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

2017; Society of Nuclear Medicine and Molecular Imaging; Volume: 58; Issue: 10 Linguagem: Inglês

10.2967/jnumed.117.191395

1535-5667

Clemens Kratochwil, Frank Bruchertseifer, Hendrik Rathke, Marcus Bronzel, Christos Apostolidis, Wilko Weichert, Uwe Haberkorn, Frederik L. Giesel, Aliyah Morgenstern,

Peptidase Inhibition and Analysis

The aim of this study was to develop a treatment protocol for 225 Ac-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 177 Lu-PSMA-617 scans extrapolated to the physical half-life of 225 Ac, 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 225 Ac-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 225 Ac-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 225 Ac-PSMA-617 per cycle repeated every 8 wk presents a reasonable trade-off between toxicity and biochemical response.