物和开发了新的靶向药物，最近对体内给药放射性药物的靶向放疗重新产生了兴趣。在任何形式的放射治疗中，存活细胞的分数、健康器官毒性和肿瘤反应主要取决于沉积的能量的量。吸收剂量与恶性组织反应或正常组织毒性之间的关系是任何放射治疗方法的主题。本提案将解决以下问题：1.相对于目前更简单的基于体模的方法，我们能否提高特定患者辐射吸收剂量估计的准确性，但这种方法对于常规临床使用足够有效？2)通过使用已知的放射生物学模型来解释时间和空间剂量率梯度和组织反应异质性，是否会提高治疗疗效和骨髓和肾脏毒性的预测值？使用PI在先前NIH支持下开发的具有定量SPECT/CT基于体素的剂量引擎的超快速离散坐标方法（DOM），提出以下目标来解决这些问题：1）通过测量和蒙特卡罗模拟验证DOM-QSPECT/CT在体模中的准确性，2）在DOM-QSPECT/CT剂量估计中结合已知的放射生物学效应剂量（BED）模型，并生成肾脏的BED体积直方图，3）回顾性比较DOM-QSPECT/CT剂量估计值与MIRD和Monte Carlo剂量估计值，用于在II期临床试验中使用Sm-153 EDTMP治疗的患者队列，以及4）将临床结果（骨痛指数和对骨和肾的毒性水平）与DOM-QSPECT/CT-BED剂量估计值相关联。所提出的工作是创新的，因为它利用了一种新的方法来执行人体组织中的辐射传输，我们已经证明这种方法与蒙特卡罗模拟一样准确，但对于复杂的外部射束放射治疗方案（即，计算结果可以在几分钟内获得，相比之下，对于蒙特卡罗来说可以在几小时或几天内获得）。此外，我们建议纳入放射生物学建模，以评估使用生物有效剂量概念的治疗计划。关于预期成果，四个具体目标中提出的工作的结合有望为放射性药物剂量测定创建一个新的平台，这将对核医学治疗领域产生积极影响，从而从根本上推进患者特异性体内放射性核素治疗规划领域。 公共卫生相关性：由于发现了更好的肿瘤生物标志物和开发了新的靶向药物，最近对体内给药放射性药物的靶向放射治疗重新产生了兴趣。我们的长期目标是开发与放射肿瘤学实践中使用的靶向放射性核素治疗计划工具（例如，用于外部射束和近距离放射治疗），以帮助试验设计和肿瘤反应和毒性预测，以及取代当前的低水平平面图像/基于MIRD的剂量测定方法。我们开发了一种确定性的辐射传输方法，我们计划在一组患者中进行验证和测试，这些患者来自骨骼靶向治疗放射性药物在乳腺癌骨转移患者中的II期临床试验。

DESCRIPTION (provided by applicant): Targeted radiotherapy with internally administered radiopharmaceuticals has recently experienced renewed interest due to identification of better tumor biomarkers and development of new targeting agents. In any form of radiotherapy, the fraction of surviving cells, healthy organ toxicity and tumor response depend primarily on the quantity of energy deposited. The relationship between absorbed dose and malignant tissue response or normal tissue toxicity is the theme of any radiotherapy approach. The following questions will be addressed by this proposal: 1. Can we improve the accuracy of radiation absorbed dose estimate to a specific patient relative to current, simpler phantom-based methods, yet such a method be efficient enough for routine clinical use? 2) Will accounting for the temporal and spatial dose-rate gradient and tissue-response heterogeneity by using known radiobiologic models improve the predictive value of treatment efficacy and toxicity to bone marrow and kidney? Using an ultra fast discrete ordinate method (DOM) with quantitative SPECT/CT voxel-based dose engine developed by the PI with previous NIH support, the following aims are proposed to address these questions: 1) Validate the accuracy of DOM-QSPECT/CT in phantom with measurements and Monte Carlo simulations, 2) Incorporate known radiobiological effect dose (BED) models in the DOM-QSPECT/CT dose estimate and generate BED-volume-histograms for kidney, 3) Compare retrospectively DOM-QSPECT/CT dose estimates to MIRD and Monte Carlo dose estimates for a cohort of patients treated using Sm-153 EDTMP in a phase II clinical trial, and 4) Correlate the clinical outcomes (bone pain index and toxicity level to bone and kidney) to the DOM-QSPECT/CT-BED dose estimates. The proposed work is innovative because it capitalizes on a novel method to perform radiation transport in human tissue, a method that we have demonstrated to be as accurate as Monte Carlo simulations yet far more efficient for complex external beam radiotherapy regimens (i.e., computational results can be obtained within minutes compared to many hours or days for Monte Carlo). In addition, we propose the incorporation of radiobiological modeling to assess the treatment plan using the biological effective dose concept. With respect to expected outcomes, the combination of the work proposed in the four specific aims is expected to create a new platform for radiopharmaceutical dosimetry that will have a positive impact on the therapy field of nuclear medicine, in a way that will fundamentally advance the field of patient-specific internal radionuclide therapy treatment planning. PUBLIC HEALTH RELEVANCE: Targeted radiotherapy with internally administered radiopharmaceuticals has recently experienced renewed interest due to identification of better tumor biomarkers and development of new targeting agents. Our long term goal is to develop targeted radionuclide therapy planning tools comparable to those used in radiation oncology practice (e.g., for external beam and brachytherapy), in order to aid in trial design and tumor response and toxicity prediction, as well as replace the current, inferior planar image/MIRD-based dosimetry methodology. We developed a deterministic radiation transport method that we plan to validate and test in a cohort of patients from a phase II clinical trial of a skeletal targeted therapy radiopharmaceutical in Breast Cancer Patients with Bone Only Metastases.