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Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding
The Journal of Nuclear Medicine ( IF 9.1 ) Pub Date : 2017-10-01 , DOI: 10.2967/jnumed.117.191395
Clemens Kratochwil , Frank Bruchertseifer , Hendrik Rathke , Marcus Bronzel , Christos Apostolidis , Wilko Weichert , Uwe Haberkorn , Frederik L. Giesel , Alfred Morgenstern

The aim of this study was to develop a treatment protocol for 225Ac-PSMA-617 α-radiation therapy in advanced-stage, metastatic castration-resistant prostate cancer patients with prostate-specific membrane antigen (PSMA)–positive tumor phenotype. Methods: A dosimetry estimate was calculated on the basis of time–activity curves derived from serially obtained 177Lu-PSMA-617 scans extrapolated to the physical half-life of 225Ac, assuming instant decay of unstable daughter nuclides. Salvage therapies empirically conducted with 50 (n = 4), 100 (n = 4), 150 (n = 2), and 200 kBq/kg (n = 4) of 225Ac-PSMA-617 were evaluated retrospectively regarding toxicity and treatment response. Eight of 14 patients received further cycles in either 2- or 4-mo intervals with identical or deescalated activities. Results: Dosimetry estimates for 1 MBq of 225Ac-PSMA-617 assuming a relative biologic effectiveness of 5 revealed mean doses of 2.3 Sv for salivary glands, 0.7 Sv for kidneys, and 0.05 Sv for red marrow that are composed of 99.4% α, 0.5% β, and 0.1% photon radiation, respectively. In clinical application, severe xerostomia became the dose-limiting toxicity if treatment activity exceeded 100 kBq/kg per cycle. At 100 kBq/kg, the duration of prostate-specific antigen decline was less than 4 mo, but if therapy was repeated every 2 mo patients experienced additive antitumor effects. Treatment activities of 50 kBq/kg were without toxicity but induced insufficient antitumor response in these high-tumor-burden patients. Remarkable antitumor activity by means of objective radiologic response or tumor marker decline was observed in 9 of 11 evaluable patients. Conclusion: For advanced-stage patients, a treatment activity of 100 kBq/kg of 225Ac-PSMA-617 per cycle repeated every 8 wk presents a reasonable trade-off between toxicity and biochemical response.



中文翻译:

225 Ac-PSMA-617靶向靶向治疗转移性去势抵抗性前列腺癌:剂量估算和经验剂量发现

这项研究的目的是为患有前列腺特异性膜抗原(PSMA)阳性表型的晚期转移性去势抵抗性前列腺癌患者制定225 Ac-PSMA-617α放射疗法的治疗方案。方法:假设从不稳定的子核素立即衰变,根据从连续获得的177 Lu-PSMA-617扫描得出的时间-活动曲线得出剂量学估计值,该扫描推断到225 Ac的物理半衰期。凭经验进行抢救疗法的50(n = 4),100(n = 4),150(n = 2)和200 kBq / kg(n = 4)为225对Ac-PSMA-617的毒性和治疗反应进行了回顾性评估。14例患者中有8例以2个月或4个月的间隔接受了相同或降级活动的进一步循环。结果:225的1 MBq的剂量学估计假设相对生物有效性为5的Ac-PSMA-617,其唾液腺的平均剂量为2.3 Sv,肾脏的平均剂量为0.7 Sv,红骨髓的平均剂量为0.7 Sv,由99.4%α,0.5%β和0.1%光子辐射组成, 分别。在临床应用中,如果每个周期的治疗活性超过100 kBq / kg,则严重的口干症将成为剂量限制性毒性。在100 kBq / kg时,前列腺特异性抗原下降的持续时间少于4 mo,但是如果每2 mo重复治疗,则患者会产生累加的抗肿瘤作用。在这些高肿瘤负荷患者中,50 kBq / kg的治疗活性无毒性,但诱导的抗肿瘤反应不足。在11名可评估患者中,有9名患者通过客观的放射学反应或肿瘤标志物下降显示出显着的抗肿瘤活性。结论:对于晚期患者,每8周重复一次,每个周期100 kBq / kg的225 Ac-PSMA-617的治疗活性在毒性和生化反应之间进行了合理的权衡。

更新日期:2017-10-02
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