Andrea Schaefer-Schuler

Purpose: Terbium-161 ( ¹⁶¹ Tb) has emerged as a promising radionuclide for radioligand therapy (RLT) due to its emission of Auger and conversion electrons, which may support therapeutic efficacy through increased local energy deposition. Despite growing research efforts aimed at the clinical potential of ¹⁶¹ Tb, dosimetric data, particularly for tumor lesions, remain scarce. To address this gap, we assessed tumor and organ dosimetry in mCRPC patients treated with [ ¹⁶¹ Tb]Tb-PSMA-617. Methods: The study involved n = 15 patients with metastasized castration-resistant prostate cancer (mCRPC) participating in a registry (NCT04833517) and receiving [ ¹⁶¹ Tb]Tb-PSMA-617. All patients received a median of 2 (range: 1–3) cycles with mean administered activity of 6.0 ± 1.3 GBq and mean cumulative activity of 12.3 ± 4.6 GBq [ ¹⁶¹ Tb]Tb-PSMA-617. Hybrid dosimetry of organs at risk, including the salivary glands, the kidneys, the liver, and tumor lesions was performed analyzing whole-body planar and SPECT/CT images. Absorbed doses were estimated using OLINDA/EXM for ¹⁶¹ Tb. Tumor-to-organ ratios (TR) of mean tumor-absorbed doses over relevant organs at risk were calculated. Results: Mean absorbed dose to kidneys, parotid glands, submandibular glands and liver was 0.70 ± 0.41 Gy/GBq, 0.40 ± 0.20 Gy/GBq, 0.36 ± 0.14 Gy/GBq and 0.13 ± 0.08 Gy/GBq, respectively. Tumor kinetics in 43 lesions demonstrated stable activity over time (mean half-life of all lesions: 44.07 h ± 15.88 h) delivering a mean overall absorbed tumor dose of 5.95 ± 3.60 Gy/GBq, the resulting TR over kidney and parotid gland were 10.55 ± 8.32 and 16.15 ± 11.85, respectively. Conclusion: [ ¹⁶¹ Tb]Tb-PSMA-617 delivers high tumor-absorbed doses with tolerable doses to relevant organs at risk, translating into favorable tumor-to-normal-organ ratios. Dosimetry results confirm ¹⁶¹ Tb as a promising radionuclide for PSMA-targeted radioligand therapy in mCRPC.

Large language models (LLMs) are increasingly explored for clinical use. However, the extent to which such models can reliably support physicians in reporting, staging, and the assessment of classification remains an active area of research. This study aimed to evaluate and compare multiple LLMs for automated PROMISE V2 classification for prostate cancer. A total of 126 unambiguous German-language PSMA PET/CT text reports were retrospectively analyzed, with reference standards established by expert consensus based on image interpretation and the original report text. Five LLMs (GPT-5.4, DeepSeek-V3.2, Claude Sonnet 4.6, Gemini 3 Flash and Grok 4) were assessed using two English-language prompting strategies of varying complexity. Agreement with the reference standard served as the primary endpoint. Performance varied in the short-prompt setting (36.5–79.4%) but improved consistently with the long prompt (74.6–86.5%), with Gemini 3 Flash achieving the highest agreement. Across PROMISE V2 subcategories, agreement rates were high (miT: 81.0–92.1%, miN: 92.9–96.0%, miM: 92.9–95.2%), despite inter-model differences. In conclusion, contemporary LLMs demonstrate promising performance in deriving PROMISE V2 scores from unambiguous original report texts, particularly when guided by detailed prompts.

Introduction: To enhance the effectiveness of radioligand therapy (RLT), new prostate-specific membrane antigen (PSMA) targeting radiopharmaceuticals utilizing alternative radionuclides are under active investigation. One promising alternative to the established ¹⁷⁷ Lu is the use of ¹⁶¹ Tb. A key advantage of ¹⁶¹ Tb is its emission of a higher proportion of low-energy conversion and Auger electrons, which may contribute to enhanced therapeutic effectiveness. This study provides a first exploratory evaluation of the efficacy and safety of [ ¹⁶¹ Tb]Tb-PSMA-617 in patients with progression after [ ¹⁷⁷ Lu]Lu-PSMA-617, aiming to generate early clinical insights. Methods: The study included 15 patients with mCRPC, who were enrolled in the “prospective registry to assess outcome and toxicity of targeted radionuclide therapy in patients with mCRPC in clinical routine“ (REALITY Study; NCT04833517). All patients had received conventional PSMA RLT using [ ¹⁷⁷ Lu]Lu-PSMA-617, which resulted in initial biochemical response (PSA decline ≥50%), followed by a biochemical relapse, prompting the re-initiation of PSMA RLT using [ ¹⁶¹ Tb]Tb-PSMA-617. Patients received a median of 3 (range: 2–7) cycles with mean administered activity of 5.4 ± 1.1 GBq and mean cumulative activity of 19.2 ± 6.4 GBq [ ¹⁶¹ Tb]Tb-PSMA-617. Treatment response was assessed both biochemically by serum PSA levels and through molecular imaging by total lesion PSMA (TLP) on [ ⁶⁸ Ga]Ga-PSMA-11 PET/CT scans. Adverse events were assessed at baseline and follow-up using the “Common Terminology Criteria for Adverse Events“ (Version 5.0). Results: [ ¹⁶¹ Tb]Tb-PSMA-617 RLT showed response rates of 66.7% (10/15 patients) based on biochemical assessment and 86.7% (13/15 patients) based on molecular imaging assessment. Beginning with the initiation of [ ¹⁶¹ Tb]Tb-PSMA-617 RLT, the median progression-free survival (PFS) was 6.4 months, and the median overall survival (OS) was 15.5 months. In total, 6 CTCAE grade deteriorations from grade 2 to grade 3 or from grade 3 to grade 4 were observed. No discontinuation of PSMA RLT due to adverse events was reported. Conclusions: [ ¹⁶¹ Tb]Tb-PSMA-617 RLT emerges as a promising treatment option, demonstrating encouraging response rates, preliminary clinical outcomes, and a favorable safety profile as second-line RLT in progressing patients who previously benefited from [ ¹⁷⁷ Lu]Lu-PSMA-617 RLT.

Purpose: With increasing life expectancy, the number of older patients with metastatic castration-resistant prostate cancer (mCRPC) continues to rise, but this group is currently underrepresented in clinical trials. This study aims to assess the efficacy and safety of prostate-specific membrane antigen (PSMA) targeted radioligand therapy (RLT) in patients over 85 years old with mCRPC. Materials and Methods: A retrospective analysis was conducted on 21 mCRPC patients aged 85 years or older receiving PSMA-RLT (range: 85–96 y). The median number of treatment cycles was 4 (range: 1–13 cycles), with a mean cumulative administered activity of 26.9±17.3 GBq (range: 8.0–87.2 GBq) of [¹⁷⁷Lu]Lu-PSMA-617. Adverse events, including anemia, thrombocytopenia, leukopenia, renal impairment, fatigue, and xerostomia were classified according to CTCAE version 5.0. Results: The mean best PSA response across the cohort was –37.6±73.3%, with 62% (13 of 21 patients) showing partial remission. Median progression-free survival and overall survival were 4.6 and 14.7 months, respectively. Severe adverse events were rare, occurring in 2 patients: 1 case of grade 3 anemia and 1 of grade 3 thrombocytopenia. Conclusions: The results demonstrate that PSMA-RLT is an effective and well-tolerated treatment for mCRPC patients over 85 years, with clinical outcomes and safety comparable to those observed in studies involving younger populations. This highlights its potential as a valuable therapeutic option for this aging patient group.

Background: Even though the introduction of ¹⁷⁷Lu-PSMA-617 RLT represents a major milestone in the treatment of mCRPC, there are still patients who do not respond adequately to this therapy and for whom there are only limited options left. Augmenting ¹⁷⁷Lu-PSMA-617 RLT with the alpha-emitter ²²⁵Ac-PSMA-617 may present an escalating treatment option to increase efficacy. In this study, we aim to evaluate outcome and safety of ²²⁵Ac-PSMA-617 augmentation to ¹⁷⁷Lu-PSMA-617 RLT in patients who present insufficient response to monotherapy with ¹⁷⁷Lu-PSMA-617 RLT. Patients and Methods: The study included n = 51 mCRPC patients enrolled in a prospective registry receiving ¹⁷⁷Lu-PSMA-617 monotherapy and showing insufficient response, followed by initiation of ²²⁵Ac-PSMA-617 augmentation, with adjusted activities depending on individual patient characteristics. Biochemical response, progression-free survival, and overall survival were assessed. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE v.5.0). Results: After initiation of ²²⁵Ac-PSMA-617 augmentation to ¹⁷⁷Lu-PSMA-617 RLT, 24/51 patients (47.1%) exhibited partial remission, 16/51 (31.4%) stable disease, and 11/51 (21.6%) progressive disease. The median progression-free survival and overall survival rates were 6.3 months and 9.1 months, respectively. The majority of CTCAE gradings remained stable after initiating augmentation. Severe adverse events were rare, and no treatment termination due to side effects was recorded. Conclusions: ²²⁵Ac-PSMA-617 augmented ¹⁷⁷Lu-PSMA-617 radioligand therapy seems to be an effective escalating treatment option in patients after failure of conventional ¹⁷⁷Lu-PSMA-617 RLT and represents a promising approach balancing antitumor effect and tolerable side effects.

Purpose: This study aims to evaluate the outcome and renal safety of prostate-specific membrane antigen (PSMA)–radioligand therapy (RLT) in patients with metastatic castration-resistant prostate carcinoma (mCRPC) and preexisting renal impairment. Methods: Ninety-four patients with preexisting renal impairment were included in this retrospective analysis. Inclusion criterion was a glomerular filtration rate (GFR) of ≤60 mL/min (equivalent to Common Terminology Criteria of Adverse Events [CTCAE] ≥2). Patients underwent either [¹⁷⁷Lu]Lu-PSMA-617 RLT exclusively (n = 63) or additionally in augmented manner with [²²⁵Ac]Ac-PSMA-617 (n = 31). The median number of administered cycles was 4 (range, 1–16 cycles) with a mean cumulative activity of 29.9 ± 16.3 GBq (range, 6.9–87.2 GBq) [¹⁷⁷Lu]Lu-PSMA-617. Main blood parameters of interest were creatinine, cystatin C, and the respective GFR values. Changes in GFR were categorized according to CTCAE v5.0. Results: In the entire cohort, mean best PSA response was −56.73% ± 45.71%, with 63 of 94 patients (67%) experiencing partial remission. The median progression-free survival and overall survival were 6.7 and 14.1 months, respectively. Under PSMA-RLT, 5 of 94 patients (5.3%) improved to CTCAE grade 0, and 23 of 94 (24.5%) improved to CTCAE grade 1. Three of 94 patients (3.2%) improved from CTCAE grade 3 to grade 2, and only 5 of 94 (5.3%) decreased. The majority (58/94 [61.7%]) of patients stayed stable in terms of CTCAE grading. Conclusion: PSMA-RLT is an effective and safe treatment in mCRPC patients with preexisting impaired renal function (CTCAE ≥2). In daily clinical practice, patients should not be categorically excluded from enrolment to PSMA-RLT due to renal impairment.

Background/Objectives: The augmentation of [¹⁷⁷Lu]Lu-PSMA-617 radioligand therapy by alpha emitting [²²⁵Ac]Ac-PSMA-617, known as the tandem therapy concept, is a promising escalating treatment option in advanced mCRPC. In this study, we evaluated the value of [¹⁸F]FDG PET/CT-derived molecular imaging biomarkers for predicting response and outcome to PSMA tandem RLT in n = 33 patients with insufficient response on [¹⁷⁷Lu]Lu-PSMA-617 monotherapy. Methods: Six different molecular imaging parameters at baseline, i.e., before initiation of PSMA tandem RLT with respect to SUV_max, SUV_peak, SUV₅, SUV_mean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were tested for association with response and overall survival (OS). Results: After the initiation of augmentation, 24.2% of patients with a previously insufficient response experienced partial remission, and 39.4% experienced stable disease. The median OS was 7 months (95% CI: 4–11 months). None of the tested parameters were able to predict the response (all p > 0.529). In contrast, the [¹⁸F]FDG PET/CT-derived whole-body molecular imaging parameter TLG was significantly (p = 0.029) associated with OS of patients undergoing [²²⁵Ac]Ac-PSMA-617 augmented [¹⁷⁷Lu]Lu-PSMA-617 RLT after insufficient response to [¹⁷⁷Lu]Lu-PSMA-617 monotherapy. Conclusion: Implementing [¹⁸F]FDG PET/CT in the management of PSMA-RLT in clinical practice may contribute to outcome prediction and provide a route to more individualized management in mCRPC.

The aim of this retrospective study was to identify pre-therapeutic predictive laboratory and molecular imaging biomarkers for response and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT). Pre-therapeutic laboratory and [⁶⁸Ga]Ga-PSMA-11 PET/CT data of n = 102 mCRPC patients receiving [¹⁷⁷Lu]Lu-PSMA-617 RLT within a prospective registry (REALITY Study, NCT04833517) were analyzed including laboratory parameters such as alkaline phosphatase (ALP), prostate-specific antigen (PSA), gamma glutamyl transferase (GGT), glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), neuron specific enolase (NSE), hemoglobin (Hb), and imaging parameters such as maximum standardized uptake value of the tumor lesions (SUV_max), the mean standardized uptake value of all tumor lesions (SUV_mean), the whole-body molecular tumor volume (MTV), and the whole-body total lesion PSMA (TLP). Mann–Whitney U test, univariate and multivariable Cox-regression were performed to test for association of the parameters with response and OS. The SUV_mean of all lesions was significantly different between responders and non-responders (SUV_mean responders 8.95 ± 2.83 vs. non-responders 7.88 ± 4.46, p = 0.003), whereas all other tested biochemical and imaging parameters did not reveal significant differences. Hb and the molecular imaging parameters MTV and TLP showed a significant association with OS (p = 0.013, p = 0.005; p = 0.009) in univariant Cox regression; however, only TLP remained significant in multivariable analysis (Hazard ratio 1.033, p = 0.009). This study demonstrates a statistically significant association between the quantitative PET/CT imaging parameter SUV_mean and PSA response, as well as between the baseline TLP and OS of mCRPC patients undergoing RLT.

“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.

Background: Dosimetry is of high importance for optimization of patient-individual PSMA-targeted radioligand therapy (PSMA-RLT). The aim of our study was to evaluate and compare the feasibility of different approaches of image-based absorbed dose estimation in terms of accuracy and effort in clinical routine. Methods: Whole-body planar images and SPECT/CT images were acquired from 24 patients and 65 cycles at 24h, 48h, and ≥96h after administration of a mean activity of 6.4 GBq [¹⁷⁷Lu]Lu-PSMA-617 (range 3–10.9 GBq). Dosimetry was performed by use of the following approaches: 2D planar-based dosimetry, 3D SPECT/CT-based dosimetry, and hybrid dosimetry combining 2D and 3D data. Absorbed doses were calculated according to IDAC 2.1 for the kidneys, the liver, the salivary glands, and bone metastases. Results: Mean absorbed doses estimated by 3D dosimetry (the reference method) were 0.54 ± 0.28 Gy/GBq for the kidneys, 0.10 ± 0.05 Gy/GBq for the liver, 0.81 ± 0.34 Gy/GBq for the parotid gland, 0.72 ± 0.39 Gy/GBq for the submandibular gland, and 1.68 ± 1.32 Gy/GBq for bone metastases. Absorbed doses of normal organs estimated by hybrid dosimetry showed small, non-significant differences (median up to 4.0%) to the results of 3D dosimetry. Using 2D dosimetry, in contrast, significant differences (median up to 10.9%) were observed. Regarding bone metastases, small, but significant differences (median up to 7.0%) of absorbed dose were found for both, 2D dosimetry and hybrid dosimetry. Bland-Altman analysis revealed high agreement between hybrid dosimetry and 3D dosimetry for normal organs and bone metastases, but substantial differences between 2D dosimetry and 3D dosimetry. Conclusion: Hybrid dosimetry provides high accuracy in estimation of absorbed dose in comparison to 3D dosimetry for all important organs and is therefore feasible for use in individualized PSMA-RLT.