A Novel Dose Calculation Method for Targeted Radionuclide Therapy

描述(申请人提供)：由于发现了更好的肿瘤生物标记物和开发了新的靶向制剂，使用内部给药的靶向放射治疗最近重新引起了人们的兴趣。在任何形式的放射治疗中，存活细胞的比例、健康器官毒性和肿瘤反应主要取决于储存的能量的数量。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。这项提议将解决以下问题：1.相对于目前更简单的基于体模的方法，我们能否提高对特定患者的辐射吸收剂量估计的准确性，而这样的方法对于常规临床应用足够有效？2)使用已知的放射生物学模型来考虑时间和空间剂量率梯度和组织反应的异质性是否能够改善治疗效果和对骨髓和肾脏的毒性的预测价值？使用PI在先前NIH支持下开发的基于SPECT/CT体素的定量剂量引擎的超快速离散纵坐标方法(DOM)，提出了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)将已知的放射生物学效应剂量(BED)模型纳入DOM-QSPECT/CT剂量估计中，并生成肾脏的床体积直方图；3)在II期临床试验中，将DOM-QSPECT/CT剂量估计与MIRD和蒙特卡罗剂量估计进行回顾比较4)将临床结果(骨痛指数和对骨和肾脏的毒性程度)与DOM-QSPECT/CT-BED剂量估算相关联。这项拟议的工作具有创新性，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，但对于复杂的外照射放射治疗方案来说，效率要高得多(即，与蒙特卡罗的几小时或几天相比，计算结果可以在几分钟内获得)。此外，我们建议结合放射生物学模型来使用生物有效剂量的概念来评估治疗计划。关于预期结果，四个具体目标中提议的工作的结合预计将为放射性药物剂量测定创造一个新的平台，这将对核医学治疗领域产生积极影响，从而从根本上推进针对患者的内部放射性核素治疗计划领域。 与公共卫生相关：由于发现了更好的肿瘤生物标记物和开发了新的靶向制剂，使用内部给药的靶向放射治疗最近重新引起了人们的兴趣。我们的长期目标是开发可与放射肿瘤学实践中使用的放射性核素治疗计划工具相媲美的靶向放射性核素治疗计划工具(例如，外照射和近距离放射治疗)，以帮助试验设计和肿瘤反应及毒性预测，并取代目前劣质的平面图像/MIRD剂量学方法。我们开发了一种确定性的辐射传输方法，我们计划在骨靶向治疗乳腺癌仅有骨转移患者的第二阶段临床试验的一组患者中验证和测试该方法。

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.