Dose-Response in Radionuclide Therapy

描述(由申请人提供)：放射性药物治疗(RPT)是转移性癌症患者为数不多的可行的化疗替代方案之一。在非霍奇金淋巴瘤(NHL)中，RPT对治疗难治的患者产生了持久的缓解。RPT是治疗神经内分泌和转移性甲状腺癌的唯一疗法，是治疗卵巢、前列腺癌和其他转移性癌症的新兴疗法。ClinTrials.gov列出了136项放射性核素治疗试验。RPT的给药方式与化疗相似，假定剂量递增试验中定义的最大耐受给药活度(AA)适用于所有患者。这种非专利剂量导致了保守的治疗，产生了低毒性，但代价是肿瘤控制。在NIH先前的支持下，我们已经开发出患者特有的剂量学(PSD)方法，并表明它优于普通疗法，例如，能够对甲状腺癌的弥漫性肺转移进行更积极但安全的治疗，以及针对骨肉瘤的XRT/RPT联合治疗计划，在提高肿瘤剂量的同时将邻近脊髓剂量保持在MTD以下。这一竞争性续展申请的目标是进一步提高准确性，并评估对RPT的总体影响。具体地说：1.我们建议开发一种能够从宏观(成像)数据进行微观剂量测量的方法。基于成像的PSD精度受到成像分辨率的限制。在某些情况下，微尺度吸收剂量(AD)分布是了解和避免正常器官毒性的关键。2.在评价影响时，统计不确定性对于解释结果和指导治疗很重要。我们将开发一种方法来计算剂量测量结果的不确定度和置信度。3.需要以标准化方式积累大量剂量反应研究，以评估目标1和目标2以及私营部门司司长总体上对通过RPT改善肿瘤控制的影响。在美国国立卫生研究院先前的支持下开发并在AIMS 1和2中修订的3-D放射生物剂量学(3D-RD)软件包将用于对大量现有的和预期的、内部的和合作的机构研究进行PSD计算。单机构研究产生的数据有限；合作者研究的3D-RD分析利用来自其他站点的数据并增加患者人口库，为剂量反应研究产生稳健的数据集。4.3D-RD包括剂量率和剂量不均匀的放射生物学建模。这些模型的参数值目前不能单独测量。取而代之的是文学价值。如果没有标准化，不同的研究人员/机构将使用不同的价值观，使跨研究的反应比较变得困难。为了支持目标3剂量反应研究所需的标准化，我们将建立一个参考放射生物学参数值的在线数据库。这样的数据库将类似于ICRP器官质量和组成的参考手册汇编。RPT是治疗转移性癌症的一种有前途的治疗方法。RPT目前是根据化疗范例提供的。对这一提议的支持将有助于为RPT交付带来一种理性的、基于AD的方法。

DESCRIPTION (provided by applicant): Radiopharmaceutical therapy (RPT) is one of the few viable alternatives to chemotherapy for patients with metastatic cancer. In non-Hodgkin's lymphoma (NHL), RPT has yielded durable remissions in treatment- refractory patients. RPT is the only treatment for neuroendocrine and metastatic thyroid cancer and is an emerging treatment for metastatic ovarian, prostate and other cancers. ClinTrials.gov lists 136 radionuclide therapy trials. RPT is administered like chemotherapy, by assuming that a maximum tolerated administered activity (AA) defined in a dose escalation trial applies to all patients. Such generic dosing has led to conservative treatment, yielding low toxicity at the expense of tumor control. With prior NIH support we have developed a patient-specific dosimetry (PSD) methodology and have shown it to be superior to generic treatment by enabling, for example, more aggressive yet safe therapy of diffuse lung metastases in thyroid cancer and a combined XRT/RPT treatment plan for osteogenic sarcoma, boosting tumor dose while keeping adjacent spinal cord dose below the MTD. The objectives of this competing renewal application are to further improve accuracy and to evaluate overall impact on RPT. Specifically: 1. We propose to develop a method to enable micro-scale dosimetry from macro-scale (imaging) data. Imaging-based PSD accuracy is limited by imaging resolution. In some cases, micro-scale absorbed dose (AD) distributions are key to understanding and thereby avoiding normal organ toxicity. 2. In evaluating impact, statistical uncertainty is important to interpreting results and guiding treatment. We will develop a method to calculate the uncertainty and confidence level of dosimetry results. 3. Accrual of a large number of dose-response studies, in a standardized manner, is needed to evaluate the impact of Aims 1 and 2, and PSD, generally, on improving tumor control with RPT. The software package, 3-D Radiobiological Dosimetry (3D-RD) developed with prior NIH support, and revised in Aims 1 and 2, will be used to perform PSD calculations for a large number of existing and prospective, in- house, and collaborating institution studies. Single-institution studies yield limited data; 3D-RD analysis for collaborator studies leverages data from other sites and increases the patient population pool to yield a robust data set for dose-response studies. 4. 3D-RD includes radiobiological modeling for dose rate and dose non- uniformity. Parameters values for these models cannot currently be measured in individuals. Instead, literature values are used. Without standardization, different investigators/institutions will use different values making response comparisons across studies difficult. To support the standardization needed for the dose-response studies of aim 3 we will establish an on-line database of reference radiobiological parameter values. Such a database would be analogous to the ICRP reference man compilation of organ masses and compositions. RPT is a promising treatment for metastatic cancer. RPT is currently delivered according to a chemotherapy paradigm. Support for this proposal will help bring a rational, AD-based approach, to RPT delivery.