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Wang Y, Wang Z, Mao X, Zhang H, Zhang L, Yang Y, Liu B, Li X, Luo F, Sun H. Cutting-edge technologies illuminate the neural landscape of cancer: Insights into tumor development. Cancer Lett 2025; 619:217667. [PMID: 40127813 DOI: 10.1016/j.canlet.2025.217667] [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: 01/26/2025] [Revised: 03/18/2025] [Accepted: 03/21/2025] [Indexed: 03/26/2025]
Abstract
Neurogenesis constitutes a pivotal facet of malignant tumors, wherein cancer and its therapeutic interventions possess the ability to reconfigure the nervous system, establishing a pathologic feedback loop that exacerbates tumor progression. Recent strides in high-resolution imaging, single-cell analysis, multi-omics technologies, and experimental models have opened unprecedented avenues in cancer neuroscience. This comprehensive review summarizes the latest advancements of these emerging technologies in elucidating the biological mechanisms underlying tumor initiation, invasion, metastasis, and the dynamic heterogeneity of the tumor microenvironment(TME), with a specific focus on neuron-glial-tumor interactions in glioblastoma(GBM) and other neurophilic cancers. Moreover, we innovatively propose target screening processes based on sequencing technologies and database frameworks. It rigorously evaluates ongoing clinical trial drugs and efficacy while spotlighting characteristic cells in the central and peripheral TME, consolidating cancer biomarkers pivotal for future targeted therapies and management strategies. By integrating these cutting-edge findings, this review aims to offer fresh insights into tumor-nervous system interactions, establishing a robust foundation for forthcoming clinical advancements.
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Affiliation(s)
- Yajing Wang
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Zhaojun Wang
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Xinyuan Mao
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China; The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hongrui Zhang
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lu Zhang
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yufei Yang
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Beibei Liu
- The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xinxu Li
- The First School of Clinical Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Feiyang Luo
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Haitao Sun
- Clinical Biobank Center, Microbiome Medicine Center, Department of Laboratory Medicine, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Zhujiang Hospital and the Second Clinical Medical College, Southern Medical University, Guangzhou, China; Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital Institute for Brain Science and Intelligence, Zhujiang Hospital, Southern Medical University, Guangzhou, China; Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou, China.
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Pecora G, Mancini C, Mazzilli R, Zamponi V, Telese S, Scalera S, Maugeri-Saccà M, Ciuffreda L, De Nicola F, Fanciulli M, La Salvia A, Mancini M, Vecchione A, Siciliani A, Ibrahim M, Bellavia D, Isidori AM, Faggiano A, Mancini R, De Vitis C. Genetic insight into lung neuroendocrine tumors: Notch and Wnt signaling pathways as potential targets. J Transl Med 2025; 23:538. [PMID: 40361150 PMCID: PMC12076951 DOI: 10.1186/s12967-025-06442-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2025] [Accepted: 03/28/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND The molecular landscape of lung neuroendocrine neoplasms is still poorly characterized, making it difficult to develop a molecular classification and personalized therapeutic approaches. Significant clinical heterogeneity of these malignancies has been highlighted among poorly differentiated histotypes and within the subgroup of well-differentiated neuroendocrine tumors (NET). Currently, the main prognostic factors of lung NET include stage, histotype, grade, peripheral location, and demographic parameters. To gain deeper insights into the genomic underpinnings of lung NETs, we conducted a pilot investigation to uncover potential genetic mutations and copy number variations (CNVs) implicated in their pathogenesis. METHODS Formalin-fixed, paraffin-embedded intraoperative tumor biopsies and matched peripheral blood mononuclear cell samples were collected from six consecutive patients with lung NETs. The whole exome sequencing (WES) was performed to profile germline and somatic mutations, identify novel genetic alterations, and detect CNVs. Clinical and pathological data were systematically documented at diagnosis and during follow-up. RESULTS The WES analysis identified a subset of mutations shared between germline and somatic; some were of particular clinical interest as they were associated with tumor proliferation and potential therapeutic targets such as the genes KDM5C, ATR, COL7A1, NOTCH4, PTPRS, SMO, SPEN, SPTA1, TAF1. These mutations were predominantly linked to chromatin remodeling and were involved in critical oncogenic pathways such as Notch and Wnt signaling. CONCLUSIONS This pilot study highlights the potential role of NGS analysis on solid biopsy in the assessment of the mutational profile of lung NET. A comparison of germline and somatic mutations is critical to identifying putative tumor driver mutations. In perspective, the enrichment of a subpopulation of cancer cells in the blood, with one or more specific mutations, is information of enormous clinical relevance, either for prognosis or therapeutic decisions. Translational studies on large prospective series are required to establish the role of liquid biopsy in lung NET.
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Affiliation(s)
- Giulia Pecora
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, AOU Sant'Andrea, ENETS Center of Excellence, Rome, Italy
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Camilla Mancini
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, AOU Sant'Andrea, ENETS Center of Excellence, Rome, Italy
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Rossella Mazzilli
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, AOU Sant'Andrea, ENETS Center of Excellence, Rome, Italy
| | - Virginia Zamponi
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, AOU Sant'Andrea, ENETS Center of Excellence, Rome, Italy
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Stefano Telese
- Department of Clinical and Molecular Medicine, Sant'Andrea Hospital-Sapienza University of Rome, Rome, Italy
| | - Stefano Scalera
- Clinical Trial Center, Biostatistics and Bioinformatics Division, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Marcello Maugeri-Saccà
- Clinical Trial Center, Biostatistics and Bioinformatics Division, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Ludovica Ciuffreda
- UOSD SAFU, Department of Research, Diagnosis and Innovative Technologies, Translational Research Area, IRCCS Istituto Nazionale Tumori Regina Elena, Rome, Italy
| | - Francesca De Nicola
- UOSD SAFU, Department of Research, Diagnosis and Innovative Technologies, Translational Research Area, IRCCS Istituto Nazionale Tumori Regina Elena, Rome, Italy
| | - Maurizio Fanciulli
- UOSD SAFU, Department of Research, Diagnosis and Innovative Technologies, Translational Research Area, IRCCS Istituto Nazionale Tumori Regina Elena, Rome, Italy
| | - Anna La Salvia
- National Center for Drug Research and Evaluation, National Institute of Health (ISS), Rome, Italy
| | - Massimiliano Mancini
- Morphologic and Molecular Pathology Unit, S. Andrea University Hospital, Rome, Italy
| | - Andrea Vecchione
- Department of Clinical and Molecular Medicine, Sant'Andrea Hospital-Sapienza University of Rome, Rome, Italy
- Morphologic and Molecular Pathology Unit, S. Andrea University Hospital, Rome, Italy
| | | | - Mohsen Ibrahim
- Department of Thoracic Surgery, Sant'Andrea University Hospital, Rome, Italy
| | - Diana Bellavia
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Antongiulio Faggiano
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, Sapienza University of Rome, AOU Sant'Andrea, ENETS Center of Excellence, Rome, Italy.
| | - Rita Mancini
- Department of Clinical and Molecular Medicine, Sant'Andrea Hospital-Sapienza University of Rome, Rome, Italy
- Morphologic and Molecular Pathology Unit, S. Andrea University Hospital, Rome, Italy
| | - Claudia De Vitis
- Department of Clinical and Molecular Medicine, Sant'Andrea Hospital-Sapienza University of Rome, Rome, Italy
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Capdevila J, Pubul V, Anido U, Walter T, Molina-Cerrillo J, Alonso-Gordoa T, Garcia-Carbonero R, San-Roman-Gil M, Llana B, Jimenez-Fonseca P, Benavent Viñuales M, Ansquer C, Baudin E, Lepage C, Del Olmo-García M, Ruffinelli JC, Beron A, Haissaguerre M, Deshayes E, Taïeb D, Baldari S, Sansovini M, Cingarlini S, Filice A, Panzuto F, Álvarez-Álvarez R, Lousberg L, Aboubakar Nana F, Hernando J, García-Álvarez A, García-Burillo A, Villacampa G, Vandamme T, Fazio N, Durand A. A Randomized clinical trial evaluating the impact on survival and quality of life of 177Lutetium[Lu]-edotreotide versus everolimus in patients with neuroendocrine tumors of the lung and thymus: the LEVEL study (GETNE T-2217). BMC Cancer 2025; 25:613. [PMID: 40186126 PMCID: PMC11971812 DOI: 10.1186/s12885-025-13941-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 03/14/2025] [Indexed: 04/07/2025] Open
Abstract
BACKGROUND Everolimus is the only approved therapy for patients with advanced neuroendocrine tumors (NET) of lung and thymus and new treatment options are urgently needed. Expression of somatostatin receptor 2 (SSTR2) is frequently seen in functional imaging in lung-NETs opening the opportunity to treat SSTR2 positive patients with radioligand therapies (RLT). Retrospective data suggest a potential meaningful benefit of RLT directed to SSTR2 in lung-NET patients. METHODS The LEVEL trial is a randomized, open-label, phase III international trial of 177Lu-edotreotide versus everolimus in patients with progressive, locally advanced or metastatic, and well/moderately differentiated NETs of lung (typical/atypical) or thymic origin. Patients could be treatment-naïve or have progressed (PD) on somatostatin analogues or ≤ 2 additional systemic treatments. Prior RLT or mTOR inhibitors are not permitted. Eligible patients are randomly assigned 3:2 to 6 cycles of 177Lu-edotreotide (total administered activity 7.5 ± 0.7 GBq / cycle) or to oral everolimus 10 mg once daily until PD or unacceptable toxicity. Only patients with positivity in somatostatin receptor imaging will be included. CT or MRI scans are performed every 12 weeks until PD. Blood samples are analyzed at baseline, at 1st tumor assessment, and at PD for pharmacodynamic endpoints. Archival tumor tissue samples will be analyzed for ancillary studies. The primary endpoint is progression-free survival (PFS) according to RECIST v1.1 based on local investigator assessment. Secondary endpoints include overall survival, overall response rate, safety, and quality of life (EORTC QLQ-C30). The expected sample size is 120 patients to demonstrate statistical significant risk reduction of 46.4% (HR = 0.536) in PFS with the experimental treatment using an overall 5% two-sided alpha error with 80% power. An interim PFS analysis was included using the Lan-DeMets with O'Brian-Fleming-like boundaries. DISCUSSION The LEVEL trial will investigate if 177Lu-edotreotide has the potential to be incorporated as a standard treatment option for patients with NETs from the lung and Thymus. TRIAL REGISTRATION EU CT: 2022-502154-13-00 / www. CLINICALTRIALS gov : NCT05918302 (June 23rd, 2023).
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Affiliation(s)
- Jaume Capdevila
- Medical Oncology Department. Vall, Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain.
| | - Virginia Pubul
- Department of Nuclear Medicine, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain
| | - Urbano Anido
- Molecular Imaging Research Group, Nuclear Medicine Department, University Clinical Hospital of Santiago de Compostela, Santiago de Compostela, Spain
| | - Thomas Walter
- Medical Oncology Department, Edouard Herriot Hospital, Lyon, France
| | | | - Teresa Alonso-Gordoa
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Rocio Garcia-Carbonero
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
- Center of Experimental Oncology. Gastrointestinal and Neuroendrocrine Tumors Research Group. Hospital 12 de Octubre Research Institute (Imas12), Madrid, Spain
- Facultad de Medicina, Departamento de Medicina, Universidad Complutense de Madrid (UCM), Madrid, Spain
| | - Maria San-Roman-Gil
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Belen Llana
- Nuclear Medicine Department, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Paula Jimenez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | - Marta Benavent Viñuales
- Medical Oncology Department, University Hospital Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), Seville, Spain
| | - Catherine Ansquer
- Service de Médecine Nucléaire, CHU de Nantes, Nantes Université, Nantes, France
| | - Eric Baudin
- Department of Endocrine Oncology and Nuclear Medicine, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France
| | - Come Lepage
- Department of Digestive Oncology, University Hospital Dijon, University of Burgundy and Franche Comté, Dijon, France
| | - Maribel Del Olmo-García
- Endocrinology and Nutrition Department, Endocrinology, Nutrition and Diet Therapy Research Unit, University and Polytechnic Hospital La Fe, Valencia, Spain
- Departamento de Medicina, Universidad de Valencia, Valencia, Spain
| | - José Carlos Ruffinelli
- Medical Oncology Department, Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Amandine Beron
- Service de Médecine Nucléaire, Hôpital Claude Huriez, CHU Lille, Lille, France
| | | | - Emmanuel Deshayes
- Department of Nuclear Medicine, Institut du Cancer de Montpellier, Université de Montpellier, Cedex 5, Montpellier, France
| | - David Taïeb
- Department of Nuclear Medicine, Aix-Marseille University, La Timone University Hospital, Marseille, France
| | - Sergio Baldari
- Nuclear Medicine Unit, Department of Biomedical and Dental Sciences and of Morpho-Functional Imaging, University of Messina, Messina, Italy
| | - Maddalena Sansovini
- Therapeutic Nuclear Medicine, IRCCS Istituto Romagnolo Per Lo Studio Dei Tumori (IRST) ''Dino Amadori'', Meldola, Italy
| | - Sara Cingarlini
- Medical Oncology, University and Hospital Trust of Verona, Verona, Italy
| | - Angelina Filice
- Servizio Di Medicina Nucleare, Azienda USL-IRCCS Di Reggio Emilia, Reggio Emilia, Italy
| | - Francesco Panzuto
- Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, Digestive Disease Unit, ENETS Center of Excellence, Sant'Andrea University Hospital, Rome, Italy
| | - Rosa Álvarez-Álvarez
- Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | | | - Frank Aboubakar Nana
- Department of Pulmonology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1200, Brussels, Belgium
- Institut de Recherche Expérimentale Et Clinique (IREC), Université Catholique de Louvain, 1200, Brussels, Belgium
| | - Jorge Hernando
- Medical Oncology Department. Vall, Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Alejando García-Álvarez
- Medical Oncology Department. Vall, Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Amparo García-Burillo
- Medical Oncology Department. Vall, Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - Timon Vandamme
- Department of Oncology and Netwerk, University Hospital Antwerp, Edegem, Belgium
- Center for Oncological Research, Integrated Personalized &Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Alice Durand
- Medical Oncology Department, Edouard Herriot Hospital, Lyon, France
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Waliany S, Hung YP, Rous FA, Luo F, Capelletti M, Ressler S, Do A, Peterson J, Meservey C, Digumarthy SR, Ou SHI, Gadgeel SM, Lin JJ, Meador CB. Lung Carcinoid Tumors With Potentially Actionable Genomic Alterations and Responses to Targeted Therapies. Clin Lung Cancer 2025:S1525-7304(25)00055-5. [PMID: 40234130 DOI: 10.1016/j.cllc.2025.03.009] [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: 10/06/2024] [Revised: 01/26/2025] [Accepted: 03/20/2025] [Indexed: 04/17/2025]
Abstract
BACKGROUND Effective treatments for patients with advanced lung carcinoids remain limited. The prevalence of potentially actionable genomic alterations (AGAs) among lung carcinoids is not well-understood. MATERIALS AND METHODS Lung carcinoids submitted for next-generation sequencing (NGS) at a Clinical Laboratory Improvement Amendments (CLIA)-certified genomics laboratory from September 2013 to March 2024 were retrospectively investigated to determine prevalence of AGAs. We evaluated outcomes with genotype-matched targeted therapies in patients with advanced lung carcinoids with AGAs identified across 3 institutions and comprehensive literature search. RESULTS Among 321 cases of lung carcinoids profiled by NGS, 8 (2.5%) harbored potential AGAs (4 [1.2%] with commercially available targeted therapies), including KRAS mutations (n = 4, 1.2%: G12C, G12D, G12R, G12V), ALK fusions (n = 2, 0.6%), BRAF D594N (n = 1, 0.3%), and RET fusion (n = 1, 0.3%). None of the 24 typical carcinoids harbored an AGA. Collectively across these database-identified patients, our multi-institutional cohort, and literature review, we identified 36 cases of lung carcinoids with potential AGAs (24 with commercially available targeted therapies), predominantly comprising fusions of ALK (n = 14), RET (n = 5), and NTRK (n = 2). Of 27 with known disease stage, 19 had stage 4 disease, and 13 (68.4%) had outcomes reported following targeted therapies. Median treatment duration was 12.0 months (95% CI: 6.7-16.0). Median progression-free survival (PFS) was 10.6 months (95% CI: 6.7-16.0) across all targeted therapy lines and 14.0 months (95% CI: 1.3-NA) with first-line targeted therapies. Objective response rate with at least one targeted therapy was 61.5%. CONCLUSIONS Patients with advanced lung carcinoids harboring AGAs can derive meaningful benefit from genotype-matched targeted therapies, highlighting potential role for NGS in patients with advanced carcinoids.
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Affiliation(s)
- Sarah Waliany
- Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Yin P Hung
- Department of Pathology, Massachusetts General Hospital, Boston, MA
| | - Fawzi Abu Rous
- Henry Ford Cancer Institute/Henry Ford Health, Detroit, MI
| | - Faustine Luo
- Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA
| | | | | | - Andrew Do
- Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Jennifer Peterson
- Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA
| | | | | | - Sai-Hong Ignatius Ou
- Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA
| | | | - Jessica J Lin
- Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA.
| | - Catherine B Meador
- Massachusetts General Hospital Cancer Center and Department of Medicine, Massachusetts General Hospital, Boston, MA.
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Medici B, Caffari E, Maculan Y, Benatti S, Piacentini F, Dominici M, Gelsomino F. Everolimus in the Treatment of Neuroendocrine Tumors: Lights and Shadows. Biomedicines 2025; 13:455. [PMID: 40002868 PMCID: PMC11853220 DOI: 10.3390/biomedicines13020455] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 02/03/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms that originate from neuroendocrine cells, characterized by their ability to secrete hormones and peptides. Once considered rare, the incidence of NETs has steadily increased due to improved diagnostic modalities. The therapeutic landscape is multifaceted, ranging from surgery for localized disease to pharmacological interventions for advanced cases. However, the absence of robust predictive biomarkers precludes patient stratification and optimization of therapy. Everolimus, an oral mTOR inhibitor, has emerged as a key therapeutic agent due to its dual role in inhibiting cell proliferation and angiogenesis. Nevertheless, challenges such as resistance mechanisms, toxicity and optimal treatment sequencing remain unresolved. This article provides a comprehensive review of the role of everolimus in the management of NETs, focusing in particular on unresolved issues, from the absence of predictive biomarkers to the unavailability of defined guidelines for determining the correct therapeutic sequence.
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Affiliation(s)
| | | | | | | | | | | | - Fabio Gelsomino
- Department of Oncology and Hematology, Division of Oncology, University Hospital of Modena, 41124 Modena, Italy; (B.M.); (E.C.); (Y.M.); (S.B.); (F.P.); (M.D.)
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Melhorn P, Raderer M, Kiesewetter B. Selecting systemic treatment for metastatic neuroendocrine tumors of the lung-current evidence and clinical implications. Cancer Treat Rev 2025; 133:102878. [PMID: 39787793 DOI: 10.1016/j.ctrv.2024.102878] [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: 09/20/2024] [Revised: 12/15/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025]
Abstract
Neuroendocrine tumors (NET) of the lung are a slowly growing subtype of lung cancer that has a different treatment paradigm than aggressive and more common forms of lung neuroendocrine neoplasms (NEN) like small cell lung cancer (SCLC). Current guidelines for metastatic lung NET advocate a handful of treatment options, including somatostatin analogs (SSA), everolimus, temozolomide- or platin-based chemotherapy, and peptide receptor radionuclide therapy (PRRT). However, there is no clear treatment sequence, and the therapy of choice may depend on several factors such as tumor grade / growth rate, tumor burden / symptoms, disease progression status, and somatostatin receptor (SSTR) expression. In order to tailor treatment to each individual patient, the latest scientific findings and patient-specific clinical features must be considered together. This review critically evaluates the available evidence with regards to relevant patient characteristics, inclusion and exclusion criteria, and outcome metrics of clinical trials given the presumed natural disease course. Specific patient subgroups with an unmet therapeutic need are identified and discussed in the context of ongoing clinical trials.
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Affiliation(s)
- Philipp Melhorn
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Austria
| | - Markus Raderer
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Austria
| | - Barbara Kiesewetter
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Austria.
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Sen T, Dotsu Y, Corbett V, Puri S, Sen U, Boyle TA, Mack P, Hirsch F, Aljumaily R, Naqash AR, Sukrithan V, Karim NA. Pulmonary neuroendocrine neoplasms: the molecular landscape, therapeutic challenges, and diagnosis and management strategies. Lancet Oncol 2025; 26:e13-e33. [PMID: 39756451 DOI: 10.1016/s1470-2045(24)00374-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 05/20/2024] [Accepted: 06/25/2024] [Indexed: 01/07/2025]
Abstract
Lung neuroendocrine neoplasms are a group of diverse, heterogeneous tumours that range from well-differentiated, low-grade neuroendocrine tumours-such as typical and atypical carcinoids-to high-grade, poorly differentiated aggressive malignancies, such as large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC). While the incidence of SCLC has decreased, the worldwide incidence of other pulmonary neuroendocrine neoplasms has been increasing over the past decades. In addition to the standard histopathological classification of lung neuroendocrine neoplasms, the introduction of molecular and sequencing techniques has led to new advances in understanding the biology of these diseases and might influence future classifications and staging that can subsequently improve management guidelines in the adjuvant or metastatic settings. Due to the rarity of neuroendocrine neoplasms, there is a paucity of prospective studies that focus on the lungs, especially in rare, well-differentiated carcinoids and LCNECs. In contrast with the success of targeted therapies in non-small-cell lung cancer (NSCLC), high-grade neuroendocrine carcinomas of the lung often only have a few specific targetable gene alterations. Optimal therapy for LCNECs is not well defined and treatment recommendations are based on extrapolating guidelines for the management of patients with SCLC and NSCLC. This Review explores the epidemiology, diagnosis, and staging of lung neuroendocrine neoplasms to date. In addition, we focus on the evolving molecular landscape and biomarkers, ranging from tumour phenotypes to functional imaging studies and novel molecular biomarkers. We outline the various clinical outcomes, challenges, the treatment landscape, ongoing clinical trials, and future directions.
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Affiliation(s)
- Triparna Sen
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Yosuke Dotsu
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Virginia Corbett
- Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sonam Puri
- Division of Clinical Oncology, The Huntsman Cancer Institute at The University of Utah, Salt Lake City, UT, USA
| | - Utsav Sen
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Phil Mack
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Fred Hirsch
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Raid Aljumaily
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
| | - Abdul Rafeh Naqash
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK, USA
| | - Vineeth Sukrithan
- Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
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8
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Martin J, Alrehaili M, Marginean H, Goodwin R, Wheatley-Price P. Low to intermediate grade lung neuroendocrine tumours. A single centre real world experience. Cancer Treat Res Commun 2024; 41:100846. [PMID: 39366307 DOI: 10.1016/j.ctarc.2024.100846] [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: 07/22/2024] [Revised: 09/17/2024] [Accepted: 09/24/2024] [Indexed: 10/06/2024]
Abstract
INTRODUCTION Lung neuroendocrine tumours (LNETs) are a rare heterogenous group of tumours whose incidence has been increasing. We investigated the diagnosis, treatment, and survival patterns of patients with low to intermediate grade LNETs. METHODS A retrospective chart review of patients with low to intermediate grade LNETs, treated at a Canadian tertiary-level cancer centre was performed. RESULTS We identified 59 patients. Most were G1or G2 and well or moderately differentiated. Forty-seven patients presented with local or locally advanced disease, of which 57.4 % received curative intent surgery. The rest were treated with definitive radiation, radical chemoradiation with platinum and etoposide, palliative chemotherapy with doxorubicin, or supportive care. The five-year overall survival (OS) for those treated surgically was 83 % versus 44 % in the non-surgical group. Metastatic disease was seen in 24/59 patients, with a five-year OS in patients with stage IV disease of 39 %. Of those with advanced or unresectable disease (n = 32), 21 received palliative systemic treatment with up to three lines of therapy. First-line treatment was most commonly chemotherapy with platinum/etoposide combination or somatostatin analogue therapy. Second-line treatment involved chemotherapy or targeted everolimus. PRRT was used once as a first-line and once as second-line therapy. Third-line included lanreotide or chemotherapy with capecitabine/temozolomide combination. CONCLUSION Overall, patients with surgically resectable disease had a good five-year OS. However, inoperable or more advanced disease was associated with a poorer OS. Despite many treatment options, the sequence of treatments is poorly established. This highlights the need for further development and dissemination of evidence-based guidelines for LNET patients.
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Affiliation(s)
| | - Mohammad Alrehaili
- University of Ottawa Division of Medical Oncology, Ottawa, Ontario, Canada; The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada; Department of Medical Oncology, King Abdullah Medical City, Makkah, Saudi Arabia
| | - Horia Marginean
- The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Rachel Goodwin
- University of Ottawa Division of Medical Oncology, Ottawa, Ontario, Canada; The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada; The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Paul Wheatley-Price
- University of Ottawa Division of Medical Oncology, Ottawa, Ontario, Canada; The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada; The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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9
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Baudin E, Capdevila J, Hörsch D, Singh S, Caplin ME, Wolin EM, Buikhuisen W, Raderer M, Dansin E, Grohe C, Ferone D, Houchard A, Truong-Thanh XM, Reidy-Lagunes D, the SPINET Study Group. Treatment of advanced BP-NETS with lanreotide autogel/depot vs placebo: the phase III SPINET study. Endocr Relat Cancer 2024; 31:e230337. [PMID: 38913539 PMCID: PMC11301421 DOI: 10.1530/erc-23-0337] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 06/24/2024] [Indexed: 06/26/2024]
Abstract
Prospective data are lacking on early somatostatin analog (SSA) therapy in bronchopulmonary neuroendocrine tumors (BP-NETs; typical carcinoids and atypical carcinoids (TCs and ACs)). SPINET (EudraCT: 2015-004992-62; NCT02683941) was a phase III, double-blind study of lanreotide autogel/depot (LAN; 120 mg every 28 days) plus best supportive care (BSC) vs placebo plus BSC, with an optional open-label treatment phase (LAN plus BSC). Patients had metastatic/unresectable, somatostatin receptor (SSTR)-positive TCs or ACs. Recruitment was stopped early owing to slow accrual; eligible patients from the double-blind phase transitioned to open-label LAN. The adapted primary endpoint was progression-free survival (PFS) during either phase for patients receiving LAN. Seventy-seven patients were randomized (LAN, n = 51 (TCs, n = 29; ACs, n = 22); placebo, n = 26 (TCs, n = 16; ACs, n = 10)). Median (95% CI) PFS during double-blind and open-label phases in patients receiving LAN was 16.6 (11.3; 21.9) months overall (primary endpoint), 21.9 (12.8, not calculable (NC)) months in TCs, and 13.8 (5.4; 16.6) months in ACs. During double-blind treatment, median (95% CI) PFS was 16.6 (11.3; 21.9) months for LAN vs 13.6 (8.3; NC) months for placebo (not significant); corresponding values were 21.9 (13.8; NC) and 13.9 (13.4; NC) months, respectively, in TCs and 13.8 (5.4; 16.6) and 11.0 (2.8; 16.9) months, respectively, in ACs. Patients' quality of life did not deteriorate and LAN was well tolerated. Although recruitment stopped early and the predefined sample size was not met, SPINET is the largest prospective study to date of SSA therapy in SSTR-positive TCs and ACs and suggests clinical benefit in TCs.
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Affiliation(s)
- E Baudin
- Endocrine Oncology Unit, Imaging Department, Gustave Roussy, Villejuif, France
| | - J Capdevila
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), IOB Quirón-Teknon, Barcelona, Spain
| | - D Hörsch
- ENETS Center of Excellence, Zentralklinik Bad Berka GmbH, Bad Berka, Germany
| | - S Singh
- Division of Medical Oncology, University of Toronto, Sunnybrook Odette Cancer Center, Sunnybrook HSC, Toronto, Ontario, Canada
| | - M E Caplin
- Neuroendocrine Tumour Unit, Royal Free Hospital School of Medicine, London, UK
| | - E M Wolin
- Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - W Buikhuisen
- Department of Thorax Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - M Raderer
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - E Dansin
- Thoracic Oncology Unit, Centre Oscar Lambret, Lille, France
| | - C Grohe
- Department of Respiratory Diseases, Evangelische Lungenklinik, Berlin, Germany
| | - D Ferone
- Neuroendocrine Tumour Unit, Department of Internal Medicine and Medical Specialties, University of Genova, Genova, Italy
| | - A Houchard
- Data and Insights Generation and Strategy, Ipsen, Boulogne-Billancourt, France
| | | | - D Reidy-Lagunes
- Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, New York, New York, USA
| | - the SPINET Study Group
- Endocrine Oncology Unit, Imaging Department, Gustave Roussy, Villejuif, France
- Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), IOB Quirón-Teknon, Barcelona, Spain
- ENETS Center of Excellence, Zentralklinik Bad Berka GmbH, Bad Berka, Germany
- Division of Medical Oncology, University of Toronto, Sunnybrook Odette Cancer Center, Sunnybrook HSC, Toronto, Ontario, Canada
- Neuroendocrine Tumour Unit, Royal Free Hospital School of Medicine, London, UK
- Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Department of Thorax Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
- Thoracic Oncology Unit, Centre Oscar Lambret, Lille, France
- Department of Respiratory Diseases, Evangelische Lungenklinik, Berlin, Germany
- Neuroendocrine Tumour Unit, Department of Internal Medicine and Medical Specialties, University of Genova, Genova, Italy
- Data and Insights Generation and Strategy, Ipsen, Boulogne-Billancourt, France
- Medical Affairs, Ipsen, Boulogne-Billancourt, France
- Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, New York, New York, USA
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10
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Rutherford M, Wheless M, Thomas K, Ramirez RA. Current and emerging strategies for the management of advanced/metastatic lung neuroendocrine tumors. Curr Probl Cancer 2024; 49:101061. [PMID: 38281845 DOI: 10.1016/j.currproblcancer.2024.101061] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/13/2023] [Accepted: 12/26/2023] [Indexed: 01/30/2024]
Abstract
Pulmonary neuroendocrine tumors represent a spectrum of disease ranging from typical carcinoid tumors to small cell lung cancers. The incidence of low-grade pulmonary NETs has been increasing, leading to improved awareness and the need for more treatment options for this rare cancer. Somatostatin analogs continue to be the backbone of therapy and may be followed or accompanied by targeted therapy, chemotherapy, and immune therapy. The recent addition of peptide receptor radionuclide therapy (PRRT) to the treatment armamentarium of NETs has led to the development of targeted alpha therapy to overcome PRRT resistance and minimize off-target adverse effects. Herein, we aim to highlight current treatment options for patients with advanced low grade pulmonary NETs along with emerging therapies, sequencing of therapies, upcoming clinical trials, and the importance of a multidisciplinary team to improve patient outcomes.
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Affiliation(s)
- Megan Rutherford
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Margaret Wheless
- Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Katharine Thomas
- Department of Medicine, Division of Hematology Oncology, Renown Medical Center Reno, NV, USA; Department of Medicine, University of Reno Nevada, Reno, NV, USA
| | - Robert A Ramirez
- Department of Medicine, Division of Hematology Oncology, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
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11
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Granberg D, Juhlin CC, Falhammar H, Hedayati E. Lung Carcinoids: A Comprehensive Review for Clinicians. Cancers (Basel) 2023; 15:5440. [PMID: 38001701 PMCID: PMC10670505 DOI: 10.3390/cancers15225440] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 11/13/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
Lung carcinoids are neuroendocrine tumors, categorized as typical or atypical carcinoids based on their histological appearance. While most of these tumors are slow-growing neoplasms, they still possess malignant potential. Many patients are diagnosed incidentally on chest X-rays or CT scans. Presenting symptoms include cough, hemoptysis, wheezing, dyspnea, and recurrent pneumonia. Endocrine symptoms, such as carcinoid syndrome or ectopic Cushing's syndrome, are rare. Surgery is the primary treatment and should be considered in all patients with localized disease, even when thoracic lymph node metastases are present. Patients with distant metastases may be treated with somatostatin analogues, chemotherapy, preferably temozolomide-based, mTOR inhibitors, or peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE. Most patients have an excellent prognosis. Poor prognostic factors include atypical histology and lymph node metastases at diagnosis. Long-term follow-up is mandatory since metastases may occur late.
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Affiliation(s)
- Dan Granberg
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden;
- Department of Breast, Endocrine Tumors and Sarcomas, Karolinska University Hospital Solna, 17176 Stockholm, Sweden;
| | - Carl Christofer Juhlin
- Department of Oncology-Pathology, Karolinska Institutet, 17164 Stockholm, Sweden;
- Department of Pathology and Cancer Diagnostics, Karolinska University Hospital Solna, 17176 Stockholm, Sweden
| | - Henrik Falhammar
- Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden;
- Department of Endocrinology, Karolinska University Hospital Solna, 17176 Stockholm, Sweden
| | - Elham Hedayati
- Department of Breast, Endocrine Tumors and Sarcomas, Karolinska University Hospital Solna, 17176 Stockholm, Sweden;
- Department of Oncology-Pathology, Karolinska Institutet, 17164 Stockholm, Sweden;
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12
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Duponchelle L, Baudin E, Subtil F, Do Cao C, Dansin E, Perrier M, Teissier MP, Haissaguerre M, Cansouline X, Hadoux J, Jepiral G, Lombard-Bohas C, Mercier O, Tronc F, Walter T. Surgery of primary lung carcinoid tumors at metastatic stage: A national study from the French Group of Endocrine Tumors (GTE) and ENDOCAN-RENATEN network. J Neuroendocrinol 2023; 35:e13331. [PMID: 37602933 DOI: 10.1111/jne.13331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 07/07/2023] [Accepted: 08/01/2023] [Indexed: 08/22/2023]
Abstract
The outcome following surgery for patients with primary lung neuroendocrine tumors at metastatic stage remains poorly characterized. We conducted a retrospective national study including patients with metastatic lung neuroendocrine tumors at diagnosis. We performed a safety study to evaluate major morbidity and mortality of surgical resection of the primary tumor and compared patients in the operative to the nonoperative group. A total of 155 patients were included: 41 in the operative group and 114 in the nonoperative group, median age was 64 years. Metastases were mainly located in the liver (74.2%) and the bone (49.7%). The primary endpoint was met as the rate of major complications was 4.9% and there was no postoperative mortality. In the operative group 42.5% of patients had improvement of their pulmonary symptoms versus 14.4% in the nonoperative group. The median overall survival was not reached in the operative group and was 4.3 years (95% CI [3.5;4.9]) in the nonoperative group (univariate analysis, HR = 0.42 95% CI [0.23-0.77], p = .002). After multivariate analysis, only an ECOG-PS ≥1 (vs. 0, HR = 2.44, 95% CI [1.46;4.07], p = .001) and >1 metastatic site (vs. 1; HR = 1.83, 95% CI [1.06;3.16], p = .030) remained significantly associated with overall survival. The resection of the primary tumor was not significantly associated with overall survival (HR = 0.63, 95% CI [0.32;1.24], p = .183). In conclusion, surgery of primary lung neuroendocrine tumors at metastatic stage is a safe option that should be considered in selected patients in order to improve symptoms with a view to improving their quality of life. Larger studies are warranted to evaluate the impact of surgery on survival.
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Affiliation(s)
- Lucie Duponchelle
- Service de Chirurgie Thoracique, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
| | - Eric Baudin
- Service de Médecine Nucléaire et Cancérologie Endocrinienne, Institut Gustave Roussy, Villejuif, France
| | - Fabien Subtil
- Service de Biostatistiques, Hospices Civils de Lyon, Lyon, France
- Université de Lyon, Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Evolutive UMR 5588, Villeurbanne, France
| | - Christine Do Cao
- Service d'Endocrinologie, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Eric Dansin
- Comité d'Oncologie Thoracique, CLCC Oscar Lambret, Lille, France
| | - Marine Perrier
- Service d'Hépato-Gastro-Entérologie, Centre Hospitalier Universitaire de Reims et Champagne-Ardenne, Reims, France
| | - Marie-Pierre Teissier
- Service d'Endocrinologie, Diabète et Maladies Métaboliques, Centre Hospitalier Universitaire de Limoges, Limoges, France
| | - Magalie Haissaguerre
- Service d'Endocrinologie et Oncologie Endocrinienne, Hôpital Haut Leveque, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Xavier Cansouline
- INSERM N2C UMR 1069, Université de Tours, Service de Chirurgie Thoracique, Centre Hospitalier Universitaire de Tours, Tours, France
| | - Julien Hadoux
- Service de Cancérologie Endocrinienne, Institut Gustave Roussy, Villejuif, France
| | - Galina Jepiral
- Groupe d'étude des Tumeurs Endocrines (GTE), Paris, France
| | - Catherine Lombard-Bohas
- Oncologie Médicale, Groupement Hospitalier Centre, Institut de Cancérologie des Hospices Civils de Lyon, Lyon, France
| | - Olaf Mercier
- Service de Chirurgie Thoracique et Transplantation Cardio-Pulmonaire, Hôpital Marie Lannelongue, Université Paris-Saclay, Centre International des Cancers Thoraciques, GHPSJ, Le Plessis Robinson, France
| | - François Tronc
- Service de Chirurgie Thoracique, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
- University of Lyon, Université Lyon 1, Lyon, France
| | - Thomas Walter
- Oncologie Médicale, Groupement Hospitalier Centre, Institut de Cancérologie des Hospices Civils de Lyon, Lyon, France
- University of Lyon, Université Lyon 1, Lyon, France
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13
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Abele M, Kunstreich M, Lessel L, Seitz G, Vokuhl C, Lapa C, Schneider DT, Brecht IB, Redlich A, Kuhlen M. Bronchial carcinoid tumors in children and adolescents - A report and management considerations from the German MET studies. Lung Cancer 2023; 183:107320. [PMID: 37549472 DOI: 10.1016/j.lungcan.2023.107320] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/09/2023]
Abstract
OBJECTIVES Bronchial carcinoid tumors (BC) are exceptionally rare in childhood, with an incidence of <0.2/1,000,000 per year. Typical low-grade BCs are distinguished from atypical, intermediate-grade BCs. Little is known about BCs in pediatric patients and management guidelines are missing. In this study, we explored characteristics and outcome of pediatric patients with BC prospectively registered with the Malignant Endocrine Tumor studies. MATERIAL AND METHODS We performed a retrospective multicenter study in children, adolescents, and young adults (aged 0-20 years) with BC reported to the German MET registry between January 1997 and December 2022. Data were last updated on 28 of February 2023. RESULTS Thirty-two patients were diagnosed at a median age of 15.0 years (range, 9.8-19.2). Atypical BCs (23.3%) were less frequent than typical, but more common than in adulthood. Lymph node metastases were present in 14.3% of cases (atypical BC: 28.6%, typical BC: 10.5%), distant metastases in one (3.1%) patient with atypical BC. 92.6% of patients were in complete remission after surgical resection (median follow-up: 2.7 years). The patient with metastatic spread and one patient with atypical BC and multiple recurrences were on treatment at last follow-up. 5-year event-free survival of typical BC was 100% and 83.3% in atypical BC. CONCLUSIONS Completely resected localized BCs in pediatric patients have a favorable outcome also with lung tissue sparing surgery. Atypical BC with risk of metastatic spread and recurrence occurred more frequently compared to adults. Interdisciplinary management and collaborative efforts are needed to improve our understanding and the management of pediatric BC.
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Affiliation(s)
- Michael Abele
- Pediatric Hematology/Oncology, Department of Pediatrics, University Hospital Tuebingen, Tuebingen, Germany.
| | - Marina Kunstreich
- Department of Pediatrics, Pediatric Hematology/Oncology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Lienhard Lessel
- Department of Pediatrics, Pediatric Hematology/Oncology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Guido Seitz
- Department of Pediatric Surgery and Urology, University Hospital Giessen-Marburg, Marburg, Germany
| | - Christian Vokuhl
- Section of Pediatric Pathology, Department of Pathology, University Hospital Bonn, Bonn, Germany
| | - Constantin Lapa
- Nuclear Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Dominik T Schneider
- Clinic of Pediatrics, Klinikum Dortmund, University Witten/Herdecke, Dortmund, Germany
| | - Ines B Brecht
- Pediatric Hematology/Oncology, Department of Pediatrics, University Hospital Tuebingen, Tuebingen, Germany
| | - Antje Redlich
- Department of Pediatrics, Pediatric Hematology/Oncology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| | - Michaela Kuhlen
- Pediatrics and Adolescent Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany.
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14
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Glaviano A, Foo ASC, Lam HY, Yap KCH, Jacot W, Jones RH, Eng H, Nair MG, Makvandi P, Geoerger B, Kulke MH, Baird RD, Prabhu JS, Carbone D, Pecoraro C, Teh DBL, Sethi G, Cavalieri V, Lin KH, Javidi-Sharifi NR, Toska E, Davids MS, Brown JR, Diana P, Stebbing J, Fruman DA, Kumar AP. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol Cancer 2023; 22:138. [PMID: 37596643 PMCID: PMC10436543 DOI: 10.1186/s12943-023-01827-6] [Citation(s) in RCA: 682] [Impact Index Per Article: 341.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 07/18/2023] [Indexed: 08/20/2023] Open
Abstract
The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.
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Affiliation(s)
- Antonino Glaviano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Aaron S C Foo
- Department of Surgery, National University Hospital Singapore, National University of Singapore, Singapore, Singapore
| | - Hiu Y Lam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore
| | - Kenneth C H Yap
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119077, Singapore
| | - William Jacot
- Department of Medical Oncology, Institut du Cancer de Montpellier, Inserm U1194, Montpellier University, Montpellier, France
| | - Robert H Jones
- Cardiff University and Velindre Cancer Centre, Museum Avenue, Cardiff, CF10 3AX, UK
| | - Huiyan Eng
- Department of Surgery, National University Hospital Singapore, National University of Singapore, Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Madhumathy G Nair
- Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore, 560034, India
| | - Pooyan Makvandi
- The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital, Quzhou, 324000, Zhejiang, China
| | - Birgit Geoerger
- Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Inserm U1015, Université Paris-Saclay, Paris, France
| | - Matthew H Kulke
- Section of Hematology and Medical Oncology, Boston University and Boston Medical Center, Boston, MA, USA
| | - Richard D Baird
- Cancer Research UK Cambridge Centre, Hills Road, Cambridge, CB2 0QQ, UK
| | - Jyothi S Prabhu
- Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore, 560034, India
| | - Daniela Carbone
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Camilla Pecoraro
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Daniel B L Teh
- Departments of Ophthalmology and Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, and Neurobiology Programme, National University of Singapore, Singapore, Singapore
| | - Gautam Sethi
- Department of Surgery, National University Hospital Singapore, National University of Singapore, Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Vincenzo Cavalieri
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Kevin H Lin
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | | | - Eneda Toska
- Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, USA
| | - Matthew S Davids
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jennifer R Brown
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Patrizia Diana
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy
| | - Justin Stebbing
- Division of Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK
| | - David A Fruman
- Department of Molecular Biology and Biochemistry, University of California, 216 Sprague Hall, Irvine, CA, USA
| | - Alan P Kumar
- Department of Surgery, National University Hospital Singapore, National University of Singapore, Singapore, Singapore.
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
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15
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Kiesewetter B, Melhorn P, Macheiner S, Wolff L, Kretschmer-Chott E, Haug A, Mazal P, Raderer M. Does the dose matter? Antiproliferative efficacy and toxicity of everolimus in patients with neuroendocrine tumors - Experiences from a tertiary referral center. J Neuroendocrinol 2023; 35:e13319. [PMID: 37485760 DOI: 10.1111/jne.13319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 05/12/2023] [Accepted: 06/26/2023] [Indexed: 07/25/2023]
Abstract
The mTOR-inhibitor everolimus has been approved for the treatment of advanced neuroendocrine tumors (NETs) but is associated with relevant toxicities in clinical practice. Hence, optimal treatment sequencing and the impact of dose reductions have yet to be clarified. This retrospective analysis assessed patients with advanced, well-differentiated NET treated with everolimus at the Medical University of Vienna. The primary objective was to evaluate the efficacy of everolimus in a real-world cohort. A total of 52 patients treated with everolimus for advanced NET grade 1 (G1) or G2 (or typical or atypical carcinoid) 2010-2021 were included in this analysis. The most common sites of origin were pancreas (44%) and lung (29%). The initial dose was decided by the treating physician based on clinical assessment and 25 patients (48%) each were started at 10 mg/day and 5 mg/day. Median progression-free survival (PFS) following everolimus in the overall cohort was 9.8 months (95% CI: 4.3-15.3), with a statistically significant PFS difference (p = .03) between NET G1/typical carcinoids (42.9 months) and NET G2/atypical carcinoids (8.9 months). PFS was numerically but not significantly shorter in patients treated with a reduced dose (7.5 months vs. 12.4 months, p = .359). Even in this mixed full/half dose cohort, 93% developed treatment-related side effects (mostly grade I, no grade IV), 63% had dose reductions or interruptions, and five stopped due to toxicity. Median survival following treatment was 40.9 months (95% CI: 21.5-60.3) and no difference with regard to dosing was observed (p = .517). These data from an unselected patient cohort show long-term outcomes similar to those reported in the pivotal studies. Comparing everolimus starting dose, median PFS did not significantly differ for patients treated at a lower dose. While this finding is limited by the sample size and warrants prospective verification, initiating therapy at a reduced dose might be practicable and safe in a distinct subset of patients.
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Affiliation(s)
- Barbara Kiesewetter
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - Philipp Melhorn
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - Simon Macheiner
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - Ladislaia Wolff
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
| | - Elisabeth Kretschmer-Chott
- Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Alexander Haug
- Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - Peter Mazal
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Markus Raderer
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Vienna, Austria
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16
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Jelli B, Brandão M, Mekinda Z, Durieux V, Berghmans T. Systemic treatment for neuroendocrine non-small cell lung carcinoma: A cases series and a systematic review of the literature. Lung Cancer 2023; 181:107232. [PMID: 37216840 DOI: 10.1016/j.lungcan.2023.107232] [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: 01/21/2023] [Revised: 04/25/2023] [Accepted: 05/01/2023] [Indexed: 05/24/2023]
Abstract
INTRODUCTION Neuroendocrine lung cancer constitutes a continuum from carcinoid tumours (CT) to large cell neuroendocrine (LCNEC) and small-cell carcinomas (SCLC). Except for SCLC, there is no consensual agreement on systemic therapy. The aim of this study is to review our clinical experience among patients with CT and LCNEC in the light of a systematic review of the literature. METHODS A retrospective study of all patients with CT and LCNEC receiving a systemic therapy at Institut Jules Bordet and Erasme Hospital between 01/01/2000-31/12/2020. A systematic review of the literature was performed in Ovid Medline. RESULTS 53 patients (21 CT and 32 LCNEC) were included. Despite limited response rates, patients with CT receiving a "carcinoid-like" 1st-line regimen (somatostatin analogues (SSA), everolimus, peptide receptor radionuclide therapy (PRRT)) had a numerically longer survival compared to those receiving other type of regimens (median 51.4 vs 18.6 months, respectively; p = 0.17). We observed a similar survival between 1st line "SCLC-like" vs "non-small cell lung cancer (NSCLC)-like" schemes in LCNEC (median 11.2 vs 12.6 months, respectively; p = 0.46). The systematic review identified 23 studies (12 prospective, 15 and 8 for CT and LCNEC respectively). For CT, everolimus and SSA led to prolonged disease control with an acceptable toxicity profile, while higher response rates but lower tolerance were associated with PRRT and chemotherapy regimens including oxaliplatine and dacarbazine. For LCNEC, no difference emerged when comparing "SCLC-like" and "NSCLC-like" regimens considering response rate, progression-free or overall survival. CONCLUSIONS SSA, everolimus and PRRT present a good therapeutic index for CT, while the role of chemotherapy remains limited to aggressive and rapidly evolving CT. The best type of chemotherapy regimen remains an open question in LCNEC.
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Affiliation(s)
- Blandine Jelli
- Thoracic Oncology Unit, Institut Jules Bordet, Hôpitaux Universitaires de Bruxelles, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Mariana Brandão
- Thoracic Oncology Unit, Institut Jules Bordet, Hôpitaux Universitaires de Bruxelles, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Zita Mekinda
- Thoracic Oncology Unit, Pneumology department, Hôpital Erasme, Hôpitaux Universitaires de Bruxelles, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Valérie Durieux
- Université libre de Bruxelles (ULB), Bibliothèque des Sciences de la Santé, Bruxelles, Belgium
| | - Thierry Berghmans
- Thoracic Oncology Unit, Institut Jules Bordet, Hôpitaux Universitaires de Bruxelles, Université Libre de Bruxelles, Bruxelles, Belgium.
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17
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Lamberti G, Prinzi N, Bongiovanni A, Torniai M, Andrini E, de Biase D, Malvi D, Mosca M, Berardi R, Ibrahim T, Pusceddu S, Campana D. Targeted Genomic Profiling and Chemotherapy Outcomes in Grade 3 Gastro-Entero-Pancreatic Neuroendocrine Tumors (G3 GEP-NET). Diagnostics (Basel) 2023; 13:1595. [PMID: 37174986 PMCID: PMC10178589 DOI: 10.3390/diagnostics13091595] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/23/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
BACKGROUND Grade 3 gastro-entero-pancreatic neuroendocrine tumors (G3 GEP-NET) are poorly characterized in terms of molecular features and response to treatments. METHODS Patients with G3 GEP-NET were included if they received capecitabine and temozolomide (CAPTEM) or oxaliplatin with either 5-fluorouracile (FOLFOX) or capecitabine (XELOX) as first-line treatment (chemotherapy cohort). G3 NET which successfully undergone next-generation sequencing (NGS) were included in the NGS cohort. RESULTS In total, 49 patients were included in the chemotherapy cohort: 15 received CAPTEM and 34 received FOLFOX/XELOX. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were 42.9%, 9.0 months, and 33.6 months, respectively. Calculating a Ki67 cutoff using ROC curve analysis, tumors with Ki67 ≥ 40% had lower ORR (51.2% vs. 0%; p = 0.007) and shorter PFS (10.6 months vs. 4.4 months; p < 0.001) and OS (49.4 months vs. 10.0 months; p = 0.023). In patients who received FOLFOX/XELOX as a first-line treatment, ORR, PFS, and OS were 38.2%, 7.9 months, and 30.0 months, respectively. In the NGS cohort (N = 13), the most mutated genes were DAXX/ATRX (N = 5, 38%), MEN1 (N = 4, 31%), TP53 (N = 4, 31%), AKT1 (N = 2, 15%), and PIK3CA (N = 1, 8%). CONCLUSIONS FOLFOX/XELOX chemotherapy is active as the first-line treatment of patients with G3 GEP-NET. The mutational landscape of G3 NET is more similar to well-differentiated NETs than NECs.
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Affiliation(s)
- Giuseppe Lamberti
- Department of Medical or Surgical Sciences, University of Bologna, 40126 Bologna, Italy; (G.L.); (E.A.); (M.M.)
- Medical Oncology Department, IRCCS Azienda Ospedaliero-Universitaria Sant’Orsola-Malpighi di Bologna, 40138 Bologna, Italy
| | - Natalie Prinzi
- Medical Oncology, Foundation IRCCS National Cancer Institute, 20133 Milano, Italy; (N.P.); (S.P.)
| | - Alberto Bongiovanni
- Osteoncology and Rare Tumor Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (A.B.); (T.I.)
| | - Mariangela Torniai
- Department of Oncology, Università Politecnica delle Marche-AOU delle Marche, 60126 Ancona, Italy; (M.T.); (R.B.)
| | - Elisa Andrini
- Department of Medical or Surgical Sciences, University of Bologna, 40126 Bologna, Italy; (G.L.); (E.A.); (M.M.)
| | - Dario de Biase
- Department of Pharmacy and Biotechnology, University of Bologna, 40126 Bologna, Italy;
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Deborah Malvi
- Pathology Unit, IRCCS Azienda-Ospedaliero Universitaria di Bologna, 40138 Bologna, Italy;
| | - Mirta Mosca
- Department of Medical or Surgical Sciences, University of Bologna, 40126 Bologna, Italy; (G.L.); (E.A.); (M.M.)
| | - Rossana Berardi
- Department of Oncology, Università Politecnica delle Marche-AOU delle Marche, 60126 Ancona, Italy; (M.T.); (R.B.)
| | - Toni Ibrahim
- Osteoncology and Rare Tumor Center (CDO-TR), IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy; (A.B.); (T.I.)
| | - Sara Pusceddu
- Medical Oncology, Foundation IRCCS National Cancer Institute, 20133 Milano, Italy; (N.P.); (S.P.)
| | - Davide Campana
- Department of Medical or Surgical Sciences, University of Bologna, 40126 Bologna, Italy; (G.L.); (E.A.); (M.M.)
- Medical Oncology Department, IRCCS Azienda Ospedaliero-Universitaria Sant’Orsola-Malpighi di Bologna, 40138 Bologna, Italy
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18
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Diagnosis and Treatment of Lung Neuroendocrine Neoplasms: Somatostatin Receptor PET Imaging and Peptide Receptor Radionuclide Therapy. PET Clin 2023; 18:223-231. [PMID: 36585338 DOI: 10.1016/j.cpet.2022.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Recently, advancement of somatostatin receptor (SSTR) imaging and theragnostic approach using peptide receptor radionuclide therapy (PRRT) have changed the paradigm of diagnosis and management of neuroendocrine tumor. 68Ga-DOTATATE PET/CT can diagnose the lung carcinoids with high SSTR expression. With combination of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT, tumor heterogeneity of lung carcinoid can be identified, which may guide optimal patient selection for PRRT. PRRT may be an effective and safe treatment of advanced lung carcinoids during progression with first-line somatostatin analog therapy. This review provides updates on the diagnosis and management of lung carcinoids, focusing on SSTR imaging and PRRT.
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19
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Hertelendi M, Belguenani O, Cherfi A, Folitar I, Kollar G, Polack BD. Efficacy and Safety of [177Lu]Lu-DOTA-TATE in Adults with Inoperable or Metastatic Somatostatin Receptor-Positive Pheochromocytomas/Paragangliomas, Bronchial and Unknown Origin Neuroendocrine Tumors, and Medullary Thyroid Carcinoma: A Systematic Literature Review. Biomedicines 2023; 11:biomedicines11041024. [PMID: 37189646 DOI: 10.3390/biomedicines11041024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/20/2023] [Accepted: 03/22/2023] [Indexed: 03/29/2023] Open
Abstract
Background: We have performed a systematic review to evaluate the efficacy and safety of [177Lu]Lu-DOTA-TATE, a radioligand therapy, in advanced somatostatin receptor-positive pheochromocytoma/paraganglioma (PPGL), thymic neuroendocrine tumor (NET), bronchial NET, unknown primary NET, or medullary thyroid carcinoma (MTC). Methods: Studies identified in PubMed from inception to 13 May 2021 must have assessed [177Lu]Lu-DOTA-TATE as a single agent and reported outcome data for the specific NET types of interest. Results: Two independent reviewers performed the screening and data extraction, resulting in 16 publications: PPGL (n = 7), bronchial NETs (n = 6; one also included NETs of unknown origin), and MTC (n = 3). Overall, [177Lu]Lu-DOTA-TATE offers encouraging antitumor activity (overall tumor response rates and disease control rates) across NET types. Safety was favorable with most adverse events mild to moderate in severity, transient, and consistent with those seen in patients with gastroenteropancreatic (GEP)-NETs. Conclusions: [177Lu]Lu-DOTA-TATE has been used effectively in clinical practice to treat NETs of non-GEP origin.
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20
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Hiro S, Teranishi S, Sawazumi T, Nagaoka S, Sugimoto C, Nagayama H, Segawa W, Kajita Y, Maeda C, Kubo S, Seki K, Tashiro K, Kobayashi N, Yamamoto M, Kudo M, Kaneko T. Thymic atypical carcinoid tumors with elevated mitotic counts in a patient with multiple endocrine neoplasia: A case report. Thorac Cancer 2023; 14:1311-1315. [PMID: 36941083 PMCID: PMC10175031 DOI: 10.1111/1759-7714.14863] [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: 02/13/2023] [Revised: 03/05/2023] [Accepted: 03/06/2023] [Indexed: 03/22/2023] Open
Abstract
Thymic neuroendocrine tumors associated with multiple endocrine neoplasia are only defined as carcinoid and are not associated with large-cell neuroendocrine carcinoma (LCNEC). We report the case of a multiple endocrine neoplasia type 1 patient with atypical carcinoid tumors with elevated mitotic counts (AC-h), an intermediate condition between carcinoid and LCNEC. A 27-year-old man underwent surgery for an anterior mediastinal mass and was diagnosed with thymic LCNEC. Fifteen years later, a mass appeared at the same site, which was determined to be a postoperative recurrence based on the pathological results of a needle biopsy and the clinical course. The patient's disease remained stable for 10 months on anti-programmed death-ligand 1 antibody and platinum-containing chemotherapy. The needle biopsy specimen was submitted for next-generation sequencing, which revealed a MEN1 gene mutation, and after further examination, a diagnosis of multiple endocrine neoplasia type 1 was made. A re-examination of the surgical specimen from 15 years prior showed that it corresponded to AC-h. Although thymic AC-h is classified as thymic LCNEC according to the current definition, our data suggests that a search for multiple endocrine neoplasia is warranted in such patients.
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Affiliation(s)
- Shuntaro Hiro
- Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Shuhei Teranishi
- Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Tomoe Sawazumi
- Division of Pathology, Yokohama City University Medical Center, Yokohama, Japan
| | - Satoshi Nagaoka
- Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Chihiro Sugimoto
- Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Hirokazu Nagayama
- Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Wataru Segawa
- Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Yukihito Kajita
- Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Chihiro Maeda
- Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Sousuke Kubo
- Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Kenichi Seki
- Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Ken Tashiro
- Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Nobuaki Kobayashi
- Department of Pulmonology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
| | - Masaki Yamamoto
- Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Makoto Kudo
- Respiratory Disease Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Takeshi Kaneko
- Department of Pulmonology, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Japan
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21
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Owen DH, Benner B, Wei L, Sukrithan V, Goyal A, Zhou Y, Pilcher C, Suffren SA, Christenson G, Curtis N, Jukich M, Schwarz E, Savardekar H, Norman R, Ferguson S, Kleiber B, Wesolowski R, Carson WE, Otterson GA, Verschraegen CF, Shah MH, Konda B. A Phase II Clinical Trial of Nivolumab and Temozolomide for Neuroendocrine Neoplasms. Clin Cancer Res 2023; 29:731-741. [PMID: 36255391 PMCID: PMC9932582 DOI: 10.1158/1078-0432.ccr-22-1552] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/25/2022] [Accepted: 10/13/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE Treatment options are limited in patients with metastatic neuroendocrine neoplasms (NEN). We present the results for a phase II trial of combination nivolumab and temozolomide in patients with advanced NEN along with results of immune changes in peripheral blood. PATIENTS AND METHODS NCT03728361 is a nonrandomized, phase II study of nivolumab and temozolomide in patients with NEN. The primary endpoint was response rate using RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Immune profiling was performed by mass cytometry to evaluate the effect on peripheral blood immune cell subsets. RESULTS Among all 28 patients with NEN, the confirmed response rate was 9/28 [32.1%, 95% confidence interval (CI): 15.9-52.4]. Of 11 patients with lung NEN, the response rate was 64% (n = 7); there was a significant difference in responses by primary tumor location (lung vs. others, P = 0.020). The median PFS was 8.8 months (95% CI: 3.9-11.1 months), and median OS was 32.3 months (95% CI: 20.7-not reached months). Exploratory blood immune cell profiling revealed an increase in circulating CD8+ T cells (27.9% ± 13.4% vs. 31.7% ± 14.6%, P = 0.03) and a decrease in CD4+ T cells (59.6% ± 13.1% vs. 56.5% ± 13.0%, P = 0.001) after 2 weeks of treatment. LAG-3-expressing total T cells were lower in patients experiencing a partial response (0.18% ± 0.24% vs. 0.83% ± 0.55%, P = 0.028). Myeloid-derived suppressor cell levels increased during the study and did not correlate with response. CONCLUSIONS Combination nivolumab and temozolomide demonstrated promising activity in NEN. See related commentary by Velez and Garon, p. 691.
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Affiliation(s)
- Dwight H. Owen
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio.,Corresponding Author: Dwight H. Owen, The Ohio State University - James Comprehensive Cancer Center, 1800 Cannon Drive, Columbus, OH 43201. Phone: 614-685-2039; E-mail:
| | - Brooke Benner
- Division of Surgical Oncology, Department of Surgery, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Lai Wei
- Department of Biomedical Informatics and Center for Biostatistics, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Vineeth Sukrithan
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Ashima Goyal
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Ye Zhou
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Carly Pilcher
- Clinical Trials Office, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Sheryl-Ann Suffren
- Clinical Trials Office, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Gwen Christenson
- Clinical Trials Office, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Nancy Curtis
- Clinical Trials Office, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Megan Jukich
- Clinical Trials Office, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Emily Schwarz
- Division of Surgical Oncology, Department of Surgery, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Himanshu Savardekar
- Division of Surgical Oncology, Department of Surgery, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Ruthann Norman
- Division of Surgical Oncology, Department of Surgery, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Sarah Ferguson
- Clinical Trials Office, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Barbara Kleiber
- Clinical Trials Office, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Robert Wesolowski
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - William E. Carson
- Division of Surgical Oncology, Department of Surgery, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Gregory A. Otterson
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Claire F. Verschraegen
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Manisha H. Shah
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
| | - Bhavana Konda
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University - James Comprehensive Cancer Center, Columbus, Ohio
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22
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Ruggeri RM, Benevento E, De Cicco F, Fazzalari B, Guadagno E, Hasballa I, Tarsitano MG, Isidori AM, Colao A, Faggiano A. Neuroendocrine neoplasms in the context of inherited tumor syndromes: a reappraisal focused on targeted therapies. J Endocrinol Invest 2023; 46:213-234. [PMID: 36038743 DOI: 10.1007/s40618-022-01905-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 08/16/2022] [Indexed: 01/25/2023]
Abstract
PURPOSE Neuroendocrine neoplasms can occur as part of inherited disorders, usually in the form of well-differentiated, slow-growing tumors (NET). The main predisposing syndromes include: multiple endocrine neoplasias type 1 (MEN1), associated with a large spectrum of gastroenteropancreatic and thoracic NETs, and type 4 (MEN4), associated with a wide tumour spectrum similar to that of MEN1; von Hippel-Lindau syndrome (VHL), tuberous sclerosis (TSC), and neurofibromatosis 1 (NF-1), associated with pancreatic NETs. In the present review, we propose a reappraisal of the genetic basis and clinical features of gastroenteropancreatic and thoracic NETs in the setting of inherited syndromes with a special focus on molecularly targeted therapies for these lesions. METHODS Literature search was systematically performed through online databases, including MEDLINE (via PubMed), and Scopus using multiple keywords' combinations up to June 2022. RESULTS Somatostatin analogues (SSAs) remain the mainstay of systemic treatment for NETs, and radiolabelled SSAs can be used for peptide-receptor radionuclide therapy for somatostatin receptor (SSTR)-positive NETs. Apart of these SSTR-targeted therapies, other targeted agents have been approved for NETs: the mTOR inhibitor everolimus for lung, gastroenteropatic and unknown origin NET, and sunitinib, an antiangiogenic tyrosine kinase inhibitor, for pancreatic NET. Novel targeted therapies with other antiangiogenic agents and immunotherapies have been also under evaluation. CONCLUSIONS Major advances in the understanding of genetic and epigenetic mechanisms of NET development in the context of inherited endocrine disorders have led to the recognition of molecular targetable alterations, providing a rationale for the implementation of treatments and development of novel targeted therapies.
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Affiliation(s)
- R M Ruggeri
- Unit of Endocrinology, Department of Clinical and Experimental Medicine, University of Messina, AOU Policlinico "Gaetano Martino" University Hospital, 98125, Messina, Italy.
| | - E Benevento
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
| | - F De Cicco
- SSD Endocrine Disease and Diabetology, ASL TO3, Pinerolo, TO, Italy
| | - B Fazzalari
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - E Guadagno
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
| | - I Hasballa
- Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - M G Tarsitano
- Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - A M Isidori
- Gruppo NETTARE, Policlinico Umberto I, Università Sapienza, Rome, Italy
| | - A Colao
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
- UNESCO Chair "Education for Health and Sustainable Development", Federico II University, Naples, Italy
| | - A Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
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23
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Perrier M, Scoazec JY, Walter T. A practical proposal on treatment sequencing of metastatic well-differentiated neuroendocrine tumours. Ther Adv Med Oncol 2023; 15:17588359231171041. [PMID: 37152421 PMCID: PMC10155015 DOI: 10.1177/17588359231171041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 04/04/2023] [Indexed: 05/09/2023] Open
Abstract
According to the neuroendocrine tumour (NET) characteristics, 3 to 7 different treatment options are available, corresponding to 6 to 5,040 theoretical different sequences. Even though each patient is unique and despite a large heterogeneity in NET characteristics, the present review aims to discuss the main sequences and addresses how one can propose the best sequence to treat metastatic NET (mNET) on a case-by-case basis. Each treatment must be discussed during dedicated multi-disciplinary meetings, and inclusions in clinical trials should be favoured. After a thorough characterization of patients and their mNET, and taking into account the availability of drugs, the first-line treatment should be chosen according to the treatment aim. The latter is determined based on three main topics (efficacy, safety, and patient preferences) that do not necessarily converge and must be defined a priori. At baseline, physicians should design an a priori full therapeutic sequence, which may evolve at each step depending on the response to previous treatment, the occurrence of chronic toxicities, and the patients' perception of the prior treatment. To improve knowledge in terms of effectiveness and risk of cumulative toxicities regarding the different sequences, real-world data using long follow-up durations are necessary; such issues will not be resolved by randomized clinical trials.
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Affiliation(s)
- Marine Perrier
- Université Reims Champagne-Ardenne, Department
of Gastroenterology and Digestive Oncology, Reims University Hospital,
Reims, France
| | - Jean-Yves Scoazec
- Department of Surgical and Molecular Pathology,
Gustave Roussy, Villejuif, France
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Viol F, Sipos B, Fahl M, Clauditz TS, Amin T, Kriegs M, Nieser M, Izbicki JR, Huber S, Lohse AW, Schrader J. Novel preclinical gastroenteropancreatic neuroendocrine neoplasia models demonstrate the feasibility of mutation-based targeted therapy. Cell Oncol (Dordr) 2022; 45:1401-1419. [PMID: 36269546 PMCID: PMC9747820 DOI: 10.1007/s13402-022-00727-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2022] [Indexed: 12/15/2022] Open
Abstract
PURPOSE Gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) form a rare and remarkably heterogeneous group of tumors. Therefore, establishing personalized therapies is eminently challenging. To achieve progress in preclinical drug development, there is an urgent need for relevant tumor models. METHODS We successfully established three gastroenteropancreatic neuroendocrine tumor (GEP-NET) cell lines (NT-18P, NT-18LM, NT-36) and two gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) cell lines (NT-32 and NT-38). We performed a comprehensive characterization of morphology, NET differentiation, proliferation and intracellular signaling pathways of these five cell lines and, in addition, of the NT-3 GEP-NET cell line. Additionally, we conducted panel sequencing to identify genomic alterations suitable for mutation-based targeted therapy. RESULTS We found that the GEP-NEN cell lines exhibit a stable neuroendocrine phenotype. Functional kinome profiling revealed a higher activity of serine/threonine kinases (STK) as well as protein tyrosine kinases (PTK) in the GEP-NET cell lines NT-3 and NT-18LM compared to the GEP-NEC cell lines NT-32 and NT-38. Panel sequencing revealed a mutation in Death Domain Associated Protein (DAXX), sensitizing NT-18LM to the Ataxia telangiectasia and Rad3 related (ATR) inhibitor Berzosertib, and a mutation in AT-Rich Interaction Domain 1A (ARID1A), sensitizing NT-38 to the Aurora kinase A inhibitor Alisertib. Small interfering RNA-mediated knock down of DAXX in the DAXX wild type cell line NT-3 sensitized these cells to Berzosertib. CONCLUSIONS The newly established GEP-NET and GEP-NEC cell lines represent comprehensive preclinical in vitro models suitable to decipher GEP-NEN biology and pathogenesis. Additionally, we present the first results of a GEP-NEN-specific mutation-based targeted therapy. These findings open up new potentialities for personalized therapies in GEP-NEN.
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Affiliation(s)
- Fabrice Viol
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
| | - Bence Sipos
- Internal Medicine VIII, University Hospital Tübingen, Tübingen, Germany
| | - Martina Fahl
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tania Amin
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Malte Kriegs
- Laboratory of Radiobiology & Experimental Radiation Oncology, UCCH Kinomics Core Facility, Hubertus Wald Tumorzentrum, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maike Nieser
- Center for Genomics and Transcriptomics, Tübingen, Germany
| | - Jakob R Izbicki
- Department for General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Samuel Huber
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Ansgar W Lohse
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany
| | - Jörg Schrader
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
- Department for General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Medicine, Klinikum Nordfriesland, Husum, Germany.
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25
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Ramirez RA, Cass AS, Das S, Low SW, Mehrad M, Rickman OB, Scherer PM, Thomas KE, Gillaspie EA. A multidisciplinary approach to the work up and management of pulmonary carcinoid tumors and DIPNECH: a narrative review. Transl Lung Cancer Res 2022; 11:2567-2587. [PMID: 36636417 PMCID: PMC9830261 DOI: 10.21037/tlcr-22-415] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 11/06/2022] [Indexed: 12/12/2022]
Abstract
Background and Objective Low and intermediate grade neuroendocrine tumors of the lung are uncommon malignancies representing 2% of all lung cancers. These are termed typical and atypical pulmonary carcinoid tumors. These can arise in the setting of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). The presentation, workup, management and outcomes of patients with these tumors can overlap with more common lung cancers but differ in that many of these patients have a prolonged clinical course. The objective of this narrative review is to summarize the literature and provide evidence and expert-based algorithms for work up and treatment of pulmonary carcinoids and DIPNECH. Methods A search of PubMed and Web of Science databases ending April 15, 2022, with the following keywords "lung carcinoid", "DIPNECH", "lung neuroendocrine," and "bronchopulmonary carcinoid". Key Content and Findings Pulmonary carcinoid tumors benefit from a multidisciplinary approach. Pre-treatment imaging with contrast-enhanced computed tomography, and DOTATATE positron emission tomography is required. Surgical resection is the gold standard for curative intent, and possibly including sublobar resections. Patients can recur or develop new primaries thus emphasizing the importance of surveillance; national guidelines recommend at least a 10-year follow up. A growing body of literature support the use of endobronchial therapy, with long responses documented. Systemic therapy consists of everolimus, somatostatin analogs, peptide receptor radionuclide therapy, and chemotherapy. Diffuse idiopathic pulmonary neuroendocrine tumor cell hyperplasia is rare, but series suggest somatostatin analogs may confer clinical benefit. Conclusions Pulmonary carcinoid tumors and DIPNECH are rare. Despite lack of regulatory approvals for advanced disease, multiple options are available but should be sequenced according to the clinical status and disease biology. Each patient should be discussed in a multidisciplinary setting and clinical trials should be considered if available.
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Affiliation(s)
- Robert A. Ramirez
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Amanda S. Cass
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Satya Das
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - See-Wei Low
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Mitra Mehrad
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Otis B. Rickman
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Philip M. Scherer
- Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Katharine E. Thomas
- Division of Hematology and Oncology, Department of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Erin A. Gillaspie
- Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
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Lau J, Ioan Cvasciuc T, Simpson D, C de Jong M, Parameswaran R. Continuing challenges of primary neuroendocrine tumours of the thymus: A concisereview. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2022; 48:2360-2368. [PMID: 35922282 DOI: 10.1016/j.ejso.2022.07.017] [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: 01/19/2022] [Revised: 07/13/2022] [Accepted: 07/18/2022] [Indexed: 12/14/2022]
Abstract
Primary neuroendocrine tumours of the thymus (NETTs) are exceedingly rare tumours, usually presenting around mid-life, which have a propensity towards males and smokers. They are seen more often in those with MEN-1, but multiple different genetic mutations have been found to be involved in the tumorigenesis of NETTs. Histologically, NETTs are classified according to number of mitoses, the presence of necrosis, and the presence or absence of small cell features. NETTs display a wide spectrum of behavior, and they can be incidentally found on chest imaging, on screening in MEN-1, or present with symptoms of local compression. Advanced disease and paraneoplastic syndromes are common. CT-, PET/CT-, MRI-scans, and somatostatin receptor scintigraphy are the imaging modalities of choice both for the initial assessment as well as for monitoring after treatment. For patients with localized disease, complete surgical resection with lymphadenectomy provides the best chance of long-term, disease-free survival, and can be achieved through either an open or thoracoscopic approach. While chemotherapy-regimens based on platinum, taxane, and temozolomide are used most often, the optimum chemotherapy regimen in the adjuvant and palliative settings remains unclear, as does the role of radiotherapy. Ongoing research on the most effective use of somatostatin analogues, peptide receptor radionuclide therapy (PPRT), kinase inhibitors and immunotherapy in patients with other types of advanced neuroendocrine tumours may lead to further treatment options for NETTs in the future.
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Affiliation(s)
- Joel Lau
- Division of Endocrine Surgery, National University Health System, 119074, Singapore
| | - Titus Ioan Cvasciuc
- Division of Endocrine Surgery, Royal Victoria Hospital, Grosvenor Road, Belfast, 274 Grosvenor Rd, Belfast, BT12 6BA, UK
| | - Duncan Simpson
- Division of Endocrine Surgery, Royal Victoria Hospital, Grosvenor Road, Belfast, 274 Grosvenor Rd, Belfast, BT12 6BA, UK
| | - Mechteld C de Jong
- Division of Endocrine Surgery, National University Health System, 119074, Singapore
| | - Rajeev Parameswaran
- Division of Endocrine Surgery, National University Health System, 119074, Singapore; Yong Loo Lin School of Medicine, 10 Medical Dr, 117597, Singapore.
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Ali MA, Shah SS, Tahir N, Rehman S, Saeed M, Bajwa SF, Ali R, Aiman W, Anwar MY. Efficacy and toxicity of surufatinib in neuroendocrine tumors: A systematic review and meta-analysis. J Neuroendocrinol 2022; 34:e13149. [PMID: 35665971 DOI: 10.1111/jne.13149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 12/12/2021] [Accepted: 04/15/2022] [Indexed: 02/05/2023]
Abstract
The incidence and prevalence of neuroendocrine neoplasms (NENs) has increased in the US in recent decades. These are well-vascularized tumors, but no antiangiogenic drug has been approved for treatment of extra-pancreatic NENs. The aim is to assess efficacy and safety of surufatinib in pancreatic and extra-pancreatic NETs. We searched PubMed, Embase, Cochrane Library, Web of Science and Clinicaltrials.gov. Clinical trials and observational studies that provided safety and efficacy data in clinical terms were included. Characteristics of the study, baseline characteristics of participants, treatment drugs, measures of efficacy, and toxicity (≥grade 3 adverse effects) were extracted. The meta-analysis was performed using the "R" programming language. Risk ratio (RR) of objective response (OR)/partial response (PR) was 8.55 (95% CI: 1.68-43.66, I2 = 0) in favor of surufatinib. The hazard ratio (HR) of progression-free survival (PFS) was 0.48 (95% CI: 0.25-0.92, I2 = 77%) in favor of surufatinib. The risk of ≥grade 3 adverse effects: diarrhea, hypertension, hypertriglyceridemia, proteinuria, and vomiting were high with the use of surufatinib. Quality of life (QoL) was similar in surufatinib and placebo groups except for the diarrhea that was high with surufatinib. Lack of randomized clinical trials in non-Chinese population. Surufatinib is well tolerated and is more effective than placebo in both pancreatic and extra-pancreatic NETs. More multicenter randomized, double-blinded clinical trials are needed to confirm these results.
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Affiliation(s)
- Muhammad Ashar Ali
- Beth Israel Deconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Syed S Shah
- University of Kentucky, Lexington, Kentucky, USA
| | - Nayha Tahir
- Rosalind Franklin University of Medical Sciences/Chicago Medical School, North Chicago, Illinois, USA
| | - Sana Rehman
- Shaikh Khalifa Bin Zayed Al Nahyan Medical and Dental College, Lahore, Pakistan
| | | | | | - Rimsha Ali
- Rawalpindi Medical College, Rawalpindi, Pakistan
| | - Wajeeha Aiman
- Beth Israel Deconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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Sun F, Grenert JP, Tan L, Van Ziffle J, Joseph NM, Mulvey CK, Bergsland E. Checkpoint Inhibitor Immunotherapy to Treat Temozolomide-Associated Hypermutation in Advanced Atypical Carcinoid Tumor of the Lung. JCO Precis Oncol 2022; 6:e2200009. [PMID: 35737914 PMCID: PMC9249272 DOI: 10.1200/po.22.00009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 04/06/2022] [Accepted: 05/04/2022] [Indexed: 01/23/2023] Open
Affiliation(s)
- Fangdi Sun
- Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - James P. Grenert
- Department of Pathology, University of California, San Francisco, San Francisco, CA
| | - Lisa Tan
- Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Jessica Van Ziffle
- Department of Pathology, University of California, San Francisco, San Francisco, CA
| | - Nancy M. Joseph
- Department of Pathology, University of California, San Francisco, San Francisco, CA
| | - Claire K. Mulvey
- Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Emily Bergsland
- Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA
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29
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Kiesewetter B, Mazal P, Kretschmer-Chott E, Mayerhoefer ME, Raderer M. Pulmonary neuroendocrine tumours and somatostatin receptor status: an assessment of unlicensed use of somatostatin analogues in the clinical practice. ESMO Open 2022; 7:100478. [PMID: 35525183 PMCID: PMC9271480 DOI: 10.1016/j.esmoop.2022.100478] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 03/14/2022] [Accepted: 03/18/2022] [Indexed: 11/30/2022] Open
Abstract
Background The use of somatostatin analogues (SSAs) has not been formally approved in pulmonary neuroendocrine tumours (NETs) in the absence of positive controlled trials, even though it is recommended as a potential therapeutic option in recent guidelines. Patients and methods We have assessed the use of SSA in the general practice in Austria by retrospectively analysing patients with pulmonary NETs referred to our European Neuroendocrine Tumor Society centre in Vienna for second opinion or further therapy. In addition, we have analysed the somatostatin receptor (SSTR) expression of those patients by immunohistochemistry (IHC) and SSTR imaging, e.g. 68Ga-DOTANOC-positron emission tomography/computed tomography, and whether such analyses had been carried out before referral at our centre. Results Out of 34 patients (19 atypical and 15 typical carcinoids) with metastatic or advanced disease, 10/34 (29%) had been prescribed SSA before referral. No IHC for SSTR had been carried out, and only 9/34 (27%) had undergone SSTR imaging by nuclear medicine. Sufficient material for IHC was available in 29/34 (85%) patients and SSTR-IHC was rated negative in 13/29 (45%), weakly positive in 4/29 (14%), moderately positive in 5/29 (17%) and strongly positive in 7/29 (24%) patients. On SSTR imaging, 8/34 patients (24%) were positive, 13/34 (38%) negative and 13/34 patients (38%) showed a mix of positive and negative NET lesions. In 11/29 (38%) patients with both IHC and imaging available, discordance of SSTR expression on imaging and histological assessment was detected. Conclusions These data show that uncritical use of SSA should be discouraged, and assessment of SSTR, preferably by imaging, is mandatory before prescription of SSA in pulmonary NETs.
SSAs are not formally approved in pulmonary NETs. SSAs are recommended as a potential therapeutic option for advanced lung NETs in guidelines. We assessed the use of SSAs for lung NET in the general practice in Austria. Only 27% had undergone SSTR imaging before referral and receptor status was highly heterogeneous. Our data emphasize that uncritical use of SSAs should be discouraged; assessment of SSTRs is recommended.
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Affiliation(s)
| | | | - E Kretschmer-Chott
- Departments of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria
| | - M E Mayerhoefer
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, USA; Department of Biomedical Imaging and Image-guided Therapy, Division of General and Paediatric Radiology, Medical University of Vienna, Vienna, Austria
| | - M Raderer
- Departments of Medicine I, Division of Oncology.
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Survival According to Therapy Regimen for Small Intestinal Neuroendocrine Tumors. J Clin Med 2022; 11:jcm11092358. [PMID: 35566487 PMCID: PMC9104547 DOI: 10.3390/jcm11092358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/14/2022] [Accepted: 04/16/2022] [Indexed: 11/28/2022] Open
Abstract
Introduction: Scarce data exist for therapy regimens other than somatostatin analogues (SSA) and peptide receptor radiotherapy (PRRT) for siNET. We analyzed real world data for differences in survival according to therapy. Patients and methods: Analysis of 145 patients, diagnosed between 1993 and 2018 at a single institution, divided in treatment groups. Group (gr.) 0: no treatment (n = 10), gr 1: TACE and/or PRRT (n = 26), gr. 2: SSA (n = 32), gr. 3: SSA/PRRT (n = 8), gr. 4: chemotherapy (n = 8), gr. 5: not metastasized (at diagnosis), surgery only (n = 53), gr. 6 = metastasized (at diagnosis), surgery only (n = 10). Results: 45.5% female, median age 60 years (range, 27–84). A total of 125/145 patients with a resection of the primary tumor. For all patients, 1-year OS (%) was 93.8 (95%-CI: 90–98), 3-year OS = 84.3 (CI: 78–90) and 5-year OS = 77.5 (CI: 70–85). For analysis of survival according to therapy, only stage IV patients (baseline) that received treatment were included. Compared with reference gr. 2 (SSA only), HR for OS was 1.49 (p = 0.47) for gr. 1, 0.72 (p = 0.69) for gr. 3, 2.34 (p = 0.19) for gr. 4. The 5 y OS rate of patients whose primary tumor was resected (n = 125) was 73.1%, and without PTR was 33.3% (HR: 4.31; p = 0.003). Individual patients are represented in swimmer plots. Conclusions: For stage IV patients in this analysis (limited by low patient numbers in co. 3/4), multimodal treatment did not significantly improve survival over SSA treatment alone. A resection of primary tumor significantly improves survival.
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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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Sun TY, Hendifar A, Padda SK. Lung Neuroendocrine Tumors: How Does Molecular Profiling Help? Curr Oncol Rep 2022; 24:819-824. [PMID: 35305210 DOI: 10.1007/s11912-022-01253-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2021] [Indexed: 01/01/2023]
Abstract
PURPOSE OF REVIEW Lung neuroendocrine tumors (NETs)-typical carcinoids and atypical carcinoids-have unique molecular alterations that are distinct from neuroendocrine carcinomas of the lung and non-small cell lung cancers. Here, we review the role of molecular profiling in the prognosis and treatment of lung NETs. RECENT FINDINGS There have been no recently identified molecular prognostic factors for lung NETs and none that have been routinely used to guide management of patients with lung NETs. Previous findings suggest that patients with loss of chromosome 11q may have a worse prognosis along with upregulation of anti-apoptotic pathways (e.g., loss of CD44 and OTP protein expression). Lung NETs rarely harbor driver mutations commonly found in non-small cell lung cancer (NSCLC) or TP53/RB1 mutations found universally in small cell lung cancer. Lung NETs also have low tumor mutation burden and low PD-L1 expression. Everolimus, an mTOR inhibitor and the only FDA approved therapy for unresectable lung NETs, is an effective treatment but the presence of a molecular alteration in the PI3K/AKT/mTOR pathway is not known to predict treatment response. The predominant mutations in lung NETs occur in genes regulating chromatin remodeling and histone modification, with potential targeted therapies emerging in clinical trials. Lung NETs have recurring alterations in genes that regulate the epigenome. Future targeted therapy interfering with epigenetic pathways may hold promise.
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Affiliation(s)
- Thomas Yang Sun
- Department of Medicine, Division of Oncology, Stanford University School of Medicine, 875 Blake Wilbur Drive, Stanford, CA, USA
| | - Andrew Hendifar
- Department of Medicine, Division of Oncology, Cedars-Sinai Medical Center, 127 S San Vicente Blvd, 7th Floor, Los Angeles, CA, USA
| | - Sukhmani K Padda
- Department of Medicine, Division of Oncology, Cedars-Sinai Medical Center, 127 S San Vicente Blvd, 7th Floor, Los Angeles, CA, USA.
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Levy S, Verbeek WH, Eskens FA, van den Berg JG, de Groot DJA, van Leerdam ME, Tesselaar ME. First-line everolimus and cisplatin in patients with advanced extrapulmonary neuroendocrine carcinoma: a nationwide phase 2 single-arm clinical trial. Ther Adv Med Oncol 2022; 14:17588359221077088. [PMID: 35251315 PMCID: PMC8891910 DOI: 10.1177/17588359221077088] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 01/12/2022] [Indexed: 11/23/2022] Open
Abstract
Background: Extrapulmonary neuroendocrine carcinoma (EP-NEC) are an aggressive subgroup of neuroendocrine neoplasms (NEN). Advanced EP-NEC is generally treated with platinum-based cytotoxic regimens, but progressive disease occurs rapidly, resulting in a poor prognosis. Genetic alterations in the mammalian target for rapamycin (mTOR) pathway have been identified in NEN, providing a rationale for treatment with the mTOR-inhibitor everolimus. Methods: A prospective phase 2 single-arm study included patients with advanced EP-NEC from three Dutch NEN expertise centres between March 2016 and January 2020. Treatment consisted of cisplatin 75 mg/m2 every 3 weeks in combination with daily everolimus 7.5 mg for a maximum of six cycles, followed by maintenance everolimus until disease progression. Primary endpoint was disease control rate (DCR), defined as the sum of overall response rate (ORR) plus the rate of stable disease according to RECIST 1.1, assessed at 9-week intervals. Toxicity was evaluated according to CTCAE version 5.0. Results: Thirty-nine patients, with a median age of 64 years (range: 28–74), of whom 20 (51%) were male, were enrolled. DCR was 82.1% (95% confidence interval (CI): 66.4–92.4), with an ORR of 58.9% (CI: 42.1–74.4). Median duration of response was 6.4 (CI: 5.8–7.0) months and median progression-free survival was 6.0 (CI: 4.3–7.8) months. Three patients (8%) had durable responses lasting > 12 months. Median overall survival was 8.7 (CI: 7.8–9.6) months. Most common grade 3/4 toxicities were haematological (36%) and renal (21%). Conclusion: Everolimus in combination with cisplatin is an effective first-line treatment option for advanced EP-NEC, especially in highly selected patients. Trial registration: Clinicaltrials.gov, NCT02695459, https://clinicaltrials.gov/ct2/show/NCT02695459.
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Affiliation(s)
- Sonja Levy
- Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - Wieke H.M. Verbeek
- Department of Gastroenterological Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Ferry A.L.M. Eskens
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - José G. van den Berg
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Derk Jan A. de Groot
- Department of Medical Oncology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Monique E. van Leerdam
- Department of Gastroenterological Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Margot E.T. Tesselaar
- Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
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Araujo-Castro M, Pascual-Corrales E, Molina-Cerrillo J, Moreno Mata N, Alonso-Gordoa T. Bronchial Carcinoids: From Molecular Background to Treatment Approach. Cancers (Basel) 2022; 14:520. [PMID: 35158788 PMCID: PMC8833538 DOI: 10.3390/cancers14030520] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/19/2022] [Accepted: 01/19/2022] [Indexed: 02/05/2023] Open
Abstract
A better understanding of the genetic and molecular background of bronchial carcinoids (BCs) would allow a better estimation of the risk of disease progression and the personalization of treatment in cases of advanced disease. Molecular studies confirmed that lungs neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are different entities; thus, no progression of NET to NEC is expected. In BCs, MEN1 gene mutations and deletions and decreased gene expression have been associated with a poor prognosis. ATRX mutation has also been linked to a shorter disease-specific survival. In terms of therapeutic targets, PI3K/AKT/mTOR pathway mutations have been described in 13% of typical carcinoids (TCs) and 39% of atypical carcinoids (ACs), representing a targetable mutation with kinase inhibitors. Regarding treatment, surgical resection is usually curative in localized BCs and adjuvant treatment is not routinely recommended. Multiple options for systemic therapy exist for patients with advanced BCs, although limited by a heterogeneity in the scientific evidence behind their use recommendation. These options include somatostatin analogues, everolimus, peptide receptor radionuclide therapy, chemotherapy, radiotherapy, antiangiogenic agents, and immunotherapy. In this article, we provide a comprehensive review about the molecular and genetic background of BCs, and about the treatment of local and metastatic disease, as well as the main paraneoplastic syndromes that have been associated with this tumor.
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Affiliation(s)
- Marta Araujo-Castro
- Neuroendocrinology Unit, Endocrinology and Nutrition Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain;
- Instituto de Investigación Biomédica Ramón y Cajal (IRICYS), 28034 Madrid, Spain;
- Universidad de Alcalá, 28801 Madrid, Spain
| | - Eider Pascual-Corrales
- Neuroendocrinology Unit, Endocrinology and Nutrition Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain;
- Instituto de Investigación Biomédica Ramón y Cajal (IRICYS), 28034 Madrid, Spain;
| | - Javier Molina-Cerrillo
- Instituto de Investigación Biomédica Ramón y Cajal (IRICYS), 28034 Madrid, Spain;
- Universidad de Alcalá, 28801 Madrid, Spain
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Nicolás Moreno Mata
- Thoracic Surgery Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain;
| | - Teresa Alonso-Gordoa
- Instituto de Investigación Biomédica Ramón y Cajal (IRICYS), 28034 Madrid, Spain;
- Universidad de Alcalá, 28801 Madrid, Spain
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
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35
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Williams SJ, Rilling WS, White SB. Quality of Life and Cost Considerations: Y-90 Radioembolization. Semin Intervent Radiol 2021; 38:482-487. [PMID: 34629718 DOI: 10.1055/s-0041-1735570] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Objective Transarterial radioembolization (TARE) offers a minimally invasive and safe treatment option for primary and metastatic hepatic malignancies. The benefits of TARE are manifold including prolonged overall survival, low associated morbidities, and improved time to progression allowing prolonged treatment-free intervals. The rapid development of new systemic therapies including immunotherapy has radically changed the treatment landscape for primary and metastatic liver cancer. Given the current climate, it is critical for interventional oncologists to understand the benefits of TARE relative to these other therapies. Therefore, this report aims to review quality-of-life outcomes and the cost comparisons of TARE as compared with systemic therapies.
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Affiliation(s)
- Stephen J Williams
- Division of Vascular and Interventional Radiology, Department of Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - William S Rilling
- Division of Vascular and Interventional Radiology, Department of Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Sarah B White
- Division of Vascular and Interventional Radiology, Department of Radiology, Medical College of Wisconsin, Milwaukee, Wisconsin
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Application of FLIC model to predict adverse events onset in neuroendocrine tumors treated with PRRT. Sci Rep 2021; 11:19490. [PMID: 34593940 PMCID: PMC8484673 DOI: 10.1038/s41598-021-99048-8] [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: 07/05/2021] [Accepted: 09/16/2021] [Indexed: 02/02/2023] Open
Abstract
To develop predictive models of side effect occurrence in GEPNET treated with PRRT. Metastatic GEPNETs patients treated in our centre with PRRT (177Lu-Oxodotreotide) from 2019 to 2020 were considered. Haematological, liver and renal toxicities were collected and graded according to CTCAE v5. Patients were grouped according with ECOG-PS, number of metastatic sites, previous treatment lines and therapies received before PRRT. A FLIC model with backward selection was used to detect the most relevant predictors. A subsampling approach was implemented to assess variable selection stability and model performance. Sixty-seven patients (31 males, 36 females, mean age 63) treated with PRRT were considered and followed up for 30 weeks from the beginning of the therapy. They were treated with PRRT as third or further lines in 34.3% of cases. All the patients showed at least one G1-G2, meanwhile G3-G5 were rare events. No renal G3-G4 were reported. Line of PRRT administration, age, gender and ECOG-PS were the main predictors of haematological, liver and renal CTCAE. The model performance, expressed by AUC, was > 65% for anaemia, creatinine and eGFR. The application of FLIC model can be useful to improve GEPNET decision-making, allowing clinicians to identify the better therapeutic sequence to avoid PRRT-related adverse events, on the basis of patient characteristics and previous treatment lines.
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Ramirez RA, Thomas K, Jacob A, Lin K, Bren-Mattison Y, Chauhan A. Adjuvant therapy for lung neuroendocrine neoplasms. World J Clin Oncol 2021; 12:664-674. [PMID: 34513600 PMCID: PMC8394158 DOI: 10.5306/wjco.v12.i8.664] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/19/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
Pulmonary neuroendocrine neoplasms (NENs) represent a minority of lung cancers and vary from slower growing pulmonary carcinoid (PC) tumors to aggressive small cell lung cancer (SCLC). While SCLC can account for up to 15% of lung cancer, PCs are uncommon and represent about 2% of lung cancers. Surgical resection is the standard of care for early-stage PCs and should also be considered in early stage large cell neuroendocrine carcinoma (LCNEC) and SCLC. Adjuvant treatment is generally accepted for aggressive LCNEC and SCLC, however, less well established for PCs. Guidelines admit a lack of trials to support a high-level recommendation for adjuvant therapy. This manuscript will discuss the role for adjuvant therapy in NENs and review the available literature.
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Affiliation(s)
- Robert A Ramirez
- Department of Medicine-Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, United States
| | - Katharine Thomas
- Department of Hematology and Oncology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, United States
| | - Aasems Jacob
- Division of Medical Oncology, University of Kentucky, Lexington, KY 40536, United States
| | - Karen Lin
- Department of Oncology, Brookwood Baptist Health, Birmingham, AL 35209, United States
| | - Yvette Bren-Mattison
- Department of Surgery, Louisiana State University Health Sciences Center, New Orleans, LA 70112, United States
- New Orleans Louisiana Neuroendocrine Tumor Specialists (NOLANETS), Ochsner Medical Center, Kenner, LA 70065, United States
| | - Aman Chauhan
- Division of Medical Oncology, University of Kentucky, Lexington, KY 40536, United States
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Zidan L, Iravani A, Oleinikov K, Ben-Haim S, Gross DJ, Meirovitz A, Maimon O, Akhurst T, Michael M, Hicks RJ, Grozinsky-Glasberg S, Kong G. Efficacy and safety of 177Lu-DOTATATE in lung neuroendocrine tumors: a bi-center study. J Nucl Med 2021; 63:218-225. [PMID: 34049983 DOI: 10.2967/jnumed.120.260760] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 04/21/2021] [Indexed: 11/16/2022] Open
Abstract
To assess the efficacy and safety of 177Lu-DOTATATE in patients with somatostatin receptor (SSR) positive lung neuroendocrine tumor (NET). Methods: This is a retrospective review of the outcome of patients with typical carcinoid (TC) and atypical carcinoid (AC), treated with 177Lu-DOTATATE at two ENETS Centres of Excellence. Morphological imaging (RECIST 1.1) and 68Ga-DOTATATE PET/CT responses were assessed at 3 months after completion of 177Lu-DOTATATE. Concordance between two response assessment methods was evaluated by Kappa statistics. Progression-free survival (PFS) and overall survival (OS) was estimated by Kaplan-Meier analysis and compared by Log-rank test. Treatment-related adverse events (AEs) were graded based on CTCAE version 5. Results: Of 48 patients (median age, 63 years, 13 female), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Majority (40, 83%) received somatostatin analogs and 10 patients (20%) had prior everolimus, chemotherapy or both. All patients had high SSR expression (≥ modified Krenning score 3) on pre-treatment 68Ga-DOTATATE PET/CT. Patients received a median 4 (range 1-4) cycles of 177Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27GBq (range 6-43GBq). At median follow-up of 42 months, the median PFS and OS were 23 months (95% CI 18-28 months) and 59 months (95% CI 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68Ga-DOTATATE PET/CT response categories were: partial response, 20% (95% CI 10-35%) and 44% (95% CI 30-59%); stable disease, 68% (95% CI 52-80%) and 44% (95% CI 30-59%) and progressive disease 12% (95% CI 5-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68Ga-DOTATATE PET/CT, weighted Kappa of 0.51 (95% CI 0.21-0.68). Of patients with stable disease by RECIST, those with partial response on 68Ga-DOTATATE PET/CT had longer OS compared to those with no response, NR vs 52 months (95% CI 28-64), HR 0.2 (95% CI 0.1-0.6), p 0.001. Most grade 3/4 AEs were reversible and the most common was lymphopenia (14%) with no incidence of myelodysplasia/leukemia. Conclusion: In patients with advanced progressive lung NET and satisfactory SSR expression, 177Lu-DOTATATE is effective and safe with a high disease control rate and encouraging PFS and OS.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Grace Kong
- Peter MacCallum Cancer Centre, Australia
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39
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Paludan-Müller AS, Créquit P, Boutron I. Reporting of harms in oncological clinical study reports submitted to the European Medicines Agency compared to trial registries and publications-a methodological review. BMC Med 2021; 19:88. [PMID: 33827569 PMCID: PMC8028762 DOI: 10.1186/s12916-021-01955-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 03/01/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND An accurate and comprehensive assessment of harms is a fundamental part of an accurate weighing of benefits and harms of an intervention when making treatment decisions; however, harms are known to be underreported in journal publications. Therefore, we sought to compare the completeness of reporting of harm data, discrepancies in harm data reported, and the delay to access results of oncological clinical trials between three sources: clinical study reports (CSRs), clinical trial registries and journal publications. METHODS We used the EMA clinical data website to identify all trials submitted to the EMA between 2015 and 2018. We retrieved all CSRs and included all phase II, II/III or III randomised controlled trials (RCTs) assessing targeted therapy and immunotherapy for cancer. We then identified related records in clinical trial registries and journals. We extracted harms data for eight pre-specified variables and determined the completeness of reporting of harm data in each of the three sources. RESULTS We identified 42 RCTs evaluating 13 different drugs. Results were available on the EMA website in CSRs for 37 (88%) RCTs, ClinicalTrials.gov for 36 (86%), the European Clinical Trials Register (EUCTR) for 20 (48%) and in journal publications for 32 (76%). Harms reporting was more complete in CSRs than other sources. We identified marked discrepancies in harms data between sources, e.g. the number of patients discontinuing due to adverse events differed in CSRs and clinical trial registers for 88% of trials with data in both sources. For CSRs and publications, the corresponding number was 90%. The median (interquartile range) delay between the primary trial completion date and access to results was 4.34 (3.09-7.22) years for CSRs, 2.94 (1.16-4.52) years for ClinicalTrials.gov, 5.39 (4.18-7.33) years for EUCTR and 2.15 (0.64-5.04) years for publications. CONCLUSIONS Harms of recently approved oncological drugs were reported more frequently and in more detail in CSRs than in trial registries and journal publications. Systematic reviews seeking to address harms of oncological treatments should ideally use CSRs as the primary source of data; however, due to problems with access, this is currently not feasible.
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Affiliation(s)
- Asger S Paludan-Müller
- Centre for Evidence-Based Medicine Odense (CEBMO) and Cochrane Denmark , Department of Clinical Research, University of Southern Denmark, JB Winsløwsvej 9b, 3rd Floor, 5000, Odence C, Denmark. .,Open Patient data Exploratory Network (OPEN) , Odense University Hospital , Odense, Denmark.
| | - Perrine Créquit
- Direction de la recherche Clinique, Hôpital Foch, Suresnes, France.,Université de Paris, CRESS, INSERM, INRA, F-75004, Paris, France.,Cochrane France, Paris, France
| | - Isabelle Boutron
- Université de Paris, CRESS, INSERM, INRA, F-75004, Paris, France.,Cochrane France, Paris, France.,Centre d'Epidémiologie Clinique, AP-HP (Assistance Publique des Hôpitaux de Paris), Hôpital Hôtel Dieu, Paris, France
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Targeted Cancer Therapy: What's New in the Field of Neuroendocrine Neoplasms? Cancers (Basel) 2021; 13:cancers13071701. [PMID: 33916707 PMCID: PMC8038369 DOI: 10.3390/cancers13071701] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 12/18/2022] Open
Abstract
Neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms of increasing incidence and high prevalence due to their relatively indolent nature. Their wide anatomic distribution and their characteristic ability to secrete hormonally active substances pose unique challenges for clinical management. They are also characterized by the common expression of somatostatin receptors, a target that has been extremely useful for diagnosis and treatment (i.e., somatostatin analogues (SSAs) and peptide-receptor radionuclide therapy (PRRT)). Chemotherapy is of limited use for NETs of non-pancreatic origin, and the only approved targeted agents for advanced progressive NETs are sunitinib for those of pancreatic origin, and everolimus for lung, gastrointestinal and pancreatic primaries. Despite recent therapeutic achievements, thus, systemic treatment options remain limited. In this review we will discuss the state-of-the-art targeted therapies in the field of NETs, and also future perspectives of novel therapeutic drugs or strategies in clinical development, including recently presented results from randomized trials of yet unapproved antiangiogenic agents (i.e., pazopanib, surufatinib and axitinib), PRRT including both approved radiopharmaceuticals (177Lu-Oxodotreotide) and others in development (177Lu-Edotreotide, 177Lu-Satoreotide Tetraxetan), immunotherapy and other innovative targeted strategies (antibody-drug conjugates, bites,…) that shall soon improve the landscape of personalized treatment options in NET patients.
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Baudin E, Caplin M, Garcia-Carbonero R, Fazio N, Ferolla P, Filosso PL, Frilling A, de Herder WW, Hörsch D, Knigge U, Korse CM, Lim E, Lombard-Bohas C, Pavel M, Scoazec JY, Sundin A, Berruti A. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up ☆. Ann Oncol 2021; 32:439-451. [PMID: 33482246 DOI: 10.1016/j.annonc.2021.01.003] [Citation(s) in RCA: 135] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 12/23/2020] [Accepted: 01/07/2021] [Indexed: 12/24/2022] Open
Affiliation(s)
- E Baudin
- Endocrine Oncology and Nuclear Medicine Unit, Gustave Roussy, Villejuif, France
| | - M Caplin
- Centre for Gastroenterology, Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK
| | - R Garcia-Carbonero
- Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Madrid, Spain
| | - N Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology IEO, IRCCS, Milan, Italy
| | - P Ferolla
- Multidisciplinary NET Group, Department of Medical Oncology, Umbria Regional Cancer Network and University of Perugia, Perugia, Italy
| | - P L Filosso
- Department of Surgical Sciences Unit of Thoracic Surgery Corso Dogliotti, University of Torino, Torino, Italy
| | - A Frilling
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - W W de Herder
- Department of Internal Medicine, Sector of Endocrinology, Erasmus MC, ENETS Centre of Excellence, Rotterdam, The Netherlands
| | - D Hörsch
- ENETS Centre of Excellence Zentralklinik Bad Berka, Bad Berka, Germany
| | - U Knigge
- Department of Surgery and Department of Endocrinology, ENETS Centre of Excellence, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - C M Korse
- Department of Laboratory Medicine, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - E Lim
- Imperial College and the Academic Division of Thoracic Surgery, The Royal Brompton Hospital, London, UK
| | - C Lombard-Bohas
- Cancer Institute Hospices Civils de Lyon, Hôpital E Herriot, Lyon, France
| | - M Pavel
- Department of Medicine 1, Endocrinology, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - J Y Scoazec
- Department of Pathology, Gustave Roussy, Villejuif, France
| | - A Sundin
- Department of Radiology and Nuclear Medicine, Department of Surgical Sciences (IKV), Uppsala University, Uppsala, Sweden
| | - A Berruti
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology Unit, University of Brescia, Brescia, Italy
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Al-Toubah T, Grozinsky-Glasberg S, Strosberg J. An Update on the Management of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH). Curr Treat Options Oncol 2021; 22:28. [PMID: 33641079 DOI: 10.1007/s11864-021-00828-1] [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] [Accepted: 01/18/2021] [Indexed: 11/30/2022]
Abstract
OPINION STATEMENT DIPNECH is caused by an idiopathic proliferation of pulmonary neuroendocrine cells which can lead to bronchiolitis and multifocal lung neuroendocrine tumors. Patients often present with chronic cough and dyspnea. Larger NETs may develop malignant potential. Somatostatin analogs can palliate chronic symptoms, particularly cough. Surgical resection can be considered for relatively large (e.g. >1 cm), progressive tumors.
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Affiliation(s)
- Taymeyah Al-Toubah
- Department of GI Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA
| | - Simona Grozinsky-Glasberg
- Neuroendocrine Tumor Unit, ENETS Center of Excellence, Department of Endocrinology and Metabolism, Hadassah-Hebrew University Medical Center, P.O.B. 12000, 91120, Jerusalem, Israel
| | - Jonathan Strosberg
- Department of GI Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
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Kurz S, Kollmeier J, Schmidt B, Schneider P, Utzig M, Grohé C. [Clinical Course of Typical and Atypical Carcinoids (bpNET): Evaluation of PneuNET Register Berlin Data for the Identification of Indicators for Prognosis Determination and Therapy Planning]. Pneumologie 2021; 75:276-283. [PMID: 33461225 DOI: 10.1055/a-1237-3617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
AIM Retrospective analysis of data from PneuNET registry to evaluate clinical follow up of patients with typical and atypical bronchopulmonary carcinoid (bpNET). METHOD Three lung cancer centres in Berlin included patients in the registry between 2007 and 2016. Inclusion criteria were: diagnosis of typical or atypical carcinoid, age > 18 years, follow-up for not less than 2 years. Frequency, gender, functional status, smoking status, localisation of the tumour, biomarker, diagnostic and therapeutic procedures and follow-up were evaluated. RESULTS Since 01. 01. 2007, 187 patients with bronchopulmonary carcinoid had been included in the registry. The ratio between TC and AC was 8:2. The median age was 65.4 years and 64 % of patients were women. 10.7 % of patients had pulmonary symptoms, 2 patients a carcinoid syndrome, no patient was detected with MEN-1-syndrome. 87.7 % of patients had undergone surgery, 69.5 % as lobectomy with systematic lymphadenectomy. Only 10 % of patients were diagnosed with Stage IV disease, with atypical carcinoid predominating Systemic therapies included chemotherapy, everolimus and somatostatin analogues. CONCLUSION Bronchopulmonary carcinoids are well differentiated tumours of the lung. The early stage diagnosis offers the possibility of local therapy with excellent prognosis. We have improved systemic treatment options with mTOR-inhibitor everolimus and somatostatin analogues also in advanced stage of the disease. Because of the rareness of this heterogenous group of tumours, it is meaningful to collect data systematically in order to have a standardised algorithm of diagnostic procedures and therapy assessment.
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Affiliation(s)
- S Kurz
- Evangelische Lungenklinik Berlin
| | - J Kollmeier
- Helios Klinikum Emil von Behring - Lungenklinik Heckeshorn
| | - B Schmidt
- DRK-Kliniken Berlin, Lungenklinik Mitte
| | | | - M Utzig
- DRK-Kliniken Berlin, Lungenklinik Mitte, Klinik für Thoraxchirurgie
| | - C Grohé
- Evangelische Lungenklinik Berlin
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Liu Y, Xu R, Gu H, Zhang E, Qu J, Cao W, Huang X, Yan H, He J, Cai Z. Metabolic reprogramming in macrophage responses. Biomark Res 2021; 9:1. [PMID: 33407885 PMCID: PMC7786975 DOI: 10.1186/s40364-020-00251-y] [Citation(s) in RCA: 322] [Impact Index Per Article: 80.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 11/20/2020] [Indexed: 12/16/2022] Open
Abstract
Macrophages are critical mediators of tissue homeostasis, with the function of tissue development and repair, but also in defense against pathogens. Tumor-associated macrophages (TAMs) are considered as the main component in the tumor microenvironment and play an important role in tumor initiation, growth, invasion, and metastasis. Recently, metabolic studies have revealeded specific metabolic pathways in macrophages are tightly associated with their phenotype and function. Generally, pro-inflammatory macrophages (M1) rely mainly on glycolysis and exhibit impairment of the tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS), whereas anti-inflammatory macrophages (M2) are more dependent on mitochondrial OXPHOS. However, accumulating evidence suggests that macrophage metabolism is not as simple as previously thought. This review discusses recent advances in immunometabolism and describes how metabolism determines macrophage phenotype and function. In addition, we describe the metabolic characteristics of TAMs as well as their therapeutic implications. Finally, we discuss recent obstacles facing this area as well as promising directions for future study.
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Affiliation(s)
- Yang Liu
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Ruyi Xu
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Huiyao Gu
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Enfan Zhang
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Jianwei Qu
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Wen Cao
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Xi Huang
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Haimeng Yan
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Jingsong He
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Zhen Cai
- Bone Marrow Transplantation Center, The First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. .,Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China. .,Zhejiang Laboratory for Systems & Precison Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China.
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Prinzi N, Rossi RE, Leuzzi G, Pusceddu S. NETs of the Lung. NEUROENDOCRINE NEOPLASIA MANAGEMENT 2021:163-178. [DOI: 10.1007/978-3-030-72830-4_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Mirvis E, Toumpanakis C, Mandair D, Gnanasegaran G, Caplin M, Navalkissoor S. Efficacy and tolerability of peptide receptor radionuclide therapy (PRRT) in advanced metastatic bronchial neuroendocrine tumours (NETs). Lung Cancer 2020; 150:70-75. [DOI: 10.1016/j.lungcan.2020.10.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/06/2020] [Accepted: 10/09/2020] [Indexed: 12/31/2022]
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Abstract
Neuroendocrine neoplasms are a heterogeneous group of tumors arising from cells distributed throughout the body. Local and regional disease is managed with surgical resection; however, treatment of higher-grade neuroendocrine tumors (NETs), unresectable or metastatic disease is complex involving a combination of systemic targeted agents, transarterial embolization, and peptide receptor targeted therapies and is discussed in detail. The most important concept in modern NET workup is that an optimal diagnostic strategy requires combination of both anatomic and functional imaging modalities. NETs often present with unknown primary site of disease, and 68Ga-DOTATATE PET can now diagnose these lesions with great sensitivity.
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Affiliation(s)
- Agata E Migut
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Harmeet Kaur
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Rony Avritscher
- Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Interventional Radiology, 1400 Pressler Street, Unit 1471, Houston, TX 77030, USA.
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48
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Singh S, Bergsland EK, Card CM, Hope TA, Kunz PL, Laidley DT, Lawrence B, Leyden S, Metz DC, Michael M, Modahl LE, Myrehaug S, Padda SK, Pommier RF, Ramirez RA, Soulen M, Strosberg J, Sung A, Thawer A, Wei B, Xu B, Segelov E. Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines for the Diagnosis and Management of Patients With Lung Neuroendocrine Tumors: An International Collaborative Endorsement and Update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines. J Thorac Oncol 2020; 15:1577-1598. [PMID: 32663527 DOI: 10.1016/j.jtho.2020.06.021] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 06/14/2020] [Accepted: 06/29/2020] [Indexed: 12/12/2022]
Abstract
Lung neuroendocrine tumors (LNETs) are uncommon cancers, and there is a paucity of randomized evidence to guide practice. As a result, current guidelines from different neuroendocrine tumor societies vary considerably. There is a need to update and harmonize global consensus guidelines. This article reports the best practice guidelines produced by a collaboration between the Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society. We performed a formal endorsement and updating process of the 2015 European Neuroendocrine Tumor Society expert consensus article on LNET. A systematic review from January 2013 to October 2017 was conducted to procure the most recent evidence. The stepwise endorsement process involved experts from all major subspecialties, patients, and advocates. Guided by discussion of the most recent evidence, each statement from the European Neuroendocrine Tumor Society was either endorsed, modified, or removed. New consensus statements were added if appropriate. The search yielded 1109 new publications, of which 230 met the inclusion criteria. A total of 12 statements were endorsed, 22 statements were modified or updated, one was removed, and two were added. Critical answered questions for each topic in LNET were identified. Through the consensus process, guidelines for the management of patients with local and metastatic neuroendocrine tumors have been updated to include both recent evidence and practice changes relating to technological and definitional advances. The guidelines provide clear, evidence-based statements aimed at harmonizing the global approach to patients with LNETs, on the basis of the principles of person-centered and LNET-specific care. The importance of LNET-directed research and person-centered care throughout the diagnosis, treatment, and follow-up journey is emphasized along with directions for future collaborative research.
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Affiliation(s)
- Simron Singh
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
| | - Emily K Bergsland
- Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California
| | | | - Thomas A Hope
- Department of Radiology and Biomedical Imaging, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California
| | - Pamela L Kunz
- Department of Medicine, Yale University, New Haven, Connecticut
| | - David T Laidley
- Department of Medical Imaging, Division of Nuclear Medicine, London Health Sciences Centre, London, Ontario, Canada
| | - Ben Lawrence
- Discipline of Oncology, University of Auckland, Auckland, New Zealand
| | - Simone Leyden
- Unicorn Foundation, Blairgowrie, Victoria, Australia
| | - David C Metz
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Michael Michael
- Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia
| | - Lucy E Modahl
- Auckland Radiology Group, Auckland City Hospital, Auckland, New Zealand
| | - Sten Myrehaug
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Sukhmani K Padda
- Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California
| | | | - Robert A Ramirez
- Department of Medical Oncology, Ochsner Medical Center, New Orleans, Louisiana
| | - Michael Soulen
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Arthur Sung
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, California
| | - Alia Thawer
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Benjamin Wei
- Department of Surgery, Birmingham Medical Center, University of Alabama, Birmingham, Alabama
| | - Bin Xu
- Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Eva Segelov
- Department of Oncology, Monash Health, Monash University, Melbourne, Victoria, Australia
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Uprety D, Halfdanarson TR, Molina JR, Leventakos K. Pulmonary Neuroendocrine Tumors: Adjuvant and Systemic Treatments. Curr Treat Options Oncol 2020; 21:86. [PMID: 32862320 DOI: 10.1007/s11864-020-00786-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OPINION STATEMENT Bronchial carcinoids are uncommon tumors accounting for 20 to 30% of all neuroendocrine tumors and about 1-2% of all cancers of pulmonary origin. Bronchial carcinoids are well-differentiated neuroendocrine tumors and have a favorable survival outcome when compared with other subtypes of lung cancers. Treatment of bronchial carcinoids is not simple owing to intricacy of symptom presentation and heterogeneity of disease biology. Successful treatment of patients requires a multimodality approach. Resection is curative in the majority of patients with localized tumors and adjuvant treatment is not routinely recommended. Multiple options for systemic therapy exist for patients with advanced disease. To date, very few randomized clinical trials have been done, partly owing to the relative rarity of this malignancy. Somatostatin analogs (SSAs) are reasonable first-line choice for patients with tumors expressing somatostatin receptors. Everolimus is an appropriate first-line choice for somatostatin receptor negative tumors and for any patients with progressive disease. PRRT can also be considered for progressive tumors expressing somatostatin receptors. Based on retrospective series, cytotoxic chemotherapy can be selected in patients with progressive tumors, primarily when cytoreduction is needed. Herein, we will discuss evidence supporting the role of adjuvant and systemic treatment therapies for those with bronchial carcinoid tumors by focusing on various studies.
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Affiliation(s)
- Dipesh Uprety
- Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA
| | | | - Julian R Molina
- Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA
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Somatostatinoma and Neurofibromatosis Type 1-A Case Report and Review of the Literature. Diagnostics (Basel) 2020; 10:diagnostics10090620. [PMID: 32825782 PMCID: PMC7555390 DOI: 10.3390/diagnostics10090620] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/11/2020] [Accepted: 08/17/2020] [Indexed: 02/06/2023] Open
Abstract
Somatostatinomas are rare neuroendocrine tumors (NET) that arise in the gastrointestinal (GI) tract. Because of their insidious growth, they are usually asymptomatic until late stages, presenting as malignant disease. We report the case of a 50-year-old woman who presented with epigastric abdominal pain, diarrhea and significant weight loss in the last two years. On clinical examination the patient met the criteria for neurofibromatosis type 1 (NF1). Abdominal CT and MRI revealed an infiltrative duodenal mass, with pancreatic invasion, locoregional enlarged lymph nodes and disseminated hepatic nodules. Microscopy and immunohistochemistry uncovered a neuroendocrine tumor, staining positive for chromogranin A (CgA), synaptophysin and somatostatin, with a Ki67 = 1%. Somatostatin receptors (SSTRs) type 2 were negative and SSTRs type 5 were positive in less than 50% of tumoral cells. Our patient was classified as a T3N1M1 stage IV metastatic duodenal grade 1 somatostatinoma and treatment with somatostatin analogues and chemotherapy with capecitabine and temozolomide was started, with so far abdominal imaging follow-up showing stable disease. When a patient is diagnosed with a rare NET, such as a somatostatinoma, it is of utmost importance to determine if it is a sporadic tumor or just a feature of a genetic disorder.
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