The Effect of Total Tumor Volume on the Biologically Effective Dose to Tumor and Kidneys for 177Lu-Labeled PSMA Peptides

The aim of this work was to simulate the effect of prostate-specific membrane antigen (PSMA)-positive total tumor volume (TTV) on the biologically effective doses (BEDs) to tumors and organs at risk in patients with metastatic castration-resistant prostate cancer who are undergoing Lu-177-PSMA radioligand therapy. Methods: A physiologically based pharmacokinetic model was fitted to the data of 13 patients treated with Lu-177-PSMA I&T (a PSMA inhibitor for imaging and therapy). The tumor, kidney, and salivary gland BEDs were simulated for TTVs of 0.1-10 L. The activity and peptide amounts leading to an optimal tumor-to-kidneys BED ratio were also investigated. Results: When the TTV was increased from 0.3 to 3 L, the simulated BEDs to tumors, kidneys, parotid glands, and submandibular glands decreased from 22 +/- 15 to 11.0 +/- 6.0 Gy(1.49), 6.5 +/- 2.3 to 3.7 +/- 1.4 Gy(2.5), 11.0 +/- 2.7 to 6.4 +/- 1.9 Gy(4.5), and 10.9 +/- 2.7 to 6.3 +/- 1.9 Gy(4.5), respectively (where the subscripts denote that an alpha/beta of 1.49, 2.5, or 4.5 Gy was used to calculate the BED). The BED to the red marrow increased from 0.17 +/- 0.05 to 0.32 +/- 0.11 Gy(15). For patients with a TTV of more than 0.3 L, the optimal amount of peptide was 273 +/- 136 nmol and the optimal activity was 10.4 +/- 4.4 GBq. Conclusion: This simulation study suggests that in patients with large PSMA-positive tumor volumes, higher activities and peptide amounts can be safely administered to maximize tumor BEDs without exceeding the tolerable BED to the organs at risk.