Tumor Sink Effect with Prostate-Specific Membrane Antigen-Targeted Theranostics in Patients with Metastatic Castration-Resistant Prostate Cancer: Intra-Individual Evaluations

SIMPLE SUMMARY: The toxicity and dosing of radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) may be impacted by the “tumor sink effect”. This phenomenon occurs when a bulky tumor accumulates so much radiopharmaceutical that uptake of the agent significantly decreases in healthy organs-at-risk of radiation-related damage. We assessed the tumor sink effects of prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals via three within-patient comparisons in 33 men with mCRPC given two cycles of lutetium-177-PSMA-617 RLT. The comparisons involved changes in the relationships between total lesion PSMA, reflecting the body’s overall tumor burden, and/or the mean standardized uptake value, reflecting radiopharmaceutical accumulation, in the parotid salivary glands, spleen, liver, and kidney. Tumor sink effects were found in the salivary glands and spleen, and possibly the liver. These findings support everyday use and additional study of individualized lutetium-177-PSMA-617 activities adjusted based on tumor burden changes over the course of RLT in men with advanced prostate cancer, to try to improve the efficacy/toxicity ratio. ABSTRACT: “Tumor sink effects”, decreased physiological uptake of radiopharmaceuticals due to sequestration by a tumor, may impact radioligand therapy (RLT) toxicity and dosing. We investigated these effects with prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals in the healthy organs-at-risk (the parotid glands, kidneys, liver, and spleen) of 33 patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively performed three intra-individual comparisons. First, we correlated changes from baseline to post-RLT (after two 177-lutetium (177Lu)-PSMA-617 cycles) in total lesional PSMA (∆TLP) and organ mean standardized uptake values (∆SUVmean). Second, in 25 RLT responders, we compared the organ SUVmean post-RLT versus that at baseline. Lastly, we correlated the baseline TLP and organ SUVmean. Data were acquired via 68-gallium-PSMA-11 positron emission tomography before the first and after the second 177Lu-PSMA-617 cycle. In the parotid glands and spleen, ∆TLP and ∆SUVmean showed a significant inverse correlation (r = −0.40, p = 0.023 and r = −0.36, p = 0.042, respectively). Additionally, in those tissues, the median organ SUVmean rose significantly from baseline after the response to RLT (p ≤ 0.022), and the baseline TLP and SUVmean were significantly negatively correlated (r = −0.44, p = 0.01 and r = −0.42, p = 0.016, respectively). These observations suggest tumor sink effects with PSMA-targeted radiopharmaceuticals in the salivary glands and spleen of patients with mCRPC.