Dose-Response in Radionuclide Therapy

描述（由申请人提供）：放射性药物治疗（RPT）是转移性癌症患者化疗的少数可行替代方案之一。在非霍奇金淋巴瘤（NHL）中，RPT在治疗难治性患者中产生了持久缓解。RPT是神经内分泌癌和转移性甲状腺癌的唯一治疗方法，也是转移性卵巢癌、前列腺癌和其他癌症的新兴治疗方法。ClinTrials.gov列出了136项放射性核素治疗试验。RPT的给药方式与化疗类似，假设剂量递增试验中定义的最大耐受给药活性（AA）适用于所有患者。这种通用剂量导致保守治疗，以肿瘤控制为代价产生低毒性。在先前NIH的支持下，我们开发了一种患者特异性剂量测定（PSD）方法，并已证明其上级优于一般治疗，例如，甲状腺癌弥漫性肺转移的更具侵略性但安全的治疗，以及骨肉瘤的XRT/RPT联合治疗计划，提高肿瘤剂量，同时保持相邻脊髓剂量低于MTD。此竞争性更新应用程序的目标是进一步提高准确性并评估对RPT的总体影响。具体而言：1.我们建议开发一种方法，使微观尺度剂量从宏观尺度（成像）数据。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）分布是理解和避免正常器官毒性的关键。2.在评估影响时，统计不确定性对于解释结果和指导治疗非常重要。我们将发展一种方法来计算剂量测定结果的不确定度和置信水平。3.需要以标准化的方式积累大量的剂量反应研究，以评价目标1和2以及PSD对RPT改善肿瘤控制的影响。在NIH之前的支持下开发并在目标1和2中修订的软件包三维放射生物学剂量测定（3D-RD）将用于对大量现有和前瞻性、内部和合作机构研究进行PSD计算。单机构研究产生的数据有限;合作研究的3D-RD分析利用了来自其他研究中心的数据，并增加了患者人群库，为剂量反应研究产生了稳健的数据集。4. 3D-RD包括剂量率和剂量不均匀性的放射生物学建模。这些模型的参数值目前无法在个体中测量。相反，使用文献值。如果没有标准化，不同的研究者/机构将使用不同的值，使研究之间的反应比较变得困难。为了支持目标3的剂量反应研究所需的标准化，我们将建立一个放射生物学参数参考值的在线数据库。这种数据库类似于ICRP参考人汇编的器官质量和组成。RPT是转移性癌症的一种有前途的治疗方法。RPT目前根据化疗范例进行递送。支持这一建议将有助于带来一个合理的，基于广告的方法，RPT交付。

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.