Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Dosimetry Estimate and Empiric Dose Finding

To develop a treatment protocol for 225Ac-PSMA-617 alpha-radiation therapy in advanced stage, metastatic castration resistant prostate cancer patients with PSMA-positive tumor phenotype. Methods: A dosimetry estimate was calculated based on time-activity-curves derived from serially performed 177Lu-PSMA-617 scans extrapolated to the physical half-life of 225Ac, assuming instant decay of instable daughter nuclides. Salvage therapies empirically conducted with 50kBq/kg (n=4), 100kBq/kg (n=4), 150kBq/kg (n=2), 200kBq/kg (n=4) 225Ac-PSMA-617 were evaluated retrospectively regarding toxicity and treatment response. 8 out of 14 patients received further cycles in either 2 or 4 months interval with identical or de-escalated activities. Results: Dosimetry estimates for 1 MBq of 225Ac-PSMA-617 assuming a relative biological 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% alpha, 0.5% beta and 0.1% photon radiation, respectively. In clinical application, severe xerostomia became the dose limiting toxicity if treatment activity exceeded 100kBq/kg per cycle. At 100kBq/kg duration of PSA-decline was <4 months, but if therapy was repeated every 2 months patients experienced additive anti-tumor effects. Treatment activities of 50kBq/kg were without toxicity but induced insufficient anti-tumor response in these high tumor burden patients. Remarkable antitumor activity by means of objective radiological response or tumor marker decline was observed in 9/11 evaluable patients. Conclusion: For advanced stage patients, we propose a treatment activity of 100kBq/kg 225Ac-PSMA-617 per cycle repeated every 8 weeks as a therapeutically effective protocol for PSMA targeting alpha-radiation therapy with moderate side effects.

KRATOCHWIL Clemens;  BRUCHERTSEIFER Frank;  RATHKE H;  BRONZEL M;  APOSTOLIDIS Christos;  WEICHERT W;  HABERKORN Uwe;  GIESEL Frederik;  MORGENSTERN Alfred; 

2017-10-12

SOC NUCLEAR MEDICINE INC

JRC105916

0161-5505,   

https://publications.jrc.ec.europa.eu/repository/handle/JRC105916,   

10.2967/jnumed.117.191395,