Impact of [177Lu]Lu-PSMA-617 Radioligand Therapy on Reference Organ Uptake Assessed by [68Ga]Ga-PSMA-11-PET/CT

Simple Summary The transmembrane protein prostate-specific membrane antigen (PSMA) has emerged as a target for both molecular imaging and PSMA-directed radioligand therapy (RLT). Normal organs, including the liver and salivary glands, exhibit physiological PSMA-ligand accumulation and have, therefore, gained interest as decisive landmarks for the semiquantitative classification of tumoral uptake on [Ga-68]Ga-PSMA-11 PET/CT imaging. The presented study aims to assess the change in uptake to reference organs, including the liver, parotid and salivary glands after radioligand therapy (RLT) with [Lu-177]Lu-PSMA-617 in relation to pretreatment imaging metrics. This study aims to assess the change in uptake to reference organs, including the liver, parotid and salivary glands after radioligand therapy (RLT) with [Lu-177]Lu-PSMA-617 in relation to pretreatment imaging metrics. Eighty-five patients with mCRPC underwent [Ga-68]Ga-PSMA-11 PET/CT imaging prior to (pre RLT PET) and after (post RLT PET) a median of 3 (IQR 2-6) RLT cycles with [Lu-177]Lu-PSMA-617. PSMA-positive tumor burden was stratified into 4 groups based on modified PROMISE criteria (oligofocal, multifocal, disseminated, diffuse). Uptake (SUVmean, SUVmax) in liver tissue, parotid and submandibular glands was measured. A control group was established with 54 patients who had received two separate PET acquisitions following the same protocol (PET1, PET2) within 12 months for localized or oligofocal prostate cancer without RLT in the interim. Baseline uptake values (SUVmean, SUVmax) in parotid (10.8 & PLUSMN; 3.2, 16.8 & PLUSMN; 5.4) and submandibular glands (11.3 & PLUSMN; 2.8, 18.1 & PLUSMN; 4.7) are 2-fold compared to liver uptake (4.9 & PLUSMN; 1.4, 7.7 & PLUSMN; 2.0), with no significant change between PET 1 and PET 2 in the control group. In the RLT group, increasing tumor burden class is significantly associated with decreasing uptake in the liver (p = 0.013), parotid (p < 0.001) and submandibular glands (p < 0.001); this tumor sink effect by respective tumor burden is widely maintained after RLT (p = 0.011, p < 0.001, p < 0.001). RLT has a significant impact on salivary gland uptake with decreasing values per patient in all groups of disease burden change (up to -30.4% in submandibular glands, p < 0.001), while liver tissue shows rising values in patients with declining tumor burden throughout RLT (+18.6%, p = 0.020). Uptake in liver tissue and salivary glands on [Ga-68]Ga-PSMA-11 PET/CT imaging is inversely related to tumor burden prior to and following RLT with [Lu-177]Lu-PSMA-617. Per patient, salivary gland uptake is further reduced throughout RLT independently from tumor burden, while changes in liver uptake remain burden-dependent. Liver and salivary gland uptake-derived metrics and segmentation thresholds may thus be of limited value when used as reference for response assessment to RLT.