Wessels Barry W, Konijnenberg Mark W, Dale Roger G, Breitz Hazel B, Cremonesi Marta, Meredith Ruby F, Green Alan J, Bouchet Lionel G, Brill A Bertrand, Bolch Wesley E, Sgouros George, Thomas Stephen R
Department of Radiation Oncology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
J Nucl Med. 2008 Nov;49(11):1884-99. doi: 10.2967/jnumed.108.053173. Epub 2008 Oct 16.
Renal toxicity associated with small-molecule radionuclide therapy has been shown to be dose-limiting for many clinical studies. Strategies for maximizing dose to the target tissues while sparing normal critical organs based on absorbed dose and biologic response parameters are commonly used in external-beam therapy. However, radiopharmaceuticals passing though the kidneys result in a differential dose rate to suborgan elements, presenting a significant challenge in assessing an accurate dose-response relationship that is predictive of toxicity in future patients. We have modeled the multiregional internal dosimetry of the kidneys combined with the biologic response parameters based on experience with brachytherapy and external-beam radiation therapy to provide an approach for predicting radiation toxicity to the kidneys.
The multiregion kidney dosimetry model of MIRD pamphlet no. 19 has been used to calculate absorbed dose to regional structures based on preclinical and clinical data. Using the linear quadratic model for radiobiologic response, we computed regionally based surviving fractions for the kidney cortex and medulla in terms of their concentration ratios for several examples of radiopharmaceutical uptake and clearance. We used past experience to illustrate the relationship between absorbed dose and calculated biologically effective dose (BED) with radionuclide-induced nephrotoxicity.
Parametric analysis for the examples showed that high dose rates associated with regions of high activity concentration resulted in the greatest decrease in tissue survival. Higher dose rates from short-lived radionuclides or increased localization of radiopharmaceuticals in radiosensitive kidney subregions can potentially lead to greater whole-organ toxicity. This finding is consistent with reports of kidney toxicity associated with early peptide receptor radionuclide therapy and (166)Ho-phosphonate clinical investigations.
Radionuclide therapy dose-response data, when expressed in terms of biologically effective dose, have been found to be consistent with external-beam experience for predicting kidney toxicity. Model predictions using both the multiregion kidney and linear quadratic models may serve to guide the investigator in planning and optimizing future clinical trials of radionuclide therapy.
在许多临床研究中，小分子放射性核素疗法相关的肾毒性已被证明是剂量限制因素。基于吸收剂量和生物反应参数，在外部束流治疗中通常采用使靶组织剂量最大化同时保护正常关键器官的策略。然而，通过肾脏的放射性药物会导致对亚器官成分的剂量率差异，这在评估准确的剂量反应关系以预测未来患者的毒性方面构成了重大挑战。我们基于近距离放射治疗和外部束流放射治疗的经验，对肾脏的多区域体内剂量学与生物反应参数进行了建模，以提供一种预测肾脏放射毒性的方法。
使用MIRD手册第19号的多区域肾脏剂量学模型，根据临床前和临床数据计算区域结构的吸收剂量。利用放射生物学反应的线性二次模型，针对几种放射性药物摄取和清除的示例，根据肾脏皮质和髓质的浓度比计算区域存活分数。我们利用过去的经验来说明吸收剂量与放射性核素诱导的肾毒性所计算的生物有效剂量（BED）之间的关系。
示例的参数分析表明，与高活性浓度区域相关的高剂量率导致组织存活率下降最大。短寿命放射性核素的较高剂量率或放射性药物在放射敏感的肾脏亚区域中定位增加，可能会导致更大的全器官毒性。这一发现与早期肽受体放射性核素疗法和（166）Ho - 膦酸盐临床研究相关的肾脏毒性报告一致。
当以生物有效剂量表示时，放射性核素疗法的剂量反应数据已被发现与预测肾脏毒性的外部束流经验一致。使用多区域肾脏模型和线性二次模型的模型预测可能有助于指导研究人员规划和优化未来的放射性核素疗法临床试验。
