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Karimi A, Bogdani C, O'Dwyer E, Siolas D. Emerging innovations in theranostics for pancreatic neuroendocrine tumors. NPJ Precis Oncol 2025; 9:146. [PMID: 40389624 PMCID: PMC12089376 DOI: 10.1038/s41698-025-00938-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 05/06/2025] [Indexed: 05/21/2025] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) often overexpress somatostatin receptor type 2 (SSTR2), making them ideal targets for theranostics, which integrates molecular imaging with targeted radionuclide therapy. 177Lu-DOTATATE significantly extends progression-free survival (22.8 vs. 8.5 months) compared to octreotide LAR. Despite these advances, challenges remain, including treatment resistance and long-term toxicities. In this review, we explore advancements in specialized imaging techniques, rationale combination strategies, and exploring next-generation radiopharmaceuticals.
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Affiliation(s)
- Anita Karimi
- Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY, USA
| | - Christina Bogdani
- New York Institute of Technology College of Osteopathic Medicine, Old Westbury, New York, NY, USA
| | - Elisabeth O'Dwyer
- Division of Molecular Imaging and Therapeutics, Department of Radiology, Weill Cornell Medicine, New York, NY, USA
| | - Despina Siolas
- Department of Medicine, Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
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Campos Ramírez SE, Andrés García A, Blanco Abad C, Gomila Pons P, Gómez Mugarza P, Ruffini Egea SE, Gallart Caballero L, Polo Marques E, Alonso Orduña V. Evaluation of the Real-Life Efficacy and Safety of the Treatment with Lutetium-177 Dotatate for Metastatic Neuroendocrine Tumors. J Clin Med 2025; 14:2384. [PMID: 40217834 PMCID: PMC11989597 DOI: 10.3390/jcm14072384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2025] [Revised: 03/20/2025] [Accepted: 03/29/2025] [Indexed: 04/14/2025] Open
Abstract
Background: Therapy using lutetium-177 dotatate (177LU) was approved in Europe for the treatment of advanced neuroendocrine tumors (NETs) in 2017. Since then, it has become part of the strategies in the treatment of NETs, making it now possible to evaluate real-life results. Research Design and Methods: Single-arm, retrospective, multicenter, cohort study of all the patients with metastatic NETs treated with 177LU (four cycles of 200 mCi every 8 weeks) in the two medical centers dedicated to the treatment of NETs from the region of Aragón, Spain, from 2017 to 2024. Descriptive analysis of demographic characteristics, efficacy, and survival analysis were performed using the statistics software Jamovi 2.6.14. Results: Sixty-eight patients were included. The majority were male, and the most frequent primary location was the pancreas. The ORR was 30.9%. The DCR was 88%. The median OS was 47.4 months [95% CI, 25.6-NE]. The median PFS was 26.1 months [95% CI, 18.5-68.3]. High-grade tumors, multiple previous treatments, and pancreatic location presented worse OS. In total, 42.6% presented any grade adverse event (17.2% hematologic, 30.9% GI symptoms). Conclusions: The efficacy of 177LU in our study is like that observed in similar studies. Acceptable tolerance has been shown. Pancreatic tumors, previous treatments, and higher grades demonstrated worse outcomes. The new research line must consider the use of treatment with 177LU in earlier lines for metastatic disease as well as its possible use in local or locally advanced disease.
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Affiliation(s)
| | - Alejandro Andrés García
- Department of Nuclear Medicine, Hospital Clínico Universitario Lozano Blesa, 50009 Zaragoza, Spain
| | - Carmen Blanco Abad
- Department of Medical Oncology, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
| | - Paula Gomila Pons
- Department of Medical Oncology, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
| | - Pablo Gómez Mugarza
- Department of Medical Oncology, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
| | | | - Luis Gallart Caballero
- Department of Medical Oncology, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
| | - Eduardo Polo Marques
- Department of Medical Oncology, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
| | - Vicente Alonso Orduña
- Department of Medical Oncology, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
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Zhao J, Pei X, Li Y. Efficacy and Safety of Peptide Receptor Radionuclide Therapy for the Treatment of Pancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis of Comparative Studies. Cureus 2025; 17:e80817. [PMID: 40190903 PMCID: PMC11970540 DOI: 10.7759/cureus.80817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/19/2025] [Indexed: 04/09/2025] Open
Abstract
Peptide receptor radionuclide therapy (PRRT) showed promising potential in the management of patients with pancreatic neuroendocrine tumors (pNETs). However, there is still a lack of evidence on its relative efficacy and safety compared with other treatment options. This review aims to synthesize the existing evidence on the efficacy and safety of PRRT for pNETs compared to different treatments. An electronic search was conducted from inception to May 2024. Comparative studies, including randomized controlled trials (RCTs), cohort studies, and case-control studies, that focused on the use of PRRT for treating pNETs were included. Efficacy outcomes included disease control rate (DCR), complete response (CR), partial response (PR), stable disease (SD), progression-free survival (PFS), and overall survival (OS). Safety outcomes were grade 3-4 hematological and renal toxicity and adverse events (AEs). Nine studies met the inclusive criteria. Among them, only one (11.1%) study was an RCT. Meta-analysis between full and reduced dosages of 177Lu-DOTATATE for G1-G2 pNETs revealed no significant differences in DCR, CR, PR, SD, and PFS between the groups. However, the full dosage group showed superior efficacy in some outcomes (DCR, CR, and PR). When PRRT was compared to other treatments such as surgery, chemotherapy, and targeted agents, it was associated with longer PFS and OS. Additionally, PRRT combined with capecitabine and salvage PRRT also showed efficacy in advanced cases. Safety analysis indicated that PRRT is well-tolerated, with minimal severe toxicity reported. PRRT is a promising therapeutic option for patients with advanced pNETs, offering a balance of efficacy and safety compared to other available treatments based on the low quality of evidence. Full-dosage PRRT may provide better outcomes than reduced dosages, and salvage PRRT remains effective for progressive disease. However, further high-quality RCTs are needed to confirm these findings and optimize PRRT usage in pNETs.
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Affiliation(s)
- Jun Zhao
- Department of General Surgery, Second Hospital of Lanzhou University, Lanzhou, CHN
| | - Xiaxia Pei
- Department of Oncology, Second Hospital of Lanzhou University, Lanzhou, CHN
| | - Yumin Li
- Key Laboratory of the Digestive System Tumors of Gansu Province, Second Hospital of Lanzhou University, Lanzhou, CHN
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Lee DY, Kim YI. Efficiency and Safety of Targeted Alpha Therapy in Metastatic Neuroendocrine Tumors: A Meta-analysis. Clin Nucl Med 2025; 50:e1-e6. [PMID: 39169519 DOI: 10.1097/rlu.0000000000005404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/23/2024]
Abstract
PURPOSE Despite the effectiveness of 177 Lu-based peptide receptor radionuclide therapy in treating metastatic neuroendocrine tumors (NETs), disease progression posttreatment remains a significant challenge. Targeted alpha therapy (TAT) has emerged as a promising option for patients experiencing such progression. This study aims to assess the therapeutic efficiency and toxicity of TAT in patients with metastatic NET through a meta-analysis. PATIENTS AND METHODS We conducted a comprehensive search of PubMed, Embase, Cochrane Library, and CINAHL using relevant keywords. The analysis focused on the pooled proportions of objective response rate (ORR) and disease control rate (DCR) to determine therapeutic efficiency. We also evaluated the incidence of serious hematologic and renal adverse events (grade 3 or 4) to assess toxicity. A subgroup analysis was performed to identify factors influencing therapeutic outcomes. RESULTS Our meta-analysis included 7 studies comprising 162 patients. The results showed that TAT achieved ORR of 49.5% (95% confidence interval [CI]: 41.7%-57.4%) and DCR of 87.0% (95% CI: 72.1%-96.8%). The incidences of hematologic and renal toxicities were low, at 2.1% (95% CI: 0.5%-5.5%) and 3.4% (95% CI: 1.2%-7.3%), respectively. Subgroup analysis indicated consistent therapeutic efficiency across different variables, including prior 177 Lu-based peptide receptor radionuclide therapy treatment, 225 Ac-based TAT, absence of radiosensitizer, and methods of response evaluation, with ORR ranging from 46.6% to 57.1% and DCR from 82.0% to 91.5%. CONCLUSIONS TAT is an effective treatment for metastatic NET, demonstrating substantial disease control and response rates with minimal toxicity. These findings suggest that TAT is a viable therapeutic alternative for patients with metastatic NET.
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Affiliation(s)
- Dong Yun Lee
- From the Department of Nuclear Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Mallak N, Yilmaz B, Meyer C, Winters C, Mench A, Jha AK, Prasad V, Mittra E. Theranostics in Neuroendocrine Tumors: Updates and Emerging Technologies. Curr Probl Cancer 2024; 52:101129. [PMID: 39232443 DOI: 10.1016/j.currproblcancer.2024.101129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 05/22/2024] [Indexed: 09/06/2024]
Abstract
Advancements in somatostatin receptor (SSTR) targeted imaging and treatment of well-differentiated neuroendocrine tumors (NETs) have revolutionized the management of these tumors. This comprehensive review delves into the current practice, discussing the use of the various FDA-approved SSTR-agonist PET tracers and the predictive imaging biomarkers, and elaborating on Lu177-DOTATATE peptide receptor radionuclide therapy (PRRT) including the evolving areas of post-therapy imaging practices, PRRT retreatment, and the potential role of dosimetry in optimizing patient treatments. The future directions sections highlight ongoing research on investigational PET imaging radiotracers, future prospects in alpha particle therapy, and combination therapy strategies.
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Affiliation(s)
- Nadine Mallak
- Department of Diagnostic Radiology, Molecular Imaging and Therapy Section, Oregon Health & Sciences University, Portland, OR, USA
| | - Burcak Yilmaz
- Department of Diagnostic Radiology, Molecular Imaging and Therapy Section, Oregon Health & Sciences University, Portland, OR, USA
| | - Catherine Meyer
- Department of Diagnostic Radiology, Medical Physics Section, Oregon Health & Sciences University, Portland, OR, USA
| | - Celeste Winters
- Department of Diagnostic Radiology, Medical Physics Section, Oregon Health & Sciences University, Portland, OR, USA
| | - Anna Mench
- Department of Diagnostic Radiology, Medical Physics Section, Oregon Health & Sciences University, Portland, OR, USA
| | - Abhinav K Jha
- Department of Biomedical Engineering, Washington University, St. Louis, MO, USA; Department of Radiology, Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, US
| | - Vikas Prasad
- Department of Radiology, Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, US
| | - Erik Mittra
- Department of Diagnostic Radiology, Molecular Imaging and Therapy Section, Oregon Health & Sciences University, Portland, OR, USA.
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Tan B, Zhang B, Chen H. Gastroenteropancreatic neuroendocrine neoplasms: epidemiology, genetics, and treatment. Front Endocrinol (Lausanne) 2024; 15:1424839. [PMID: 39411312 PMCID: PMC11474919 DOI: 10.3389/fendo.2024.1424839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 09/10/2024] [Indexed: 10/19/2024] Open
Abstract
The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) is increasing at a rapid pace and is becoming an increasingly important consideration in clinical care. Epidemiological data from multiple countries indicate that the incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) exhibits regional, site-specific, and gender-based variations. While the genetics and pathogenesis of some GEP NEN, particularly pancreatic NENs, have been investigated, there are still many mechanisms that require further investigation. The management of GEP NEN is diverse, but surgery remains the primary option for most cases. Peptide receptor radionuclide therapy (PRRT) is an effective treatment, and several clinical trials are exploring the potential of immunotherapy and targeted therapy, as well as combination therapy.
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Affiliation(s)
- Baizhou Tan
- Department of Histology and Embryology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Beiyu Zhang
- Department of Histology and Embryology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Hongping Chen
- Department of Histology and Embryology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Experimental Animals, Nanchang University, Nanchang, China
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Sedlack AJH, Varghese DG, Naimian A, Yazdian Anari P, Bodei L, Hallet J, Riechelmann RP, Halfdanarson T, Capdevilla J, Del Rivero J. Update in the management of gastroenteropancreatic neuroendocrine tumors. Cancer 2024; 130:3090-3105. [PMID: 39012928 DOI: 10.1002/cncr.35463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 05/15/2024] [Accepted: 05/30/2024] [Indexed: 07/18/2024]
Abstract
Neuroendocrine neoplasms are a diverse group of neoplasms that can occur in various areas throughout the body. Well-differentiated neuroendocrine tumors (NETs) most often arise in the gastrointestinal tract, termed gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Although GEP-NETs are still uncommon, their incidence and prevalence have been steadily increasing over the past decades. The primary treatment for GEP-NETs is surgery, which offers the best chance for a cure. However, because GEP-NETs are often slow-growing and do not cause symptoms until they have spread widely, curative surgery is not always an option. Significant advances have been made in systemic and locoregional treatment options in recent years, including peptide-receptor radionuclide therapy with α and β emitters, somatostatin analogs, chemotherapy, and targeted molecular therapies.
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Affiliation(s)
- Andrew J H Sedlack
- Medical Scientist Training Program, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Diana Grace Varghese
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Amirkia Naimian
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Pouria Yazdian Anari
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
- Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Lisa Bodei
- Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Julie Hallet
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, East York, Ontario, Canada
| | | | | | | | - Jaydira Del Rivero
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
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Grewal US, Loeffler BT, Paschke A, Dillon JS, Chandrasekharan C. Repeat Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors: A NET Center of Excellence Experience. J Gastrointest Cancer 2024; 55:1165-1170. [PMID: 38780680 DOI: 10.1007/s12029-024-01065-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/05/2024] [Indexed: 05/25/2024]
Abstract
INTRODUCTION The available data for the safety and efficacy of repeat peptide receptor radionuclide therapy (PRRT) are almost exclusively from European centers. We present an updated experience with repeat PRRT in a cohort of US patients with neuroendocrine tumors (NETs) at our NET center of excellence. METHODS We used our single-center longitudinal NET registry to identify patients who had been previously treated with at least one dose of PRRT (PRRT 1, either 177Lu DOTATATE or 90Y DOTATOC) and following radiographic disease progression were re-treated with a second course of PRRT (PRRT 2). We reviewed patient, tumor and treatment characteristics, objective response rates, and toxicities after PRRT 1 and PRRT 2. RESULTS A total of 11 patients were included in the analysis. 45.5% (5/11) of patients received 177Lu DOTATATE PRRT only, both for PRRT1 and PRRT 2, while 54.5% (6/11) of patients received 90Y DOTATOC PRRT for PRRT1. At first restaging scan after PRRT2 (3-6 months), 18.2% (2/11), 36.4% (4/11), and 27.3% (3/11) of patients had PR, SD, and PD, respectively; 2/11 patients (18.2%) died before the first restaging scan. Therefore, 5/11 (45.5%) patients were noted to have disease progression. Median PFS for PRRT1 was 25.4 months and median PFS for PRRT2 was 13.1 months (p = 0.0001). We did not find a statistically significant difference between the occurrence of short and long-term hematological toxicities as well as renal toxicity after PRRT1 and PRRT2. CONCLUSION We show that repeat PRRT may benefit select patients and have an acceptable safety profile. In our cohort, PFS was significantly lower after PRRT2 as compared to PRRT1.
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Affiliation(s)
- Udhayvir S Grewal
- Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
- University of Iowa Holden Comprehensive Cancer Center, Iowa City, IA, USA
| | - Bradley T Loeffler
- University of Iowa Holden Comprehensive Cancer Center, Iowa City, IA, USA
| | - Alexander Paschke
- Department of Internal Medicine, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Joseph S Dillon
- University of Iowa Holden Comprehensive Cancer Center, Iowa City, IA, USA
- Division of Endocrinology and Metabolism, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
- Holden Comprehensive Cancer Center, ENETS Center of Excellence, Iowa City, IA, USA
| | - Chandrikha Chandrasekharan
- Division of Hematology, Oncology, and Blood and Marrow Transplantation, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
- University of Iowa Holden Comprehensive Cancer Center, Iowa City, IA, USA.
- Holden Comprehensive Cancer Center, ENETS Center of Excellence, Iowa City, IA, USA.
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Lamarca A, Bartsch DK, Caplin M, Kos-Kudla B, Kjaer A, Partelli S, Rinke A, Janson ET, Thirlwell C, van Velthuysen MLF, Vullierme MP, Pavel M. European Neuroendocrine Tumor Society (ENETS) 2024 guidance paper for the management of well-differentiated small intestine neuroendocrine tumours. J Neuroendocrinol 2024; 36:e13423. [PMID: 38977327 DOI: 10.1111/jne.13423] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 05/28/2024] [Accepted: 06/02/2024] [Indexed: 07/10/2024]
Abstract
Both the incidence and prevalence of well-differentiated neuroendocrine tumours from the small intestine (Si-NET) are gradually increasing. Most patients have non-functioning tumours with subtle GI symptoms and tumours are often discovered incidentally by endoscopy or at advanced disease stages by imaging depicting mesenteric lymph node and /or liver metastases while around 30% of the patients present with symptoms of the carcinoid syndrome. Adequate biochemical assessment and staging including functional imaging is crucial for treatment-related decision-making that should take place in an expert multidisciplinary team setting. Preferably, patients should be referred to specialised ENETS Centres of Excellence or centres of high expertise in the field. This guidance paper provides the current evidence and best knowledge for the management of Si-NET grade (G) 1-3 following 10 key questions of practical relevance for the diagnostic and therapeutic decision making.
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Affiliation(s)
- Angela Lamarca
- Department of Oncology - Onco Health Institute, Fundación Jiménez Díaz University Hospital, Madrid, Spain
- Department of Medical Oncology, The Christie NHS Foundation, Manchester, Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Detlef K Bartsch
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Martyn Caplin
- Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK
| | - Beata Kos-Kudla
- Department of Endocrinology and Neuroendocrine Tumors, ENETS Center of Excellence, Department of Pathophysiology and Endocrinology, Medical University of Silesia, Katowice, Poland
| | - Andreas Kjaer
- Department of Clinical Physiology and Nuclear Medicine and Cluster for Molecular Imaging, Copenhagen University of Copenhagen-Rigshospitalet, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stefano Partelli
- Pancreas Translational and Clinical Research Centre, Pancreatic and Transplant Surgery Unit, Vita-Salute San Raffaele University, Milan, Italy
| | - Anja Rinke
- Department of Gastroenterology, University Hospital Marburg and Philipps University Marburg, Marburg, Germany
| | - Eva Tiensuu Janson
- Department of Medical Sciences, Endocrine Oncology Unit, Uppsala University, Uppsala, Sweden
| | - Christina Thirlwell
- Department of Medical Oncology, University of Exeter Medical School, Exeter, UK
| | | | - Marie-Pierre Vullierme
- Department of Radiology, Paul Brousse University Hospital, AP-HP-University Paris Saclay, Villejuif, France
| | - Marianne Pavel
- Department of Medicine 1, Friedrich-Alexander University Erlangen-Nürnberg, ENETS Center of Excellence Erlangen, CCC Erlangen- EMN, and Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Germany
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van de Weijer T, Bemer F, de Vos-Geelen J, Hermans B, Mitea C, van der Pol JAJ, Lodewick T, Wildberger JE, Mottaghy FM. Altered biodistribution of [ 68Ga]Ga-DOTA-TOC during somatostatin analogue treatment. Eur J Nucl Med Mol Imaging 2024; 51:2420-2427. [PMID: 38403723 PMCID: PMC11178651 DOI: 10.1007/s00259-024-06659-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 02/15/2024] [Indexed: 02/27/2024]
Abstract
PURPOSE The need for an interval between the administration of long-acting Somatostatin Receptor Analogues (SSA) and the [68Ga]Ga-DOTA-TATE PET has been questioned based on recent literature in the new EANM guidelines. Here an earlier studies showed that SSA injection immediately before SSTR PET had minimal effect on normal organ and tumor uptake (1). However, data are scarce and there are (small) differences between [68Ga]Ga-DOTA-TATE and [68Ga]Ga-DOTA-TOC binding affinity, and it remains unknown whether these findings can be directly translated to scans with [68Ga]Ga-DOTA-TOC as well. The purpose of this study was to assess the effect of SSA use on the biodistribution in a subsequent [68Ga]Ga-DOTA-TOC PET/CT and compare this intra-individually across several cycles of SSA treatments. METHODS Retrospectively, 35 patients with NENs were included. [68Ga]Ga-DOTA-TOC PET at staging and after the 1st and 2nd cycle of SSA were included. SUVmean and SUVmax of blood, visceral organs, primary tumor and two metastases were determined. Also, the interval between SSA therapy and the PET scan was registered. RESULTS Treatment with SSA resulted in a significantly higher bloodpool activity and lower visceral tracer uptake. This effect was maintained after a 2nd cycle of SSA therapy. Furthermore, there was an inverse relationship between bloodpool tracer availability and visceral tracer binding and a positive correlation between bloodpool tracer availability and primary tumor tracer uptake. With an interval of up to 5 days, there was a significantly higher bloodpool activity than at longer intervals. CONCLUSION Absolute comparison of the SUV on [68Ga]Ga-DOTA-TOC PET should be done with caution as the altered biodistribution of the tracer after SSA treatment should be taken into account. We recommend not to perform a scan within the first 5 days after the injection of lanreotide.
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Affiliation(s)
- T van de Weijer
- Department of Radiology and Nuclear Medicine, ENETS Center of Excellence, Maastricht University Medical Center (MUMC+), P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands
- School of Nutrition and Translational Research in Metabolism (NUTRIM), University of Maastricht (UM), P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands
| | - F Bemer
- Department of Radiology and Nuclear Medicine, ENETS Center of Excellence, Maastricht University Medical Center (MUMC+), P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands
| | - J de Vos-Geelen
- Department of Medical Oncology, ENETS Center of Excellence, MUMC+, P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands
- School for Oncology and Reproduction (GROW), UM, P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands
| | - B Hermans
- Department of Medical Oncology, ENETS Center of Excellence, MUMC+, P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands
- School for Oncology and Reproduction (GROW), UM, P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands
| | - C Mitea
- Department of Radiology and Nuclear Medicine, ENETS Center of Excellence, Maastricht University Medical Center (MUMC+), P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands
- School for Oncology and Reproduction (GROW), UM, P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands
| | - J A J van der Pol
- Department of Radiology and Nuclear Medicine, ENETS Center of Excellence, Maastricht University Medical Center (MUMC+), P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), UM, P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands
| | - T Lodewick
- Department of Radiology and Nuclear Medicine, ENETS Center of Excellence, Maastricht University Medical Center (MUMC+), P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands
| | - J E Wildberger
- Department of Radiology and Nuclear Medicine, ENETS Center of Excellence, Maastricht University Medical Center (MUMC+), P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands
- School for Cardiovascular Diseases (CARIM), UM, P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands
| | - F M Mottaghy
- Department of Radiology and Nuclear Medicine, ENETS Center of Excellence, Maastricht University Medical Center (MUMC+), P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands.
- School for Oncology and Reproduction (GROW), UM, P. Debeylaan 25, P.O. Box 5800, 6202, 6229 HX, AZ, Maastricht, The Netherlands.
- Department of Nuclear Medicine, University Hospital RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
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Yang H, Zhang Y, Li H, Zhang Y, Feng Y, Yang X, Chen Y. Efficacy and Safety of 225 Ac-DOTATATE in the Treatment of Neuroendocrine Neoplasms With High SSTR Expression. Clin Nucl Med 2024; 49:505-512. [PMID: 38498615 DOI: 10.1097/rlu.0000000000005149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2024]
Abstract
PURPOSE We aimed to evaluate the efficacy and safety of 225 Ac-DOTATATE targeted α therapy (TAT) in various neuroendocrine neoplasms (NENs) with high somatostatin receptor (SSTR) expression. PATIENTS AND METHODS This single-center prospective study included 10 patients with histologically diagnosed NENs that exhibited increased SSTR expression on 68 Ga-DOTATATE PET/CT imaging. All patients received 225 Ac-DOTATATE TAT. The primary end points were molecular imaging-based response and disease control rate (DCR), measured using the slightly modified Positron Emission Tomography Response Criteria in Solid Tumors 1.0. The secondary end points were adverse event profiles and clinical responses. The adverse event profile was determined according to the Common Terminology Criteria for Adverse Events version 5.0. Clinical response was assessed using the EORTC QLQ-C30 v3.0 (European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire version 3.0). RESULTS A molecular imaging-based partial response was observed in 40% of all patients, SD in 40%, PD in 20%, and DCR in 80%. The DCR was 83.3% (5/6) in patients who were previously treated with 177 Lu-DOTATATE. According to the EORTC QLQ-C30 v3.0 score, most symptoms improved after 225 Ac-DOTATATE treatment, with only diarrhea showing no improvement. Grade III/IV hematological, kidney, and liver toxicities were not observed. The median follow-up time was 14 months (7-22 months), and no deaths were reported. CONCLUSIONS This initial study suggests that 225 Ac-DOTATATE is a potentially promising option for treating NENs with elevated SSTR expression, with an acceptable toxicity profile and well-tolerated adverse effects.
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Affiliation(s)
| | | | | | | | | | - Xiqun Yang
- Department of Dermatology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
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12
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Dubois J, Tosato G, Garrigue P, Taieb D, Guillet B, Nail V. Short-Term Biological Toxicity Prediction of [ 177Lu]Lutetium-Oxodotreotide: An Original Retrospective Analysis. Cancer Biother Radiopharm 2024; 39:381-389. [PMID: 38655905 PMCID: PMC11304756 DOI: 10.1089/cbr.2023.0195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2024] Open
Abstract
Introduction: [177Lu]Lutetium (Lu)-oxodotreotide is a radiopharmaceutical drug used as peptide receptor radionuclide therapy (PRRT) for somatostatin receptor-expressing neuroendocrine neoplasms. It provides an additional effective alternative treatment for these rare cancers. Although well tolerated, its safety profile must continue to be characterized to support its use as a first-line treatment or for additional cycles. This study evaluated factors associated with the occurrence of [177Lu]Lu-oxodotreotide induced short-term toxicity. Materials and Methods: A retrospective observational monocentric study was carried out from July 2013 to October 2021. Inclusion criteria were defined as follows: patients who received at least four cycles of [177Lu]Lu-oxodotreotide and were followed up for 6 months after the last injection. Graduated toxicity was defined using the National Cancer Institute Common Terminology Criteria for Adverse Events 5.0. Cox regression was used in the analysis. Results: Forty patients were included. The most frequent toxicities occurred during the first cycle and were graded as G1 or G2. As expected, toxicities were predominantly hematological and hepatic, with incomplete reversibility after each cycle. The following factors were significantly related to the occurrence of hematological or hepatic toxicity during PRRT: gastrointestinal primary tumor diagnosis, bone metastases, peritoneal metastases, pancreatic metastases or pulmonary metastases, and high tumor grade. Conclusion: Knowledge and consideration of these factors in adjusting [177Lu]Lu-oxodotreotide treatment regimen could help prevent or reduce the severity of these toxicities. Further studies are still warranted to refine these results and improve treatment management.
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Affiliation(s)
- Julien Dubois
- Department of Radiopharmacy, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France
- Department of Radiopharmacy, Montpellier University Hospital, Montpellier University, Montpellier, France
- Cancer Research Institute of Montpellier (IRCM), University of Montpellier, Montpellier, France
| | - Guillaume Tosato
- Montpellier University Hospital, Montpellier University, Montpellier, France
| | - Philippe Garrigue
- Department of Radiopharmacy, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France
| | - David Taieb
- Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France
| | - Benjamin Guillet
- Department of Radiopharmacy, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France
| | - Vincent Nail
- Department of Radiopharmacy, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France
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13
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Di Franco M, Zanoni L, Fortunati E, Fanti S, Ambrosini V. Radionuclide Theranostics in Neuroendocrine Neoplasms: An Update. Curr Oncol Rep 2024; 26:538-550. [PMID: 38581469 PMCID: PMC11063107 DOI: 10.1007/s11912-024-01526-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2024] [Indexed: 04/08/2024]
Abstract
PURPOSE OF REVIEW This paper aims to address the latest findings in neuroendocrine tumor (NET) theranostics, focusing on new evidence and future directions of combined diagnosis with positron emission tomography (PET) and treatment with peptide receptor radionuclide therapy (PRRT). RECENT FINDINGS Following NETTER-1 trial, PRRT with [177Lu]Lu-DOTATATE was approved by FDA and EMA and is routinely employed in advanced G1 and G2 SST (somatostatin receptor)-expressing NET. Different approaches have been proposed so far to improve the PRRT therapeutic index, encompassing re-treatment protocols, combinations with other therapies and novel indications. Molecular imaging holds a potential added value in characterizing disease biology and heterogeneity using different radiopharmaceuticals (e.g., SST and FDG) and may provide predictive and prognostic parameters. Response assessment criteria are still an unmet need and new theranostic pairs showed preliminary encouraging results. PRRT for NET has become a paradigm of modern theranostics. PRRT holds a favorable toxicity profile, and it is associated with a prolonged time to progression, reduction of symptoms, and improved patients' quality of life. In light of further optimization, different new strategies have been investigated, along with the development of new radiopharmaceuticals.
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Affiliation(s)
- Martina Di Franco
- Nuclear Medicine, Alma Mater Studiorum, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.
| | - Lucia Zanoni
- Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Emilia Fortunati
- Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Stefano Fanti
- Nuclear Medicine, Alma Mater Studiorum, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
- Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
| | - Valentina Ambrosini
- Nuclear Medicine, Alma Mater Studiorum, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
- Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
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14
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Blakkisrud J, Peterson AB, Wildermann SJ, Kingkiner G, Wong KK, Wang C, Frey KA, Stokke C, Dewaraja YK. SPECT/CT Image-Derived Absorbed Dose to Red Marrow Correlates with Hematologic Toxicity in Patients Treated with [ 177Lu]Lu-DOTATATE. J Nucl Med 2024; 65:753-760. [PMID: 38548350 PMCID: PMC11064826 DOI: 10.2967/jnumed.123.266843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 02/21/2024] [Indexed: 05/03/2024] Open
Abstract
Hematologic toxicity, although often transient, is the most common limiting adverse effect during somatostatin peptide receptor radionuclide therapy. This study investigated the association between Monte Carlo-derived absorbed dose to the red marrow (RM) and hematologic toxicity in patients being treated for their neuroendocrine tumors. Methods: Twenty patients each receiving 4 treatment cycles of [177Lu]Lu-DOTATATE were included. Multiple-time-point 177Lu SPECT/CT imaging-based RM dosimetry was performed using an artificial intelligence-driven workflow to segment vertebral spongiosa within the field of view (FOV). This workflow was coupled with an in-house macroscale/microscale Monte Carlo code that incorporates a spongiosa microstructure model. Absorbed dose estimates to RM in lumbar and thoracic vertebrae within the FOV, considered as representations of the whole-body RM absorbed dose, were correlated with hematologic toxicity markers at about 8 wk after each cycle and at 3- and 6-mo follow-up after completion of all cycles. Results: The median of absorbed dose to RM in lumbar and thoracic vertebrae within the FOV (D median,vertebrae) ranged from 0.019 to 0.11 Gy/GBq. The median of cumulative absorbed dose across all 4 cycles was 1.3 Gy (range, 0.6-2.5 Gy). Hematologic toxicity was generally mild, with no grade 2 or higher toxicity for platelets, neutrophils, or hemoglobin. However, there was a decline in blood counts over time, with a fractional value relative to baseline at 6 mo of 74%, 97%, 57%, and 97%, for platelets, neutrophils, lymphocytes, and hemoglobin, respectively. Statistically significant correlations were found between a subset of hematologic toxicity markers and RM absorbed doses, both during treatment and at 3- and 6-mo follow-up. This included a correlation between the platelet count relative to baseline at 6-mo follow up: D median,vertebrae (r = -0.64, P = 0.015), D median,lumbar (r = -0.72, P = 0.0038), D median,thoracic (r = -0.58, P = 0.029), and D average,vertebrae (r = -0.66, P = 0.010), where D median,lumbar and D median,thoracic are median absorbed dose to the RM in the lumbar and thoracic vertebrae, respectively, within the FOV and D average,vertebrae is the mass-weighted average absorbed dose of all vertebrae. Conclusion: This study found a significant correlation between image-derived absorbed dose to the RM and hematologic toxicity, including a relative reduction of platelets at 6-mo follow up. These findings indicate that absorbed dose to the RM can potentially be used to understand and manage hematologic toxicity in peptide receptor radionuclide therapy.
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Affiliation(s)
- Johan Blakkisrud
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan;
- Department of Physics and Computational Radiology, Oslo University Hospital, Oslo, Norway
| | - Avery B Peterson
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan
- Department of Radiation Oncology, Wayne State University, Detroit, Michigan
| | - Scott J Wildermann
- Department of Nuclear Engineering and Radiologic Science, University of Michigan, Ann Arbor, Michigan
| | - Griffen Kingkiner
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan
| | - Ka Kit Wong
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan
| | - Chang Wang
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan; and
| | - Kirk A Frey
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan
| | - Caroline Stokke
- Department of Physics and Computational Radiology, Oslo University Hospital, Oslo, Norway
- Department of Physics, University of Oslo, Oslo, Norway
| | - Yuni K Dewaraja
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, University of Michigan, Ann Arbor, Michigan
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15
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Strosberg JR, Al-Toubah T, El-Haddad G, Reidy Lagunes D, Bodei L. Sequencing of Somatostatin-Receptor-Based Therapies in Neuroendocrine Tumor Patients. J Nucl Med 2024; 65:340-348. [PMID: 38238038 DOI: 10.2967/jnumed.123.265706] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 12/20/2023] [Indexed: 03/03/2024] Open
Abstract
Most well-differentiated neuroendocrine tumors (NETs) express high levels of somatostatin receptors, particularly subtypes 2 and 5. Somatostatin analogs (SSAs) bind to somatostatin receptors and are used for palliation of hormonal syndromes and control of tumor growth. The long-acting SSAs octreotide long-acting release and lanreotide are commonly used in the first-line metastatic setting because of their tolerable side effect profile. Radiolabeled SSAs are used both for imaging and for treatment of NETs. 177Lu-DOTATATE is a β-emitting radiolabeled SSA that has been proven to significantly improve progression-free survival among patients with progressive midgut NETs and is approved for treatment of metastatic gastroenteropancreatic NETs. A key question in management of patients with gastroenteropancreatic and lung NETs is the sequencing of 177Lu-DOTATATE in relation to other systemic treatments (such as everolimus) or liver-directed therapies. This question is particularly complicated given the heterogeneity of NETs and the near absence of randomized trials comparing active treatment options. This state-of-the-art review examines the evidence supporting use of somatostatin-receptor-targeted treatments within the larger landscape of NET therapy and offers insights regarding optimal patient selection, assessment of benefit versus risk, and treatment sequencing.
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Affiliation(s)
- Jonathan R Strosberg
- Department of GI Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida;
| | - Taymeyah Al-Toubah
- Department of GI Oncology, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Ghassan El-Haddad
- Department of Radiology, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Diane Reidy Lagunes
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; and
| | - Lisa Bodei
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
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16
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Kos-Kudła B, Castaño JP, Denecke T, Grande E, Kjaer A, Koumarianou A, de Mestier L, Partelli S, Perren A, Stättner S, Valle JW, Fazio N. European Neuroendocrine Tumour Society (ENETS) 2023 guidance paper for nonfunctioning pancreatic neuroendocrine tumours. J Neuroendocrinol 2023; 35:e13343. [PMID: 37877341 DOI: 10.1111/jne.13343] [Citation(s) in RCA: 85] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/23/2023] [Accepted: 09/25/2023] [Indexed: 10/26/2023]
Abstract
This ENETS guidance paper for well-differentiated nonfunctioning pancreatic neuroendocrine tumours (NF-Pan-NET) has been developed by a multidisciplinary working group, and provides up-to-date and practical advice on the management of these tumours. Using the extensive experience of centres treating patients with NF-Pan-NEN, the authors of this guidance paper discuss 10 troublesome questions in everyday clinical practice. Our many years of experience in this field are still being verified in the light of the results of new clinical, which set new ways of proceeding in NEN. The treatment of NF-Pan-NEN still requires a decision of a multidisciplinary team of specialists in the field of neuroendocrine neoplasms.
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Affiliation(s)
- Beata Kos-Kudła
- Department of Endocrinology and Neuroendocrine Tumours, Department of Pathophysiology and Endocrinology, Medical University of Silesia, Katowice, Poland
| | - Justo P Castaño
- Maimonides Biomedical Research Institute of Córdoba, University of Córdoba, Hospital Universitario Reina Sofía, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Córdoba, Spain
| | - Timm Denecke
- Department of Diagnostic and Interventional Radiology, University Medical Centre Leipzig, Leipzig, Germany
| | - Enrique Grande
- Medical Oncology Department, MD Anderson Cancer Centre Madrid, Madrid, Spain
| | - Andreas Kjaer
- Department of Clinical Physiology and Nuclear Medicine and Cluster for Molecular Imaging, Copenhagen University Hospital - Righospitalet and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Anna Koumarianou
- Hematology Oncology Unit, Fourth Department of Internal Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Louis de Mestier
- Université Paris-Cité, Department of Pancreatology and Digestive Oncology, Beaujon Hospital (APHP.Nord) and INSERM U1149, Paris, France
| | - Stefano Partelli
- Pancreatic Translational and Clinical Research Centre, Pancreatic and Transplant Surgery Unit, Vita-Salute San Raffaele University, Milan, Italy
| | - Aurel Perren
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Stefan Stättner
- Department of General, Visceral and Vascular Surgery, Salzkammergut Klinikum, OÖG, Vöcklabruck, Austria
| | - Juan W Valle
- Division of Cancer Sciences, University of Manchester, Manchester, UK
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology (IEO), IRCCS, Milan, Italy
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17
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Oron-Herman M, Kirmayer D, Lupp A, Schulz S, Kostenich G, Afargan M. Expression prevalence and dynamics of GPCR somatostatin receptors 2 and 3 as cancer biomarkers beyond NET: a paired immunohistochemistry approach. Sci Rep 2023; 13:20857. [PMID: 38012197 PMCID: PMC10682014 DOI: 10.1038/s41598-023-47877-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 11/16/2023] [Indexed: 11/29/2023] Open
Abstract
Somatostatin receptors are clinically validated GPCR biomarkers for diagnosis and treatment of various neuroendocrine tumors (NET). Among the five somatostatin receptors, SST2 and SST3 are associated with apoptosis and cell cycle arrest, making these receptor subtypes better differentiated targets in precision oncology. In this study we performed immunohistochemistry of paired tissue microarrays containing 1125 cores, representing 43 tumor types, each stained for SST2 and SST3. A 12-point immunoreactive scoring (IRS) range was used for interpretation of the staining results. We analyzed the results twice, using the conventional positivity IRS cutoffs ≥ 3 and more stringent ≥ 6. Evaluation of receptors expression dynamics was performed for tumor-nodes-metastases (TNM) defined subgroups (ovarian and hepatocellular adenocarcinomas) as a function of their tumor stage. Our results indicate that two-thirds of tested cores exhibit clinically significant expression of at least SST2 or SST3 (IRS ≥ 6). The expression prevalence of both receptors tends to decline with tumor progression. However, an unexpected upregulation of both SST2 and SST3 reemerged in metastases suggesting conserved receptors genetic potential during tumor life cycle. We suggest that SST2 and SST3 should be further explored as potential biomarkers and therapeutic tools for maximizing the efficiency of somatostatin-based precision oncology of solid tumors beyond NET.
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Affiliation(s)
- Mor Oron-Herman
- Starget Pharma, 26 Snir st., 4704086, Ramat Hasharon, Israel.
| | - David Kirmayer
- Starget Pharma, 26 Snir st., 4704086, Ramat Hasharon, Israel
| | - Amelie Lupp
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Str. 1, 07747, Jena, Germany
| | - Stefan Schulz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, Drackendorfer Str. 1, 07747, Jena, Germany
| | - Genady Kostenich
- Starget Pharma, 26 Snir st., 4704086, Ramat Hasharon, Israel
- The Advanced Technology Center, Sheba Medical Center, Tel Hashomer, 5262000, Ramat Gan, Israel
| | - Michel Afargan
- Starget Pharma, 26 Snir st., 4704086, Ramat Hasharon, Israel
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18
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Al-Toubah T, Strosberg J, Hallanger-Johnson J, El-Haddad G. Targeted radionuclide therapy in endocrine-related cancers: advances in the last decade. Front Endocrinol (Lausanne) 2023; 14:1187870. [PMID: 38053729 PMCID: PMC10694449 DOI: 10.3389/fendo.2023.1187870] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 10/26/2023] [Indexed: 12/07/2023] Open
Abstract
Targeted radionuclide therapy plays an increasingly important role in managing endocrine-related tumors and significantly advances the therapeutic landscape for patients with these diseases. With increasing FDA-approved therapies and advances in the field, come an increased knowledge of the potential for long-term toxicities associated with these therapies and the field must develop new strategies to increase potency and efficacy while individualizing the selection of patients to those most likely to respond to treatment. Novel agents and modalities of therapy are also being explored. This review will discuss the current landscape and describe the avenues for growth in the field currently being explored.
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Affiliation(s)
- Taymeyah Al-Toubah
- Department of GI Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Jonathan Strosberg
- Department of GI Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Julie Hallanger-Johnson
- Department of Head and Neck - Endocrine Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Ghassan El-Haddad
- Department of Radiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Department of Nuclear Medicine, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
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19
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Jiao F, Cui J, Fu D, Li Q, Wu Z, Teng Z, Zhang H, Zhou J, Zhang Z, Chen X, Zhou Y, Li Y, Mou Y, Qin R, Sun Y, Jin G, Cheng Y, Wang J, Ren G, Yue J, Jin G, Xiao X, Wang L. Chinese Medical Association consensus for standardized diagnosis and treatment of pancreatic neuroendocrine neoplasms. Chin Med J (Engl) 2023; 136:2397-2411. [PMID: 37690992 PMCID: PMC10586833 DOI: 10.1097/cm9.0000000000002848] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Indexed: 09/12/2023] Open
Affiliation(s)
- Feng Jiao
- Department of Oncology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Jiujie Cui
- Department of Oncology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Deliang Fu
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Qi Li
- Department of Oncology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200080, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, Shaanxi 710061, China
| | - Zan Teng
- Department of Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110801, China
| | - Hongmei Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Air Force Medical University, Xi'an, Shaanxi 710032, China
| | - Jun Zhou
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Zhihong Zhang
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Xiaobing Chen
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450003, China
| | - Yuhong Zhou
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yixiong Li
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yiping Mou
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
| | - Renyi Qin
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Yongwei Sun
- Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Gang Jin
- Department of Hepatobiliary Pancreatic Surgery, Changhai Hospital, Naval Medical University, Shanghai 200433, China
| | - Yuejuan Cheng
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Jian Wang
- Department of Radiology, Shanghai Changzheng Hospital, Naval Medical University, Shanghai 200003, China
| | - Gang Ren
- Department of Radiotherapy, Peking University Shougang Hospital, Beijing 100144, China
| | - Jiang Yue
- Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Guangxin Jin
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Xiuying Xiao
- Department of Oncology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Liwei Wang
- Department of Oncology, State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
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20
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Halfdanarson TR, Mallak N, Paulson S, Chandrasekharan C, Natwa M, Kendi AT, Kennecke HF. Monitoring and Surveillance of Patients with Gastroenteropancreatic Neuroendocrine Tumors Undergoing Radioligand Therapy. Cancers (Basel) 2023; 15:4836. [PMID: 37835530 PMCID: PMC10571645 DOI: 10.3390/cancers15194836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 09/13/2023] [Accepted: 09/15/2023] [Indexed: 10/15/2023] Open
Abstract
Radioligand therapy (RLT) with [177Lu]Lu-DOTA-TATE is a standard of care for adult patients with somatostatin-receptor (SSTR)-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Taking advantage of this precision nuclear medicine approach requires diligent monitoring and surveillance, from the use of diagnostic SSTR-targeted radioligand imaging for the selection of patients through treatment and assessments of response. Published evidence-based guidelines assist the multidisciplinary healthcare team by providing acceptable approaches to care; however, the sheer heterogeneity of GEP-NETs can make these frameworks difficult to apply in individual clinical circumstances. There are also contradictions in the literature regarding the utility of novel approaches in monitoring and surveilling patients with GEP-NETs receiving RLT. This article discusses the emerging evidence on imaging, clinical biochemistry, and tumor assessment criteria in the management of patients receiving RLT for GEP-NETs; additionally, it documents our own best practices. This allows us to offer practical guidance on how to effectively implement monitoring and surveillance measures to aid patient-tailored clinical decision-making.
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Affiliation(s)
| | - Nadine Mallak
- Division of Molecular Imaging and Therapy, Oregon Health and Science University, Portland, OR 97239, USA;
| | | | | | - Mona Natwa
- Langone Health, New York University, New York, NY 10016, USA
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21
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Silva MM, Canha M, Salazar D, Neves JS, Ferreira G, Carvalho D, Duarte H. Efficacy, Toxicity, and Prognostic Factors of Re-treatment With [177Lu]Lu-DOTA-TATE in Patients With Progressing Neuroendocrine Tumors: The Experience of a Single Center. Cureus 2023; 15:e47506. [PMID: 38021538 PMCID: PMC10663964 DOI: 10.7759/cureus.47506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2023] [Indexed: 12/01/2023] Open
Abstract
PURPOSE Peptide receptor radionuclide therapy (PRRT) is an effective and safe treatment of unresectable or metastatic, progressive neuroendocrine tumours (NETs). However, if progression occurs after the initial PRRT, treatment options remain limited. Our aim was to evaluate the efficacy and safety of a repeat 177Lutetium-[DOTA°,Tyr3]octreotate ([177Lu]Lu-DOTA-TATE) PRRT course in patients with progressive NET after the first [177Lu]Lu-DOTA-TATE PRRT (peptide receptor radionuclide therapy first treatment (PRRT1)). METHODS This is a nine-year retrospective observational study of 20 patients who were re-treated with PRRT (peptide receptor radionuclide therapy retreatment (PRRTR)) after PRRT1. RESULTS The median progression-free survival (PFS) following PRRT1 was 32 months (interquartile range (IQR): 16.5-44.5). After PRRT1, all 20 patients progressed. Of the 20 patients included, two were lost during follow-up. The median PFS after PRRTR was 17.5 months (IQR: 7-39). At the time of analysis, 15/18 patients progressed, and 3/18 had stable disease after PRRTR. Among those patients who progressed, the median time to progression was nine months (IQR: 0-17). The median overall survival from the time of the first cycle of PRRT1 was 66 months (IQR: 65-90). No significant renal or liver toxicity was reported, nor was there a drop in haemoglobin. The decrease in platelet count after PRRTR was statistically significant (p=0.03). Two cycles at PRRTR (vs. 1) were associated with a longer PFS (p=0.014) and the presence of metastases pre-PRRTR was associated with a shorter time to progression following PRRTR (p=0.04). Conclusion: Patients who progressed after PRRT1 can achieve good PFS and minor toxicity. Our study reinforces the efficacy and safety of PRRTR and provides an analysis of factors associated with better outcomes, which can aid clinicians in clinical decision-making.
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Affiliation(s)
- Maria Manuel Silva
- Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, PRT
| | - Marta Canha
- Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, PRT
| | - Daniela Salazar
- Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, PRT
| | - João Sergio Neves
- Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, PRT
| | - Gonçalo Ferreira
- Nuclear Medicine, Instituto Português de Oncologia Porto, Porto, PRT
| | - Davide Carvalho
- Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, PRT
| | - Hugo Duarte
- Nuclear Medicine, Instituto Português de Oncologia Porto, Porto, PRT
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22
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Singh S, Hope TA, Bergsland EB, Bodei L, Bushnell DL, Chan JA, Chasen BR, Chauhan A, Das S, Dasari A, Del Rivero J, El-Haddad G, Goodman KA, Halperin DM, Lewis MA, Lindwasser OW, Myrehaug S, Raj NP, Reidy-Lagunes DL, Soares HP, Strosberg JR, Kohn EC, Kunz PL. Consensus report of the 2021 National Cancer Institute neuroendocrine tumor clinical trials planning meeting. J Natl Cancer Inst 2023; 115:1001-1010. [PMID: 37255328 PMCID: PMC10483264 DOI: 10.1093/jnci/djad096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 05/01/2023] [Accepted: 05/11/2023] [Indexed: 06/01/2023] Open
Abstract
Important progress has been made over the last decade in the classification, imaging, and treatment of neuroendocrine neoplasm (NENs), with several new agents approved for use. Although the treatment options available for patients with well-differentiated neuroendocrine tumors (NETs) have greatly expanded, the rapidly changing landscape has presented several unanswered questions about how best to optimize, sequence, and individualize therapy. Perhaps the most important development over the last decade has been the approval of 177Lu-DOTATATE for treatment of gastroenteropancreatic-NETs, raising questions around optimal sequencing of peptide receptor radionuclide therapy (PRRT) relative to other therapeutic options, the role of re-treatment with PRRT, and whether PRRT can be further optimized through use of dosimetry among other approaches. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trial planning meeting in 2021 with multidisciplinary experts from academia, the federal government, industry, and patient advocates to develop NET clinical trials in the era of PRRT. Key clinical trial recommendations for development included 1) PRRT re-treatment, 2) PRRT and immunotherapy combinations, 3) PRRT and DNA damage repair inhibitor combinations, 4) treatment for liver-dominant disease, 5) treatment for PRRT-resistant disease, and 6) dosimetry-modified PRRT.
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Affiliation(s)
- Simron Singh
- Department of Medicine, Sunnybrook Health Sciences Centre, Odette Cancer Center, University of Toronto, Toronto, ON, Canada
| | - Thomas A Hope
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA
| | - Emily B Bergsland
- Department of Medicine, University of California, San Francisco, CA, USA
| | - Lisa Bodei
- Department of Radiology, Memorial Sloan Kettering Cancer Center, Molecular Imaging and Therapy Service, New York, NY, USA
| | | | - Jennifer A Chan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Beth R Chasen
- Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Aman Chauhan
- Department of Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Satya Das
- Late-Stage Development, Oncology R&D AstraZeneca, Gaithersburg, MD, USA
| | - Arvind Dasari
- Department of GI Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jaydira Del Rivero
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ghassan El-Haddad
- Department of Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, Tampa, FL, USA
| | - Karyn A Goodman
- Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA
| | - Daniel M Halperin
- Department of GI Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mark A Lewis
- Department of Medicine, Intermountain Health, Salt Lake City, UT, USA
| | - O Wolf Lindwasser
- Coordinating Center for Clinical Trials, National Cancer Institute, Bethesda, MD, USA
| | - Sten Myrehaug
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Center, Toronto, ON, Canada
| | - Nitya P Raj
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Heloisa P Soares
- Department of Medicine, Huntsman Cancer Institute at University of Utah, Salt Lake City, UT, USA
| | | | | | - Pamela L Kunz
- Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
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23
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Fortunati E, Bonazzi N, Zanoni L, Fanti S, Ambrosini V. Molecular imaging Theranostics of Neuroendocrine Tumors. Semin Nucl Med 2023; 53:539-554. [PMID: 36623974 DOI: 10.1053/j.semnuclmed.2022.12.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 12/23/2022] [Indexed: 01/08/2023]
Abstract
Neuroendocrine neoplasms (NEN) are rare and heterogeneous tumors, originating mostly from the gastro-entero-pancreatic (GEP) tract followed by the lungs. Multidisciplinary discussion is mandatory for optimal diagnostic and therapeutic management. Well-differentiated NEN (NET) present a high expression of somatostatin receptors (SSTR) and can be studied with [68Ga]-DOTA-peptides ([68Ga]Ga-DOTANOC, [68Ga]Ga-DOTATOC, [68Ga]Ga-DOTATATE) PET/CT to assess disease extension and the eligibility for peptide receptor radionuclide therapy (PRRT). SSTR-analogues labelled with 90Y or 177Lu have been used since mid-90s for NET therapy. PRRT is now considered an effective and safe treatment option for SSTR-expressing NET: following the approval of 177Lu-DOTATATE by FDA and EMA, PRRT is now part of the therapeutic algorithms of the main scientific societies. New strategies to improve PRRT efficacy and to reduce its toxicity are under evaluation (eg, personalization of treatment schemes, the selection of the most suitable patients, improvement of response assessment criteria, optimization of treatment sequencing, feasibility of PRRT-retreatment, combination of PRRT with other treatments options). Recently, several emerging radiopharmaceuticals showed encouraging results for both imaging and therapy (eg, SSTR-analogues labelled with 18F, SSTR-antagonists for both diagnosis and therapy, alpha-labelling for therapy, radiopharmaceuticals binding to new cellular targets). Aim of this review is to focus on current knowledge and to outline emerging perspectives for NEN's diagnosis and therapy.
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Affiliation(s)
- Emilia Fortunati
- Nuclear Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy.
| | - Norma Bonazzi
- Nuclear Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Lucia Zanoni
- Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Stefano Fanti
- Nuclear Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy; Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Valentina Ambrosini
- Nuclear Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy; Nuclear Medicine, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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24
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Burkett BJ, Bartlett DJ, McGarrah PW, Lewis AR, Johnson DR, Berberoğlu K, Pandey MK, Packard AT, Halfdanarson TR, Hruska CB, Johnson GB, Kendi AT. A Review of Theranostics: Perspectives on Emerging Approaches and Clinical Advancements. Radiol Imaging Cancer 2023; 5:e220157. [PMID: 37477566 PMCID: PMC10413300 DOI: 10.1148/rycan.220157] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 03/06/2023] [Accepted: 05/31/2023] [Indexed: 07/22/2023]
Abstract
Theranostics is the combination of two approaches-diagnostics and therapeutics-applied for decades in cancer imaging using radiopharmaceuticals or paired radiopharmaceuticals to image and selectively treat various cancers. The clinical use of theranostics has increased in recent years, with U.S. Food and Drug Administration (FDA) approval of lutetium 177 (177Lu) tetraazacyclododecane tetraacetic acid octreotate (DOTATATE) and 177Lu-prostate-specific membrane antigen vector-based radionuclide therapies. The field of theranostics has imminent potential for emerging clinical applications. This article reviews critical areas of active clinical advancement in theranostics, including forthcoming clinical trials advancing FDA-approved and emerging radiopharmaceuticals, approaches to dosimetry calculations, imaging of different radionuclide therapies, expanded indications for currently used theranostic agents to treat a broader array of cancers, and emerging ideas in the field. Keywords: Molecular Imaging, Molecular Imaging-Cancer, Molecular Imaging-Clinical Translation, Molecular Imaging-Target Development, PET/CT, SPECT/CT, Radionuclide Therapy, Dosimetry, Oncology, Radiobiology © RSNA, 2023.
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Affiliation(s)
- Brian J. Burkett
- From the Department of Radiology (B.J.B., D.J.B., D.R.J., M.K.P.,
A.T.P., C.B.H., G.B.J., A.T.K.) and Division of Medical Oncology (P.W.M.,
A.R.L., T.R.H.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and
Department of Nuclear Medicine, Anadolu Medical Center, Gebze/Kocaeli, Turkey
(K.B.)
| | - David J. Bartlett
- From the Department of Radiology (B.J.B., D.J.B., D.R.J., M.K.P.,
A.T.P., C.B.H., G.B.J., A.T.K.) and Division of Medical Oncology (P.W.M.,
A.R.L., T.R.H.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and
Department of Nuclear Medicine, Anadolu Medical Center, Gebze/Kocaeli, Turkey
(K.B.)
| | - Patrick W. McGarrah
- From the Department of Radiology (B.J.B., D.J.B., D.R.J., M.K.P.,
A.T.P., C.B.H., G.B.J., A.T.K.) and Division of Medical Oncology (P.W.M.,
A.R.L., T.R.H.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and
Department of Nuclear Medicine, Anadolu Medical Center, Gebze/Kocaeli, Turkey
(K.B.)
| | - Akeem R. Lewis
- From the Department of Radiology (B.J.B., D.J.B., D.R.J., M.K.P.,
A.T.P., C.B.H., G.B.J., A.T.K.) and Division of Medical Oncology (P.W.M.,
A.R.L., T.R.H.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and
Department of Nuclear Medicine, Anadolu Medical Center, Gebze/Kocaeli, Turkey
(K.B.)
| | - Derek R. Johnson
- From the Department of Radiology (B.J.B., D.J.B., D.R.J., M.K.P.,
A.T.P., C.B.H., G.B.J., A.T.K.) and Division of Medical Oncology (P.W.M.,
A.R.L., T.R.H.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and
Department of Nuclear Medicine, Anadolu Medical Center, Gebze/Kocaeli, Turkey
(K.B.)
| | - Kezban Berberoğlu
- From the Department of Radiology (B.J.B., D.J.B., D.R.J., M.K.P.,
A.T.P., C.B.H., G.B.J., A.T.K.) and Division of Medical Oncology (P.W.M.,
A.R.L., T.R.H.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and
Department of Nuclear Medicine, Anadolu Medical Center, Gebze/Kocaeli, Turkey
(K.B.)
| | - Mukesh K. Pandey
- From the Department of Radiology (B.J.B., D.J.B., D.R.J., M.K.P.,
A.T.P., C.B.H., G.B.J., A.T.K.) and Division of Medical Oncology (P.W.M.,
A.R.L., T.R.H.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and
Department of Nuclear Medicine, Anadolu Medical Center, Gebze/Kocaeli, Turkey
(K.B.)
| | - Annie T. Packard
- From the Department of Radiology (B.J.B., D.J.B., D.R.J., M.K.P.,
A.T.P., C.B.H., G.B.J., A.T.K.) and Division of Medical Oncology (P.W.M.,
A.R.L., T.R.H.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and
Department of Nuclear Medicine, Anadolu Medical Center, Gebze/Kocaeli, Turkey
(K.B.)
| | - Thorvardur R. Halfdanarson
- From the Department of Radiology (B.J.B., D.J.B., D.R.J., M.K.P.,
A.T.P., C.B.H., G.B.J., A.T.K.) and Division of Medical Oncology (P.W.M.,
A.R.L., T.R.H.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and
Department of Nuclear Medicine, Anadolu Medical Center, Gebze/Kocaeli, Turkey
(K.B.)
| | - Carrie B. Hruska
- From the Department of Radiology (B.J.B., D.J.B., D.R.J., M.K.P.,
A.T.P., C.B.H., G.B.J., A.T.K.) and Division of Medical Oncology (P.W.M.,
A.R.L., T.R.H.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and
Department of Nuclear Medicine, Anadolu Medical Center, Gebze/Kocaeli, Turkey
(K.B.)
| | - Geoffrey B. Johnson
- From the Department of Radiology (B.J.B., D.J.B., D.R.J., M.K.P.,
A.T.P., C.B.H., G.B.J., A.T.K.) and Division of Medical Oncology (P.W.M.,
A.R.L., T.R.H.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and
Department of Nuclear Medicine, Anadolu Medical Center, Gebze/Kocaeli, Turkey
(K.B.)
| | - A. Tuba Kendi
- From the Department of Radiology (B.J.B., D.J.B., D.R.J., M.K.P.,
A.T.P., C.B.H., G.B.J., A.T.K.) and Division of Medical Oncology (P.W.M.,
A.R.L., T.R.H.), Mayo Clinic, 200 First St SW, Rochester, MN 55905; and
Department of Nuclear Medicine, Anadolu Medical Center, Gebze/Kocaeli, Turkey
(K.B.)
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25
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Abstract
Neuroendocrine neoplasms (NENs) are tumors originating from neuroendocrine cells distributed throughout the human body. With an increasing incidence over the past few decades, they represent a highly heterogeneous group of neoplasms, mostly expressing somatostatin receptors (SSTRs) on their cell surface. Peptide receptor radionuclide therapy (PRRT) has emerged as a crucial strategy for treating advanced, unresectable neuroendocrine tumors by administering radiolabeled somatostatin analogs intravenously to target SSTRs. This article will focus on the multidisciplinary theranostic approach, treatment effectiveness (such as response rates and symptom relief), patient outcomes, and toxicity profile of PRRT for NEN patients. We will review the most significant studies, such as the phase III NETTER-1 trial, and discuss promising new radiopharmaceuticals, including alpha-emitting radionuclide-labeled somatostatin analogs and SSTR antagonists.
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Affiliation(s)
- Elettra Merola
- Gastroenterology Unit, G.B. Grassi Hospital (ASL Roma 3), Lido di Ostia, 00122 Rome, Italy
| | - Chiara Maria Grana
- Radiometabolic Therapy Unit, Division of Nuclear Medicine, IRCCS European Institute of Oncology, 20141 Milan, Italy
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26
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Merola E, Grana CM. Peptide Receptor Radionuclide Therapy (PRRT): Innovations and Improvements. Cancers (Basel) 2023; 15:2975. [PMID: 37296936 PMCID: PMC10251822 DOI: 10.3390/cancers15112975] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/27/2023] [Accepted: 05/28/2023] [Indexed: 06/12/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are tumors originating from neuroendocrine cells distributed throughout the human body. With an increasing incidence over the past few decades, they represent a highly heterogeneous group of neoplasms, mostly expressing somatostatin receptors (SSTRs) on their cell surface. Peptide receptor radionuclide therapy (PRRT) has emerged as a crucial strategy for treating advanced, unresectable neuroendocrine tumors by administering radiolabeled somatostatin analogs intravenously to target SSTRs. This article will focus on the multidisciplinary theranostic approach, treatment effectiveness (such as response rates and symptom relief), patient outcomes, and toxicity profile of PRRT for NEN patients. We will review the most significant studies, such as the phase III NETTER-1 trial, and discuss promising new radiopharmaceuticals, including alpha-emitting radionuclide-labeled somatostatin analogs and SSTR antagonists.
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Affiliation(s)
- Elettra Merola
- Gastroenterology Unit, G.B. Grassi Hospital (ASL Roma 3), Lido di Ostia, 00122 Rome, Italy
| | - Chiara Maria Grana
- Radiometabolic Therapy Unit, Division of Nuclear Medicine, IRCCS European Institute of Oncology, 20141 Milan, Italy;
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27
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Marques P. The Effects of Peptide Receptor Radionuclide Therapy on the Neoplastic and Normal Pituitary. Cancers (Basel) 2023; 15:2710. [PMID: 37345047 PMCID: PMC10216433 DOI: 10.3390/cancers15102710] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/07/2023] [Accepted: 05/08/2023] [Indexed: 06/23/2023] Open
Abstract
Pituitary neuroendocrine tumours (PitNETs) are usually benign and slow-growing; however, in some cases, they may behave aggressively and become resistant to conventional treatments. Therapeutic options for aggressive or metastatic PitNETs are limited, and currently mainly consist of temozolomide, with little experience of other emerging approaches, including peptide receptor radionuclide therapy (PRRT). Somatostatin receptor expression in PitNETs explains the effectiveness of somatostatin analogues for treating PitNETs, particularly those hypersecreting pituitary hormones, such as growth hormone or adrenocorticotropic hormone. The expression of such receptors in pituitary tumour cells has provided the rationale for using PRRT to treat patients with aggressive or metastatic PitNETs. However, the PRRT efficacy in this setting remains unestablished, as knowledge on this today is based only on few case reports and small series of cases, which are reviewed here. A total of 30 PRRT-treated patients have been thus far reported: 23 aggressive PitNETs, 5 carcinomas, and 2 of malignancy status unspecified. Of the 27 published cases with information regarding the response to PRRT, 5 (18%) showed a partial response, 8 (30%) had stable disease, and 14 (52%) had progressive disease. No major adverse effects have been reported, and there is also no increased risk of clinically relevant hypopituitarism in patients with pituitary or non-pituitary neuroendocrine tumours following PRRT. PRRT may be regarded as a safe option for patients with aggressive or metastatic PitNETs if other treatment approaches are not feasible or have failed in controlling the disease progression, with tumour shrinkage occurring in up to a fifth of cases, while about a third of aggressive pituitary tumours may achieve stable disease. Here, the data on PRRT in the management of patients with aggressive pituitary tumours are reviewed, as well as the effects of PRRT on the pituitary function in other PRRT-treated cancer patients.
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Affiliation(s)
- Pedro Marques
- Pituitary Tumor Unit, Endocrinology Department, Hospital CUF Descobertas, 1998-018 Lisbon, Portugal;
- Faculdade de Medicina, Universidade Católica Portuguesa, 2635-631 Lisbon, Portugal
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28
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Urso L, Nieri A, Uccelli L, Castello A, Artioli P, Cittanti C, Marzola MC, Florimonte L, Castellani M, Bissoli S, Porto F, Boschi A, Evangelista L, Bartolomei M. Lutathera® Orphans: State of the Art and Future Application of Radioligand Therapy with 177Lu-DOTATATE. Pharmaceutics 2023; 15:pharmaceutics15041110. [PMID: 37111596 PMCID: PMC10142322 DOI: 10.3390/pharmaceutics15041110] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/28/2023] [Accepted: 03/29/2023] [Indexed: 04/03/2023] Open
Abstract
Lutathera® is the first EMA- and FDA-approved radiopharmaceutical for radioligand therapy (RLT). Currently, on the legacy of the NETTER1 trial, only adult patients with progressive unresectable somatostatin receptor (SSTR) positive gastroenteropancreatic (GEP) neuroendocrine neoplasms (NET) can be treated with Lutathera®. Conversely, patients with SSTR-positive disease arising from outside the gastroenteric region do not currently have access to Lutathera® treatment despite several papers in the literature reporting the effectiveness and safety of RLT in these settings. Moreover, patients with well-differentiated G3 GEP-NET are also still “Lutathera orphans”, and retreatment with RLT in patients with disease relapse is currently not approved. The aim of this critical review is to summarize current literature evidence assessing the role of Lutathera® outside the approved indications. Moreover, ongoing clinical trials evaluating new possible applications of Lutathera® will be considered and discussed to provide an updated picture of future investigations.
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Affiliation(s)
- Luca Urso
- Department of Translational Medicine, University of Ferrara, Via Aldo Moro 8, 44124 Ferrara, Italy; (L.U.); (C.C.); (F.P.)
- Department of Nuclear Medicine, PET/CT Centre, S. Maria della Misericordia Hospital, 45100 Rovigo, Italy;
| | - Alberto Nieri
- Nuclear Medicine Unit, Oncological Medical and Specialist Department, University Hospital of Ferrara, 44124 Cona, Italy; (A.N.); (M.B.)
| | - Licia Uccelli
- Department of Translational Medicine, University of Ferrara, Via Aldo Moro 8, 44124 Ferrara, Italy; (L.U.); (C.C.); (F.P.)
- Nuclear Medicine Unit, Oncological Medical and Specialist Department, University Hospital of Ferrara, 44124 Cona, Italy; (A.N.); (M.B.)
- Correspondence: ; Tel.: +39-053-232-6387
| | - Angelo Castello
- Nuclear Medicine Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.C.); (L.F.); (M.C.)
| | - Paolo Artioli
- Nuclear Medicine Unit, AULSS1 Dolomiti, San Martino Hospital, 32100 Belluno, Italy; (P.A.); (S.B.)
| | - Corrado Cittanti
- Department of Translational Medicine, University of Ferrara, Via Aldo Moro 8, 44124 Ferrara, Italy; (L.U.); (C.C.); (F.P.)
- Nuclear Medicine Unit, Oncological Medical and Specialist Department, University Hospital of Ferrara, 44124 Cona, Italy; (A.N.); (M.B.)
| | - Maria Cristina Marzola
- Department of Nuclear Medicine, PET/CT Centre, S. Maria della Misericordia Hospital, 45100 Rovigo, Italy;
| | - Luigia Florimonte
- Nuclear Medicine Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.C.); (L.F.); (M.C.)
| | - Massimo Castellani
- Nuclear Medicine Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.C.); (L.F.); (M.C.)
| | - Sergio Bissoli
- Nuclear Medicine Unit, AULSS1 Dolomiti, San Martino Hospital, 32100 Belluno, Italy; (P.A.); (S.B.)
| | - Francesca Porto
- Department of Translational Medicine, University of Ferrara, Via Aldo Moro 8, 44124 Ferrara, Italy; (L.U.); (C.C.); (F.P.)
| | - Alessandra Boschi
- Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy;
| | - Laura Evangelista
- Department of Medicine DIMED, University of Padua, 35128 Padua, Italy;
| | - Mirco Bartolomei
- Nuclear Medicine Unit, Oncological Medical and Specialist Department, University Hospital of Ferrara, 44124 Cona, Italy; (A.N.); (M.B.)
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29
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Graillon T, Tabouret E, Salgues B, Horowitz T, Padovani L, Appay R, Farah K, Dufour H, Régis J, Guedj E, Barlier A, Chinot O. Innovative treatments for meningiomas. Rev Neurol (Paris) 2023; 179:449-463. [PMID: 36959063 DOI: 10.1016/j.neurol.2023.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/06/2023] [Accepted: 03/07/2023] [Indexed: 03/25/2023]
Abstract
Multi-recurrent high-grade meningiomas remain an unmet medical need in neuro-oncology when iterative surgeries and radiation therapy sessions fail to control tumor growth. Nevertheless, the last 10years have been marked by multiple advances in the comprehension of meningioma tumorigenesis via the discovery of new driver mutations, the identification of activated intracellular signaling pathways, and DNA methylation analyses, providing multiple potential therapeutic targets. Today, Anti-VEGF and mTOR inhibitors are the most used and probably the most active drugs in aggressive meningiomas. Peptide radioactive radiation therapy aims to target SSTR2A receptors, which are strongly expressed in meningiomas, but have an insufficient effect in most aggressive meningiomas, requiring the development of new techniques to increase the dose applied to the tumor. Based on the multiple potential intracellular targets, multiple targeted therapy clinical trials targeting Pi3K-Akt-mTOR and MAP kinase pathways as well as cell cycle and particularly, cyclin D4-6 are ongoing. Recently discovered driver mutations, SMO, Akt, and PI3KCA, offer new targets but are mostly observed in benign meningiomas, limiting their clinical relevance mainly to rare aggressive skull base meningiomas. Therefore, NF2 mutation remains the most frequent mutation and main challenging target in high-grade meningioma. Recently, inhibitors of focal adhesion kinase (FAK), which is involved in tumor cell adhesion, were tested in a phase 2 clinical trial with interesting but insufficient activity. The Hippo pathway was demonstrated to interact with NF2/Merlin and could be a promising target in NF2-mutated meningiomas with ongoing multiple preclinical studies and a phase 1 clinical trial. Recent advances in immune landscape comprehension led to the proposal of the use of immunotherapy in meningiomas. Except in rare cases of MSH2/6 mutation or high tumor mass burden, the activity of PD-1 inhibitors remains limited; however, its combination with various radiation therapy modalities is particularly promising. On the whole, therapeutic management of high-grade meningiomas is still challenging even with multiple promising therapeutic targets and innovations.
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Affiliation(s)
- T Graillon
- Aix-Marseille University, AP-HM, Inserm, MMG, Neurosurgery department, La Timone Hospital, Marseille, France.
| | - E Tabouret
- Aix-Marseille University, AP-HM, CNRS, INP, Inst Neurophysiopathol, CHU Timone, Service de Neurooncologie, Marseille, France
| | - B Salgues
- Nuclear Medicine Department, Groupe Hospitalier Pitié-Salpêtrière-Charles-Foix, Assistance publique-Hôpitaux de Paris, Sorbonne Université, Paris, France
| | - T Horowitz
- AP-HM, CNRS, centrale Marseille, Institut Fresnel, Timone Hospital, CERIMED, Nuclear Medicine Department, Aix-Marseille University, Marseille, France
| | - L Padovani
- AP-HM, Timone Hospital, Radiotherapy Department, Marseille, France
| | - R Appay
- AP-HM, CHU Timone, Service d'Anatomie Pathologique et de Neuropathologie, Marseille, France; Aix-Marseille University, CNRS, INP, Inst Neurophysiopathol, Marseille, France
| | - K Farah
- Aix-Marseille University, Institut de Neurosciences des Systèmes, UMR Inserm 1106, Functional Neurosurgery and Radiosurgery, Timone University Hospital, Marseille, France
| | - H Dufour
- Aix-Marseille University, AP-HM, Inserm, MMG, Neurosurgery department, La Timone Hospital, Marseille, France
| | - J Régis
- Aix-Marseille University, Institut de Neurosciences des Systèmes, UMR Inserm 1106, Functional Neurosurgery and Radiosurgery, Timone University Hospital, Marseille, France
| | - E Guedj
- AP-HM, CNRS, centrale Marseille, Institut Fresnel, Timone Hospital, CERIMED, Nuclear Medicine Department, Aix-Marseille University, Marseille, France
| | - A Barlier
- Aix-Marseille University, AP-HM, Inserm, MMG, Laboratory of Molecular Biology Hospital La Conception, Marseille, France
| | - O Chinot
- Aix-Marseille University, AP-HM, CNRS, INP, Inst Neurophysiopathol, CHU Timone, Service de Neurooncologie, Marseille, France
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Kong G, Boehm E, Prall O, Murray WK, Tothill RW, Michael M. Integrating Functional Imaging and Molecular Profiling for Optimal Treatment Selection in Neuroendocrine Neoplasms (NEN). Curr Oncol Rep 2023; 25:465-478. [PMID: 36826704 PMCID: PMC10110720 DOI: 10.1007/s11912-023-01381-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/05/2023] [Indexed: 02/25/2023]
Abstract
PURPOSE OF REVIEW Gastroenteropancreatic NEN (GEP-NEN) are group of malignancies with significant clinical, anatomical and molecular heterogeneity. High-grade GEP-NEN in particular present unique management challenges. RECENT FINDINGS In the current era, multidisciplinary management with access to a combination of functional imaging and targeted molecular profiling can provide important disease characterisation, guide individualised management and improve patient outcome. Multiple treatment options are now available, and combination and novel therapies are being explored in clinical trials. Precision medicine is highly relevant for a heterogenous disease like NEN. The integration of dual-tracer functional PET/CT imaging, molecular histopathology and genomic data has the potential to be used to gain a more comprehensive understanding of an individual patient's disease biology for precision diagnosis, prognostication and optimal treatment allocation.
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Affiliation(s)
- Grace Kong
- Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia. .,The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.
| | - Emma Boehm
- Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC, 3000, Australia.,Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Owen Prall
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - William K Murray
- Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Richard W Tothill
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.,Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Melbourne, VIC, Australia
| | - Michael Michael
- The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia.,Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
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Chauhan A, Del Rivero J, Ramirez RA, Soares HP, Li D. Treatment Sequencing Strategies in Advanced Neuroendocrine Tumors: A Review. Cancers (Basel) 2022; 14:5248. [PMID: 36358667 PMCID: PMC9656186 DOI: 10.3390/cancers14215248] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 10/04/2022] [Accepted: 10/14/2022] [Indexed: 10/15/2023] Open
Abstract
Neuroendocrine tumor (NET) incidence has grown. The treatment landscape for advanced NETs is rapidly evolving, but there are limited head-to-head data to guide treatment sequencing decisions. We assessed the available clinical data to aid practicing clinicians in their routine clinical decision-making. Clinical trials have demonstrated efficacy benefits for new therapies in advanced NETs. Emerging long-term data from these trials have enabled clinicians to make more accurate risk-benefit assessments, particularly for patients receiving multiple lines of therapy. However, clinical data specifically regarding treatment sequencing are limited. In lieu of definitive data, treatment sequencing should be based on disease-related factors (e.g., site of tumor origin, volume of disease) and patient-related characteristics (e.g., comorbidities, patient preferences). Clinical decision-making in advanced NETs remains highly individualized and complex; important evidence gaps regarding treatment sequencing remain. Given this, advanced NET management should be a joint effort of multidisciplinary teams at referring and high-volume centers. Additional clinical trial and real-world evidence are needed to meet the challenge of understanding how to sequence available NET therapies. Until these trials are conducted, the best practices provided in this review may serve as a guide for clinicians making treatment sequencing decisions based on the available data.
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Affiliation(s)
- Aman Chauhan
- Division of Medical Oncology, Department of Internal Medicine, Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA
| | - Jaydira Del Rivero
- Developmental Therapeutics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
| | - Robert A. Ramirez
- Division of Hematology Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Heloisa P. Soares
- Division of Medical Oncology, Department of Internal Medicine, Huntsman Cancer Institute at University of Utah, Salt Lake City, UT 84112, USA
| | - Daneng Li
- Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA
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Ballal S, Yadav MP, Tripathi M, Sahoo RK, Bal C. Survival Outcomes in Metastatic Gastroenteropancreatic Neuroendocrine Tumor Patients receiving Concomitant 225Ac-DOTATATE Targeted Alpha Therapy and Capecitabine: A Real-world Scenario Management Based Long-term Outcome Study. J Nucl Med 2022; 64:jnumed.122.264043. [PMID: 35863893 DOI: 10.2967/jnumed.122.264043] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 07/15/2022] [Indexed: 11/16/2022] Open
Abstract
Rationale: Although the short-term results of targeted alpha therapy (TAT) with 225Ac-DOTATATE in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have proven effective, none have assessed the long-term outcome results. In this study, we aimed to evaluate the long-term outcome of 225Ac-DOTATATE targeted alpha therapy (TAT) in patients with somatostatin receptor (SSTR)-expressing advanced-stage metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Methods: Patients with 68Ga-DOTANOC PET/CT scans showing moderate-to-high SSTR expression were recruited. Systemic TAT was performed in 91 adults with GEP-NET [54 males, and 37 females] mean age 54 years (y) (range: 25-75y)] using 225Ac-DOTATATE (100-120 kBq/kg body weight). All patients were given capecitabine therapy as a radiosensitizer (dose 2 g/day) from day 0 to 14 of every 225Ac-DOTATATE treatment cycle. Patients were categorized into three groups based on the status of prior 177Lu-PRRT: prior 177Lu-PRRT-refractory-group; prior 177Lu-PRRT-disease-control group; and 177Lu-PRRT naïve group. Primary endpoints were overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective tumour response, clinical response, and the assessment of treatment-related toxicities. Results: Among the 91 patients, 57 underwent prior 177Lu-DOTATATE therapy [24 disease controlled (PR/SD), 33 progressive diseases (PD)]. A total of 453 225Ac-DOTATATE TAT cycles were administered [median four cycles per patient; range 1-10] in a median follow-up duration of 24 months (range 5-41mo). Median OS was not attained with a 24-month overall survival probability of 70.8%. In multivariate analysis, prognostic factors associated with a poor OS included, the presence bone metastases [HR: 2.501; 95% CI: 1.826 - 5.791; P<0.032], and 225Ac-DOTATATE therapy refractory disease [HR: 8.781; 95% CI: 3.843 - 20.062; P<0.0001]. Median PFS was also not reached with a 24-month progression-free survival probability of 67.5%. The multivariate analysis revealed only 177Lu-PRRT refractory disease significantly associated with a reduced PFS. [HR: 14.338; 95% CI: 1.853 - 97.698; P = 0.011]. Two of 79 patients (2.5%) with assessable disease experienced complete response; 38 (48%) had a partial response, 23 (29%) had SD, and 16 (20.2%) had PD. PD was observed in more patients from the prior 177Lu-PRRT-refractory group (11/33; 34%) as compared to 177Lu-PRRT-naïve patients (4/24; 11%), P-0.056. Patients from the prior 177Lu-PRRT-refractory group had the highest risk of poor PFS [HR:13.91; 95% CI: 4.45 - 42.271; P = 0.0009]. A significant clinical benefit was achieved post 225Ac-DOTATATE therapy with minimal treatment-related toxicities. Conclusion: The long-term results reveal 225Ac-DOTATATE TAT has shown promising results and improves overall survival, even in patients refractory to prior 177Lu-DOTATATE treatment, with transient and acceptable adverse effects.
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Bartolomei M, Berruti A, Falconi M, Fazio N, Ferone D, Lastoria S, Pappagallo G, Seregni E, Versari A. Clinical Management of Neuroendocrine Neoplasms in Clinical Practice: A Formal Consensus Exercise. Cancers (Basel) 2022; 14:2501. [PMID: 35626105 PMCID: PMC9140035 DOI: 10.3390/cancers14102501] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 05/16/2022] [Indexed: 02/01/2023] Open
Abstract
Many treatment approaches are now available for neuroendocrine neoplasms (NENs). While several societies have issued guidelines for diagnosis and treatment of NENs, there are still areas of controversy for which there is limited guidance. Expert opinion can thus be of support where firm recommendations are lacking. A group of experts met to formulate 14 statements relative to diagnosis and treatment of NENs and presented herein. The nominal group and estimate-talk-estimate techniques were used. The statements covered a broad range of topics from tools for diagnosis to follow-up, evaluation of response, treatment efficacy, therapeutic sequence, and watchful waiting. Initial prognostic characterization should be based on clinical information as well as histopathological analysis and morphological and functional imaging. It is also crucial to optimize RLT for patients with a NEN starting from accurate characterization of the patient and disease. Follow-up should be patient/tumor tailored with a shared plan about timing and type of imaging procedures to use to avoid safety issues. It is also stressed that patient-reported outcomes should receive greater attention, and that a multidisciplinary approach should be mandatory. Due to the clinical heterogeneity and relative lack of definitive evidence for NENs, personalization of diagnostic-therapeutic work-up is crucial.
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Affiliation(s)
- Mirco Bartolomei
- Azienda Ospedaliero-Universitaria di Ferrara, Presidio Ospedaliero Arcispedale Sant’Anna di Cona, 44124 Ferrara, Italy;
| | - Alfredo Berruti
- Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili di Brescia, 25123 Brescia, Italy
| | - Massimo Falconi
- Pancreas Surgical Unit, ENETS Center of Excellence, San Raffaele Hospital IRCCS, Vita Salute University, 20132 Milan, Italy;
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncologya and Neuroendocrine Tumors, European Institute of Oncology, 20132 Milan, Italy;
| | - Diego Ferone
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties, IRCCS, Ospedale Policlinico San Martino, Università di Genova, 16132 Genova, Italy;
| | - Secondo Lastoria
- Nuclear Medicine Unit, Istituto Nazionale Tumori, Fondazione G. Pascale, 80131 Naples, Italy;
| | - Giovanni Pappagallo
- School of Clinical Methodology IRCCS “Sacred Heart–Don Calabria” Hospital; 37024 Negrar di Valpolicella, Italy;
| | - Ettore Seregni
- Nuclear Medicine Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20132 Milano, Italy;
| | - Annibale Versari
- Nuclear Medicine Unit, Azienda Unità Sanitaria Locale-IRCCS of Reggio Emilia, 42100 Reggio Emilia, Italy;
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Grey N, Silosky M, Lieu CH, Chin BB. Current status and future of targeted peptide receptor radionuclide positron emission tomography imaging and therapy of gastroenteropancreatic-neuroendocrine tumors. World J Gastroenterol 2022; 28:1768-1780. [PMID: 35633909 PMCID: PMC9099199 DOI: 10.3748/wjg.v28.i17.1768] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 01/07/2022] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
Theranostics is the highly targeted molecular imaging and therapy of tumors. Targeted peptide receptor radionuclide therapy has taken the lead in demonstrating the safety and effectiveness of this molecular approach to treating cancers. Metastatic, well-differentiated gastroenteropancreatic neuroendocrine tumors may be most effectively imaged and treated with DOTATATE ligands. We review the current practice, safety, advantages, and limitations of DOTATATE based theranostics. Finally, we briefly describe the exciting new areas of development and future directions of gastroenteropancreatic neuroendocrine tumor theranostics.
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Affiliation(s)
- Neil Grey
- Radiology-Nuclear Medicine, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Michael Silosky
- Department of Radiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Christopher H Lieu
- Medical Oncology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Bennett B Chin
- Department of Radiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO 80045, United States
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Capdevila J, Grande E, García-Carbonero R, Simó M, del Olmo-García MI, Jiménez-Fonseca P, Carmona-Bayonas A, Pubul V. Position Statement on the Diagnosis, Treatment, and Response Evaluation to Systemic Therapies of Advanced Neuroendocrine Tumors, With a Special Focus on Radioligand Therapy. Oncologist 2022; 27:e328-e339. [PMID: 35380724 PMCID: PMC8982404 DOI: 10.1093/oncolo/oyab041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 10/08/2021] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND The aim of this study was to provide a guidance for the management of neuroendocrine tumors (NETs) in clinical practice. MATERIAL AND METHODS Nominal group and Delphi techniques were used. A steering committee of 8 experts reviewed the current management of NETs, identified controversies and gaps, critically analyzed the available evidence, and formulated several guiding statements for clinicians. Subsequently, a panel of 26 experts, was selected to test agreement with the statements through 2 Delphi rounds. Items were scored on a 4-point Likert scale from 1 = totally agree to 4 = totally disagree. The agreement was considered if ≥75% of answers pertained to Categories 1 and 2 (consensus with the agreement) or Categories 3 and 4 (consensus with the disagreement). RESULTS Overall, 132 statements were proposed, which incorporated the following areas: (1) overarching principles; (2) progression and treatment response criteria; (3) advanced gastro-enteric NETs; (4) advanced pancreatic NETs; (5) advanced NETs in other locations; (6) re-treatment with radioligand therapy (RLT); (7) neoadjuvant therapy. After 2 Delphi rounds, only 4 statements lacked a clear consensus. RLT was not only recommended in the sequencing of different NETs but also as neoadjuvant treatment, while several indications for retreatment with RLT were also established. CONCLUSION This document sought to pull together the experts' attitudes when dealing with different clinical scenarios of patients suffering from NETs, with RLT having a specific role where evidence-based data are limited.
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Affiliation(s)
- Jaume Capdevila
- Department of Medical Oncology, Vall Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), IOB-Quiron-Teknon Barcelona, Barcelona, Spain
| | - Enrique Grande
- Department of Medical Oncology, MD Anderson Cancer Center, Madrid, Spain
| | | | - Marc Simó
- Department of Nuclear Medicine and Molecular Imaging, Hospital Universitari Vall d’Hebron, Barcelona, Spain
| | - Mª Isabel del Olmo-García
- Department of Endocrinology, Hospital Universitario y Politécnico la Fe de Valencia, Valencia, Spain
| | - Paula Jiménez-Fonseca
- Department of Medical Oncology, Hospital Universitario Central de Asturias, ISPA, Madrid, Spain
| | - Alberto Carmona-Bayonas
- Department of Hematology and Medical Oncology, Hospital General Universitario Morales Meseguer, University of Murcia, IMIB, CP13/00126, PI17/0050 (ISCIII & FEDER) and Fundación Séneca (04515/GERM/06), Murcia, Spain
| | - Virginia Pubul
- Department of Nuclear Medicine Department and Molecular Imaging Research Group, University Hospital and Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
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Puliani G, Chiefari A, Mormando M, Bianchini M, Lauretta R, Appetecchia M. New Insights in PRRT: Lessons From 2021. Front Endocrinol (Lausanne) 2022; 13:861434. [PMID: 35450421 PMCID: PMC9016202 DOI: 10.3389/fendo.2022.861434] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/07/2022] [Indexed: 11/16/2022] Open
Abstract
Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogs has been used for over two decades for the treatment of well-differentiated neuroendocrine tumors (NETs), and the publication of the NETTER-1 trials has further strengthened its clinical use. However, many aspects of this treatment are still under discussion. The purpose of this review is to collect and discuss the new available evidence, published in 2021, on the use of 177Lu-Oxodotreotide (DOTATATE) or 90Y-Edotreotide (DOTATOC) in adult patients with NETs focusing on the following hot topics: 1) PRRT use in new clinical settings, broaden its indications; 2) the short- and long-term safety; and 3) the identification of prognostic and predictive factors. The review suggests a possible future increase of PRRT applications, using it in other NETs, as a neoadjuvant treatment, or for rechallenge. Regarding safety, available studies, even those with long follow-up, supported the low rates of adverse events, even though 1.8% of treated patients developed a second malignancy. Finally, there is a lack of prognostic and predictive factors for PRRT, with the exception of the crucial role of nuclear imaging for both patient selection and treatment response estimation.
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Affiliation(s)
- Giulia Puliani
- Oncological Endocrinology Unit, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Regina Elena National Cancer Institute, Rome, Italy
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Alfonsina Chiefari
- Oncological Endocrinology Unit, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Regina Elena National Cancer Institute, Rome, Italy
| | - Marilda Mormando
- Oncological Endocrinology Unit, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Regina Elena National Cancer Institute, Rome, Italy
| | - Marta Bianchini
- Oncological Endocrinology Unit, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Regina Elena National Cancer Institute, Rome, Italy
| | - Rosa Lauretta
- Oncological Endocrinology Unit, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Regina Elena National Cancer Institute, Rome, Italy
| | - Marialuisa Appetecchia
- Oncological Endocrinology Unit, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Regina Elena National Cancer Institute, Rome, Italy
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Targeted Endoradiotherapy with Lu 2O 3-iPSMA/-iFAP Nanoparticles Activated by Neutron Irradiation: Preclinical Evaluation and First Patient Image. Pharmaceutics 2022; 14:pharmaceutics14040720. [PMID: 35456554 PMCID: PMC9026501 DOI: 10.3390/pharmaceutics14040720] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 12/22/2022] Open
Abstract
Prostate-specific membrane antigen (PSMA) is expressed in a variety of cancer cells, while the fibroblast activation protein (FAP) is expressed in the microenvironment of tumors. Previously, we reported the ability of iPSMA and iFAP ligands to specifically target PSMA and FAP proteins, as well as the preparation of stable 177Lu2O3 nanoparticles (<100 nm) functionalized with target-specific peptides. This research aimed to evaluate the dosimetry and therapeutic response of Lu2O3-iPSMA and Lu2O3-iFAP nanoparticles activated by neutron irradiation to demonstrate their potential for theranostic applications in nuclear medicine. The biokinetic behavior, radiation absorbed dose, and metabolic activity ([18F]FDG/micro-PET, SUV) in preclinical tumor tissues (athymic mice), following treatment with 177Lu2O3-iPSMA, 177Lu2O3-iFAP or 177Lu2O3 nanoparticles, were assessed. One patient with multiple colorectal liver metastases (PSMA-positive) received 177Lu2O3-iPSMA under a “compassionate use” protocol. Results indicated no significant difference (p < 0.05) between 177Lu2O3-iPSMA and 177Lu2O3-iFAP, regarding tumor radiation absorbed doses (105 ± 14 Gy, 99 ± 12 Gy and 58 ± 7 Gy for 177Lu2O3-iPSMA, 177Lu2O3-iFAP, and 177Lu2O3, respectively) and tumor metabolic activity (SUV of 0.421 ± 0.092, 0.375 ± 0.104 and 1.821 ± 0.891 for 177Lu2O3-iPSMA, 177Lu2O3-iFAP, and 177Lu2O3, respectively) in mice after treatment, which correlated with the observed therapeutic response. 177Lu2O3-iPSMA and 177Lu2O3-iFAP significantly inhibited tumor progression, due to the prolonged tumor retention and a combination of 177Lu radiotherapy and iPSMA or iFAP molecular recognition. There were negligible uptake values in non-target tissues and no evidence of liver and renal toxicity. The doses received by the patient’s liver metastases (42−210 Gy) demonstrated the potential of 177Lu2O3-iPSMA for treating colorectal liver metastases.
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Merola E, Michielan A, Rozzanigo U, Erini M, Sferrazza S, Marcucci S, Sartori C, Trentin C, de Pretis G, Chierichetti F. Therapeutic strategies for gastroenteropancreatic neuroendocrine neoplasms: State-of-the-art and future perspectives. World J Gastrointest Surg 2022; 14:78-106. [DOI: - merola e, michielan a, rozzanigo u, et al.therapeutic strategies for gastroenteropancreatic neuroendocrine neoplasms: state-of-the-art and future perspectives.world j gastrointestinal surgery, volume 14 number 2 february 27, 2022, doi: 10.4240/wjgs.v14.i2.78] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/16/2025] Open
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Merola E, Michielan A, Rozzanigo U, Erini M, Sferrazza S, Marcucci S, Sartori C, Trentin C, de Pretis G, Chierichetti F. Therapeutic strategies for gastroenteropancreatic neuroendocrine neoplasms: State-of-the-art and future perspectives. World J Gastrointest Surg 2022; 14:78-106. [PMID: 35317548 PMCID: PMC8908345 DOI: 10.4240/wjgs.v14.i2.78] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 10/18/2021] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have always been considered rare tumors, their incidence has risen over the past few decades. They represent a highly heterogeneous group of neoplasms with several prognostic factors, including disease stage, proliferative index (Ki67), and tumor differentiation. Most of these neoplasms express somatostatin receptors on the cell surface, a feature that has important implications in terms of prognosis, diagnosis, and therapy. Although International Guidelines propose algorithms aimed at guiding therapeutic strategies, GEP-NEN patients are still very different from one another, and the need for personalized treatment continues to increase. Radical surgery is always the best option when feasible; however, up to 80% of cases are metastatic upon diagnosis. Regarding medical treatments, as GEP-NENs are characterized by relatively long overall survival, multiple therapy lines are adopted during the lifetime of these patients, but the optimum sequence to be followed has never been clearly defined. Furthermore, although new molecular markers aimed at predicting the response to therapy, as well as prognostic scores, are currently being studied, their application is still far from being part of daily clinical practice. As they represent a complex disease, with therapeutic protocols that are not completely standardized, GEP-NENs require a multidisciplinary approach. This review will provide an overview of the available therapeutic options for GEP-NENs and attempts to clarify the possible approaches for the management of these patients and to discuss future perspectives in this field.
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Affiliation(s)
- Elettra Merola
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Andrea Michielan
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Umberto Rozzanigo
- Department of Radiology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Marco Erini
- Department of Nuclear Medicine, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Sandro Sferrazza
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Stefano Marcucci
- Department of Surgery, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Chiara Sartori
- Department of Pathology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Chiara Trentin
- Department of Medical Oncology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Giovanni de Pretis
- Department of Gastroenterology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
| | - Franca Chierichetti
- Department of Nuclear Medicine, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento 38122, Italy
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Role of Somatostatin Signalling in Neuroendocrine Tumours. Int J Mol Sci 2022; 23:ijms23031447. [PMID: 35163374 PMCID: PMC8836266 DOI: 10.3390/ijms23031447] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
Somatostatin (SST) is a small peptide that exerts inhibitory effects on a wide range of neuroendocrine cells. Due to the fact that somatostatin regulates cell growth and hormone secretion, somatostatin receptors (SSTRs) have become valuable targets for the treatment of different types of neuroendocrine tumours (NETs). NETs are a heterogeneous group of tumours that can develop in various parts of the body, including the digestive system, lungs, and pituitary. NETs are usually slow growing, but they are often diagnosed in advanced stages and can display aggressive behaviour. The mortality rate of NETs is not outstandingly increased compared to other malignant tumours, even in the metastatic setting. One of the intrinsic properties of NETs is the expression of SSTRs that serve as drug targets for SST analogues (SSAs), which can delay tumour progression and downregulate hormone overproduction. Additionally, in many NETs, it has been demonstrated that the SSTR expression level provides a prognostic value in predicting a therapeutic response. Furthermore, higher a SSTR expression correlates with a better survival rate in NET patients. In recent studies, other epigenetic regulators affecting SST signalling or SSA–mTOR inhibitor combination therapy in NETs have been considered as novel strategies for tumour control. In conclusion, SST signalling is a relevant regulator of NET functionality. Alongside classical SSA treatment regimens, future advanced therapies and treatment modalities are expected to improve the disease outcomes and overall health of NET patients.
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Peptide Receptor Radionuclide Therapy with [ 177Lu]Lu-DOTA-TATE in Patients with Advanced GEP NENS: Present and Future Directions. Cancers (Basel) 2022; 14:cancers14030584. [PMID: 35158852 PMCID: PMC8833790 DOI: 10.3390/cancers14030584] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/17/2022] [Accepted: 01/20/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Neuroendocrine neoplasms have been usually described as infrequent tumors, but their incidence has been rising over time. [177Lu]Lu-DOTA-TATE (PRRT-Lu) was approved by the European Medicines Agency and by the Food and Drug Administration as the first radiopharmaceutical for peptide receptor radionuclide therapy in progressive gastroenteropancreatic NET. PRRT-Lu is considered a therapeutic option in progressive SSTR-positive NETs with homogenous SSTR expression. The NETTER-1 study demonstrated that PRRT-Lu yielded a statistically and clinically significant improvement in PFS as a primary endpoint (HR: 0.18, p < 0.0001), as well as a clinical trend towards improvement in OS. These results made scientific societies incorporate PRRT-Lu into their clinical guidelines; however, some questions still remain unanswered. Abstract This review article summarizes findings published in the last years on peptide receptor radionuclide therapy in GEP NENs, as well as potential future developments and directions. Unanswered questions remain, such as the following: Which is the correct dose and individual dosimetry? Which is the place for salvage PRRT-Lu? Whicht is the role of PRRT-Lu in the pediatric population? Which is the optimal sequencing of PRRT-Lu in advanced GEP NETs? Which is the place of PRRT-Lu in G3 NENs? These, and future developments such as inclusion new radiopharmaceuticals and combination therapy with different agents, such as radiosensitizers, will be discussed.
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Zhu M, Bekaii-Saab T. OUP accepted manuscript. Oncologist 2022; 27:e534-e535. [PMID: 35403684 PMCID: PMC9177096 DOI: 10.1093/oncolo/oyac068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 12/07/2021] [Indexed: 11/14/2022] Open
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Terapia con péptidos radiomarcados con [177Lu]Lu-DOTA-TATE. Rev Esp Med Nucl Imagen Mol 2022. [DOI: 10.1016/j.remn.2021.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Harris PE, Zhernosekov K. The evolution of PRRT for the treatment of neuroendocrine tumors; What comes next? Front Endocrinol (Lausanne) 2022; 13:941832. [PMID: 36387893 PMCID: PMC9659917 DOI: 10.3389/fendo.2022.941832] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 10/12/2022] [Indexed: 12/02/2022] Open
Abstract
Lu-177 has been developed for the treatment of patients with peptide receptor radionuclide therapy (PRRT). A second generation pure no-carrier-added Lu-177 has a high specific activity and has waste disposal advantages over the first generation carrier-added Lu-177. PRRT has recently been developed for the treatment of neuroendocrine tumors (NETs). The majority of pancreatic and gastroenteric NETs (GEP-NETs) express the somatostatin receptors (SSTRs) 2 and 5. These receptors can be specifically targeted with a somatostatin peptide analogue (DOTATOC/DOTATATE) which can be chelated to a positron emission tomography (PET) emitting radioisotope such as Ga-68 for imaging or to a β-emitting radioisotope Lu-177 for therapy. A key advantage of this approach is that the receptor expression can be demonstrated by PET imaging before the patient is treated. Clinical studies in G1 and G2 GEP-NETS have demonstrated that PRRT is extremely effective in terms of progression free survival (PFS), symptom control and quality of life, with a well-established safety profile. A beneficial effect on outcome survival awaits to be confirmed. The first commercially available product Lu-177-DOTATATE was approved following the NETTER-1 trial in G1 and G2 GE-NETS. Lu-177-DOTATATE 7,4 GBq every 8 weeks for 4 cycles, together with octreotide LAR 30 mg monthly, demonstrated a median PFS of 28,4 months compared to 8,5 months for octreotide LAR 60 mg monthly. A second pivotal study COMPETE is currently in progress, comparing no carrier-added (n.c.a.) Lu-177-DOTATOC to the m-TOR inhibitor Everolimus in both GE-NETs and PNETs. Two studies, NETTER-2 and COMPOSE are currently underway in patients with high grade G2 and G3 NETs. Novel SSTR antagonists are being developed as next generation targeting molecules for SSTR2-expressing tumors. Antagonists have a higher tumor binding to receptors than agonists, opening up the potential indications for SSTR2 targeting to tumors which have a relatively lower expression of SSTR2 compared to NET such as small cell lung cancer, hepatocellular carcinoma and breast cancer. In addition to Lu-177, radioisotopes with different radiation properties such as Tb-161 and the α-emitter Ac-225 are being developed which have the potential to improve treatment efficacy across the range of G1 to G3 NETs.
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Prado-Wohlwend S, Bernal-Vergara JC, Utrera-Costero A, Cañón-Sánchez JR, Agudelo-Cifuentes M, Bello-Arques P. Peptide receptor radionuclide therapy with [ 177Lu]Lu-DOTA-TATE. Rev Esp Med Nucl Imagen Mol 2021; 41:55-65. [PMID: 34920969 DOI: 10.1016/j.remnie.2021.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 11/10/2021] [Indexed: 11/30/2022]
Abstract
This continuing education aims to present in a clear and easy-to-understand way, the biology of neuroendocrine tumors (NETs), the characteristics of somatostatin receptors, the selection of patients for radiolabelled peptide therapy (PRRT), the inclusion criteria to benefit from treatment with the minimum possible adverse effects, the administration protocol, follow-up and response evaluation. The functional imaging studies necessary to explore the biology of the tumor and to individualize the treatment are also carried out, and constitute the cornerstone for the development of teragnosis. Clinical trials are being developed to better define the position of PRRT within the broad therapeutic options, and among the future perspectives, there are several lines of research to improve the objective response rate and survival with PRRT, focused on the development of new agonists and somatostatin receptor antagonists, new radionuclides and radiosensitizing combination therapies. In conclusion, PRRT is a great therapeutic, well-tolerated and safe tool with generally mild and self-limited acute side effects, that must be sequenced at the best moment of the evolution of the disease of patients with NET. Candidate patients for PRRT should always be evaluated by a multidisciplinary clinical committee.
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Affiliation(s)
- S Prado-Wohlwend
- Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
| | - J C Bernal-Vergara
- Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - A Utrera-Costero
- Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - J R Cañón-Sánchez
- Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - M Agudelo-Cifuentes
- Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - P Bello-Arques
- Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain
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- Servicio de Medicina Nuclear, Hospital Universitario y Politécnico La Fe, Valencia, Spain
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Geenen L, Nonnekens J, Konijnenberg M, Baatout S, De Jong M, Aerts A. Overcoming nephrotoxicity in peptide receptor radionuclide therapy using [ 177Lu]Lu-DOTA-TATE for the treatment of neuroendocrine tumours. Nucl Med Biol 2021; 102-103:1-11. [PMID: 34242948 DOI: 10.1016/j.nucmedbio.2021.06.006] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 06/21/2021] [Accepted: 06/21/2021] [Indexed: 12/29/2022]
Abstract
Peptide receptor radionuclide therapy (PRRT) is used for the treatment of patients with unresectable or metastasized somatostatin receptor type 2 (SSTR2)-expressing gastroenteropancreatic neuroendocrine tumours (GEP-NETs). The radiolabelled somatostatin analogue [177Lu]Lu-DOTA-TATE delivers its radiation dose to SSTR2-overexpressing tumour cells, resulting in selective cell killing during radioactive decay. While tumour control can be achieved in many patients, complete remissions remain rare, causing the majority of patients to relapse after a certain period of time. This raises the question whether the currently fixed treatment regime (4 × 7.4 GBq) leaves room for dose escalation as a means of improving therapy efficacy. The kidneys have shown to play an important role in defining a patient's tolerability to PRRT. As a consequence of the proximal tubular reabsorption of [177Lu]Lu-DOTA-TATE, via the endocytic megalin/cubilin receptor complex, the radionuclides are retained in the renal interstitium. This results in extended retention of radioactivity in the kidneys, generating a risk for the development of radiation nephropathy. In addition, a decreased kidney function has shown to be associated with a prolonged circulation of [177Lu]Lu-DOTA-TATE, causing increased irradiation to the bone marrow. This can on its turn lead to myelosuppression and haematological toxicity, owing to the marked radio sensitivity of the rapidly proliferating cells in the bone marrow. In contrast to external beam radiotherapy (EBRT), the exact absorbed dose limits for these critical organs (kidneys and bone marrow) in PRRT with [177Lu]Lu-DOTA-TATE are still unclear. Better insights into these uncertainties, can help in optimizing PRRT to reach its maximum therapeutic potential, while avoiding severe adverse events, like nephropathy and hematologic toxicities. In this review we focus on the nephrotoxic effects of PRRT with [177Lu]Lu-DOTA-TATE for the treatment of GEP-NETs. If the absorbed dose to the kidneys can be lowered, higher activities can be administered, enlarging the therapeutic window for PRRT. Therefore, we evaluated the renal protective potential of current and promising future strategies and discuss the importance of (renal) dosimetry in PRRT.
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Affiliation(s)
- Lorain Geenen
- Radiobiology Unit, Interdisciplinary Biosciences, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium; Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands
| | - Julie Nonnekens
- Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands; Department of Molecular Genetics, Erasmus MC, Rotterdam, the Netherlands; Oncode Institute, Erasmus MC, Rotterdam, the Netherlands
| | - Mark Konijnenberg
- Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands; Department of Medical Imaging, Radboud UMC, Nijmegen, the Netherlands
| | - Sarah Baatout
- Radiobiology Unit, Interdisciplinary Biosciences, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium; Department of Molecular Biotechnology, Faculty of Bioengineering Sciences, Ghent University, Belgium.
| | - Marion De Jong
- Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands
| | - An Aerts
- Radiobiology Unit, Interdisciplinary Biosciences, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK CEN), Mol, Belgium
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Wehrend J, Silosky M, Xing F, Chin BB. Automated liver lesion detection in 68Ga DOTATATE PET/CT using a deep fully convolutional neural network. EJNMMI Res 2021; 11:98. [PMID: 34601660 PMCID: PMC8487415 DOI: 10.1186/s13550-021-00839-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 09/12/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine tumors most commonly metastasize to the liver; however, high normal background 68Ga-DOTATATE activity and high image noise make metastatic lesions difficult to detect. The purpose of this study is to develop a rapid, automated and highly specific method to identify 68Ga-DOTATATE PET/CT hepatic lesions using a 2D U-Net convolutional neural network. METHODS A retrospective study of 68Ga-DOTATATE PET/CT patient studies (n = 125; 57 with 68Ga-DOTATATE hepatic lesions and 68 without) was evaluated. The dataset was randomly divided into 75 studies for the training set (36 abnormal, 39 normal), 25 for the validation set (11 abnormal, 14 normal) and 25 for the testing set (11 abnormal, 14 normal). Hepatic lesions were physician annotated using a modified PERCIST threshold, and boundary definition by gradient edge detection. The 2D U-Net was trained independently five times for 100,000 iterations using a linear combination of binary cross-entropy and dice losses with a stochastic gradient descent algorithm. Performance metrics included: positive predictive value (PPV), sensitivity, F1 score and area under the precision-recall curve (PR-AUC). Five different pixel area thresholds were used to filter noisy predictions. RESULTS A total of 233 lesions were annotated with each abnormal study containing a mean of 4 ± 2.75 lesions. A pixel filter of 20 produced the highest mean PPV 0.94 ± 0.01. A pixel filter of 5 produced the highest mean sensitivity 0.74 ± 0.02. The highest mean F1 score 0.79 ± 0.01 was produced with a 20 pixel filter. The highest mean PR-AUC 0.73 ± 0.03 was produced with a 15 pixel filter. CONCLUSION Deep neural networks can automatically detect hepatic lesions in 68Ga-DOTATATE PET. Ongoing improvements in data annotation methods, increasing sample sizes and training methods are anticipated to further improve detection performance.
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Affiliation(s)
- Jonathan Wehrend
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, University of Colorado School of Medicine Anschutz Medical Campus, 12401 East 17th Avenue, Mail Stop L954A, Aurora, CO, 80045, USA
| | - Michael Silosky
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, University of Colorado School of Medicine Anschutz Medical Campus, 12401 East 17th Avenue, Mail Stop L954A, Aurora, CO, 80045, USA
| | - Fuyong Xing
- Department of Biostatistics and Informatics Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Bennett B Chin
- Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, University of Colorado School of Medicine Anschutz Medical Campus, 12401 East 17th Avenue, Mail Stop L954A, Aurora, CO, 80045, USA.
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Moody TW, Lee L, Ramos-Alvarez I, Iordanskaia T, Mantey SA, Jensen RT. Bombesin Receptor Family Activation and CNS/Neural Tumors: Review of Evidence Supporting Possible Role for Novel Targeted Therapy. Front Endocrinol (Lausanne) 2021; 12:728088. [PMID: 34539578 PMCID: PMC8441013 DOI: 10.3389/fendo.2021.728088] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 08/02/2021] [Indexed: 12/13/2022] Open
Abstract
G-protein-coupled receptors (GPCRs) are increasingly being considered as possible therapeutic targets in cancers. Activation of GPCR on tumors can have prominent growth effects, and GPCRs are frequently over-/ectopically expressed on tumors and thus can be used for targeted therapy. CNS/neural tumors are receiving increasing attention using this approach. Gliomas are the most frequent primary malignant brain/CNS tumor with glioblastoma having a 10-year survival <1%; neuroblastomas are the most common extracranial solid tumor in children with long-term survival<40%, and medulloblastomas are less common, but one subgroup has a 5-year survival <60%. Thus, there is an increased need for more effective treatments of these tumors. The Bombesin-receptor family (BnRs) is one of the GPCRs that are most frequently over/ectopically expressed by common tumors and is receiving particular attention as a possible therapeutic target in several tumors, particularly in prostate, breast, and lung cancer. We review in this paper evidence suggesting why a similar approach in some CNS/neural tumors (gliomas, neuroblastomas, medulloblastomas) should also be considered.
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Affiliation(s)
- Terry W. Moody
- Department of Health and Human Services, National Cancer Institute, Center for Cancer Training, Office of the Director, Bethesda, MD, United States
| | - Lingaku Lee
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
- Department of Gastroenterology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Irene Ramos-Alvarez
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Tatiana Iordanskaia
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Samuel A. Mantey
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Robert T. Jensen
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
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Peptide receptor radionuclide therapy for GEP-NET: consolidated knowledge and innovative applications. Clin Transl Imaging 2021. [DOI: 10.1007/s40336-021-00443-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Constanzo J, Faget J, Ursino C, Badie C, Pouget JP. Radiation-Induced Immunity and Toxicities: The Versatility of the cGAS-STING Pathway. Front Immunol 2021; 12:680503. [PMID: 34079557 PMCID: PMC8165314 DOI: 10.3389/fimmu.2021.680503] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 04/26/2021] [Indexed: 12/20/2022] Open
Abstract
In the past decade, radiation therapy (RT) entered the era of personalized medicine, following the striking improvements in radiation delivery and treatment planning optimization, and in the understanding of the cancer response, including the immunological response. The next challenge is to identify the optimal radiation regimen(s) to induce a clinically relevant anti-tumor immunity response. Organs at risks and the tumor microenvironment (e.g. endothelial cells, macrophages and fibroblasts) often limit the radiation regimen effects due to adverse toxicities. Here, we reviewed how RT can modulate the immune response involved in the tumor control and side effects associated with inflammatory processes. Moreover, we discussed the versatile roles of tumor microenvironment components during RT, how the innate immune sensing of RT-induced genotoxicity, through the cGAS-STING pathway, might link the anti-tumor immune response, radiation-induced necrosis and radiation-induced fibrosis, and how a better understanding of the switch between favorable and deleterious events might help to define innovative approaches to increase RT benefits in patients with cancer.
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Affiliation(s)
- Julie Constanzo
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France
| | - Julien Faget
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France
| | - Chiara Ursino
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France
| | - Christophe Badie
- Cancer Mechanisms and Biomarkers Group, Radiation Effects Department, Centre for Radiation, Chemical & Environmental Hazards Public Health England Chilton, Didcot, United Kingdom
| | - Jean-Pierre Pouget
- IRCM, Institut de Recherche en Cancérologie de Montpellier, INSERM U1194, Université de Montpellier, Institut régional du Cancer de Montpellier, Montpellier, France
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