3D small-scale dosimetry and tumor control of 225Ac radiopharmaceuticals for prostate cancer

Abstract

Abstract Radiopharmaceutical therapy using $$\upalpha$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>α</mml:mi> </mml:math> -emitting $$^{225}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mmultiscripts> <mml:mrow/> <mml:mrow/> <mml:mn>225</mml:mn> </mml:mmultiscripts> </mml:math> Ac is an emerging treatment for patients with advanced metastatic cancers. Measurement of the spatial dose distribution in organs and tumors is needed to inform treatment dose prescription and reduce off-target toxicity, at not only organ but also sub-organ scales. Digital autoradiography with $$\upalpha$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>α</mml:mi> </mml:math> -sensitive detection devices can measure radioactivity distributions at 20–40 $$\upmu {\hbox {m}}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:mi>μ</mml:mi> <mml:mtext>m</mml:mtext> </mml:mrow> </mml:math> resolution, but anatomical characterization is typically limited to 2D. We collected digital autoradiographs across whole tissues to generate 3D dose volumes and used them to evaluate the simultaneous tumor control and regional kidney dosimetry of a novel therapeutic radiopharmaceutical for prostate cancer, [ 225 Ac]Ac-Macropa-PEG 4 -YS5, in mice. 22Rv1 xenograft-bearing mice treated with 18.5 kBq of [ 225 Ac]Ac-Macropa-PEG 4 -YS5 were sacrificed at 24 h and 168 h post-injection for quantitative $$\upalpha$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mi>α</mml:mi> </mml:math> -particle digital autoradiography and hematoxylin and eosin staining. Gamma-ray spectroscopy of biodistribution data was used to determine temporal dynamics and $$^{213}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mmultiscripts> <mml:mrow/> <mml:mrow/> <mml:mn>213</mml:mn> </mml:mmultiscripts> </mml:math> Bi redistribution. Tumor control probability and sub-kidney dosimetry were assessed. Heterogeneous $$^{225}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mmultiscripts> <mml:mrow/> <mml:mrow/> <mml:mn>225</mml:mn> </mml:mmultiscripts> </mml:math> Ac spatial distribution was observed in both tumors and kidneys. Tumor control was maintained despite heterogeneity if cold spots coincided with necrotic regions. $$^{225}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mmultiscripts> <mml:mrow/> <mml:mrow/> <mml:mn>225</mml:mn> </mml:mmultiscripts> </mml:math> Ac dose-rate was highest in the cortex and renal vasculature. Extrapolation of tumor control suggested that kidney absorbed dose could be reduced by 41% while maintaining 90% TCP. The 3D dosimetry methods described allow for whole tumor and organ dose measurements following $$^{225}$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mmultiscripts> <mml:mrow/> <mml:mrow/> <mml:mn>225</mml:mn> </mml:mmultiscripts> </mml:math> Ac radiopharmaceutical therapy, which correlate to tumor control and toxicity outcomes.

Topics & Concepts