Dose-Response in Radionuclide Therapy

描述(由申请人提供)：靶向放射性核素治疗作为一种潜在的癌症治疗方式正在积极研究中。吸收剂量与肿瘤反应或正常器官毒性之间的关系对于优化放射性核素治疗具有重要意义。目前对这种关系的理解几乎完全来自于外照射，而不是放射性核素治疗经验。利用来自临床放射性治疗研究的数据，我们建议评估放射性核素剂量学在试验设计和肿瘤反应或毒性预测中的潜在作用。这项建议将解决以下问题：1.估计吸收剂量与肿瘤和正常器官反应之间的关系？2.患者特定的、基于三维成像的剂量学方法是否比更简单的、基于标准体模的方法更具优势？3.考虑吸收剂量率和均匀性差异的放射生物学建模是否改善了反应预测？4.既往治疗如何影响血液毒性和剂量-反应关系？为了解决这些问题，我们提出了以下目标：1.在3D-ID中加入放射生物学建模，以利用和解释剂量率和空间一致性信息来评估反应概率。2.1.获得I-131治疗甲状腺疾病患者的剂量-反应关系。2.2.获得非清髓性Tositumomab(Bexxar；131L-抗CD20)和Ibritumomab Tiuxetan(Zvalin；90Y-抗CD20)治疗非霍奇金淋巴瘤患者的剂量-反应关系。3.比较通过考虑剂量率、不均匀性和患者特定解剖结构(即使用3D-ID)获得的剂量-反应关系与使用更简单的基于标准体模的方法(Olinda)获得的剂量-反应关系；在NHL研究中，评估FL.T3配体在改善血液毒性剂量-反应关系中的作用。剂量学被认为是放射性核素治疗后反应的最佳预测因子。需要对放射性核素治疗数据进行标准化、严格的剂量学分析，以评估这一假设，确定所需的复杂程度，并了解其他因素如何影响吸收剂量与反应关系。

DESCRIPTION (provided by applicant): Targeted radionuclide therapy is being actively investigated as a potential cancer therapy modality. The relationship between absorbed dose and tumor response or normal organ toxicity is important in optimizing radionuclide therapy. Current understanding of this relationship is almost completely derived from external beam rather than radionuclide therapy experience. Using data derived from clinical radionuclide therapy studies we propose to evaluate the potential role of radionuclide dosimetry in trial design and tumor response or toxicity prediction. The following questions will be addressed by this proposal: 1. What is the relationship between estimated absorbed dose and tumor and normal organ response? 2. Does patient specific, 3-D imaging-based dosimetry provide an advantage over a simpler, standard phantom-based approach? 3. Does radiobiologic modeling that accounts for differences in absorbed dose rate and uniformity improve response prediction? 4. How does prior therapy influence hematologic toxicity and the dose-response relationship? Using 3D-ID, a patient-specific 3-D dosimetry package developed by the PI with previous NIH support, the following aims are proposed to address these questions 1. Incorporate radiobiologic modeling in 3D-ID to utilize and interpret dose-rate and spatial uniformity information in evaluating response probability. 2.1. Obtain dose-response relationships in thyroid disease patients treated with I-131. 2.2. Obtain dose-response relationships for non-Hodgkin's' lymphoma patients treated with nonmyeloablative Tositumomab (Bexxar; 131l-anti-CD20) and Ibritumomab Tiuxetan (Zevalin; 90Y-anti-CD20). 3. Compare dose-response relationships obtained by accounting for dose-rate, non-uniformity and patient-specific anatomy (i.e., using 3D-ID) with those obtained using a simpler, standard-phantom based methodology (OLINDA); in the NHL studies, evaluate the role of FL.T3 ligand in improving the dose-response relationship for hematologic toxicity. Dosimetry has been assumed to be the best predictor of response following radionuclide treatment. Standardized, rigorous dosimetric analyses of radionuclide therapy data are needed to evaluate this assumption, identify the level of complexity required and to understand how other factors can impact the absorbed dose vs response relationship.