Metastatic pheochromocytomas and paragangliomas (mPPGLs) are rare neuroendocrine tumours with limited therapeutic options. Peptide receptor radionuclide therapy (PRRT) using somatostatin receptor (SSTR) antagonists (e.g. [177Lu]Lu-DOTA-JR11) may achieve higher tumour and organ absorbed doses compared with standard SSTR agonist therapy (e.g. [177Lu]Lu-DOTA-TOC). This study aimed to perform an intra-patient comparison of tumour and organ dosimetry between [177Lu]Lu-DOTA-TOC and [177Lu]Lu-DOTA-JR11 in patients with mPPGLs refractory to conventional therapies. Secondary endpoints included safety and exploratory clinical efficacy of [177Lu]Lu-DOTA-JR11. In this retrospective pilot study, 6 patients with mPPGLs received 1–2 cycles of [177Lu]Lu-DOTA-TOC ( 7.4 GBq/cycle), followed by 1–2 cycles of [177Lu]Lu-DOTA-JR11 (2 GBq/m2 × body surface area) at an interval of 10–12 weeks. Endpoints included estimation of tumour and organ absorbed doses, assessment of safety according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and symptoms, and evaluation of progression-free survival (PFS) before and after [177Lu]Lu-DOTA-JR11 therapy. Intra-patient comparison showed that the median tumour absorbed dose per cycle was 1.3-fold higher (range 0.9–3.5) with [177Lu]Lu-DOTA-JR11 than with [177Lu]Lu-DOTA-TOC. This was associated with longer PFS after [177Lu]Lu-DOTA-JR11 (12.5 months; range 6 – >20) versus PFS before inclusion (3.5 months; range 1–9). The most severe adverse event was grade 3 lymphopenia in one patient. No thrombocytopenia, neutropenia, creatinine elevation or alanine aminotransferase elevation was observed. [177Lu]Lu-DOTA-JR11 resulted in higher tumour absorbed doses than [177Lu]Lu-DOTA-TOC and was associated with longer post-treatment PFS than PFS before inclusion in this small cohort. Treatment was well tolerated, supporting further prospective evaluation in patients with mPPGLs.

The successful preclinical efficacy studies prompted a Phase I clinical trial to investigate [161Tb]Tb-SibuDAB. Deeper insight into potential undesired effects on normal tissues and organs remained to be investigated. The aim of this preclinical study was, therefore, to assess and compare the tolerability of [161Tb]Tb-SibuDAB with that of [177Lu]Lu-SibuDAB, [161Tb]Tb-PSMA-I T and [177Lu]Lu-PSMA-I T. The time-dependent tissue distribution profiles of [161Tb]Tb-SibuDAB and [161Tb]Tb-PSMA-I T were assessed in immunocompetent mice for dosimetry estimations. Substructural activity distribution in kidneys was further investigated ex vivo. In Study I, [161Tb]Tb-SibuDAB, [177Lu]Lu-SibuDAB, [161Tb]Tb-PSMA-I T and [177Lu]Lu-PSMA-I T were administered at 30 MBq/mouse while in Study II, additional activities of 15 MBq and 60 MBq [161Tb]Tb-SibuDAB were applied. Blood cell counts were determined on Days 10, 28 and 56 after radioligand injection while blood and bone marrow smears, blood plasma biomarkers and selected organs were investigated at study end on Day 56. Organ uptake and absorbed doses were severalfold higher for SibuDAB than for PSMA-I T and terbium-161 delivered about 40

Abstract Background The bone marrow is a critical dose limiting organ in patients receiving radionuclide therapy, but image-based bone marrow dosimetry is not routinely performed in clinical practice. High noise levels and the limited number of vertebral cavities used in bone marrow absorbed dose calculations make absorbed dose estimates susceptible to large uncertainties. This study explores the effects of the number of included vertebrae, partial volume effects, and reconstruction parameters on image-based bone marrow absorbed dose calculations. We included sixteen patients with advanced neuroendocrine tumors treated with [177Lu]Lu–DOTATATE. Bone marrow absorbed dose estimates and their precision were analyzed based on the number of vertebrae included in the calculation. Additional evaluations were performed using both measured (Lung-Spine phantom with spherical inserts) and simulated (digital XCAT phantom) SPECT data, with noise levels matching patients’ bone marrow. Results Increasing the number of vertebrae from one to six improved precision in absorbed doses, reducing the coefficient of variation (COV) from 34 to 6.2%. Only minor differences (0.1%) in bone marrow absorbed dose were observed when adjusting reconstruction parameters from 1 subset, 60 iterations, to 12 subsets, 5 iterations. In the Lung-Spine phantom, smaller volumes (4 mL) were more sensitive to noise than larger volumes (16 mL), with COVs of 36% and 17%, respectively, at 60 updates. In the XCAT phantom, a decrease in recovery was observed in vertebrae near high-uptake regions (L5: 0.63, L1: 0.29), at 60 updates at the highest noise level. Conclusion Including multiple lesion-free vertebrae enhances precision in image-based bone marrow absorbed dose calculations. Nevertheless, careful selection of vertebrae is important, as closely located high-uptake areas can bias absorbed dose estimates. Applying partial volume correction could mitigate spill-out effects, further improving accuracy. Additionally, the minimal differences between reconstruction parameters suggest that bone marrow absorbed dose estimates remain stable across subset configurations.

A power-law model was introduced to characterize the relationship between spherical volumes-of-interest (SVs) and whole kidney parenchyma (WKP)-derived absorbed dose estimates, enabling quantitative precision for image-based dosimetry. Single photon emission computed tomography/computed tomography (SPECT/CT) images were acquired at 24, 48, and 168 h after [177Lu]Lu-DOTATATE treatment in 18 patients. Kidney activity was quantified using WKP and SV-based methods (2 and 0.6 ml) on SPECT-images. WKP and both SV approaches showed good agreement in kidney dosimetry, with normalization factors of 1.12 and 1.23 (standard error mean ≤1.2%), and improved precision when multiple SVs were used. The power-law model demonstrated excellent fit (R2 > 0.97) and high precision (~7%), with no significant difference between SV sizes (P = .15) and minimal bias (<0.003%). This power law model presents a novel method for quantifying the relative precision of SPECT-derived kidney dosimetry. Further validation is warranted to address residual uncertainty and complex noise correlation in the SV-based dose estimates.

Peptide Receptor Radionuclide Therapy (PRRT) with [177Lu]Lu-DOTA-TOC or [177Lu]Lu-DOTA-TATE provides limited response durability in neuroendocrine tumours (NETs). The somatostatin receptor subtype 2 (SSTR2) antagonist [177Lu]Lu-DOTA-JR11 may deliver higher tumour absorbed doses and enhanced efficacy. This study compared median progression-free survival (PFS) and disease control rate (DCR) after [177Lu]Lu-DOTA-JR11 rechallenge versus prior [177Lu]Lu-DOTA-TOC in the same patients with early-progressing metastatic NET. In this retrospective, single-centre compassionate-use study, 15 consecutive patients with metastatic NET who progressed ≤ 12 months after standard [177Lu]Lu-DOTA-TOC therapy (2–4 cycles; 5.6–7.5 GBq/cycle) received rechallenge PRRT: 1–2 cycles [177Lu]Lu-DOTA-TOC followed by 1–2 cycles [177Lu]Lu-DOTA-JR11 (2 GBq/m² body surface area; 2.8–4.8 GBq/cycle) at 10 ± 1 week intervals. Endpoints included comparison of median PFS, DCR, safety (CTCAE v5.0), and absorbed doses. Median PFS was 11 months (12-month DCR 20

The goal of this phase 0 study was to determine the absorbed doses in tumors and relevant organs after a test injection of [161Tb]Tb-DOTA-LM3 and [177Lu]Lu-DOTATOC in the same cohort of patients with grade 1 and 2 somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Methods: In this randomized, crossover, prospective, single-center, open-label phase 0 study, 8 patients received 1 GBq of [161Tb]Tb-DOTA-LM3 and 1 GBq of [177Lu]Lu-DOTATOC, with a 4-wk interval between injections. Quantitative SPECT/CT imaging was performed 3, 24, 72, and 168 h after administration of each radiopharmaceutical to calculate tumor and organ absorbed doses (3-dimensional dosimetry using a Monte Carlo-based ordered-subset expectation maximization algorithm). Results: After injection of 1 GBq of [161Tb]Tb-DOTA-LM3, SPECT/CT revealed excellent image quality with intense tumor uptake in all patients and a median of the mean effective tumor half-life of 103 h (range, 56-152 h) for [161Tb]Tb-DOTA-LM3 and 83 h (range, 30-122 h) for [177Lu]Lu-DOTATOC (P = 0.012). The medians of the mean tumor absorbed doses of [161Tb]Tb-DOTA-LM3 and [177Lu]Lu-DOTATOC were 36.6 Gy/GBq (range, 15-196 Gy/GBq) and 7.0 Gy/GBq (range, 2.4-14.2 Gy/GBq), respectively (P = 0.008). The median kidney and bone marrow absorbed doses were 2.4 Gy/GBq (range, 1.8-3.1 Gy/GBq) and 0.31 Gy/GBq (range, 0.24-0.48 Gy/GBq) for [161Tb]Tb-DOTA-LM3 and 0.6 Gy/GBq (range, 0.4-0.8 Gy/GBq) and 0.04 Gy/GBq (range, 0.03-0.06 Gy/GBq) for [177Lu]Lu-DOTATOC, respectively (both P = 0.008). According to Common Terminology Criteria for Adverse Events version 5.0, grade 1-3 treatment-emergent adverse events occurred in 6 of 8 patients after administration of 1 GBq of [161Tb]Tb-DOTA-LM3. Conclusion: [161Tb]Tb-DOTA-LM3 showed a 7.6-fold-higher median tumor absorbed dose than that of [177Lu]Lu-DOTATOC. The tumor-to-bone marrow absorbed dose ratio was in the same range for [161Tb]Tb-DOTA-LM3 as for [177Lu]Lu-DOTATOC. The administration of 1 GBq of [161Tb]Tb-DOTA-LM3 was safe for all patients, without relevant adverse events.

Targeted radionuclide therapy is an emerging potent therapeutic strategy in oncology. The cell surface antigen CD44v6 is a potential pan-cancer target for radionuclide therapy. This study aimed to evaluate the therapeutic efficacy, biodistribution, dosimetry, and safety profile of AKIR001, an antibody targeting CD44v6 labeled with 177Lu. Methods: The biodistribution and preclinical dosimetry of [177Lu]Lu-AKIR001 were calculated in the highly CD44v6-expressing A431 murine xenograft model, with subsequent extrapolation to predict human dosimetry. Therapeutic efficacy was evaluated across 3 xenograft models, 2 with high and 1 with moderate levels of CD44v6, using multiple dosing levels, fractionation regimens, and combinations with cisplatin. Preclinical toxicology was evaluated in a cross-reactive rabbit model and complemented by a PET imaging study using 68Ga-labeled AKIR001 in a cynomolgus macaque. Results: Biodistribution studies confirmed the high and selective tumor uptake of [177Lu]Lu-AKIR001, resulting in favorable dosimetry predictions for clinical application. Therapeutic evaluations demonstrated significant dose-dependent efficacy in all tested xenograft models, with fractionated dosing (2 doses) resulting in complete tumor regression in 80% of the animals in a radioresistant xenograft model. Biodistribution in rabbits demonstrated low uptake in normal tissues, and a good-laboratory-practice study using an excessive dose of AKIR001 was well tolerated, with no signs of adverse effects. PET imaging in a cynomolgus macaque corroborated these findings. Conclusion: Collectively, these data strongly support the therapeutic efficacy, safety, and dosimetry of [177Lu]Lu-AKIR001, justifying its advancement into clinical trials. A phase 1 clinical trial of [177Lu]Lu-AKIR001for CD44v6-positive solid cancers (NCT06639191) is currently recruiting patients.

Radiopharmaceutical therapy (RPT) is entering a new era of personalization, driven by advances in molecular imaging, radiopharmaceutical development, and a growing body of clinical evidence linking absorbed dose to treatment outcomes. Although external-beam radiotherapy has long integrated dosimetry into standard practice, RPT historically relied on fixed radiopharmaceutical activities and absorbed dose-effect relationships adapted from external-beam radiotherapy, often without accounting for the unique pharmacokinetics, absorbed dose rate dynamics, and biologic responses of systemically administered radiopharmaceuticals. As RPT expands into earlier disease stages, at which patients have longer life expectancies and better performance status, the role of dosimetry in optimizing treatment is becoming increasingly evident. However, despite growing recognition of its benefits, the implementation of dosimetry in clinical practice remains limited, partly because of a self-reinforcing cycle in which the lack of routine dosimetry limits clinical evidence, which in turn hinders its broader adoption. Breaking this cycle is essential to advancing RPT and ensuring that evaluation of dosimetry is based on clinical merit rather than logistic constraints. This article examines the current landscape of RPT dosimetry, highlighting key challenges and opportunities from a European perspective and aiming to foster a more factual and constructive discussion on the topic. We discuss the fundamental differences between dosimetry-driven treatment planning and posttherapy absorbed dose verification, emphasizing the latter as a practical entry point for clinical adoption. We underscore the need for harmonized standards, improved imaging resolution, and tailored absorbed dose-effect relationships that reflect the heterogeneity of RPT delivery and the complexity of tumor and organ responses. The paper also addresses regulatory, infrastructural, and resource barriers to RPT dosimetry implementation and highlights ongoing European initiatives to strengthen frameworks, enhance stakeholder collaboration, and integrate absorbed dose biomarkers into authorization processes and clinical decision-making. By rethinking dosimetry and promoting standardized, evidence-based approaches, the field can advance beyond fixed-activity protocols toward truly individualized RPT. However, achieving clinically feasible integration of dosimetry into routine practice requires structured efforts to generate high-quality clinical evidence and improve accessibility. Ultimately, reliable, patient-centered dosimetry has the potential to enhance therapeutic efficacy, manage toxicity more effectively, and support the long-term evolution of RPT as a cornerstone of precision oncology.

Objective . The cell surface antigen CD44v6 is a promising target for several cancers, with favorable in vivo characteristics such as high affinity and suitable biodistribution. In normal tissues, expressions are restricted to basal epithelial cells in skin and mucosa. Consequently, previous clinical studies have reported varying degrees of toxicity in these tissues. To support new radioimmunotherapies (RIT), we developed small-scale internal dosimetry models for abdominal skin and esophageal mucosa. Using published biodistribution data, we compared absorbed doses to epithelial tissues and bone marrow from four clinically relevant radionuclides: rhenium-186, lutetium-177, terbium-161, and actinium-225. Approach . From the Genotype-Tissue Expression database, 288 H&E-stained sections of abdominal skin and esophageal mucosa were obtained from donors aged 21–70 and segmented to generate voxelized models. Monte Carlo simulations were conducted for the radionuclides across multiple source/target combinations. A compartment model generated serum, skin, and bone marrow biodistributions to estimate AD to the epithelium and bone marrow. Main results . Absorbed dose estimates to the basal layer of the skin were highest for 161 Tb at 23.7 Gy GBq −1 , followed by 177 Lu and 186 Re, with values of 9.5 and 5.3 Gy GBq −1 , respectively, whereas the alpha emitter 225 Ac delivered a dose of 4.9 Gy MBq −1 . For the β -emitters, three methods produced absorbed-dose estimates for the red marrow (RM) consistent within 5% of each other, with the highest values in the hip bone: 0.36, 0.25, and 0.39 Gy GBq −1 for 186 Re, 177 Lu, and 161 Tb, respectively, compared to 0.66 Gy MBq −1 for 225 Ac. Significance . This study presents a dosimetry framework for CD44v6-targeted RIT, demonstrating that, at clinically relevant administered activities, short-ranged emitters like 161 Tb and 225 Ac deliver substantially higher doses to basal epithelial layers compared to 186 Re. RM doses were comparable for 161 Tb and 186 Re, lower for 177 Lu, and highly uncertain for 225 Ac due to daughter redistribution. Overall, these results support the use of 177 Lu for initial clinical trials.

This phase I trial aimed to assess the feasibility and toxicity of combining the poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib with 177Lu-DOTATATE in patients with somatostatin receptor-positive tumors, with the goal of enhancing treatment efficacy through the inhibition of tumor cell DNA repair mechanisms. Methods: Eighteen patients were enrolled, mostly with pancreatic or small intestinal neuroendocrine tumors or atypical lung carcinoids. Patients received a standard dose of 177Lu-DOTATATE (7,400 MBq) for up to 4 cycles, combined with escalating doses of olaparib (50-300 mg twice a day [BID]). The primary objective was to evaluate toxicity using National Cancer Institute Common Toxicity Criteria version 5.0. Secondary objectives included time to progression, overall survival, response rate, and dosimetry variables. Results: The combination of olaparib and 177Lu-DOTATATE was generally well tolerated. Five patients did not complete the 4 cycles because of progression, noncompliance, and carcinoid crisis after the first 177Lu-DOTATATE infusion. Among the remaining patients, thrombocytopenia was the primary dose-limiting toxicity, observed in 3 patients at the 300-mg dose level. Other toxicities were mild, predominantly low-grade bone marrow suppression, nausea, and fatigue. Conclusion: This study demonstrates that combining olaparib with 177Lu-DOTATATE is feasible, with toxicity primarily related to thrombocytopenia. On the basis of the findings, we recommend a starting dose of 200 mg BID for future studies, with the potential to escalate to 300 mg BID depending on patient tolerance. Further investigation in larger, randomized trials is warranted to assess the clinical efficacy of this combination and optimize dosing strategies.

Terbium-161 (161Tb) is a promising β⁻-emitter for theragnostics. However, its complex photon emission pattern—including intense X-rays and low-yield, high-energy γ-emissions—may complicate image-based quantification. This study aimed to assess the feasibility of accurate SPECT/CT-based 161Tb dosimetry through a series of phantom measurements using a GE Discovery NM/CT 670 Pro system. Three collimators were evaluated: extended low-energy general-purpose (ELEGP), low-energy high-resolution (LEHR), and medium-energy general-purpose (MEGP), using two separate energy windows: around the 75 keV γ-peak (± 10

Terbium-161 (161Tb) has emerged as a promising therapeutic radionuclide, yet standardized imaging guidelines are lacking. This study aimed to characterize a SPECT/CT system, currently used in an ongoing clinical trial (BETA PLUS; NCT05359146), focusing on sensitivity, septal penetration, and dead-time effects. Measurements were conducted on a Siemens Symbia Intevo system using two collimators: low-energy high-resolution (LEHR) and medium-energy low-penetration (MELP). Two energy windows were evaluated: 75 keV ± 10

Lymphoma remains a significant health concern, necessitating innovative treatment approaches. 161Tb's coemission of ultra-short-range conversion and Auger electrons, with its medium-energy β--particles, may enable the elimination of single cells and small clusters present in circulation, improving therapeutic outcomes. In this study, we compared 161Tb radioimmunotherapy targeting CD30-a receptor overexpressed in lymphomas-with 177Lu-radiolabeled therapy to evaluate the effect of 161Tb's additional emission of conversion and Auger electrons. Methods: The ability of 161Tb- and 177Lu-radiolabeled anti-CD30 antibody (cAC10) to reduce cell viability and survival and induce DNA damage was evaluated in vitro in CD30-positive T-cell lymphoma cell lines. The biodistribution, dosimetry, and therapeutic effect of both radioimmunoconjugates were studied in a xenograft mouse model. Xenografts treated with [161Tb]Tb-cAC10 and [177Lu]Lu-cAC10 were submitted for quantitative proteomics and phosphoproteomics analyses, followed by bioinformatics analysis. Results: [161Tb]Tb-cAC10 demonstrated superior and CD30-specific cytotoxicity across a panel of T-cell lymphoma cell lines. In vivo studies showed a favorable biodistribution, with high tumor uptake (31.0 ± 7.4 percentage of injected activity per mass of tissue after 48 h) and a higher tumor-absorbed dose for 161Tb. Importantly, a single administration of the 161Tb-radiolabeled compound significantly prolonged survival time compared with an equal injected activity of [177Lu]Lu-cAC10 (median survival, 41 d vs. 21 d). Phosphoproteomic analysis revealed that both [177Lu]Lu-cAC10 and [161Tb]Tb-cAC10 induced alterations in pathways regulating DNA damage response and cell cycle, among others, with 161Tb inducing more pronounced changes than did 177Lu. Conclusion: 161Tb radioimmunotherapy was an effective therapy for CD30-positive T-cell lymphomas. To our knowledge, this is the first evaluation of this therapeutic radionuclide for the treatment of hematologic malignancies. Additionally, in vivo phosphoproteomics provided insights into the biologic processes and pathways regulated by radioimmunotherapy administration, further supporting the superior efficacy of 161Tb over 177Lu.

Segmentation of the whole-kidney parenchyma (WKP) is considered the reference method for kidney dosimetry of radiopharmaceuticals, as it provides the average absorbed dose to the fully delineated WKP. However manual segmentation of the WKP is time consuming, and automated segmentation requires operator verification and potential manual adjustments to the VOI. The aim is to determine if a small volume of interest (SV) method can generate similar kidney absorbed doses as the WKP method. Methods: We obtained SPECT/CT of 18 patients at 24, 48, and 168 h after injection of [177Lu]Lu-DOTATATE (7.3–7.8 GBq). The SPECTs were corrected for attenuation, scatter, and collimator detector response with Monte Carlo-based OSEM reconstruction (ASCC-SPECT) and post-filtered with a 0- to 12-mm Gaussian filter or were only attenuation corrected with a Hann post-filter (AC-SPECT). Kidney dosimetry based on the manually segmented WKP was used as reference method. Recovery coefficients (RCs) for each WKP were determined by Monte Carlo simulations, and normalisation factors, NFs, for SVs were determined relative to the WKP method. Kidney absorbed doses were estimated based on measured activity concentrations fitted using the mono-exponential function. The accuracy of the absorbed dose estimates for the SV methods, corrected with the NFs, were assessed using the standard deviation of the percentage difference in agreement with the reference method across all kidneys. Accuracy for kidney dosimetry using the SV method was calculated based on 1–5 VOIs with volumes of 4 mL (SV4), 2 mL (SV2), and 0.6 mL (SV0.6). Results: The mean RCs of the WKP volumes (31–243 mL) in non-filtered ASCC-SPECT and AC-SPECT were 0.85 (0.73–0.90) and 0.62 (0.46–0.51), respectively. In non-filtered images, the absorbed dose was overestimated by a factor of 1.22. However, applying a Gaussian filter with a kernel size of approximately 5 mm yielded absorbed dose estimates comparable to the reference WKP method. The accuracy of kidney dosimetry calculation based on one SV4 on each SPECT data-point was 12

Abstract Background For dosimetry, the demand for whole-body SPECT/CT imaging, which require long acquisition durations with dual-head Anger cameras, is increasing. Here we evaluated sparsely acquired projections and assessed whether the addition of deep-learning-generated synthetic intermediate projections (SIPs) could improve the image quality while preserving dosimetric accuracy. Methods This study included 16 patients treated with 177Lu-DOTATATE with SPECT/CT imaging (120 projections, 120P) at four time points. Deep neural networks (CUSIPs) were designed and trained to compile 90 SIPs from 30 acquired projections (30P). The 120P, 30P, and three different CUSIP sets (30P + 90 SIPs) were reconstructed using Monte Carlo-based OSEM reconstruction (yielding 120P_rec, 30P_rec, and CUSIP_recs). The noise levels were visually compared. Quantitative measures of normalised root mean square error, normalised mean absolute error, peak signal-to-noise ratio, and structural similarity were evaluated, and kidney and bone marrow absorbed doses were estimated for each reconstruction set. Results The use of SIPs visually improved noise levels. All quantitative measures demonstrated high similarity between CUSIP sets and 120P. Linear regression showed nearly perfect concordance of the kidney and bone marrow absorbed doses for all reconstruction sets, compared to the doses of 120P_rec (R2 ≥ 0.97). Compared to 120P_rec, the mean relative difference in kidney absorbed dose, for all reconstruction sets, was within 3%. For bone marrow absorbed doses, there was a higher dissipation in relative differences, and CUSIP_recs outperformed 30P_rec in mean relative difference (within 4% compared to 9%). Kidney and bone marrow absorbed doses for 30P_rec were statistically significantly different from those of 120_rec, as opposed to the absorbed doses of the best performing CUSIP_rec, where no statistically significant difference was found. Conclusion When performing SPECT/CT reconstruction, the use of SIPs can substantially reduce acquisition durations in SPECT/CT imaging, enabling acquisition of multiple fields of view of high image quality with satisfactory dosimetric accuracy.