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Background Multiparametric MRI (mpMRI) is effective for detecting prostate cancer (PCa); however, there is a high rate of equivocal Prostate Imaging Reporting and Data System (PI-RADS) 3 lesions and false-positive findings. Purpose To investigate whether fluorine 18 (18F) prostate-specific membrane antigen (PSMA) 1007 PET/CT after mpMRI can help detect localized clinically significant PCa (csPCa), particularly for equivocal PI-RADS 3 lesions. Materials and Methods This prospective study included participants with elevated prostate-specific antigen (PSA) levels referred for prostate mpMRI between September 2020 and February 2022. 18F-PSMA-1007 PET/CT was performed within 30 days of mpMRI and before biopsy. PI-RADS category and level of suspicion (LOS) were assessed. PI-RADS 3 or higher lesions at mpMRI and/or LOS 3 or higher lesions at 18F-PSMA-1007 PET/CT underwent targeted biopsies. PI-RADS 2 or lower and LOS 2 or lower lesions were considered nonsuspicious and were monitored during a 1-year follow-up by means of PSA testing. Diagnostic accuracy was assessed, with histologic examination serving as the reference standard. International Society of Urological Pathology (ISUP) grade 2 or higher was considered csPCa. Results Seventy-five participants (median age, 67 years [range, 52-77 years]) were assessed, with PI-RADS 1 or 2, PI-RADS 3, and PI-RADS 4 or 5 groups each including 25 participants. A total of 102 lesions were identified, of which 80 were PI-RADS 3 or higher and/or LOS 3 or higher and therefore underwent targeted biopsy. The per-participant sensitivity for the detection of csPCa was 95% and 91% for mpMRI and 18F-PSMA-1007 PET/CT, respectively, with respective specificities of 45% and 62%. 18F-PSMA-1007 PET/CT was used to correctly differentiate 17 of 26 PI-RADS 3 lesions (65%), with a negative and positive predictive value of 93% and 27%, respectively, for ruling out or detecting csPCa. One additional significant and one insignificant PCa lesion (PI-RADS 1 or 2) were found at 18F-PSMA-1007 PET/CT that otherwise would have remained undetected. Two participants had ISUP 2 tumors without PSMA uptake that were missed at PET/CT. Conclusion 18F-PSMA-1007 PET/CT showed good sensitivity and moderate specificity for the detection of csPCa and ruled this out in 93% of participants with PI-RADS 3 lesions. Clinical trial registration no. NCT04487847 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Turkbey in this issue.
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Radioisótopos de Flúor , Imageamento por Ressonância Magnética Multiparamétrica , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Próstata , Humanos , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias da Próstata/diagnóstico por imagem , Imageamento por Ressonância Magnética Multiparamétrica/métodos , Estudos Prospectivos , Idoso , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Oligopeptídeos , Compostos Radiofarmacêuticos , Próstata/diagnóstico por imagem , Sensibilidade e EspecificidadeRESUMO
INTRODUCTION: For the implementation of suitable radiation safety measures in [177Lu]Lu-PSMA-617 therapy, additional insight into excretion kinetics is important. This study evaluates this kinetics in prostate cancer patients via direct urine measurements. METHODS: Both the short-term (up to 24 h, n = 28 cycles) and long-term kinetics (up to 7 weeks, n = 35 samples) were evaluated by collection of urine samples. Samples were measured on a scintillation counter to determine excretion kinetics. RESULTS: The mean excretion half-time during the first 20 h was 4.9 h. Kinetics was significantly different for patients with kidney function below or above eGFR 65 ml/min. Calculated skin equivalent dose in case of urinary contamination was between 50 and 145 mSv when it was caused between 0 and 8 h p.i.. Measurable amounts of 177Lu were found in urine samples up to 18 days p.i.. CONCLUSION: Excretion kinetics of [177Lu]Lu-PSMA-617 is especially relevant during the first 24 h, when accurate radiation safety measures are important to prevent skin contamination. Measures for accurate waste management are relevant up to 18 days.
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Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Masculino , Humanos , Compostos Radiofarmacêuticos/uso terapêutico , Antígeno Prostático Específico , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/tratamento farmacológico , Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Lutécio/uso terapêuticoRESUMO
INTRODUCTION: Fibroblast activation protein (FAP) is highly overexpressed in stromal tissue of various cancers. While FAP has been recognized as a potential diagnostic or therapeutic cancer target for decades, the surge of radiolabeled FAP-targeting molecules has the potential to revolutionize its perspective. It is presently hypothesized that FAP targeted radioligand therapy (TRT) may become a novel treatment for various types of cancer. To date, several preclinical and case series have been reported on FAP TRT using varying compounds and showing effective and tolerant results in advanced cancer patients. Here, we review the current (pre)clinical data on FAP TRT and discuss its perspective towards broader clinical implementation. METHODS: A PubMed search was performed to identify all FAP tracers used for TRT. Both preclinical and clinical studies were included if they reported on dosimetry, treatment response or adverse events. The last search was performed on July 22 2022. In addition, a database search was performed on clinical trial registries (date 15th of July 2022) to search for prospective trials on FAP TRT. RESULTS: In total, 35 papers were identified that were related to FAP TRT. This resulted in the inclusion of the following tracers for review: FAPI-04, FAPI-46, FAP-2286, SA.FAP, ND-bisFAPI, PNT6555, TEFAPI-06/07, FAPI-C12/C16, and FSDD. CONCLUSION: To date, data was reported on more than 100 patients that were treated with different FAP targeted radionuclide therapies such as [177Lu]Lu-FAPI-04, [90Y]Y-FAPI-46, [177Lu]Lu-FAP-2286, [177Lu]Lu-DOTA.SA.FAPI and [177Lu]Lu-DOTAGA.(SA.FAPi)2. In these studies, FAP targeted radionuclide therapy has resulted in objective responses in difficult to treat end stage cancer patients with manageable adverse events. Although no prospective data is yet available, these early data encourages further research.
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Proteínas de Membrana , Radioisótopos , Humanos , Linhagem Celular Tumoral , Proteínas de Membrana/metabolismo , Transporte Proteico , Radioisótopos/uso terapêutico , Fibroblastos/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radioisótopos de GálioRESUMO
INTRODUCTION: While [177Lu]Lu-PSMA radioligand therapy is currently only applied in end-stage metastatic castrate-resistant prostate cancer (mCRPC) patients, also low-volume hormone-sensitive metastatic prostate cancer (mHSPC) patients can benefit from it. However, there are toxicity concerns related to the sink effect in low-volume disease. This prospective study aims to determine the kinetics of [177Lu]Lu-PSMA in mHSPC patients, analyzing the doses to organs at risk (salivary glands, kidneys, liver, and bone marrow) and tumor lesions < 1 cm diameter. METHODS: Ten mHSPC patients underwent two cycles of [177Lu]Lu-PSMA therapy. Three-bed position SPECT/CT was performed at 5 time points after each therapy. Organ dosimetry and lesion dosimetry were performed using commercial software and a manual approach, respectively. Correlation between absorbed index lesion dose and treatment response (PSA drop of > 50% at the end of the study) was calculated and given as Spearman's r and p-values. RESULTS: Kinetics of [177Lu]Lu-PSMA in mHSPC patients are comparable to those in mCRPC patients. Lesion absorbed dose was high (3.25 ± 3.19 Gy/GBq) compared to organ absorbed dose (salivary glands: 0.39 ± 0.17 Gy/GBq, kidneys: 0.49 ± 0.11 Gy/GBq, liver: 0.09 ± 0.01 Gy/GBq, bone marrow: 0.017 ± 0.008 Gy/GBq). A statistically significant correlation was found between treatment response and absorbed index lesion dose (p = 0.047). CONCLUSIONS: We successfully performed small lesion dosimetry and showed that the tumor sink effect in mHSPC patients is of less concern than was expected. Tumor-to-organ ratio of absorbed dose was high and tumor uptake correlates with PSA response. Additional treatment cycles are legitimate in terms of organ toxicity and could lead to better tumor response.
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Lutécio , Antígeno Prostático Específico , Neoplasias da Próstata , Compostos Radiofarmacêuticos , Hormônios/metabolismo , Humanos , Lutécio/efeitos adversos , Lutécio/farmacocinética , Lutécio/uso terapêutico , Masculino , Órgãos em Risco/diagnóstico por imagem , Órgãos em Risco/efeitos da radiação , Estudos Prospectivos , Antígeno Prostático Específico/efeitos adversos , Antígeno Prostático Específico/sangue , Antígeno Prostático Específico/farmacocinética , Antígeno Prostático Específico/uso terapêutico , Neoplasias da Próstata/sangue , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/secundário , Doses de Radiação , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Resultado do TratamentoRESUMO
RATIONALE: Prolonged in vivo evaluation of PSMA tracers could improve tumor imaging and patient selection for 177Lu-PSMA-617 and 177Lu-PSMA-I&T. In this study, we present the radiolabeling method of PSMA-617 and PSMA-I&T with the long-lived positron emitter 89Zr to enable PET imaging up to 7 days post-injection. We compared the biodistribution of 89Zr-PSMA-617 and 89Zr-PSMA-I&T to those of 177Lu-PSMA-617 and 177Lu-PSMA-I&T, respectively, in a PSMA+ xenograft model. Moreover, we provide the first human 89Zr-PSMA-617 images. MATERIALS AND METHODS: PSMA ligands were labeled with 50-55 MBq [89Zr]ZrCl4 using a two-step labeling protocol. For biodistribution, BALB/c nude mice bearing PSMA+ and PSMA- xenografts received 0.6 µg (0.6-1 MBq) of 89Zr-PSMA-617, 89Zr-PSMA-I&T, 177Lu-PSMA-617, or 177Lu-PSMA-I&T intravenously. Ex vivo biodistribution and PET/SPECT imaging were performed up to 168 h post-injection. Dosimetry was performed from the biodistribution data. The patient received 90.5 MBq 89Zr-PSMA-617 followed by PET/CT imaging. RESULTS: 89Zr-labeled PSMA ligands showed a comparable ex vivo biodistribution to its respective 177Lu-labeled counterparts with high tumor accumulation in the PSMA+ xenografts. However, using a dose estimation model for 177Lu, absorbed radiation dose in bone and kidneys differed among the 177Lu-PSMA and 89Zr-PSMA tracers. 89Zr-PSMA-617 PET in the first human patient showed high contrast of PSMA expressing tissues up to 48 h post-injection. CONCLUSION: PSMA-617 and PSMA-I&T were successfully labeled with 89Zr and demonstrated high uptake in PSMA+ xenografts, which enabled PET up to 168 h post-injection. The biodistribution of 89Zr-PSMA-I&T and 89Zr-PSMA-617 resembled that of 177Lu-PSMA-I&T and 177Lu-PSMA-617, respectively. The first patient 89Zr-PSMA-617 PET images were of high quality warranting further clinical investigation.
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Lutécio , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Animais , Linhagem Celular Tumoral , Dipeptídeos , Compostos Heterocíclicos com 1 Anel , Humanos , Ligantes , Camundongos , Camundongos Nus , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons/métodos , Antígeno Prostático Específico , Radioisótopos , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
INTRODUCTION: Patient eligibility for [177Lu]Lu-PSMA therapy remains a challenge, with only 40-60% response rate when patient selection is done based on the lesion uptake (SUV) on [68Ga]Ga-PSMA-PET/CT. Prediction of absorbed dose based on this pre-treatment scan could improve patient selection and help to individualize treatment by maximizing the absorbed dose to target lesions while adhering to the threshold doses for the organs at risk (kidneys, salivary glands, and liver). METHODS: Ten patients with low-volume hormone-sensitive prostate cancer received a pre-therapeutic [68Ga]Ga-PSMA-11 PET/CT, followed by 3 GBq [177Lu]Lu-PSMA-617 therapy. Intra-therapeutically, SPECT/CT was acquired at 1, 24, 48, 72, and 168 h. Absorbed dose in organs and lesions (n = 22) was determined according to the MIRD scheme. Absorbed dose prediction based on [68Ga]Ga-PSMA-PET/CT was performed using tracer uptake at 1 h post-injection and the mean tissue effective half-life on SPECT. Predicted PET/actual SPECT absorbed dose ratios were determined for each target volume. RESULTS: PET/SPECT absorbed dose ratio was 1.01 ± 0.21, 1.10 ± 0.15, 1.20 ± 0.34, and 1.11 ± 0.29 for kidneys (using a 2.2 scaling factor), liver, submandibular, and parotid glands, respectively. While a large inter-patient variation in lesion kinetics was observed, PET/SPECT absorbed dose ratio was 1.3 ± 0.7 (range: 0.4-2.7, correlation coefficient r = 0.69, p < 0.01). CONCLUSION: A single time point [68Ga]Ga-PSMA-PET scan can be used to predict the absorbed dose of [177Lu]Lu-PSMA therapy to organs, and (to a limited extent) to lesions. This strategy facilitates in treatment management and could increase the personalization of [177Lu]Lu-PSMA therapy.
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Radioisótopos de Gálio , Neoplasias de Próstata Resistentes à Castração , Dipeptídeos , Compostos Heterocíclicos com 1 Anel , Humanos , Lutécio , Masculino , Órgãos em Risco/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/patologia , Compostos Radiofarmacêuticos/uso terapêuticoRESUMO
BACKGROUND: Bone marrow toxicity in advanced prostate cancer patients who receive [177Lu]Lu-PSMA-617 is a well-known concern. In early stage patients; e.g. low volume metastatic hormone sensitive prostate cancer (mHSPC) patients, prevention of late bone marrow toxicity is even more crucial due to longer life expectancy. To date, bone marrow dosimetry is primarily performed using blood sampling. This method is time consuming and does not account for possible active bone marrow uptake. Therefore other methodologies are investigated. We calculated the bone marrow absorbed dose for [177Lu]Lu-PSMA-617 in mHSPC patients using SPECT/CT imaging and compared it to the blood sampling method as reference. METHODS: Eight mHSPC patients underwent two cycles (3 and 6 GBq) of [177Lu]Lu-PSMA-617 therapy. After each cycle, five time point (1 h, 1 day, 2 days, 3 days, 7 days) SPECT/CT was performed at kidney level. Bone marrow dosimetry was performed using commercial software by drawing ten 1.5 cm diameter spheres in the lowest ten vertebrae to determine the time-integrated activity. Simplified protocols using only 2 imaging time points and 3 vertebrae were also compared. Blood-based dosimetry was based on the blood sampling method according to the EANM guideline. RESULTS: Mean bone marrow absorbed dose was significantly different (p < 0.01) for the imaging based method (25.4 ± 8.7 mGy/GBq) and the blood based method (17.2 ± 3.4 mGy/GBq), with an increasing absorbed dose ratio between both methods over time. Bland Altman analysis of both simplification steps showed that differences in absorbed dose were all within the 95% limits of agreement. CONCLUSION: This study showed that bone marrow absorbed dose after [177Lu]Lu-PSMA-617 can be determined using an imaging-based method of the lower vertebrae, and simplified using 2 time points (1 and 7 days) and 3 vertebrae. An increasing absorbed dose ratio over time between the imaging-based method and blood-based method suggests that there might be specific bone marrow binding of [177Lu]Lu-PSMA-617.
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PURPOSE: For prostate-specific membrane antigen-directed radioligand therapy (PSMA-RLT), [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T are the currently preferred compounds. Recent preclinical studies suggested ~30x higher kidney absorbed dose for [ 177 Lu]Lu-PSMA-I&T compared to [ 177 Lu]Lu-PSMA-617, which may lead to an increased risk of kidney toxicity. We performed two single-centre, prospective dosimetry studies with either [ 177 Lu]Lu-PSMA-617 or [ 177 Lu]Lu-PSMA-I&T, using an identical dosimetry protocol. We evaluated the absorbed doses of both 177 Lu-labelled radioligands in human kidneys. METHODS: 3D SPECT/computed tomography (CT) imaging of the kidneys was performed after PSMA-RLT in cancer patients with PSMA-positive disease and an adequate glomerular filtration rate (≥50 mL/min). Ten metastatic hormone-sensitive prostate cancer patients (mHSPC) were treated with [ 177 Lu]Lu-PSMA-617 and 10 advanced salivary gland cancer (SGC) patients were treated with [ 177 Lu]Lu-PSMA-I&T. SPECT/CT imaging was performed at five timepoints (1 h, 24 h, 48 h, 72 h, and 168 h post-injection). In mHSPC patients, SPECT/CT imaging was performed after cycles 1 and 2 (cumulative activity: 9 GBq) and in SGC patients only after cycle 1 (activity: 7.4 GBq). Kidney absorbed dose was calculated using organ-based dosimetry. RESULTS: The median kidney absorbed dose was 0.49 Gy/GBq (range: 0.34-0.66) and 0.73 Gy/GBq (range: 0.42-1.31) for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T, respectively (independent samples t test; P = 0.010). CONCLUSION: This study shows that the kidney absorbed dose for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T differs, with a ~1.5x higher median kidney absorbed dose for [ 177 Lu]Lu-PSMA-I&T. This difference in the clinical setting is considerably smaller than observed in preclinical studies and may not hamper treatments with [ 177 Lu]Lu-PSMA-I&T.
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Rim , Neoplasias da Próstata , Masculino , Humanos , Estudos Prospectivos , Doses de RadiaçãoRESUMO
BACKGROUND: Dosimetry in [177Lu]Lu-PSMA therapy is a valuable tool to assess treatment efficacy and toxicity. This study aims to develop a clinically implementable protocol to determine the absorbed dose in organs and tumor lesions after [177Lu]Lu-PSMA-617 therapy, by reducing the imaging time points and utilizing population-based kinetics with a single scan, with evaluation of its influence on the uncertainty in absorbed dose. METHODS: Ten patients with metastatic hormone-sensitive prostate cancer received two cycles of [177Lu]Lu-PSMA-617. Post-treatment imaging was performed at 1 h, 24 h, 48 h, 72 h and 168 h, consisting of three-bed positions SPECT/CT and a whole-body planar scan. Five-time point SPECT dosimetry was performed for lesions and organs with physiological uptake (kidneys, liver and salivary glands) and used as the reference standard. Absorbed dose values for various simplified protocols were compared to the reference standard. RESULTS: Accurate lesion dosimetry is possible using one-time point SPECT imaging at 168 h, with an increase in uncertainty (20% vs. 14% for the reference standard). By including a second time point, uncertainty was comparable to the reference standard (13%). Organ dosimetry can be performed using a single SPECT at 24 h or 48 h. Dosimetry based on planar scans did not provide accurate dose estimations. CONCLUSION: Accurate lesion dosimetry in [177Lu]Lu-PSMA therapy can be performed using a one- or two-time point protocol, making dosimetry assessments more suitable for routine clinical implementation, although dosimetry based om multiple time points is more accurate. Clinical trial registration This study was approved by the Medical Review Ethics Committee Region Arnhem-Nijmegen on January 23, 2018 and was registered on clinicaltrials.gov (NCT03828838).
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Studies to evaluate and optimize [177 Lu]Lu-PSMA treatment focus primarily on individual patient data. A population pharmacokinetic (PK) dosimetry model was developed to explore the potential of using imaging data as input for population PK models and to characterize variability in organ and tumor uptake of [177 Lu]Lu-PSMA-617 in patients with low volume metastatic prostate cancer. Simulations were performed to identify the effect of dose adjustments on absorbed doses in salivary glands and tumors. A six-compartment population PK model was developed, consisting of blood, salivary gland, kidneys, liver, tumor, and a lumped compartment representing other tissue (compartment 1-6, respectively), based on data from 10 patients who received [177 Lu]Lu-PSMA-617 (2 cycles, ~ 3 and ~ 6 GBq). Data consisted of radioactivity levels (decay corrected) in blood and tissues (9 blood samples and 5 single photon emission computed tomography/computed tomography scans). Observations in all compartments were adequately captured by individual model predictions. Uptake into salivary glands was saturable with an estimated maximum binding capacity (Bmax ) of 40.4 MBq (relative standard error 12.3%) with interindividual variability (IIV) of 59.3% (percent coefficient of variation [CV%]). IIV on other PK parameters was relatively minor. Tumor volume was included as a structural effect on the tumor uptake rate constant (k15 ), where a two-fold increase in tumor volume resulted in a 1.63-fold increase in k15 . In addition, interoccasion variability on k15 improved the model fit (43.5% [CV%]). Simulations showed a reduced absorbed dose per unit administered activity for salivary glands after increasing radioactivity dosing from 3 to 6 GBq (0.685 Gy/GBq vs. 0.421 Gy/GBq, respectively). All in all, population PK modeling could help to improve future radioligand therapy research.
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Neoplasias de Próstata Resistentes à Castração , Compostos Radiofarmacêuticos , Masculino , Humanos , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Dipeptídeos , Antígeno Prostático EspecíficoRESUMO
INTRODUCTION: Prostate specific membrane antigen (PSMA) directed radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC) patients. However, it is still poorly understood why approximately 40% of the patients does not respond to PSMA-RLT. The aims of this study were to evaluate the pretreatment PSMA expression on immunohistochemistry (IHC) and PSMA uptake on PET/CT imaging in mCRPC patients who underwent PSMA-RLT. We correlated these parameters and a cell proliferation marker (Ki67) to the therapeutic efficacy of PSMA-RLT. PATIENTS AND METHODS: In this retrospective study, mCRPC patients who underwent PSMA-RLT were analyzed. Patients biopsies were scored for immunohistochemical Ki67 expression, PSMA staining intensity and percentage of cells with PSMA expression. Moreover, the PSMA tracer uptake of the tumor lesion(s) and healthy organs on PET/CT imaging was assessed. The primary outcome was to evaluate the association between histological PSMA protein expression of tumor in pre-PSMA-RLT biopsies and the PSMA uptake on PSMA PET/CT imaging of the biopsied lesion. Secondary outcomes were to assess the relationship between PSMA expression and Ki67 on IHC and the progression free survival (PFS) and overall survival (OS) following PSMA-RLT. RESULTS: In total, 22 mCRPC patients were included in this study. Nineteen (86%) patients showed a high and homogenous PSMA expression of >80% on IHC. Three (14%) patients had low PSMA expression on IHC. Although there was limited PSMA uptake on PET/CT imaging, these 3 patients had lower PSMA uptake on PET/CT imaging compared to the patients with high PSMA expression on IHC. Yet, no correlation was found between PSMA uptake on PET/CT imaging and PSMA expression on IHC (SUVmax: R2 = 0.046 and SUVavg: R2 = 0.036). The 3 patients had a shorter PFS compared to the patients with high PSMA expression on IHC (HR: 4.76, 95% CI: 1.14-19.99; P = .033). Patients with low Ki67 expression had a longer PFS and OS compared to patients with a high Ki67 expression (HR: 0.40, 95% CI: 0.15-1.06; P = .013) CONCLUSION: The PSMA uptake on PSMA-PET/CT generally followed the PSMA expression on IHC. However, heterogeneity may be missed on PSMA-PET/CT. Immunohistochemical PSMA and Ki67 expression in fresh tumor biopsies, may contribute to predict treatment efficacy of PSMA-RLT in mCRPC patients. This needs to be further explored in prospective cohorts.
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Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Antígeno Ki-67 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Estudos Retrospectivos , Estudos Prospectivos , Antígeno Prostático Específico , Dipeptídeos/uso terapêutico , Resultado do Tratamento , BiópsiaRESUMO
BACKGROUND: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a novel treatment for patients with castration-resistant prostate cancer (CRPC). Given the mode of action, patients in an earlier disease stage, such as hormone-sensitive prostate cancer (HSPC), are also likely to benefit from [177Lu]Lu-PSMA- (177Lu-PSMA) or [225Ac]Ac-PSMA-radioligand treatment (225Ac-PSMA). In this retrospective study, we analyzed the safety and efficacy of PSMA-RLT in early-stage and hormone-sensitive metastatic prostate cancer patients. METHODS: A retrospective study was performed in patients who received 177Lu-PSMA and/or 225Ac-PSMA with early-stage metastatic prostate cancer. The primary outcome parameter evaluated in this study was the progression-free survival (PFS) after PSMA-RLT and toxicity according to the Common Terminology Criteria for Adverse Events. Secondary outcome parameters were prostate-specific antigen (PSA) response and the date of onset of CRPC state. RESULTS: In total, 20 patients were included of which 18 patients received 177Lu-PSMA radioligand and two patients received tandem treatment with both 177Lu-PSMA and 225Ac-PSMA radioligands. Patients received a median of 2 treatment cycles (range 1-6) and a median activity of 6.2 GBq 177Lu-PSMA per cycle (interquartile range (IQR) 5.2-7.4 GBq). PSMA-RLT was overall well-tolerated. The most common grade 1-2 side effects were xerostomia (n = 6) and fatigue (n = 8), which were only temporarily reported. One patient that received 225Ac-PSMA developed grade 3-4 bone marrow toxicity. The median PFS was 12 months (95% confidence interval (CI), 4.09-19.9 months). Seventeen (85%) patients had a ≥50% PSA response following PSMA-RLT. One patient developed CRPC 9 months following PSMA-RLT. CONCLUSIONS: In this small cohort study, PSMA-RLT appeared safe and showed encouraging efficacy for (metastasized) early-stage and hormone-sensitive prostate cancer patients. Prospective studies are awaited and should include long-term follow-up.
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PURPOSE: [177Lu]Lu-PSMA-617 radioligand therapy (177Lu-PSMA) is a novel treatment for metastatic castration-resistant prostate cancer (mCRPC), which could also be applied to patients with metastatic hormone-sensitive prostate cancer (mHSPC) with PSMA expression. In this prospective study (NCT03828838), we analyzed toxicity, radiation doses, and treatment effect of 177Lu-PSMA in pateints with low-volume mHSPC. PATIENTS AND METHODS: Ten progressive patients with mHSPC following local treatment, with a maximum of ten metastatic lesions on [68Ga]Ga-PSMA-11 PET/diagnostic-CT imaging (PSMA-PET) and serum PSA doubling time <6 months received two cycles of 177Lu-PSMA. Whole-body single-photon emission CT/CT (SPECT/CT) and blood dosimetry was performed to calculate doses to the tumors and organs at risk (OAR). Adverse events (AE), laboratory values (monitoring response and toxicity), and quality of life were monitored until week 24 after cycle 2, the end of study (EOS). All patients underwent PSMA-PET at screening, 8 weeks after cycle 1, 12 weeks after cycle 2, and at EOS. RESULTS: All patients received two cycles of 177Lu-PSMA without complications. No treatment-related grade III-IV adverse events were observed. According to dosimetry, none of the OAR reached threshold doses for radiation-related toxicity. Moreover, all target lesions received a higher radiation dose than the OAR. All 10 patients showed altered PSA kinetics, postponed androgen deprivation therapy, and maintained good quality of life. Half of the patients showed a PSA response of more than 50%. One patient had a complete response on PSMA-PET imaging until EOS and two others had only minimal residual disease. CONCLUSIONS: 177Lu-PSMA appeared to be a feasible and safe treatment modality in patients with low-volume mHSPC.
Assuntos
Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Antagonistas de Androgênios/uso terapêutico , Dipeptídeos/efeitos adversos , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Hormônios/uso terapêutico , Humanos , Masculino , Projetos Piloto , Estudos Prospectivos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/radioterapia , Qualidade de Vida , Radioisótopos , Compostos RadiofarmacêuticosRESUMO
BACKGROUND: Dosimetry after peptide receptor radionuclide therapy (PRRT) is increasing; however, comparing or pooling of dosimetric results can be challenging since different approaches are used. The aim of this study was to perform a head-to-head comparison of post-PRRT curve fitting and dosimetry obtained from two commercial software Hybrid Viewer Dosimetry and PLANET Dose. METHODS: Post-therapy imaging included planar scintigraphy at 0.5, 4, 24 and 72 h post-injection of [177Lu]Lu-DOTA-TATE for kinetics and SPECT/CT at 24 h for quantification. On planar imaging, 2 cm regions-of-interest were positioned within the inferior pole of the kidneys and kidney cortex was segmented on low-dose CT. On both planar and SPECT/CT, 2 cm spheres were positioned in the proximal humerus (red marrow equivalent) and in the region with the highest uptake in tumour lesions. TACs were estimated with mono- and bi-exponential fits in both software systems, after which tissue absorbed (kidney, red marrow, tumour) and biological effective doses (kidney) were calculated. Agreement-ICC, Spearman correlation and Bland-Altman plots were used to compare results. RESULTS: Mono-exponential fits showed the most comparable correlation between the measured and fitted data between both software. The ICC between absorbed dose outcomes was > 0.7 in tumour lesions and kidneys, but negative for the red marrow. Spearman correlation was > 0.9 for mono-exponential fits in kidneys and tumour lesions, and -0.7 in red marrow. Bi-exponential fits resulted in lower correlations and agreement values. Concordance between both software packages concerning the number of PRRT cycles with 7.4 GBq was observed based on a biological effective dose limit of 27 Gy to the kidneys. CONCLUSION: [177Lu]Lu-DOTA-TATE dosimetry results of two software packages were comparable in the same dataset, despite the limited number of imaging time-points. However, these results should be verified in a larger cohort before pooling of clinical data, as the obtained results will depend on acquisition protocol, timing and lesions definition.
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BACKGROUND: Personalized molecular radiotherapy based on theragnostics requires accurate quantification of the amount of radiopharmaceutical activity administered to patients both in diagnostic and therapeutic applications. This international multi-center study aims to investigate the clinical measurement accuracy of radionuclide calibrators for 7 radionuclides used in theragnostics: 99mTc, 111In, 123I, 124I, 131I, 177Lu, and 90Y. METHODS: In total, 32 radionuclide calibrators from 8 hospitals located in the Netherlands, Belgium, and Germany were tested. For each radionuclide, a set of four samples comprising two clinical containers (10-mL glass vial and 3-mL syringe) with two filling volumes were measured. The reference value of each sample was determined by two certified radioactivity calibration centers (SCK CEN and JRC) using two secondary standard ionization chambers. The deviation in measured activity with respect to the reference value was determined for each radionuclide and each measurement geometry. In addition, the combined systematic deviation of activity measurements in a theragnostic setting was evaluated for 5 clinically relevant theragnostic pairs: 131I/123I, 131I/124I, 177Lu/111In, 90Y/99mTc, and 90Y/111In. RESULTS: For 99mTc, 131I, and 177Lu, a small minority of measurements were not within ± 5% range from the reference activity (percentage of measurements not within range: 99mTc, 6%; 131I, 14%; 177Lu, 24%) and almost none were outside ± 10% range. However, for 111In, 123I, 124I, and 90Y, more than half of all measurements were not accurate within ± 5% range (111In, 51%; 123I, 83%; 124I, 63%; 90Y, 61%) and not all were within ± 10% margin (111In, 22%; 123I, 35%; 124I, 15%; 90Y, 25%). A large variability in measurement accuracy was observed between radionuclide calibrator systems, type of sample container (vial vs syringe), and source-geometry calibration/correction settings used. Consequently, we observed large combined deviations (percentage deviation > ± 10%) for the investigated theragnostic pairs, in particular for 90Y/111In, 131I/123I, and 90Y/99mTc. CONCLUSIONS: Our study shows that substantial over- or underestimation of therapeutic patient doses is likely to occur in a theragnostic setting due to errors in the assessment of radioactivity with radionuclide calibrators. These findings underline the importance of thorough validation of radionuclide calibrator systems for each clinically relevant radionuclide and sample geometry.
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BACKGROUND: Quantitative SPECT imaging in targeted radionuclide therapy with lutetium-177 holds great potential for individualized treatment based on dose assessment. The establishment of dose-effect relations requires a standardized method for SPECT quantification. The purpose of this multi-center study is to evaluate quantitative accuracy and inter-system variations of different SPECT/CT systems with corresponding commercially available quantitative reconstruction algorithms. This is an important step towards a vendor-independent standard for quantitative lutetium-177 SPECT. METHODS: Four state-of-the-art SPECT/CT systems were included: Discovery™ NM/CT 670Pro (GE Healthcare), Symbia Intevo™, and two Symbia™ T16 (Siemens Healthineers). Quantitative accuracy and inter-system variations were evaluated by repeatedly scanning a cylindrical phantom with 6 spherical inserts (0.5 - 113 ml). A sphere-to-background activity concentration ratio of 10:1 was used. Acquisition settings were standardized: medium energy collimator, body contour trajectory, photon energy window of 208 keV (± 10%), adjacent 20% lower scatter window, 2 × 64 projections, 128 × 128 matrix size, and 40 s projection time. Reconstructions were performed using GE Evolution with Q.Metrix™, Siemens xSPECT Quant™, Siemens Broad Quantification™ or Siemens Flash3D™ algorithms using vendor recommended settings. In addition, projection data were reconstructed using Hermes SUV SPECT™ with standardized reconstruction settings to obtain a vendor-neutral quantitative reconstruction for all systems. Volumes of interest (VOI) for the spheres were obtained by applying a 50% threshold of the sphere maximum voxel value corrected for background activity. For each sphere, the mean and maximum recovery coefficient (RCmean and RCmax) of three repeated measurements was calculated, defined as the imaged activity concentration divided by the actual activity concentration. Inter-system variations were defined as the range of RC over all systems. RESULTS: RC decreased with decreasing sphere volume. Inter-system variations with vendor-specific reconstructions were between 0.06 and 0.41 for RCmean depending on sphere size (maximum 118% quantification difference), and improved to 0.02-0.19 with vendor-neutral reconstructions (maximum 38% quantification difference). CONCLUSION: This study shows that eliminating sources of possible variation drastically reduces inter-system variation in quantification. This means that absolute SPECT quantification for 177Lu is feasible in a multi-center and multi-vendor setting; however, close agreement between vendors and sites is key for multi-center dosimetry and quantitative biomarker studies.
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Absolute quantification of radiotracer distribution using SPECT/CT imaging is of great importance for dosimetry aimed at personalized radionuclide precision treatment. However, its accuracy depends on many factors. Using phantom measurements, this multi-vendor and multi-center study evaluates the quantitative accuracy and inter-system variability of various SPECT/CT systems as well as the effect of patient size, processing software and reconstruction algorithms on recovery coefficients (RC). METHODS: Five SPECT/CT systems were included: Discovery™ NM/CT 670 Pro (GE Healthcare), Precedence™ 6 (Philips Healthcare), Symbia Intevo™, and Symbia™ T16 (twice) (Siemens Healthineers). Three phantoms were used based on the NEMA IEC body phantom without lung insert simulating body mass indexes (BMI) of 25, 28, and 47 kg/m2. Six spheres (0.5-26.5 mL) and background were filled with 0.1 and 0.01 MBq/mL 99mTc-pertechnetate, respectively. Volumes of interest (VOI) of spheres were obtained by a region growing technique using a 50% threshold of the maximum voxel value corrected for background activity. RC, defined as imaged activity concentration divided by actual activity concentration, were determined for maximum (RCmax) and mean voxel value (RCmean) in the VOI for each sphere diameter. Inter-system variability was expressed as median absolute deviation (MAD) of RC. Acquisition settings were standardized. Images were reconstructed using vendor-specific 3D iterative reconstruction algorithms with institute-specific settings used in clinical practice and processed using a standardized, in-house developed processing tool based on the SimpleITK framework. Additionally, all data were reconstructed with a vendor-neutral reconstruction algorithm (Hybrid Recon™; Hermes Medical Solutions). RESULTS: RC decreased with decreasing sphere diameter for each system. Inter-system variability (MAD) was 16 and 17% for RCmean and RCmax, respectively. Standardized reconstruction decreased this variability to 4 and 5%. High BMI hampers quantification of small lesions (< 10 ml). CONCLUSION: Absolute SPECT quantification in a multi-center and multi-vendor setting is feasible, especially when reconstruction protocols are standardized, paving the way for a standard for absolute quantitative SPECT.