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BACKGROUND: Actinium-225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC). We aimed to report the safety and antitumour activity of 225Ac-PSMA RLT of mCRPC in a large cohort of patients treated at multiple centres across the world. METHODS: This retrospective study included patients treated at seven centres in Australia, India, Germany, and South Africa. We pooled data of consecutive patients of any age and Eastern Cooperative Oncology Group performance status with histopathologically confirmed adenocarcinoma of the prostate who were treated with one or more cycles of 8 MBq 225Ac-PSMA RLT administered intravenously for mCRPC. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium-177 (177Lu) PSMA RLT, and radium-223 dichloride. The primary outcomes were overall survival and progression-free survival. FINDINGS: Between Jan 1, 2016, and May 31, 2023, 488 men with mCRPC received 1174 cycles of 225Ac-PSMA RLT (median two cycles, IQR 2-4). The mean age of the patients was 68·1 years (SD 8·8), and the median baseline prostate-specific antigen was 169·5 ng/mL (IQR 34·6-519·8). Previous lines of treatment were docetaxel in 324 (66%) patients, cabazitaxel in 103 (21%) patients, abiraterone in 191 (39%) patients, enzalutamide in 188 (39%) patients, 177Lu-PSMA RLT in 154 (32%) patients, and radium-223 dichloride in 18 (4%) patients. The median follow-up duration was 9·0 months (IQR 5·0-17·5). The median overall survival was 15·5 months (95% CI 13·4-18·3) and median progression-free survival was 7·9 months (6·8-8·9). In 347 (71%) of 488 patients, information regarding treatment-induced xerostomia was available, and 236 (68%) of the 347 patients reported xerostomia after the first cycle of 225Ac-PSMA RLT. All patients who received more than seven cycles of 225Ac-PSMA RLT reported xerostomia. Grade 3 or higher anaemia occurred in 64 (13%) of 488 patients, leukopenia in 19 (4%), thrombocytopenia in 32 (7%), and renal toxicity in 22 (5%). No serious adverse events or treatment-related deaths were recorded. INTERPRETATION: 225Ac-PSMA RLT shows a substantial antitumour effect in mCRPC and represents a viable therapy option in patients treated with previous lines of approved agents. Xerostomia is a common side-effect. Severe bone marrow and renal toxicity are less common adverse events. FUNDING: None.
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Actínio , Neoplasias de Próstata Resistentes à Castração , Rádio (Elemento) , Xerostomia , Idoso , Humanos , Masculino , Dipeptídeos/efeitos adversos , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/radioterapia , Radioisótopos , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Resultado do Tratamento , Xerostomia/induzido quimicamente , Xerostomia/tratamento farmacológico , Pessoa de Meia-IdadeRESUMO
Fibroblast activation protein (FAP) is a promising target for diagnosis and therapy of numerous malignant tumors. FAP-2286 is the conjugate of a FAP-binding peptide, which can be labeled with radionuclides for theranostic applications. We present the first-in-humans results using 177Lu-FAP-2286 for peptide-targeted radionuclide therapy (PTRT). Methods: PTRT using 177Lu-FAP-2286 was performed on 11 patients with advanced adenocarcinomas of the pancreas, breast, rectum, or ovary after prior confirmation of uptake on 68Ga-FAP-2286 or 68Ga-FAPI-04 PET/CT. Results: Administration of 177Lu-FAP-2286 (5.8 ± 2.0 GBq; range, 2.4-9.9 GBq) was well tolerated, with no adverse symptoms or clinically detectable pharmacologic effects being noticed or reported in any of the patients. The whole-body effective dose was 0.07 ± 0.02 Gy/GBq (range, 0.04-0.1 Gy/GBq). The mean absorbed doses for kidneys and red marrow were 1.0 ± 0.6 Gy/GBq (range, 0.4-2.0 Gy/GBq) and 0.05 ± 0.02 Gy/GBq (range, 0.03-0.09 Gy/GBq), respectively. Significant uptake and long tumor retention of 177Lu-FAP-2286 resulted in high absorbed tumor doses, such as 3.0 ± 2.7 Gy/GBq (range, 0.5-10.6 Gy/GBq) in bone metastases. No grade 4 adverse events were observed. Grade 3 events occurred in 3 patients-1 with pancytopenia, 1 with leukocytopenia, and 1 with pain flare-up; 3 patients reported a pain response. Conclusion:177Lu-FAP-2286 PTRT, applied in a broad spectrum of cancers, was relatively well tolerated, with acceptable side effects, and demonstrated long retention of the radiopeptide. Prospective clinical studies are warranted.
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Adenocarcinoma , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos de Viabilidade , Feminino , Radioisótopos de Gálio , Humanos , Peptídeos , Estudos Prospectivos , Radioisótopos/uso terapêutico , Distribuição TecidualRESUMO
Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (PSMA-RLT) with lutetium-177 (177Lu-PSMA) has been used in metastatic castrate-resistant prostate cancer (mCRPC), and retrospective data have shown this therapy to be favourably safe with attractive clinical responses. Re-challenge 177Lu-PSMA therapy in early responders has been shown to be safe and effective. We report the use of low-dose Taxol-based chemotherapy (modified dose 25 mg/m2 weekly × 6 weeks) as a radiosensitizer with re-challenge 177Lu-PSMA therapy (4 cycles). In a period of 3 years, the patient underwent a total of 8 cycles of 177Lu-PSMA with a cumulative dose of 51.8 GBq. All therapies were uneventful and well tolerated. There was a good response to re-challenge 177Lu-PSMA therapy and low-dose docetaxel (Taxol-177Lu-PSMA) with no recorded tumour resistance.
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161Tb has decay properties similar to those of 177Lu but, additionally, emits a substantial number of conversion and Auger electrons. The aim of this study was to apply 161Tb in a clinical setting and to investigate the feasibility of visualizing the physiologic and tumor biodistributions of 161Tb-DOTATOC. Methods:161Tb was shipped from Paul Scherrer Institute, Villigen-PSI, Switzerland, to Zentralklinik Bad Berka, Bad Berka, Germany, where it was used for the radiolabeling of DOTATOC. In 2 separate studies, 596 and 1,300 MBq of 161Tb-DOTATOC were administered to a 35-y-old male patient with a metastatic, well-differentiated, nonfunctional malignant paraganglioma and a 70-y-old male patient with a metastatic, functional neuroendocrine neoplasm of the pancreatic tail, respectively. Whole-body planar γ-scintigraphy images were acquired over a period of several days for dosimetry calculations. SPECT/CT images were reconstructed using a recently established protocol and visually analyzed. Patients were observed for adverse events after the application of 161Tb-DOTATOC. Results: The radiolabeling of DOTATOC with 161Tb was readily achieved with a high radiochemical purity suitable for patient application. Planar images and dosimetry provided the expected time-dependent biodistribution of 161Tb-DOTATOC in the liver, kidneys, spleen, and urinary bladder. SPECT/CT images were of high quality and visualized even small metastases in bones and liver. The application of 161Tb-DOTATOC was well tolerated, and no related adverse events were reported. Conclusion: This study demonstrated the feasibility of imaging even small metastases after the injection of relatively low activities of 161Tb-DOTATOC using γ-scintigraphy and SPECT/CT. On the basis of this essential first step in translating 161Tb to clinics, further efforts will be directed toward the application of 161Tb for therapeutic purposes.
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Tumores Neuroendócrinos , Adulto , Idoso , Estudos de Viabilidade , Humanos , Pessoa de Meia-Idade , Receptores de Somatostatina , Distribuição TecidualRESUMO
The objective of this retrospective study was to determine the role of 18F-FDG PET/CT in a large cohort of 495 patients with metastatic neuroendocrine neoplasms (NENs) who were treated with peptide receptor radionuclide therapy (PRRT) with a long-term follow-up. Methods: The 495 patients were treated with 177Lu- or 90Y-DOTATOC/DOTATATE PRRT between February 2002 and July 2018. All subjects received both 68Ga-DOTATOC/TATE/NOC and 18F-FDG PET/CT before treatment and were followed 3-189 mo. Kaplan-Meier analysis, log-rank testing (Mantel-Cox), and Cox regression analysis were performed for overall survival (OS) and progression-free survival (PFS). Results: One hundred ninety-nine patients (40.2%) presented with pancreatic NENs, 49 with cancer of unknown primary, and 139 with midgut NENs, whereas the primary tumor was present in the rectum in 20, in the lung in 38, in the stomach in 8, and in other locations in 42. 18F-FDG PET/CT was positive in 382 (77.2%) patients and negative in 113 (22.8%) before PRRT, whereas 100% were 68Ga-DOTATOC/TATE/NOC-positive. For all patients, the median PFS and OS, defined from the start of PRRT, were 19.6 mo and 58.7 mo, respectively. Positive 18F-FDG results predicted shorter PFS (18.5 mo vs. 24.1 mo; P = 0.0015) and OS (53.2 mo vs. 83.1 mo; P < 0.001) than negative 18F-FDG results. Among the cases of pancreatic NENs, the median OS was 52.8 mo in 18F-FDG-positive subjects and 114.3 mo in 18F-FDG-negative subjects (P = 0.0006). For all patients positive for 18F-FDG uptake, and a ratio of more than 2 for the highest SUVmax on 68Ga-somatostatin receptor (SSTR) PET to the most 18F-FDG-avid tumor lesions, the median OS was 53.0 mo, compared with 43.4 mo in those patients with a ratio of less than 2 (P = 0.030). For patients with no 18F-FDG uptake (complete mismatch imaging pattern), the median OS was 108.3 mo versus 76.9 mo for an SUVmax of more than 15.0 and an SUVmax of 15.0 or less on 68Ga-SSTR PET/CT, respectively. Conclusion: The presence of positive lesions on 18F-FDG PET is an independent prognostic factor in patients with NENs treated with PRRT. Metabolic imaging with 18F-FDG PET/CT complements the molecular imaging aspect of 68Ga-SSTR PET/CT for the prognosis of survival after PRRT. High SSTR expression combined with negative 18F-FDG PET/CT results is associated with the most favorable long-term prognosis.
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Fluordesoxiglucose F18 , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/radioterapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos/uso terapêutico , Somatostatina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Octreotida/análogos & derivados , Octreotida/uso terapêutico , Compostos Organometálicos/uso terapêutico , Prognóstico , Receptores de Somatostatina/metabolismo , Somatostatina/uso terapêuticoRESUMO
Radiolabeled somatostatin receptor (SSTR) antagonists have shown promise for imaging neuroendocrine neoplasms and the superiority to SSTR agonists, with lower liver background especially for the sensitive detection of liver metastases, higher tumor-to-background ratio, and favorable pharmacokinetics. The clinical data of radiolabeled SSTR antagonists for therapy are still limited. We report our experience treating a young patient with DOTATOC-negative high-grade liver metastases of a pancreatic neuroendocrine neoplasm who underwent intra-arterial peptide receptor radionuclide therapy using SSTR antagonist Lu-DOTA-LM3, demonstrating an excellent response, nearly complete remission according to molecular imaging criteria and morphological partial remission, without any significant toxicity.
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Neoplasias Hepáticas/radioterapia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Compostos Radiofarmacêuticos/uso terapêutico , Adulto , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Lutécio/uso terapêutico , Octreotida/análogos & derivados , Octreotida/uso terapêutico , Radioisótopos/uso terapêuticoRESUMO
We report here the 12-year survival after the first peptide receptor radionuclide therapy (PRRT) of a patient with metastatic rectal neuroendocrine neoplasms, who received 7 cycles of PRRT with Lu/Y-DOTATATE/DOTATOC in 4 treatment phases. The patient demonstrated excellent response to each cycle of treatment, without any adverse effect even after repeated PRRT cycles. Most recently, immunohistochemistry revealed a G3 neuroendocrine neoplasm and intraspinal metastasis were successfully resected by neurosurgical intervention. This case nicely demonstrates that several "salvage" PRRTs can be given over many years leading to repetitive benefit for the patient and saving patients of possible toxicity of alternative treatments.
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Neoplasias Ósseas/secundário , Neoplasias Cardíacas/secundário , Neoplasias Pulmonares/secundário , Tumores Neuroendócrinos/patologia , Radioterapia/métodos , Neoplasias Retais/patologia , Terapia de Salvação , Adulto , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/radioterapia , Neoplasias Cardíacas/diagnóstico por imagem , Neoplasias Cardíacas/radioterapia , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/radioterapia , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/radioterapia , Masculino , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Octreotida/uso terapêutico , Compostos Organometálicos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/radioterapia , Resultado do TratamentoRESUMO
PURPOSE: Peptide receptor radionuclide therapy (PRRT) is effective for metastatic/inoperable neuroendocrine tumors (NETs). Imaging response assessment is usually efficient subsequent to treatment completion. Blood biomarkers such as PRRT Predictive Quotient (PPQ) and NETest are effective in real-time. PPQ predicts PRRT efficacy; NETest monitors disease. We prospectively evaluated: (1) NETest as a surrogate biomarker for RECIST; (2) the correlation of NETest levels with PPQ prediction. METHODS: Three independent 177Lu-PRRT-treated GEP-NET and lung cohorts (Meldola, Italy: n = 72; Bad-Berka, Germany: n = 44; Rotterdam, Netherlands: n = 41). Treatment response: RECIST1.1 (responder (stable, partial, and complete response) vs non-responder). Blood sampling: pre-PRRT, before each cycle and follow-up (2-12 months). PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable < 40; progressive > 40). CgA (ELISA) as comparator. Samples de-identified, measurement and analyses blinded. Kaplan-Meier survival and standard statistics. RESULTS: One hundred twenty-two of the 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly (p < 0.0001) decreased in RECIST "responders" (- 47 ± 3%); in "non-responders," it remained increased (+ 79 ± 19%) (p < 0.0005). NETest monitoring accuracy was 98% (119/122). Follow-up levels > 40 (progressive) vs stable (< 40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04 (95%CI, 0.02-0.07). PPQ response prediction was accurate in 118 (97%) with a 99% accurate positive and 93% accurate negative prediction. NETest significantly (p < 0.0001) decreased in PPQ-predicted responders (- 46 ± 3%) and remained elevated or increased in PPQ-predicted non-responders (+ 75 ± 19%). Follow-up NETest categories stable vs progressive significantly correlated with PPQ prediction and mPFS (not reached vs. 10 months; HR 0.06 (95%CI, 0.03-0.12). CgA did not reflect PRRT treatment: in RECIST responders decrease in 38% and in non-responders 56% (p = NS). CONCLUSIONS: PPQ predicts PRRT response in 97%. NETest accurately monitors PRRT response and is an effective surrogate marker of PRRT radiological response. NETest decrease identified responders and correlated (> 97%) with the pretreatment PPQ response predictor. CgA was non-informative.
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Tumores Neuroendócrinos , Neoplasias Pancreáticas , Biomarcadores Tumorais , Humanos , Itália , Países Baixos , Tumores Neuroendócrinos/radioterapiaRESUMO
Patients with metastatic castration-resistant prostate cancer (mCRPC) and visceral (liver or lung) metastases have a poor prognosis and worse outcomes than those with bone disease with or without lymph nodes involvement. The high prostate-specific membrane antigen expression in prostate cancer metastases makes it a promising approach for targeted radionuclide therapy of prostate cancer. Lutetium-177 (Lu)-labeled prostate-specific membrane antigen radioligand therapy (Lu-PRLT) has demonstrated encouraging efficacy in mCRPC. We report here an mCRPC patient with lung, lymph nodes, and extensive bone metastases, who underwent Lu-PRLT and had excellent response to the treatment and complete regression of lung metastases after Lu-PRLT.
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Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/secundário , Neoplasias de Próstata Resistentes à Castração/patologia , Humanos , Lutécio , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico , Resultado do TratamentoRESUMO
Nasopharyngeal carcinoma may express somatostatin receptors (SSTR). We present a case with metastatic nasopharyngeal carcinoma in the liver, bone, and lymph nodes. The patient was in progression after chemotherapy, external beam radiation therapy (ERBT), atezolizumab, and cetuximab. Due to strong SSTR expression of the metastases, PRRT was applied. After 3 cycles of intravenous Lu-DOTATOC and 1 cycle of intraarterial Y-DOTATOC therapy, the hepatic and bone metastases showed excellent response after PRRT. No nephrotoxicity or myelotoxicity was observed.
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Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/radioterapia , Octreotida/análogos & derivados , Receptores de Peptídeos/metabolismo , Administração Intravenosa , Adulto , Humanos , Infusões Intra-Arteriais , Masculino , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/metabolismo , Metástase Neoplásica , Octreotida/administração & dosagem , Octreotida/uso terapêutico , Resultado do TratamentoRESUMO
Precision oncology is being driven by rapid advances in novel diagnostics and therapeutic interventions, with treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations. Inherent in the theranostics paradigm is the assumption that diagnostic test results can precisely determine whether an individual is likely to benefit from a specific treatment. As part and integral in the current era of precision oncology, theranostics in the context of nuclear medicine aims to identify the appropriate molecular targets in neoplasms (diagnostic tool), so that the optimal ligands and radionuclides (therapeutic tool) with favorable labeling chemistry can be selected for personalized management of a specific disease, taking into consideration the specific patient, and subsequently monitor treatment response. Over the past two decades, the use of gallium-68 labeled peptides for somatostatin receptor (SSTR)-targeted PET/CT (or PET/MRI) imaging followed by lutetium-177 and yttrium-90 labeled SSTR-agonist for peptide receptor radionuclide therapy has demonstrated remarkable success in the management of neuroendocrine neoplasms, and paved the way to other indications of theranostics. Rapid advances are being made in the development of other peptide-based radiopharmaceuticals, small molecular-weight ligands and with newer radioisotopes with more favorable kinetics, potentially useful for theranostics strategies for the clinical application. The present review features the Bad Berka experience with first-in-human studies of new radiopharmaceuticals, for example, prostate-specific membrane antigen ligand, gastrin-releasing peptide receptor, neurotensin receptor 1 ligand, novel SSTR-targeting peptides and nonpeptide, and bone-seeking radiopharmaceuticals. Also new radioisotopes, for example, actinium (225Ac), copper (64Cu), scandium (44Sc), and terbium (152Tb/161Tb) will be discussed briefly demonstrating the development from basic science to precision oncology in the clinical setting.
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Medicina Nuclear/métodos , Pesquisa Translacional Biomédica/métodos , Animais , Humanos , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêuticoRESUMO
BACKGROUND: For almost a decade, terbium radioisotopes have been explored for their potential theragnostic application in nuclear medicine: 152Tb and 155Tb are the radioisotopes identified for PET or SPECT imaging, while 149Tb and 161Tb have suitable decay characteristics for α- and combined ß-/Auger-e--therapy, respectively. In the present study, the application of 152Tb, in combination with PSMA-617 for imaging of prostate-specific membrane antigen (PSMA)-positive prostate cancer, was demonstrated in a preclinical setting and in a patient with metastatic castration-resistant prostate cancer (mCRPC). RESULTS: 152Tb was produced at the ISOLDE facility at CERN/Geneva, Switzerland, by spallation, followed by on-line mass separation. The chemical separation was performed at Paul Scherrer Institute using chromatographic methods, as previously reported. 152Tb was employed for labeling PSMA-617, and the radioligand was extensively investigated in vitro to demonstrate similar characteristics to its 177Lu-labeled counterpart. Preclinical PET/CT imaging studies performed with mice enabled visualization of PSMA-positive PC-3 PIP tumors, while uptake in PSMA-negative PC-3 flu tumors were absent. Based on these promising preclinical results, 152Tb was shipped to Zentralklinik Bad Berka, Germany, where it was used for labeling of PSMA-617, enabling PET imaging of a patient with mCRPC. PET/CT scans were performed over a period of 25 h post injection (p.i.) of the radioligand (140 MBq). The images were of diagnostic quality, particularly those acquired at later time points, and enabled the detection of the same metastatic lesions and of local recurrent tumor as previously detected by 68Ga-PSMA-11 PET/CT acquired 45 min p.i. CONCLUSIONS: The results of this study demonstrate the successful preparation and preclinical testing of 152Tb-PSMA-617 and its first application in a patient with mCRPC. This work could pave the way towards clinical application of other Tb radionuclides in the near future, most importantly 161Tb, which has promising decay characteristics for an effective treatment of mCRPC patients.
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177Lu-PSMA radioligand therapy (LuPRLT) is mainly used for patients with metastatic castration-resistant prostate cancer who are resistant to established drugs. This study describes LuPRLT, either LuPSMA I&T or LuPSMA RLT-617, for 45 patients with predominant lymph node metastatic prostate cancer (LNM PC). Thirty-five patients had LNM and ten patients had LNM and one or two bone metastases. Before LuPRLT, the patients had prostate specific antigen (PSA) of median 18 µg/l (interquartile range (IQR): 3.3-39). LuPRLT was given with a cumulative injected 177Lu activity of median 14.5 GBq (IQR: 12.2-20.4). Maximum percentage decline of PSA was median 92% (IQR: 70-99). Thirty-five patients with only LNM had a better overall survival (OS) than ten patients with LNM and one or two bone metastases. Thirty-three docetaxel-naïve patients had a longer PSMA PET/CT progression-free survival than twelve patients who were resistant to docetaxel. Twenty-two patients who received LuPRLT with a cumulative injected 177Lu activity ≥ 14.8 GBq had a better PSMA PET/CT progression-free survival than 23 patients who received LuPRLT with a lower cumulative injected 177Lu activity. Seventeen patients with relapse after LuPRLT who received rechallenge LuPRLT or ActPRLT had a better OS than five patients who received other forms for relapse treatment. LuPRLT gave mild and transitory adverse effects. The findings of the present study suggest that LuPRLT of patients with LNM may be effective and safe. The promising results motivate randomized phase II trials to further quantify the impact of LuPRLT as treatment of patients with LNM.
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Prostate-specific membrane antigen (PSMA) is overexpressed in a majority of prostate cancer cells, which has led to the development of radiolabeled small-molecule inhibitors of PSMA for molecular imaging and targeted radioligand therapy. Lu-labeled PSMA, with therapeutic ß-emission and concomitant γ radiation, permits posttherapy imaging for the assessment of biodistribution and uptake in tumors and normal organs, as well as dosimetry. We report a patient with prostate cancer and metastatic lymph nodes-related lower extremity lymphedema, who presented with dermal backflow and soft-tissue uptake in the lower extremity on posttherapeutic whole body scan after intravenous Lu-PSMA treatment.
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Dipeptídeos/farmacocinética , Compostos Heterocíclicos com 1 Anel/farmacocinética , Extremidade Inferior/diagnóstico por imagem , Linfedema/diagnóstico por imagem , Compostos Radiofarmacêuticos/farmacocinética , Idoso de 80 Anos ou mais , Humanos , Lutécio , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Antígeno Prostático Específico , Imagem Corporal TotalRESUMO
Peptide receptor radionuclide therapy (PRRT) is an effective treatment for patients with neuroendocrine neoplasms. The aim of this study was to identify clinical and treatment parameters associated with progression-free survival (PFS) and overall survival (OS). Methods: All patients treated from October 2002 until March 2016 at the Zentralklinik Bad Berka with at least 3 administrations of PRRT (maximal interval of 6 mo between consecutive administrations) were included. Data were collected in 5 categories: general patient characteristics, tumor characteristics, prior treatments, radioisotope used for PRRT, and blood chemistry. Survival was analyzed using Kaplan-Meier curves. Univariate and multivariate Cox regression analyses were performed to identify parameters associated with PFS and OS. Results: In total, 782 patients were included, with a median follow-up of 36 mo. The median PFS and OS were 22 and 53 mo, respectively. Parameters associated with lower PFS in the multivariate analysis were a Ki-67 of more than 5%, previous treatment with interferon-α and chemotherapy, presence of diabetes, and chromogranin-A (CgA) levels higher than 336 µg/L. Parameters associated with lower OS were a Ki-67 of more than 10%, performance status of at least 1, previous chemotherapy and ablation, and CgA levels higher than 112 µg/L. Conclusion: Higher Ki-67 values, as well as higher CgA levels and previous chemotherapy, had a negative outcome on both PFS and OS. Furthermore, PFS was negatively associated with previous interferon-α treatment and diabetes, whereas lower OS was related to prior ablation and higher performance status.
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Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/radioterapia , Receptores de Peptídeos/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromogranina A/sangue , Coleta de Dados , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Interferon-alfa/farmacologia , Antígeno Ki-67/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Resultado do Tratamento , Adulto JovemRESUMO
The aim of this study was to assess the safety, tolerability, and effects on renal function as well as therapeutic efficacy of prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) using 177Lu-labeled PSMA-617 in patients with metastatic castration-resistant prostate cancer and a single functioning kidney before PRLT. Methods: Sixteen patients (aged 53-78 y; mean age, 64.7 ± 6.5 y) with a single functioning kidney received PRLT with 177Lu-PSMA-617 between March 2015 and October 2018. All parameters of renal function (serum creatinine, blood urea nitrogen, and electrolytes) were prospectively documented in a structured database and analyzed before each PRLT cycle and in follow-up. Renal function was further quantified by measuring tubular extraction rate (TER) using 99mTc-mercaptoacetyltriglycine renal scintigraphy. Treatment-related adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Kaplan-Meier analysis was performed to obtain the progression-free survival and overall survival. Results: The median administered activity was 22.1 GBq (range, 15.4-33.8 GBq). The calculated absorbed radiation dose to the kidney per cycle was 5.3 ± 2.1 Gy (0.81 ± 0.32 Gy/GBq). Renal function was already impaired at baseline in 43.7% of patients, including CTCAE grade 1 renal impairment in 25.0% and CTCAE grade 2 in 18.8%. Grade 1 and 2 renal impairment, respectively, were present in 37.5% and 6.3% of the patients after the first PRLT cycle and in 31.3% and 12.5% after the second cycle. No CTCAE grade 3 or 4 nephrotoxicity was observed during or after treatment. There was no significant change in either TER or the ratio of TER to lower-limit TER after the last cycle of treatment (P > 0.05). The median PFS was 8.1 mo based on both the criteria of the European Organization for Research and Treatment of Cancer and RECIST. The median overall survival has yet to be reached with a median follow-up time of 19.3 mo (range, 5.8-45.3 mo). Conclusion: In patients with a single functioning kidney, 177Lu-PSMA-617 PRLT is feasible, seems to be effective, and is well tolerated, without any signs of acute or subacute nephrotoxicity during a mean follow-up of nearly 2 y (and up to 45.3 mo). Further long-term follow-up of this special patient group is warranted.
Assuntos
Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/radioterapia , Rim Único/complicações , Idoso , Dipeptídeos/efeitos adversos , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Rim/efeitos da radiação , Ligantes , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/complicações , Radiometria , Segurança , Resultado do TratamentoRESUMO
Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues has been shown to be highly efficacious concerning progression-free survival and response rates in patients with advanced, progressive, well-differentiated, somatostatin-receptor-positive neuroendocrine neoplasm. We report here delayed response of a midgut neuroendocrine neoplasm patient, who had stable disease after 4 cycles of PRRT and over a long period of 5 restaging admissions with excellent quality of life (full working hours), persisting for 3 years of follow-up, and presented as further partial remission according to both Response Evaluation Criteria in Solid Tumors and EORTC criteria, respectively, 36 months after the last PRRT cycle.
Assuntos
Neoplasias Intestinais/radioterapia , Neoplasias Hepáticas/radioterapia , Tumores Neuroendócrinos/radioterapia , Octreotida/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Adulto , Ensaios Clínicos como Assunto , Humanos , Neoplasias Intestinais/diagnóstico por imagem , Neoplasias Intestinais/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Masculino , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia ComputadorizadaRESUMO
177Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy using PSMA-617 and PSMA-I&T ligands (177Lu-PRLT) is an emerging treatment in metastatic castration-resistant prostate cancer (mCRPC). This retrospective study evaluates clinical outcomes of 177Lu-PRLT in earlier and later phases of mCRPC grouped by previous taxane chemotherapy. Methods: A retrospective analysis was performed on 167 patients with mCRPC who underwent 177Lu-PRLT between March 2013 and December 2016. Patients were classified as either taxane chemotherapy pretreated (T-pretreated) or naïve (T-naïve) depending on whether they had received taxane-based chemotherapy prior to 177Lu-PRLT. Clinical outcome for T-pretreated and T-naïve patients was assessed by overall survival (OS), radiographic progression-free survival, and prostate-specific antigen (PSA) response rate. Univariate and multivariable analyses were performed for both T-pretreated and T-naïve patients to determine predictors of outcome. Toxicity was categorized by the Common Terminology Criteria for Adverse Events (version 4.03). Results: Of the 167 patients treated with 177Lu-PRLT, 83 were T-pretreated and 84 were T-naïve. At baseline, T-pretreated patients had overall poorer performance status, a higher prevalence of bone metastases, higher PSA levels, lower hemoglobin levels, higher alkaline phosphatase (ALP) levels and had received more additional therapies compared with T-naïve patients. Median OS was 10.7 mo for T-pretreated patients and 27.1 mo for T-naïve patients. Median radiographic progression-free survival was 6.0 mo for T-pretreated patients and 8.8 mo for T-naïve patients. PSA response assessment was evaluable in 132 patients and seen in 25 of 62 (40%) T-pretreated patients and 40 of 70 (57%) T-naïve patients. Significant determinates of inferior OS in multivariable analysis for T-pretreated patients were poorer performance status, lower cumulative administered activity, and lower baseline hemoglobin. Higher baseline alkaline phosphatase was the only significant determinate of inferior OS in multivariable analysis for T-naïve patients. Overall 177Lu-PRLT was safe, with minimal adverse effects evident during follow-up in both T-pretreated and T-naïve patients. Conclusion: 177Lu-PRLT is a promising therapy in mCRPC, with encouraging outcomes and minimal associated toxicity seen in both our T-naïve and heavily pretreated patient cohorts.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/radioterapia , Taxoides/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Dipeptídeos/efeitos adversos , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Humanos , Ligantes , Lutécio , Masculino , Metástase Neoplásica , Intervalo Livre de Progressão , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Estudos Retrospectivos , Segurança , Fatores de Tempo , Resultado do TratamentoRESUMO
To date, limited data are available concerning peptide receptor radionuclide therapy (PRRT) of grade 3 (G3) neuroendocrine neoplasms (NENs) with a Ki-67 proliferation index of greater than 20%. The purpose of this study was to analyze the long-term outcome, efficacy, and safety of PRRT in patients with somatostatin receptor (SSTR)-expressing G3 NENs. Methods: A total of 69 patients (41 men; age, 28-81 y) received PRRT with 177Lu- or 90Y-labeled somatostatin analogs (DOTATATE or DOTATOC). Twenty-two patients had radiosensitizing chemotherapy. Kaplan-Meier analysis was performed to calculate progression-free survival (PFS) and overall survival (OS), defined from the start of PRRT, including a subgroup analysis for patients with a Ki-67 index of less than or equal to 55% and a Ki-67 index of greater than 55%. Treatment response was evaluated according to RECIST 1.1 as well as molecular imaging criteria (European Organization for Research and Treatment of Cancer). Short- and long-term toxicity was documented (Common Terminology Criteria for Adverse Events, v 5.0) using a structured database (comprising >250 items per patient) and retrospectively analyzed. Results: Forty-six patients had pancreatic NENs, 11 had unknown primary cancer, 6 had midgut NENs, 3 had gastric NENs, and 3 had rectal NENs. The median follow-up was 94.3 mo. The median PFS was 9.6 mo, and the median OS was 19.9 mo. For G3 NENs with a Ki-67 index of less than or equal to 55% (n = 53), the median PFS was 11 mo and the median OS was 22 mo. Patients with a Ki-67 index of greater than 55% (n = 11) had a median PFS of 4 mo and a median OS of 7 mo. For patients with positive SSTR imaging but no 18F-FDG uptake, the median PFS was 24 mo and the median OS was 42 mo. A significant difference was found for both PFS and OS, with median PFS of 16 mo and 5 mo and median OS of 27 mo and 9 mo for an SUVmax of greater than 15.0 and an SUVmax of less than or equal to 15.0, respectively, on SSTR PET. In the group with 18F-FDG uptake scored as 3 or 4, the median PFS was 7.1 mo and the median OS was 17.2 mo. In the group with 18F-FDG uptake scored as 0-2, the median PFS was 24.3 mo and the median OS was 41.6 mo. PRRT was well tolerated by all patients; no grade 3 or grade 4 hematotoxicity occurred, and no clinically significant decline in renal function was observed. There was no hepatotoxicity. Conclusion: PRRT was tolerated well, without significant adverse effects, and was efficacious in G3 NENs; the clinical outcome was promising, especially in patients with a Ki-67 index of less than or equal to 55% and even in patients for whom chemotherapy had failed. Baseline 18F-FDG along with SSTR molecular imaging was useful for stratifying G3 NEN patients with high uptake on SSTR PET/CT and no or minor 18F-FDG avidity-a mismatch pattern that was associated with a better long-term prognosis.
Assuntos
Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/radioterapia , Receptores de Somatostatina/metabolismo , Segurança , Somatostatina/efeitos adversos , Somatostatina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Tumores Neuroendócrinos/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prognóstico , Estudos Retrospectivos , Somatostatina/química , Somatostatina/metabolismo , Análise de Sobrevida , Resultado do TratamentoRESUMO
Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues has been proven to be very useful in the management of advanced, well-differentiated neuroendocrine neoplasms (NENs). We present here the pregnancy outcome in a NEN patient, who naturally conceived and gave birth to a healthy baby, after 4 cycles of PRRT administering a cumulative radioactivity of 27.1 GBq. This case underlines that pregnancy and birth without sequelae are possible in patients with NEN who have been treated with PRRT and offers a definitive prospect for patients of reproductive age group who plan conception despite having received or due to undergo PRRT.