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Abstract Background In the past years, there has been a notable increase in interest regarding targeted alpha therapy using Ac-225, driven by the observed promising clinical anti-tumor effects. As the production and technology has advanced, the availability of Ac-225 is expected to increase in the near future, making the treatment available to patients worldwide. Main body Ac-225 can be labelled to different biological vectors, whereby the success of developing a radiopharmaceutical depends heavily on the labelling conditions, purity of the radionuclide source, chelator, and type of quenchers used to avoid radiolysis. Multiple (methodological) challenges need to be overcome when working with Ac-225; as alpha-emission detection is time consuming and highly geometry dependent, a gamma co-emission is used, but has to be in equilibrium with the mother-nuclide. Because of the high impact of alpha emitters in vivo it is highly recommended to cross-calibrate the Ac-225 measurements for used quality control (QC) techniques (radio-TLC, HPLC, HP-Ge detector, and gamma counter). More strict health physics regulations apply, as Ac-225 has a high toxicity, thereby limiting practical handling and quantities used for QC analysis. Conclusion This overview focuses specifically on the practical and methodological challenges when working with Ac-225 labelled radiopharmaceuticals, and underlines the required infrastructure and (detection) methods for the (pre-)clinical application.

Abstract Background The [177Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [177Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [177Lu]Lu-DOTA-TATE. Furthermore, treatment with alpha emitters showed improvement of the therapeutic index of PRRT due to the high LET offered by the alpha particles compared to beta emitters. Therefore, [225Ac]Ac-DOTA-JR11 can be a potential candidate to improve the treatment of NETs (Graphical abstract). DOTA-JR11 was radiolabeled with [225Ac]Ac(NO3)3 and [177Lu]LuCl3. Stability studies were performed in phosphate buffered saline (PBS) and mouse serum. In vitro competitive binding assay has been carried out in U2OS-SSTR2 + cells for natLa-DOTA-JR11, natLu-DOTA-JR11 and DOTA-JR11. Ex vivo biodistribution studies were performed in mice inoculated with H69 cells at 4, 24, 48 and 72 h after injection of [225Ac]Ac-DOTA-JR11. A blocking group was included to verify uptake specificity. Dosimetry of selected organs was determined for [225Ac]Ac-DOTA-JR11 and [177Lu]Lu-DOTA-JR11. Results [225Ac]Ac-DOTA-JR11 has been successfully prepared and obtained in high radiochemical yield (RCY; 95%) and radiochemical purity (RCP; 94%). [225Ac]Ac-DOTA-JR11 showed reasonably good stability in PBS (77% intact radiopeptide at 24 h after incubation) and in mouse serum (~ 81% intact radiopeptide 24 h after incubation). [177Lu]Lu-DOTA-JR11 demonstrated excellent stability in both media (> 93%) up to 24 h post incubation. Competitive binding assay revealed that complexation of DOTA-JR11 with natLa and natLu did not affect its binding affinity to SSTR2. Similar biodistribution profiles were observed for both radiopeptides, however, higher uptake was noticed in the kidneys, liver and bone for [225Ac]Ac-DOTA-JR11 than [177Lu]Lu-DOTA-JR11. Conclusion [225Ac]Ac-DOTA-JR11 showed a higher absorbed dose in the kidneys compared to [177Lu]Lu-DOTA-JR11, which may limit further studies with this radiopeptide. However, several strategies can be explored to reduce nephrotoxicity and offer opportunities for future clinical investigations with [225Ac]Ac-DOTA-JR11.

Abstract The aim of this standard operational procedure is to standardize the methodology employed for the evaluation of pre- and post-treatment absorbed dose calculations in 90Y microsphere liver radioembolization. Basic assumptions include the permanent trapping of microspheres, the local energy deposition method for voxel dosimetry, and the patient–relative calibration method for activity quantification.The identity of 99mTc albumin macro-aggregates (MAA) and 90Y microsphere biodistribution is also assumed. The large observed discrepancies in some patients between 99mTc-MAA predictions and actual 90Y microsphere distributions for lesions is discussed. Absorbed dose predictions to whole non-tumoural liver are considered more reliable and the basic predictors of toxicity. Treatment planning based on mean absorbed dose delivered to the whole non-tumoural liver is advised, except in super-selective treatments. Given the potential mismatch between MAA simulation and actual therapy, absorbed doses should be calculated both pre- and post-therapy. Distinct evaluation between target tumours and non-tumoural tissue, including lungs in cases of lung shunt, are vital for proper optimization of therapy. Dosimetry should be performed first according to a mean absorbed dose approach, with an optional, but important, voxel level evaluation. Fully corrected 99mTc-MAA Single Photon Emission Computed Tomography (SPECT)/computed tomography (CT) and 90Y TOF PET/CT are regarded as optimal acquisition methodologies, but, for institutes where SPECT/CT is not available, non-attenuation corrected 99mTc-MAA SPECT may be used. This offers better planning quality than non dosimetric methods such as Body Surface Area (BSA) or mono-compartmental dosimetry. Quantitative 90Y bremsstrahlung SPECT can be used if dedicated correction methods are available. The proposed methodology is feasible with standard camera software and a spreadsheet. Available commercial or free software can help facilitate the process and improve calculation time.

Abstract Background The role of 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) in children is still expanding. Dedicated paediatric dosage regimens are needed to keep the radiation dose as low as reasonably achievable and reduce the risk of radiation-induced carcinogenesis. The aim of this study is to investigate the relation between patient-dependent parameters and [18F]FDG PET image quality in order to propose a dedicated paediatric dose regimen. Methods In this retrospective analysis, 102 children and 85 adults were included that underwent a diagnostic [18F]FDG PET/CT scan. The image quality of the PET scans was measured by the signal-to-noise ratio (SNR) in the liver. The SNR liver was normalized (SNRnorm) for administered activity and acquisition time to apply curve fitting with body weight, body length, body mass index, body weight/body length and body surface area. Curve fitting was performed with two power fits, a nonlinear two-parameter model α p−d and a linear single-parameter model α p−0.5. The fit parameters of the preferred model were combined with a user preferred SNR to obtain at least moderate or good image quality for the dosage regimen proposal. Results Body weight demonstrated the highest coefficient of determination for the nonlinear (R2 = 0.81) and linear (R2 = 0.80) models. The nonlinear model was preferred by the Akaike’s corrected information criterion. We decided to use a SNR of 6.5, based on the expert opinion of three nuclear medicine physicians. Comparison with the quadratic adult protocol confirmed the need for different dosage regimens for both patient groups. In this study, the amount of administered activity can be considerably reduced in comparison with the current paediatric guidelines. Conclusion Body weight has the strongest relation with [18F]FDG PET image quality in children. The proposed nonlinear dosage regimen based on body mass will provide a constant and clinical sufficient image quality with a significant reduction of the effective dose compared to the current guidelines. A dedicated paediatric dosage regimen is necessary, as a universal dosing regimen for paediatric and adult is not feasible.

Abstract Background Clinically applied radiopharmaceuticals have to meet quality release criteria like a high radiochemical yield and radiochemical purity. Many radiopharmaceuticals do not have marketing authorization and have no dedicated monograph within the European pharmacopeia, therefore general monographs on quality control have to be applied for clinical applications. These criteria require standardization and validation in labeling and preparation, including QC measurements according to well-defined standard operation procedures. QC measurements however, are often based on detection techniques specific for a certain LC-system. Multi-institutional research and development of new radiopharmaceuticals lead to an increase in multicenter trials. Although all institutes’ radiopharmacies are using the same standardized labeling and operation procedures, they often use different LC and radiodetection systems. Here we present a comparison of QC assessments for 3 radiopharmaceuticals with focus on the interpretation of chromatograms, data-output and potential differences in local practical performances of QC on (U)HPLC. Methods QC assessments for [111In]In-CCK, [68Ga]Ga-Bombesin and [177Lu]Lu-PSMA analogs were compared. Two of the radiopharmaceutical QC assessments were also applied in other institutes using their own HPLC-systems and concordant software. Data from the HPLC-injections and measurements is processed and summarized in chromatograms, based on a variety of smoothing algorithms for which different software programs are applied. Described radiopeptides were labeled and analyzed according their standardized labeling and operation procedures. Results Integration of main peaks on chromatograms resulted in a range of RCP, depending on the smoothing algorithm used. [111In]In-CCK(A), 68Ga-Bombesin(B) and [177Lu]Lu-PSMA(C) analogs had a RCP range of 88%–96%(A), 89–95%(B) and 92–99%(C) respectively. Important factors affecting final RCP value were site specific background radiation-levels, intrinsic system properties such as noise and sensitivity, personal interpretation e.g. peak-tailing and smoothing algorithms. Conclusion Measurement of RCP shows a strong method- and system-dependency, even when parameters are validated, standardized and SOP are followed. Release criteria are frequently based on RCP data from one central location. The lack of inter inter institutional validation and standardization in RCP determination makes the results therefore rather arbitrary. For multicenter trials, we recommend to compare locally determined RCP under validated and standardized conditions of in-line activity detection between institutes for each radiopharmaceutical.

Abstract Background Currently, the implementation of dosimetry in molecular radiotherapy (MRT) is not well investigated, and in view of the Council Directive (2013/59/Euratom), there is a need to understand the current availability of dosimetry-based MRT in clinical practice and research studies. The aim of this study was to assess the current practice of MRT and dosimetry across European countries. Methods An electronic questionnaire was distributed to European countries. This addressed 18 explicitly considered therapies, and for each therapy, a similar set of questions were included. Questions covered the number of patients and treatments during 2015, involvement of medical specialties and medical physicists, implementation of absorbed dose planning, post-therapy imaging and dosimetry, and the basis of therapy prescription. Results Responses were obtained from 26 countries and 208 hospitals, administering in total 42,853 treatments. The most common therapies were 131I-NaI for benign thyroid diseases and thyroid ablation of adults. The involvement of a medical physicist (mean over all 18 therapies) was reported to be either minority or never by 32% of the responders. The percentage of responders that reported that dosimetry was included on an always/majority basis differed between the therapies and showed a median value of 36%. The highest percentages were obtained for 177Lu-PSMA therapy (100%), 90Y microspheres of glass (84%) and resin (82%), 131I-mIBG for neuroblastoma (59%), and 131I-NaI for benign thyroid diseases (54%). The majority of therapies were prescribed based on fixed-activity protocols. The highest number of absorbed-dose based prescriptions were reported for 90Y microsphere treatments in the liver (64% and 96% of responses for resin and glass, respectively), 131I-NaI treatment of benign thyroid diseases (38% of responses), and for 131I-mIBG treatment of neuroblastoma (18% of responses). Conclusions There is a wide variation in MRT practice across Europe and for different therapies, including the extent of medical-physicist involvement and the implementation of dosimetry-guided treatments.

Abstract Background The European directive on basic safety standards (Council directive 2013/59 Euratom) mandates dosimetry-based treatment planning for radiopharmaceutical therapies. The directive comes into operation February 2018, and the aim of a report produced by the Internal Dosimetry Task Force of the European Association of Nuclear Medicine is to address this aspect of the directive. A summary of the report is presented. Results A brief review of five of the most common therapy procedures is included in the current text, focused on the potential to perform patient-specific dosimetry. In the full report, 11 different therapeutic procedures are included, allowing additional considerations of effectiveness, references to specific literature on quantitative imaging and dosimetry, and existing evidence for absorbed dose-effect correlations for each treatment. Individualized treatment planning with tracer diagnostics and verification of the absorbed doses delivered following therapy is found to be scientifically feasible for almost all procedures investigated, using quantitative imaging and/or external monitoring. Translation of this directive into clinical practice will have significant implications for resource requirements. Conclusions Molecular radiotherapy is undergoing a significant expansion, and the groundwork for dosimetry-based treatment planning is already in place. The mandated individualization is likely to improve the effectiveness of the treatments, although must be adequately resourced.