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Algeri L, Falkman L, Spada F, Frassoni S, Bagnardi V, Boselli S, Cardinale D, Zanobini M, Crona J, Benini L, Tamayo D, Mazzon C, Gervaso L, Cella CA, Zampino MG, Ciardiello D, Russo A, Badalamenti G, Welin S, Fazio N. Carcinoid heart disease in patients with advanced small-intestinal neuroendocrine tumors and carcinoid syndrome: a retrospective experience from two European referral centers. ESMO Open 2024; 9:103959. [PMID: 39442478 PMCID: PMC11538955 DOI: 10.1016/j.esmoop.2024.103959] [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: 07/07/2024] [Revised: 09/14/2024] [Accepted: 09/23/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Up to 50% of patients with advanced small-intestinal neuroendocrine tumors (SI-NETs) and carcinoid syndrome (CS) develop carcinoid heart disease (CHD). However, the true frequency and prognostic markers for CHD in CS are lacking. We described the real-world management of patients in two NET referral centers in this clinical context and relationships between clinical features, including CHD and overall survival (OS). PATIENTS AND METHODS This is a retrospective analysis of patients with stage IV SI-NET and CS, treated at the European Institute of Oncology in Milan and Uppsala University in Sweden between 2015 and 2021. CHD was defined as at least one moderate right-sided heart valve defect. Median OS and cumulative incidence of CHD were estimated from the diagnosis of metastatic disease, and the association between clinical parameters with both OS and occurrence of CHD was evaluated. RESULTS We included 165 patients, with 97% having low-intermediate-grade SI-NETs and 86% having synchronous liver metastases. Ninety-eight patients (59%) became refractory to full label dose of somatostatin analogues and 25% developed a CHD. At CHD diagnosis, baseline urine 5-hydroxyindoleacetic acid (24-h u5-HIAA) value and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) value were known in 76% of patients. Moderate-to-severe tricuspid insufficiency was the most common alteration of CHD. Prognosis was significantly impaired by CHD (multivariable hazard ratio for OS = 2.85, P < 0.001). The median OS from the CHD diagnosis was 4.5 years [95% confidence interval (CI) 2.1-7.2 years], and the 5-year survival rate was 34% (95% CI 13% to 57%). CONCLUSIONS In our study population of SI-NET patients with CS, more than half had a refractory carcinoid syndrome (RCS) and one-quarter developed a CHD, with a negative impact on OS. Therefore, it is recommended to screen and monitor patients with CS for CHD, ideally with a combination of u5-HIAA, NT-proBNP values, and echocardiography at CS baseline, preferably in NET referral centers.
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Affiliation(s)
- L Algeri
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan; Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - L Falkman
- Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden
| | - F Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan
| | - S Frassoni
- Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy; Department of Medicine and Surgery, University of Milano-Bicocca, Milan
| | - V Bagnardi
- Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy
| | - S Boselli
- Department of Data Management-Clinical Trial Office, Scientific Direction, European Institute of Oncology (IEO), IRCCS, Milan
| | - D Cardinale
- Department of Cardioncology Unit, European Institute of Oncology (IEO), IRCCS, Milan
| | - M Zanobini
- Department of Cardiac Surgery, Centro Cardiologico Monzino, Milan, Italy
| | - J Crona
- Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden
| | - L Benini
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan
| | - D Tamayo
- Department of Data Management-Clinical Trial Office, Scientific Direction, European Institute of Oncology (IEO), IRCCS, Milan
| | - C Mazzon
- Department of Data Management-Clinical Trial Office, Scientific Direction, European Institute of Oncology (IEO), IRCCS, Milan
| | - L Gervaso
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan
| | - C A Cella
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan
| | - M G Zampino
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan
| | - D Ciardiello
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan
| | - A Russo
- Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - G Badalamenti
- Department of Precision Medicine in Medical, Surgical and Critical Care (Me.Pre.C.C.), Section of Medical Oncology, University of Palermo, Palermo, Italy
| | - S Welin
- Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden
| | - N Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), IRCCS, Milan.
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Tan B, Zhang B, Chen H. Gastroenteropancreatic neuroendocrine neoplasms: epidemiology, genetics, and treatment. Front Endocrinol (Lausanne) 2024; 15:1424839. [PMID: 39411312 PMCID: PMC11474919 DOI: 10.3389/fendo.2024.1424839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 09/10/2024] [Indexed: 10/19/2024] Open
Abstract
The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) is increasing at a rapid pace and is becoming an increasingly important consideration in clinical care. Epidemiological data from multiple countries indicate that the incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) exhibits regional, site-specific, and gender-based variations. While the genetics and pathogenesis of some GEP NEN, particularly pancreatic NENs, have been investigated, there are still many mechanisms that require further investigation. The management of GEP NEN is diverse, but surgery remains the primary option for most cases. Peptide receptor radionuclide therapy (PRRT) is an effective treatment, and several clinical trials are exploring the potential of immunotherapy and targeted therapy, as well as combination therapy.
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Affiliation(s)
- Baizhou Tan
- Department of Histology and Embryology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Beiyu Zhang
- Department of Histology and Embryology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Hongping Chen
- Department of Histology and Embryology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Experimental Animals, Nanchang University, Nanchang, China
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3
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Koumarianou A, Daskalakis K, Tsoli M, Kaltsas G, Pavel M. Efficacy, safety and unmet needs of evolving medical treatments for carcinoid syndrome. J Neuroendocrinol 2022; 34:e13174. [PMID: 35794780 DOI: 10.1111/jne.13174] [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: 02/18/2022] [Revised: 04/06/2022] [Accepted: 05/31/2022] [Indexed: 11/25/2022]
Abstract
This review reports on the currently available medical treatment options for the control of symptoms due to carcinoid syndrome in patients with neuroendocrine tumors. The efficacy and adverse events (AEs) of approved drugs such as somatostatin analogues (SSA), telotristat ethyl (TE) and interferon-alpha, are reviewed. Somatostatin analogues remain the standard treatment of carcinoid syndrome based on the high expression of somatostatin receptors and the resulting inhibition of secretion of bioactive compounds; their use is associated with relatively mild AEs, involving mainly the gastrointestinal system, and being usually transient. Although dose escalation of SSA remains an unapproved option, it is clinically implemented to alleviate symptoms in refractory carcinoid syndrome and supported by the most recent guidelines. The side effects associated with the increased dose are in general mild and consistent with standard dose of SSA. Telotristat ethyl, an oral inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis, represents a rather novel innovative treatment option in patients with carcinoid syndrome suffering from diarrhea and complements the standard therapy of SSA. Given the low toxicity profile, TE may be considered an early add-on treatment to SSA in patients with uncontrolled carcinoid syndrome. However, further prolonged follow-up of patients treated with TE may be needed to exclude potential AEs, such as liver toxicity or depressed mood, in patients with long-term treatment. Interferon alpha is a cytokine with direct inhibitory effect on hormone secretion and tumor cell proliferation and an approved therapy in carcinoid syndrome but is associated with significant AEs in the majority of the patients requiring frequently dose reduction. The finding of a more favorable tolerability of pegylated interferon needs to be confirmed in a prospective study.
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Affiliation(s)
- Anna Koumarianou
- Hematology-Oncology Unit, Fourth Department of Internal Medicine, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Kosmas Daskalakis
- Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- 2nd Department of Surgery, "Korgialenio-Benakio", Red Cross General Hospital, Athens, Greece
| | - Marina Tsoli
- 1st Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Gregory Kaltsas
- 1st Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Marianne Pavel
- Department of Endocrinology, Universitatsklinikum Erlangen, Erlangen, Germany
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Dai M, Mullins CS, Lu L, Alsfasser G, Linnebacher M. Recent advances in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. World J Gastrointest Surg 2022; 14:383-396. [PMID: 35734622 PMCID: PMC9160679 DOI: 10.4240/wjgs.v14.i5.383] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/17/2022] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare group of tumors originating from neuroendocrine cells of the digestive system. Their incidence has increased over the last decades. The specific pathogenetic mechanisms underlying GEP-NEN development have not been completely revealed. Unfunctional GEP-NENs are usually asymptomatic; some grow slowly and thus impede early diagnosis, which ultimately results in a high rate of misdiagnosis. Therefore, many GEP-NEN patients present with later staged tumors. Motivated hereby, research attention for diagnosis and treatment for GEP-NENs increased in recent years. The result of which is great progress in clinical diagnosis and treatment. According to the most recent clinical guidelines, improved grading standards can accurately define poorly differentiated grade 3 neuroendocrine tumors and neuroendocrine carcinomas (NECs), which are subclassified into large and small cell NECs. Combining different functional imaging methods facilitates precise diagnosis. The expression of somatostatin receptors helps to predict prognosis. Genetic analyses of mutations affecting death domain associated protein (DAXX), multiple endocrine neoplasia type 1 (MEN 1), alpha thalassemia/intellectual disability syndrome X-linked (ATRX), retinoblastoma transcriptional corepressor 1 (RB 1), and mothers against decapentaplegic homolog 4 (SMAD 4) help distinguishing grade 3 NENs from poorly differentiated NECs. The aim of this review is to summarize the latest research progress on diagnosis and treatment of GEP-NENs.
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Affiliation(s)
- Meng Dai
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Christina S Mullins
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Lili Lu
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Guido Alsfasser
- Clinic of General Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Michael Linnebacher
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
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Dawod M, Gordoa TA, Cives M, De Mestier L, Crona J, Spada F, Oberg K, Pavel M, Lamarca A. Antiproliferative Systemic Therapies for Metastatic Small Bowel Neuroendocrine Tumours. Curr Treat Options Oncol 2021; 22:73. [PMID: 34185197 DOI: 10.1007/s11864-021-00863-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/30/2021] [Indexed: 12/16/2022]
Abstract
OPINION STATEMENT Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies with rising incidence and prevalence. Outcome and therapy of small bowel neuroendocrine tumours (SBNETs) is variable, depending on the grade, differentiation, tumour burden, as well as the site of the tumour origin. Because of this, multidisciplinary approach is essential. Large randomized clinical trials, with somatostatin analogues (PROMID, CLARINET) or with peptide receptor radionuclide therapy (PRRT) with 177-lutetium (NETTER-1 trial) as well as the mammalian target of rapamycin inhibitor (mTOR) everolimus (RADIANT trials), represent milestones for the medical management of unresectable grade 1 and 2 SBNETS over the last decade. Novel therapies, such as tyrosine kinase inhibitors (TKI), are on the cutting edge. However, multiple unsolved questions remain. This review provides a comprehensive review of the main systemic therapeutic options for advanced SBNETs and discusses the latest guideline recommendations for palliative treatment.
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Affiliation(s)
- Mohammed Dawod
- Department of Medical Oncology, ENETs, Centre of Excellence, The Christie NHS Foundation Trust, Manchester, UK
| | - Teresa Alonso Gordoa
- Department of Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Mauro Cives
- Department of Medical Oncology, University of Bari, Bari, Italy
| | - Louis De Mestier
- Department of Gastroenterology, Beaujon Hospital, Université de Paris, Clichy, France
| | - Joakim Crona
- Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden
| | - Francesca Spada
- Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit, European Institute of Oncology, Milan, Italy
| | - Kjel Oberg
- Department of Endocrinology, Universitatsklinikum Erlangen, Erlangen, Germany
| | - Marianne Pavel
- Department of Medical Oncology, ENETs, Centre of Excellence, The Christie NHS Foundation Trust, Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Angela Lamarca
- The Christie NHS Foundation Trust, Wilmslow Road, M20 4BX, Manchester, UK.
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Garcia-Torralba E, Spada F, Lim KHJ, Jacobs T, Barriuso J, Mansoor W, McNamara MG, Hubner RA, Manoharan P, Fazio N, Valle JW, Lamarca A. Knowns and unknowns of bone metastases in patients with neuroendocrine neoplasms: A systematic review and meta-analysis. Cancer Treat Rev 2021; 94:102168. [PMID: 33730627 DOI: 10.1016/j.ctrv.2021.102168] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 02/03/2021] [Accepted: 02/05/2021] [Indexed: 12/11/2022]
Abstract
OBJECTIVE This systematic review and meta-analysis aimed to develop an evidence-based summary of current knowledge of bone metastases (BMs) in neuroendocrine neoplasms (NENs), inform diagnosis and treatment and standardise management between institutions. METHODS PubMed, Medline, EMBASE and meeting proceedings were searched for eligible studies reporting data on patients with BMs and NENs of any grade of differentiation and site; poorly-differentiated large/small cell lung cancer were excluded. Data were extracted and analysed using STATA v.12. Meta-analysis of proportions for calculation of estimated pooled prevalence of BM and calculation of weighted pooled frequency and weighted pooled mean for other variables of interest was performed . RESULTS A total of 149 studies met the eligibility criteria. Pooled prevalence of BMs was 18.4% (95% CI 15.4-21.5). BMs were mainly metachronous with initial diagnosis of NEN (61.2%) and predominantly osteoblastic; around 61% were multifocal, with a predisposition in axial skeleton. PET/CT seemed to provide (together with MRI) the highest sensitivity and specificity for BM detection. Almost half of patients (46.4%) reported BM-related symptoms: pain (66%) and skeletal-related events (SREs, fracture/spinal cord compression) (26.2%; weightedweighted mean time-to-SRE 9.9 months). Management of BMs was multimodal [bisphosphonates and bone-modifying agents (45.2%), external beam radiotherapy (34.9%), surgery (14.8%)] and supported by little evidence. Overall survival (OS) from the time of diagnosis of BMs was long [weighted mean 50.9 months (95% CI 40.0-61.9)]. Patients with BMs had shorter OS [48.8 months (95% CI 37.9-59.6)] compared to patients without BMs [87.4 months (95% CI 74.9-100.0); p = 0.001]. Poor performance status and BM-related symptoms were also associated with worse OS. CONCLUSIONS BMs in patients with NENs remain underdiagnosed and undertreated. Recommendations for management of BMs derived from current knowledge are provided. Prospective studies to inform management are required.
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Affiliation(s)
- Esmeralda Garcia-Torralba
- Department of Medical Oncology, ENETS Centre of Excellence, The Christie NHS Foundation Trust, Manchester, United Kingdom; Department of Haematology and Medical Oncology, Hospital Morales Meseguer, Murcia, Spain
| | - Francesca Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Kok Haw Jonathan Lim
- Department of Medical Oncology, ENETS Centre of Excellence, The Christie NHS Foundation Trust, Manchester, United Kingdom; Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
| | - Timothy Jacobs
- Medical Library, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Jorge Barriuso
- Division of Cancer Sciences, University of Manchester, Department of Medical Oncology, ENETS Centre of Excellence, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Was Mansoor
- Department of Medical Oncology, ENETS Centre of Excellence, The Christie NHS Foundation Trust, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Mairéad G McNamara
- Division of Cancer Sciences, University of Manchester, Department of Medical Oncology, ENETS Centre of Excellence, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Richard A Hubner
- Department of Medical Oncology, ENETS Centre of Excellence, The Christie NHS Foundation Trust, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom
| | - Prakash Manoharan
- Department of Radiology and Nuclear Medicine, ENETS Centre of Excellence, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
| | - Juan W Valle
- Division of Cancer Sciences, University of Manchester, Department of Medical Oncology, ENETS Centre of Excellence, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Angela Lamarca
- Department of Medical Oncology, ENETS Centre of Excellence, The Christie NHS Foundation Trust, Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom.
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Ahmed M. Gastrointestinal neuroendocrine tumors in 2020. World J Gastrointest Oncol 2020; 12:791-807. [PMID: 32879660 PMCID: PMC7443843 DOI: 10.4251/wjgo.v12.i8.791] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 05/26/2020] [Accepted: 07/19/2020] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal neuroendocrine tumors are rare slow-growing tumors with distinct histological, biological, and clinical characteristics that have increased in incidence and prevalence within the last few decades. They contain chromogranin A, synaptophysin and neuron-specific enolase which are necessary for making a diagnosis of neuroendocrine tumor. Ki-67 index and mitotic index correlate with cellular proliferation. Serum chromogranin A is the most commonly used biomarker to assess the bulk of disease and monitor treatment and is raised in both functioning and non-functioning neuroendocrine tumors. Most of the gastrointestinal neuroendocrine tumors are non-functional. World Health Organization updated the classification of neuroendocrine tumors in 2017 and renamed mixed adenoneuroendocrine carcinoma into mixed neuroendocrine neoplasm. Gastric neuroendocrine tumors arise from enterochromaffin like cells. They are classified into 4 types. Only type I and type II are gastrin dependent. Small intestinal neuroendocrine tumor is the most common small bowel malignancy. More than two-third of them occur in the terminal ileum within 60 cm of ileocecal valve. Patients with small intestinal neuroendrocrine tumors frequently show clinical symptoms and develop distant metastases more often than those with neuroendocrine tumors of other organs. Duodenal and jejuno-ileal neuroendocrine tumors are distinct biologically and clinically. Carcinoid syndrome generally occurs when jejuno-ileal neuroendocrine tumors metastasize to the liver. Appendiceal neuroendocrine tumors are generally detected after appendectomy. Colonic neuroendocrine tumors generally present as a large tumor with local or distant metastasis at the time of diagnosis. Rectal neuroendocrine tumors are increasingly being diagnosed since the implementation of screening colonoscopy in 2000. Gastrointestinal neuroendocrine tumors are diagnosed and staged by endoscopy with biopsy, endoscopic ultrasound, serology of biomarkers, imaging studies and functional somatostatin scans. Various treatment options are available for curative and palliative treatment of gastrointestinal neuroendocrine tumors.
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Affiliation(s)
- Monjur Ahmed
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Thomas Jefferson University, Philadelphia, PA 19107, United States
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8
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Özdirik B, Tacke F, Benz F, Amthauer H, Fehrenbach U, Roderburg C, Jann H. A case report of an excellent response to interferon- α in a patient with functional metastasized neuroendocrine tumor refractory to other treatments. Medicine (Baltimore) 2020; 99:e20820. [PMID: 32569231 PMCID: PMC7310897 DOI: 10.1097/md.0000000000020820] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 04/21/2020] [Accepted: 05/21/2020] [Indexed: 11/25/2022] Open
Abstract
INTRODUCTION Interferon alpha (IFNα) has been used for a long time in patients with functionally active neuroendocrine tumors (NET). However, due to the unfavorable toxicity profile of interferon, the perceived limited efficacy as well as the development of novel substances, IFNα is only used sparingly in the treatment of NET to date. PATIENTS CONCERNS AND DIAGNOSIS We describe the case of a 63-year-old male patient with highly differentiated, functional NET of the ileum and synchronous liver metastasis. INTERVENTIONS After failure of classical therapies including dose-intensified somatostatin analog treatment and palliative primary tumor resection, a therapy with pegylated IFNα2a (135 μg/wk) was initiated. Following this treatment, the patient fully recovered from signs of hypersecretion and demonstrated an impressive tumor response. OUTCOMES Thirty months after initiating IFNα, the patient is still free of clinical symptoms and shows a sustained tumor response. Notably, no relevant side effects were observed. CONCLUSION Our case report supports the use of IFNα in patients with functional NET refractory to classical treatments.
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Affiliation(s)
- Burcin Özdirik
- Charité – University Medicine Berlin, Department of Hepatology and Gastroenterology, Campus Virchow Klinikum and Charité Campus Mitte
| | - Frank Tacke
- Charité – University Medicine Berlin, Department of Hepatology and Gastroenterology, Campus Virchow Klinikum and Charité Campus Mitte
| | - Fabian Benz
- Charité – University Medicine Berlin, Department of Hepatology and Gastroenterology, Campus Virchow Klinikum and Charité Campus Mitte
| | - Holger Amthauer
- Charité – University Medicine Berlin, Department of Nuclear Medicine, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Klinik für Nuklearmedizin
| | - Uli Fehrenbach
- Charité – University Medicine Berlin, Department of Radiology, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Klinik für Radiologie, Berlin, Germany
| | - Christoph Roderburg
- Charité – University Medicine Berlin, Department of Hepatology and Gastroenterology, Campus Virchow Klinikum and Charité Campus Mitte
| | - Henning Jann
- Charité – University Medicine Berlin, Department of Hepatology and Gastroenterology, Campus Virchow Klinikum and Charité Campus Mitte
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Hofland J, Kaltsas G, de Herder WW. Advances in the Diagnosis and Management of Well-Differentiated Neuroendocrine Neoplasms. Endocr Rev 2020; 41:bnz004. [PMID: 31555796 PMCID: PMC7080342 DOI: 10.1210/endrev/bnz004] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 02/28/2020] [Indexed: 02/07/2023]
Abstract
Neuroendocrine neoplasms constitute a diverse group of tumors that derive from the sensory and secretory neuroendocrine cells and predominantly arise within the pulmonary and gastrointestinal tracts. The majority of these neoplasms have a well-differentiated grade and are termed neuroendocrine tumors (NETs). This subgroup is characterized by limited proliferation and patients affected by these tumors carry a good to moderate prognosis. A substantial subset of patients presenting with a NET suffer from the consequences of endocrine syndromes as a result of the excessive secretion of amines or peptide hormones, which can impair their quality of life and prognosis. Over the past 15 years, critical developments in tumor grading, diagnostic biomarkers, radionuclide imaging, randomized controlled drug trials, evidence-based guidelines, and superior prognostic outcomes have substantially altered the field of NET care. Here, we review the relevant advances to clinical practice that have significantly upgraded our approach to NET patients, both in diagnostic and in therapeutic options.
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Affiliation(s)
- Johannes Hofland
- ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus MC Cancer Center, Erasmus MC, Rotterdam, The Netherlands
| | - Gregory Kaltsas
- 1st Department of Propaupedic Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Wouter W de Herder
- ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus MC Cancer Center, Erasmus MC, Rotterdam, The Netherlands
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10
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Abstract
The increased incidence and prevalence of neuroendocrine tumors (NETs) over the past few decades has been accompanied by an improvement in overall survival. There are differences in the management of small bowel NETs versus pNETs. The management of all patients with NETs must be individualized based on patient characteristics as well tumor-related factors. This article reviews the role of somatostatin analogues, historical results with chemotherapy in gastroenteropancreatic NETs (GEPNETs), and more recent evidence for the use of cytotoxic chemotherapy in GEPNETs. The article also discusses molecular targeted therapies approved for use in GEPNETs and some ongoing clinical trials.
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Affiliation(s)
- Chandrikha Chandrasekharan
- Division of Medical Oncology, University of Iowa, 200 Hawkins Drive, C GH 32, Iowa City, Iowa 52242, USA.
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11
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Abstract
Neuroendocrine tumors (NETs) originate from the neuroendocrine cell system in the bronchial and gastrointestinal tract and can produce hormones leading to distinct clinical syndromes. Systemic treatment of patients with unresectable NETs aims to control symptoms related to hormonal overproduction and tumor growth. In the last decades prognosis has improved as a result of increased detection of early stage disease and the introduction of somatostatin analogs (SSAs) as well as several new therapeutic options. SSAs are the first-line medical treatment of NETs and can control hormonal production and tumor growth. The development of next-generation multireceptor targeted and radiolabelled somatostatin analogs, as well as target-directed therapies (as second-line treatment options) further improve progression-free survival in NET patients. To date, however, a significant prolongation of overall survival with systemic treatment in NET has not been convincingly demonstrated. Several new medical options and treatment combinations will become available in the upcoming years, and although preliminary results of preclinical and clinical trials are encouraging, large, preferrably randomized clinical studies are required to provide definitive evidence of their effect on survival and symptom control.
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Saavedra C, Barriuso J, McNamara MG, Valle JW, Lamarca A. Spotlight on telotristat ethyl for the treatment of carcinoid syndrome diarrhea: patient selection and reported outcomes. Cancer Manag Res 2019; 11:7537-7556. [PMID: 31496810 PMCID: PMC6690650 DOI: 10.2147/cmar.s181439] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 06/21/2019] [Indexed: 12/12/2022] Open
Abstract
Neuroendocrine tumors (NETs) are rare cancers with an associated prolonged survival in some patients. A proportion of patients diagnosed with NETs will present with carcinoid syndrome symptoms, characterized by diarrhea, flushing and/or wheezing. This review summarizes the current treatment options for carcinoid syndrome, focusing on the latest novel treatment option, telotristat ethyl. In addition, information on patient-reported outcomes and impact of carcinoid syndrome on quality of life (QOL) and improvement of following treatment with telotristat ethyl are reviewed. This article also provides an overview of the current QOL questionnaires for patients with NETs and addresses unmet needs in this field of patient-reported outcomes.
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Affiliation(s)
- Cristina Saavedra
- Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, UK.,Medical Oncology Department, Ramon Y Cajal University Hospital, Madrid, Spain
| | - Jorge Barriuso
- Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Mairéad G McNamara
- Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Juan W Valle
- Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Angela Lamarca
- Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, UK.,Division of Cancer Sciences, University of Manchester, Manchester, UK
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Stueven AK, Kayser A, Wetz C, Amthauer H, Wree A, Tacke F, Wiedenmann B, Roderburg C, Jann H. Somatostatin Analogues in the Treatment of Neuroendocrine Tumors: Past, Present and Future. Int J Mol Sci 2019; 20:ijms20123049. [PMID: 31234481 PMCID: PMC6627451 DOI: 10.3390/ijms20123049] [Citation(s) in RCA: 117] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 06/06/2019] [Accepted: 06/19/2019] [Indexed: 12/14/2022] Open
Abstract
In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). Both the PROMID (placebo-controlled, prospective, randomized study in patients with metastatic neuroendocrine midgut tumors) and the CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine tumors) trial showed a statistically significant prolongation of time to progression/progression-free survival (TTP/PFS) upon SSA treatment, compared to placebo. Moreover, the combination of SSA with peptide receptor radionuclide therapy (PRRT) in small intestinal NETs has proven efficacy in the phase 3 neuroendocrine tumours therapy (NETTER 1) trial. PRRT is currently being tested for enteropancreatic NETs versus everolimus in the COMPETE trial, and the potential of SSTR-antagonists in PRRT is now being evaluated in early phase I/II clinical trials. This review provides a synopsis on the pharmacological development of SSAs and their use as antisecretory drugs. Moreover, this review highlights the clinical evidence of SSAs in monotherapy, and in combination with other treatment modalities, as applied to the antiproliferative management of neuroendocrine tumors with special attention to recent high-quality phase III trials.
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Affiliation(s)
- Anna Kathrin Stueven
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Antonin Kayser
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Christoph Wetz
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Nuclear Medicine, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Holger Amthauer
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Nuclear Medicine, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Alexander Wree
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Frank Tacke
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Bertram Wiedenmann
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Christoph Roderburg
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany.
| | - Henning Jann
- Charité, Campus Virchow Klinikum and Charité, Campus Mitte, Department of Hepatology and Gastroenterology, Universitätsmedizin Berlin, 10117 Berlin, Germany.
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Hofland J, Herrera-Martínez AD, Zandee WT, de Herder WW. Management of carcinoid syndrome: a systematic review and meta-analysis. Endocr Relat Cancer 2019; 26:R145-R156. [PMID: 30608900 DOI: 10.1530/erc-18-0495] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 01/03/2019] [Indexed: 12/18/2022]
Abstract
Carcinoid syndrome (CS) is a debilitating disease caused by functional neuroendocrine tumors. Several treatment options are available to alleviate the hormonal symptoms, but their relative efficacy is unknown. Online databases were searched for publications on the treatment of CS symptoms. Independent reviewers assessed relevant publications for study quality and outcome. Meta-analysis of the outcomes of the intervention on CS-related symptoms was stratified by the type of treatment. We found 3682 therapeutic interventions on CS-specific outcomes were collected from 93 studies. Overall, the study qualities were poor with only six randomized controlled clinical trials. The somatostatin analogs octreotide and lanreotide induced symptomatic improvement in 65-72% and biochemical response in 45-46% of patients. An increase in dose or frequency or interclass switch led to a reduction of flushes and/or diarrhea in 72-84% of cases. Retrospective, institutional series showed that liver-directed therapy can improve symptoms in 82% of CS patients with a liver-dominant disease. The serotonin synthesis inhibitor telotristat ethyl reduced bowel movements in 40% of patients with diarrhea refractory to somatostatin analogs. Interferon-alpha controlled CS symptoms in 45-63% of cases. Favorable response has been noted after radionuclide therapy in subgroup analyses of studies not specifically involving CS patients. Chemotherapy and everolimus did not induce a significant response in the CS. We conclude that several treatment lines can be offered to patients suffering from the carcinoid syndrome. Initiation of randomized controlled trials with a primary outcome on carcinoid syndrome symptoms is strongly recommended.
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Affiliation(s)
- Johannes Hofland
- ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Aura D Herrera-Martínez
- ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
- Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain
- Endocrinology and Nutrition Service, Reina Sofia University Hospital, Córdoba, Spain
| | - Wouter T Zandee
- ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Wouter W de Herder
- ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
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Abstract
Carcinoid syndrome (CS) is a debilitating disease caused by functional neuroendocrine tumors. Several treatment options are available to alleviate the hormonal symptoms, but their relative efficacy is unknown. Online databases were searched for publications on the treatment of CS symptoms. Independent reviewers assessed relevant publications for study quality and outcome. Meta-analysis of the outcomes of the intervention on CS-related symptoms was stratified by the type of treatment. We found 3682 therapeutic interventions on CS-specific outcomes were collected from 93 studies. Overall, the study qualities were poor with only six randomized controlled clinical trials. The somatostatin analogs octreotide and lanreotide induced symptomatic improvement in 65–72% and biochemical response in 45–46% of patients. An increase in dose or frequency or interclass switch led to a reduction of flushes and/or diarrhea in 72–84% of cases. Retrospective, institutional series showed that liver-directed therapy can improve symptoms in 82% of CS patients with a liver-dominant disease. The serotonin synthesis inhibitor telotristat ethyl reduced bowel movements in 40% of patients with diarrhea refractory to somatostatin analogs. Interferon-alpha controlled CS symptoms in 45–63% of cases. Favorable response has been noted after radionuclide therapy in subgroup analyses of studies not specifically involving CS patients. Chemotherapy and everolimus did not induce a significant response in the CS. We conclude that several treatment lines can be offered to patients suffering from the carcinoid syndrome. Initiation of randomized controlled trials with a primary outcome on carcinoid syndrome symptoms is strongly recommended.
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Abstract
The concept of neuroendocrine tumors (NETs) began in the 1900s with Oberndorfer's description of carcinoid tumors, followed by specific cytotoxic agents and the identification of somatostatin. NETs diagnosis was confirmed by World Health Organization classification. Histopathology included immunohistochemistry with specific antibodies. Imaging was refined with molecular imaging. Somatostatin is the leading agent for controlling clinical symptoms related to hormone production. Increasing interest in these tumors, previously thought rare, led to increased incidence and prevalence. Between 1960 and 1970, the true NET-concept was established with development of radioimmunoassays for peptides and hormones, and imaging with computerized tomography.
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Affiliation(s)
- Kjell Öberg
- Department of Endocrine Oncology, Uppsala University Hospital, Entrance 40:5, SE-75185, Uppsala, Sweden.
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de Celis Ferrari ACR, Glasberg J, Riechelmann RP. Carcinoid syndrome: update on the pathophysiology and treatment. Clinics (Sao Paulo) 2018; 73:e490s. [PMID: 30133565 PMCID: PMC6096975 DOI: 10.6061/clinics/2018/e490s] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 03/02/2018] [Indexed: 12/15/2022] Open
Abstract
Approximately 30-40% of patients with well-differentiated neuroendocrine tumors present with carcinoid syndrome, which is a paraneoplastic syndrome associated with the secretion of several humoral factors. Carcinoid syndrome significantly and negatively affects patients' quality of life; increases costs compared with the costs of nonfunctioning neuroendocrine tumors; and results in changes in patients' lifestyle, such as diet, work, physical activity and social life. For several decades, patients with neuroendocrine tumors and carcinoid syndrome have been treated with somatostatin analogues as the first-line treatment. While these agents provide significant relief from carcinoid syndrome symptoms, there is inevitable clinical progression, and new therapeutic interventions are needed. More than 40 substances have been identified as being potentially related to carcinoid syndrome; however, their individual contributions in triggering different carcinoid symptoms or complications, such as carcinoid heart disease, remain unclear. These substances include serotonin (5-HT), which appears to be the primary marker associated with the syndrome, as well as histamine, kallikrein, prostaglandins, and tachykinins. Given the complexity involving the origin, diagnosis and management of patients with carcinoid syndrome, we have undertaken a comprehensive review to update information about the pathophysiology, diagnostic tools and treatment sequence of this syndrome, which currently comprises a multidisciplinary approach.
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Affiliation(s)
| | - João Glasberg
- Disciplina de Radiologia e Oncologia, Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Rachel P Riechelmann
- Disciplina de Radiologia e Oncologia, Instituto do Cancer do Estado de Sao Paulo (ICESP), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
- Departamento de Oncologia, AC Camargo Cancer Center Sao Paulo, SP, BR
- *Corresponding author. E-mail:
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Bajetta E, Di Bartolomeo M, Zilembo N, Bochicchio AM. Medical Treatment of Neuroendocrine Tumors. TUMORI JOURNAL 2018; 79:380-8. [PMID: 8171735 DOI: 10.1177/030089169307900602] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background Tumors of the neuroendocrine system are characterized by amine precursor uptake and decarboxylation, and they represent a heterogeneous group of carcinomas including carcinoids, islet cell carcinomas of the pancreas, medullary thyroid carcinomas and Merkel cell carcinomas. Their similar cytochemical and ultrastructural properties sustain the hypothesis of a common embryologic origin within the neural crest. Many of these tumors grow slowly, and reducing tumor burden represents the treatment of choice. However, when surgery is not feasible, medical treatment has to be considered. Therapeutic approaches in metastatic disease often do not consider the different biologic behaviors of these neoplasms. Moreover, efficacy of the treatment is associated with lack of a clear definition of the type of response: objective, symptomatic or biochemical. Methods In this review we have analyzed the different medical approaches used in the treatment of neuroendocrine tumors in an attempt to define their precise role in the different neoplasms. Results In carcinoid tumors, immunotherapy and the somatostatin analogue can be efficaciously used for the control of carcinoid syndrome. For inhibition of tumor growth, chemotherapy should be used only in patients with rapidly progressive disease, and the results are still unsatisfactory. Conclusions Although all these tumors appear to have similar cytochemical properties, the responsiveness of the various neoplasms is very different. In the future, a specific treatment modality and a clear definition of the type of response (objective, symptomatic or biochemical) need to be defined for each type of neuroendocrine tumor.
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Affiliation(s)
- E Bajetta
- Division of Medical Oncology B, Istituto Nazionale per lo Studioe la Cura dei Tumori, Milano, Italy
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19
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Amoroso V, Pavel M, Claps M, Roca E, Ravanelli M, Maroldi R, Oberg K, Berruti A. IFN-α in advanced well-differentiated neuroendocrine tumors: the neglected drug? Future Oncol 2018. [DOI: 10.2217/fon-2017-0667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Vito Amoroso
- Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, Medical Oncology Unit, University of Brescia at ASST Spedali Civili, Brescia 25123, Italy
| | - Marianne Pavel
- Department of Medicine, Division of Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, Erlangen 91012, Germany
| | - Melanie Claps
- Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, Medical Oncology Unit, University of Brescia at ASST Spedali Civili, Brescia 25123, Italy
| | - Elisa Roca
- Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, Medical Oncology Unit, University of Brescia at ASST Spedali Civili, Brescia 25123, Italy
| | - Marco Ravanelli
- Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, Radiology Unit, University of Brescia at ASST Spedali Civili, Brescia 25123, Italy
| | - Roberto Maroldi
- Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, Radiology Unit, University of Brescia at ASST Spedali Civili, Brescia 25123, Italy
| | - Kjell Oberg
- Department of Endocrine Oncology, Uppsala University Hospital, Uppsala S-751 85, Sweden
| | - Alfredo Berruti
- Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, Medical Oncology Unit, University of Brescia at ASST Spedali Civili, Brescia 25123, Italy
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20
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Lamarca A, Nonaka D, Breitwieser W, Ashton G, Barriuso J, McNamara MG, Moghadam S, Rogan J, Mansoor W, Hubner RA, Clark C, Chakrabarty B, Valle JW. PD-L1 expression and presence of TILs in small intestinal neuroendocrine tumours. Oncotarget 2018; 9:14922-14938. [PMID: 29599916 PMCID: PMC5871087 DOI: 10.18632/oncotarget.24464] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 02/03/2018] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The extent of resistance to immune surveillance in patients with well-differentiated (Wd) (grade 1/2) small-intestinal neuroendocrine tumours (Si-NETs) is unknown. METHODS Patients diagnosed with Wd Si-NETs (excluding appendix, which are considered to have a different biology to other midgut NETs) were eligible. Tumoural programmed death (PD)-ligand(L) 1 (PD-L1)/PD-L2/PD-1 and tumour infiltrating lymphocytes (TILs) [presence and phenotype] were analysed in archival tissue by immunohistochemistry (IHC); reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used for confirmation of IHC results. RESULTS Of 109 patients screened, 62 were eligible: 54.8% were male; median age was 63.7 years (95%-CI 59.7-67.2); disease stage II: 4.8%, III: 40.3% and IV: 54.8%; 41.9% were functional. Analysed samples (67.1% from primary tumours, 32.9% from metastases) were of grade 1 (67.1%) or 2 (32.86%) with a median Ki-67 of 2%. From the total of 62 eligible patients, 70 and 63 samples were suitable for IHC and RT-qPCR analysis, respectively. PD-L1 expression within tumour cells and TILs were identified in 12.8% and 24.3% of samples respectively; 30% of samples showed PD-L1 expression within tumour cells and/or TILs. PD-1 was present in TILs in 22.8% of samples. Majority of samples showed significant presence of CD4+ (focal 42.86%; moderate 2.86%) and CD8+ (focal 92.86%; moderate 4.29%) TILs. IHC findings were confirmed with RT-qPCR; which showed higher expression levels of PD-L1 (p-value 0.007) and PD-1 (p-value 0.001) in samples positive for IHC compared to negative-IHC. CONCLUSIONS Thirty-percent of patients express PD-L1 within tumour cells and/or TILs. Identification of presence of TILs was also significant and warrant the investigation of immunotherapy in this setting.
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Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Daisuke Nonaka
- Department of Histopathology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Wolfgang Breitwieser
- Molecular Biology Core Facility, Cancer Research UK Manchester Institute, Manchester, UK
| | - Garry Ashton
- Manchester Cancer Research Centre (MCRC) BioBank, University of Manchester, Manchester, UK
| | - Jorge Barriuso
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Mairéad G. McNamara
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Sharzad Moghadam
- Manchester Cancer Research Centre (MCRC) BioBank, University of Manchester, Manchester, UK
| | - Jane Rogan
- Manchester Cancer Research Centre (MCRC) BioBank, University of Manchester, Manchester, UK
| | - Wasat Mansoor
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Richard A. Hubner
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Christopher Clark
- Molecular Biology Core Facility, Cancer Research UK Manchester Institute, Manchester, UK
| | - Bipasha Chakrabarty
- Department of Histopathology, The Christie NHS Foundation Trust, Manchester, UK
| | - Juan W. Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
- Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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Zandee WT, de Herder WW. The Evolution of Neuroendocrine Tumor Treatment Reflected by ENETS Guidelines. Neuroendocrinology 2018; 106:357-365. [PMID: 29320780 PMCID: PMC6067804 DOI: 10.1159/000486096] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 12/05/2017] [Indexed: 12/11/2022]
Abstract
In 2016, the third version of guidelines for the diagnosis and treatment of neuroendocrine tumors (NETs) has been published by the European Neuroendocrine Tumor Society (ENETS). These guidelines reflect the progress in treatment of NETs, and by comparing the newest guidelines with the first guidelines of 2001, this progress can be clearly recognized. Diagnostic accuracy has been increased by the introduction of PET-CT with Ga-labelled somatostatin analogs, and multiple new treatments and treatment schedules have been developed, like peptide receptor radiotherapy with radiolabeled somatostatin analogs, or targeted therapies. Evidence and indications for these therapies are discussed in the ENETS guidelines. In this review, we aim to show the progress in NET diagnosis and treatment on the basis of the advances in the guidelines, but also to discuss the unsolved questions and unmet needs which still remain.
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Affiliation(s)
- Wouter T. Zandee
- *Wouter T. Zandee, MD, Department of Internal Medicine, Endocrinology Sector, Erasmus Medical Center, ‘s-Gravendijkwal 230, NL–3015 CE Rotterdam (The Netherlands), E-Mail
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22
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Chauhan A, Horn M, Magee G, Hodges K, Evers M, Arnold S, Anthony L. Immune checkpoint inhibitors in neuroendocrine tumors: A single institution experience with review of literature. Oncotarget 2017; 9:8801-8809. [PMID: 29507655 PMCID: PMC5823629 DOI: 10.18632/oncotarget.23753] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Accepted: 12/18/2017] [Indexed: 12/17/2022] Open
Abstract
This unique case series and review of literature suggests that immune checkpoint inhibitors may have clinical activity in neuroendocrine tumors. Objective Summarize advances of immuno-oncology in neuroendocrine tumors with the help of a case series. Design Case series and review of literature. Intervention or Exposure The patients were treated with immune checkpoint inhibitors (pembrolizumab or nivolumab). Main Outcomes and Measuress Life expectancy, quality of life, disease progression. Results Maximum durable response of 16 months in one of the patients so far. All patients showed improvement in quality of life before disease progression. Two out of four are still on therapy. None of the patients experienced immune checkpoint inhibitor associated side-effects. All patients had failed standard of care therapy prior to the initiation of immune checkpoint inhibitors and were on the verge of hospice. Conclusions Immune checkpoint inhibitors have revolutionized cancer management and the last 5 years have seen a rapid expansion in the indications for this class of drug. Neuroendocrine tumors, unfortunately, have been slow to catch on to the immuno-oncology, partly due to difficulties in establishing relevant preclinical neuroendocrine tumors models for immune-oncology studies. In this manuscript, we review the current status of immunotherapy in neuroendocrine tumors.
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Affiliation(s)
- Aman Chauhan
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Millicent Horn
- School of Medicine, University of Kentucky, Lexington, KY, USA
| | - Gray Magee
- School of Medicine, University of Kentucky, Lexington, KY, USA
| | - Kurt Hodges
- Department of Pathology, University of Kentucky, Lexington, KY, USA
| | - Mark Evers
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Susanne Arnold
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Lowell Anthony
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
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Oronsky B, Ma PC, Morgensztern D, Carter CA. Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas. Neoplasia 2017; 19:991-1002. [PMID: 29091800 PMCID: PMC5678742 DOI: 10.1016/j.neo.2017.09.002] [Citation(s) in RCA: 461] [Impact Index Per Article: 57.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 09/06/2017] [Accepted: 09/07/2017] [Indexed: 02/07/2023]
Abstract
This review covers the diverse topic of neuroendocrine neoplasms (NENs), a relatively rare and heterogeneous tumor type, comprising ~2% of all malignancies, with a prevalence of <200,000 in the United States, which makes it an orphan disease (Basu et al., 2010).1 For functional purposes, NENs are divided into two groups on the basis of clinical behavior, histology, and proliferation rate: well differentiated (low grade to intermediate grade) neuroendocrine tumors and poorly differentiated (high grade) neuroendocrine carcinoma (Bosman et al., 2010)2; this histological categorization/dichotomization is highly clinically relevant with respect to impact on treatment and prognosis even though it is not absolute since a subset of tumors with a low-grade appearance behaves similarly to high-grade lesions. Given the relative dearth of evidenced-based literature about this orphan disease as a whole (Modlin et al., 2008),3 since the focus of most articles is on particular anatomic subtypes of NENs (i.e., gastroenteropancreatic or pulmonary), the purpose of this review is to summarize the presentation, pathophysiology, staging, current standard of care treatments, and active areas of current research.
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Affiliation(s)
- Bryan Oronsky
- EpicentRx Inc, 4445 Eastgate Mall, Suite 200, San Diego, CA 92121, USA.
| | - Patrick C Ma
- West Virginia University, Mary Babb Randolph Cancer Center, 8901 Wisconsin Ave., PO Box 9162, Morgantown, WV 26506, USA
| | - Daniel Morgensztern
- Washington University School of Medicine, Division of Oncology, 660 S. Euclid, Box 8056, St. Louis, MO 63110, USA
| | - Corey A Carter
- Walter Reed National Military Medical Center, 8901 Wisconsin Ave., Bethesda, MD 20889, USA
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Treatment Strategies for Metastatic Neuroendocrine Tumors of the Gastrointestinal Tract. Curr Treat Options Oncol 2017; 18:14. [PMID: 28286921 DOI: 10.1007/s11864-017-0461-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OPINION STATEMENT The therapeutic landscape of gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) has evolved significantly in recent years. Current and emerging treatment options include somatostatin analogs, radiolabeled somatostatin analogs, the mTOR inhibitor everolimus, and the tyrosine kinase inhibitor sunitinib. Although high-quality data from phase III trials are lacking, cytotoxic agents are commonly used for the treatment of poorly differentiated neuroendocrine carcinomas and well-differentiated NETs originating in the pancreas. Hepatic-directed therapies are recommended for patients with slow-growing, liver-predominant disease but have never been compared to systemic agents. Telotristat ethyl, a novel serotonin synthesis inhibitor, has recently demonstrated efficacy in palliating diarrhea in patients with poorly controlled carcinoid syndrome. In the absence of definite predictive biomarkers, therapeutic decisions in most cases rely on clinical and pathological criteria. However, navigating the current therapeutic algorithm may be challenging, and future trials need to address several important questions: what is the best sequence of treatment? Is there a role for combination therapies in GEP-NETs? Are neoadjuvant, adjuvant, or maintenance strategies safe and effective? Do all NET patients require active treatment? What new molecular targets can be clinically exploited? A tight integration between basic and clinical research is needed to further advance the field of NETs.
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Yalcin S, Bayram F, Erdamar S, Kucuk O, Oruc N, Coker A. Gastroenteropancreatic neuroendocrine tumors: recommendations of Turkish multidisciplinary neuroendocrine tumor study group on diagnosis, treatment and follow-up. Arch Med Sci 2017; 13:271-282. [PMID: 28261279 PMCID: PMC5332464 DOI: 10.5114/aoms.2017.65449] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Accepted: 05/20/2015] [Indexed: 02/06/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEPNETs) are a relatively rare, heterogeneous group of diseases in which important advances have been observed in the diagnosis and treatment as well as in our understanding of the biology and genetics of the disease in recent years. Given the insufficient scientific data available on evidence-based management of GEPNETs and the differences in circumstances in individual countries, a multidisciplinary study group was established to provide guidelines for the management of GEPNETS. This study group consisted of a medical oncologist, endocrinologist, surgeon, pathologist, gastroenterologist, and a nuclear medicine specialist, who aimed to prepare a practical guide in the light of existing scientific data and international guidelines, to be used in common clinical practice.
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Affiliation(s)
- Suayib Yalcin
- Department of Medical Oncology, Institute of Cancer, Hacettepe University, Ankara, Turkey
| | - Fahri Bayram
- Department of Endocrinology, Erciyes University, Kayseri, Turkey
| | - Sibel Erdamar
- Department of Pathology, Cerrahpasa Medical School, Istanbul, Turkey
| | - Ozlem Kucuk
- Department of Nuclear Medicine, Ankara University, Ankara, Turkey
| | - Nevin Oruc
- Department of Gastroenterology, Ege University, Izmir, Turkey
| | - Ahmet Coker
- Department of Gastroenterology, Ege University, Izmir, Turkey
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Riechelmann RP, Pereira AA, Rego JFM, Costa FP. Refractory carcinoid syndrome: a review of treatment options. Ther Adv Med Oncol 2017; 9:127-137. [PMID: 28203303 PMCID: PMC5298401 DOI: 10.1177/1758834016675803] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Carcinoid syndrome (CSy) is a constellation of symptoms that may commonly present in patients with well differentiated neuroendocrine tumors (NETs), with somatostatin analogs (SSAs) being the first-line option for symptom management. However, symptomatic progression eventually occurs and in this scenario of a refractory CSy; several treatment options have been studied such as dose escalation of SSA, interferon and liver-directed therapies. Nevertheless, recent phase III trials have contributed to the understanding and management of this condition. We performed a comprehensive review of interventional studies examining refractory CSy to provide the evidence for current treatment options and propose a treatment sequence.
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Affiliation(s)
- Rachel P. Riechelmann
- Instituto do Câncer do Estado de São Paulo,Universidade de São Paulo, Ave. Dr Arnaldo, 251, São Paulo, SP – Brazil
| | - Allan A. Pereira
- Department of Radiology and Oncology, Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil
| | - Juliana F. M. Rego
- Hospital Universitário Onofre Lopes, Universidade Federal do Rio Grande do Norte, Natal, Brazil
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Lee MS, O'Neil BH. Summary of emerging personalized medicine in neuroendocrine tumors: are we on track? J Gastrointest Oncol 2016; 7:804-818. [PMID: 27747094 DOI: 10.21037/jgo.2016.08.05] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Neuroendocrine tumors (NETs) comprise a heterogeneous group of malignancies, with differences in prognosis and effective therapies. Traditionally, NETs have been characterized by tumor grade, site of primary tumor, functional status, and presence of underlying familial syndrome. However, increased feasibility and utilization of next-generation sequencing and other methodologies have revealed new genomic and epigenetic aberrations. In the last decade, treatment options available for metastatic well-differentiated gastroenteropancreatic (GEP) NETs have expanded, with approval of antiangiogenic and mTOR-directed targeted therapies, and our armamentarium of active therapies is likely to further increase. Cytotoxic therapies also are an important option for pancreatic NETs, and MGMT promoter methylation and protein expression may be an important biomarker for efficacy of alkylating agents. Peptide receptor radioligand therapy is an emerging treatment that uses functional imaging to personalize dosimetry to the tumor and avoid nephrotoxicity. Nevertheless, there is a critical need for further biomarkers, particularly multianalyte biomarkers, to aid in prognostication and predict efficacy of therapies.
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Affiliation(s)
- Michael S Lee
- University of North Carolina at Chapel Hill, North Carolina, USA
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Ardill JE, Johnston BT, McCance DR, Eatock M. Neurokinin A monitoring of response to interferon alpha in a patient with an advanced small bowel neuroendocrine tumour uncontrolled by somatostatin analogue therapy. Ann Clin Biochem 2016; 54:297-301. [PMID: 27638929 DOI: 10.1177/0004563216672492] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
A 52-year-old lady presented with a history of occasional, severe abdominal cramps, postprandial diarrhoea and weight loss. After routine gastrointestinal investigations, she was diagnosed with irritable bowel syndrome. Over six months, she developed occasional facial flushing prompting assessment of neuroendocrine tumour markers. Urinary 5HIAA, 5HT, chromogranin A and neurokinin A were significantly elevated. Scans showed extensive hepatic metastases but did not show the location of a primary tumour. Somatostatin analogue therapy was commenced but despite increasing doses, symptoms increased and biomarkers rose dramatically. Interferon alpha was introduced concomitant with somatostatin analogue therapy. Biomarkers were monitored regularly. Within six months, symptoms abated and biomarkers reduced, continuing to fall over the next year, close to reference range. To manage side-effects of interferon alpha, dose was reduced from time to time. During these short periods, neurokinin A showed significant transient increases (75-150 ng/L) and carcinoid symptoms returned. For more than seven years, and with the co-operation of the patient, a balance was achieved between interferon alpha side-effects and disease control. Scans showed tumour load to be stable. The patient survived for 10 years post diagnosis. She chose to discontinue interferon alpha and received peptide receptor radiation therapy in her final year. Throughout, neurokinin A remained the most sensitive monitor of her disease progression.
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Affiliation(s)
- Joy Es Ardill
- 1 NET Group, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK
| | - Brian T Johnston
- 1 NET Group, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK
| | - David R McCance
- 1 NET Group, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK
| | - Martin Eatock
- 2 NET Group, Cancer Centre, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, UK
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29
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Mulvey CK, Bergsland EK. Systemic Therapies for Advanced Gastrointestinal Carcinoid Tumors. Hematol Oncol Clin North Am 2016; 30:63-82. [PMID: 26614369 DOI: 10.1016/j.hoc.2015.09.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Well-differentiated gastrointestinal neuroendocrine tumors (GINETs) tend to be slow growing, but treatment of advanced disease remains a challenge. Somatostatin analogues (SSAs) are considered standard therapy for carcinoid syndrome. SSAs delay tumor progression in advanced well-differentiated gastroenteropancreatic NETs. Cytotoxic chemotherapy and interferon play a limited role in the treatment of nonpancreatic GINETs. There is no standard approach to treatment of patients with disease progression. Identification of systemic agents with antitumor activity in advanced disease remains an unmet medical need. Enrollment to clinical trials is encouraged; potential therapeutic targets include the vascular endothelial growth factor and mammalian target of rapamycin signaling pathways.
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Affiliation(s)
- Claire K Mulvey
- Department of Medicine, University of California, San Francisco, 505 Parnassus Avenue, Box 0119, San Francisco, CA 94143, USA
| | - Emily K Bergsland
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, 1600 Divisadero Street, A727, San Francisco, CA 94115, USA.
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30
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Andersson T, Eriksson B, Hemmingsson A, Jung B, Lindh E, Thuomas KÅ, Öberg K. Effect of Interferon on T1 Relaxation Times of Liver Metastases from Endocrine Gastrointestinal Tumours. Acta Radiol 2016. [DOI: 10.1177/028418518802900105] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Eight patients with liver metastases from endocrine gastrointestinal tumours were examined with magnetic resonance imaging of the liver before and during treatment with interferon. T1, T2 and tumour size were measured and compared with tumour marker levels and symptomatic improvement or deterioration. Before therapy all tumours showed a long T1 and T2, in comparison to normal liver and fat, and during therapy they all showed a decrease in T1. As no change in liver T1 and fat T1 occurred, the decreased tumour T1 is considered to be a therapy effect. This cannot be fully explained but is possibly due to a reduction in tumour growth rate during interferon treatment. There was no certain correlation between tumour T1 and tumour marker levels or symptomatic changes.
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Andersson T, Eriksson B, Hemmingsson A, Lindgren PG, Öberg K. Angiography, Computed Tomography, Magnetic Resonance Imaging and Ultrasonography in Detection of Liver Metastases from Endocrine Gastrointestinal Tumours. Acta Radiol 2016. [DOI: 10.1177/028418518702800507] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Twenty-five patients with endocrine tumours (13 with endocrine pancreatic tumours and 12 with carcinoids) were examined with angiography, computed tomography, magnetic resonance imaging and ultrasonography. Seventeen patients had liver metastases and were followed between 3 and 66 months with serial examinations during treatment with chemotherapeutic agents and interferon. The efficiency of the various techniques to detect metastases was investigated. Analysis of changes in tumour size during treatment was made to see if treatment effects could be monitored with radiologic examinations. Ultrasonography was the best non-invasive method for detection of metastases and is recommended as standard method for imaging in this group of patients. Angiography was even better showing extremely small metastases, less than 5 mm, and is recommended in selected cases. With one exception, no significant change in tumour size was noted in spite of clear laboratory and clinical signs of therapy effect indicating that tumour size determination is not useful for therapy monitoring in this type of disease.
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Strosberg JR. Systemic treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETS): current approaches and future options. Endocr Pract 2016; 20:167-75. [PMID: 24014009 DOI: 10.4158/ep13262.ra] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To describe recent advances in the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS A review of the published English language literature on GEP-NET therapy with a focus on practice-changing clinical trials. RESULTS Somatostatin analog (SSA) treatment remains a cornerstone of GEP-NET therapy, primarily for patients with hormonally functional tumors and midgut carcinoids. The biologic agents everolimus and sunitinib have similar tumor-stabilizing effects in pancreatic NETs and are both approved to treat progressive low-intermediate-grade tumors. Their role in nonpancreatic NETs remains controversial. Cytotoxic chemotherapy is effective against pancreatic NETs, but modern prospective data is lacking. Radiolabeled SSAs will likely become more widely available once phase III randomized studies are completed. CONCLUSIONS New treatment options for GEP-NETs have become available and highlight the necessity of developing predictive biomarkers that will allow for appropriate and individualized therapy selection.
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Mehrvarz Sarshekeh A, Halperin DM, Dasari A. Update on management of midgut neuroendocrine tumors. INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2016; 3:175-189. [PMID: 27347369 PMCID: PMC4915384 DOI: 10.2217/ije-2015-0004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Midgut neuroendocrine tumors are typically indolent but can be fatal when advanced. They can also cause significant morbidity due to the characteristic carcinoid syndrome. Somatostatin analogs continue to be the mainstay of treatment given their antiproliferative properties, as well as inhibitory effects on hormones that cause carcinoid syndrome. There have been several recent advances in the systemic therapy of these tumors including consolidation of somatostatin analogs as the cornerstone of therapy, completion of pivotal trials with mTOR inhibitors, and the establishment of novel approaches including peptide receptor radionuclide therapy and oral inhibitors of peripheral tryptophan hydroxylase in tumor and symptom control, respectively. In this review article, the recent advances are summarized and an updated approach to management is proposed.
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Affiliation(s)
- Amir Mehrvarz Sarshekeh
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
| | - Daniel M Halperin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
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Salman T, Kazaz SN, Varol U, Oflazoglu U, Unek IT, Kucukzeybek Y, Alacacioglu A, Atag E, Semiz HS, Cengiz H, Oztop I, Tarhan MO. Prognostic Value of the Pretreatment Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio for Patients with Neuroendocrine Tumors: An Izmir Oncology Group Study. Chemotherapy 2016; 61:281-6. [PMID: 27070366 DOI: 10.1159/000445045] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 02/23/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Several studies evaluating the prognostic factors of gastrointestinal and pancreatic neuroendocrine tumors (GEP-NETs) have been published. The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) have been accepted as prognostic factors for cancer patients. MATERIALS AND METHODS This study included 132 patients diagnosed with GEP-NETs. Peripheral blood samples were collected before the pretreatment period. RESULTS NLR and PLR were increased as the grade increased in NETs. The embryonic origin analysis revealed higher NLR and PLR rates in NETs of foregut origin. NLR and PLR were also higher in pancreatic NET patients compared to the gastroenteric NET patients. Analysis of NETs by TNM indicated that an advanced stage was accompanied by significantly higher NLR and PLR. We found a strong negative correlation between progression-free survival and NLR and PLR. CONCLUSION The study verified that NLR and PLR are simple laboratory findings that can be used to identify NETs with a worse outcome.
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de Herder WW, Rehfeld JF, Kidd M, Modlin IM. A short history of neuroendocrine tumours and their peptide hormones. Best Pract Res Clin Endocrinol Metab 2016; 30:3-17. [PMID: 26971840 DOI: 10.1016/j.beem.2015.10.004] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The discovery of neuroendocrine tumours of the gastrointestinal tract and pancreas started in 1870, when Rudolf Heidenhain discovered the neuroendocrine cells, which can lead to the development of these tumours. Siegfried Oberndorfer was the first to introduce the term carcinoid in 1907. The pancreatic islet cells were first described in 1869 by Paul Langerhans. In 1924, Seale Harris was the first to describe endogenous hyperinsulinism/insulinoma. In 1942 William Becker and colleagues were the first to describe the glucagonoma syndrome. The first description of gastrinoma by Robert Zollinger and Edwin Ellison dates from 1955. The first description of the VIPoma syndrome by John Verner and Ashton Morrison dates from 1958. In 1977, the groups of Lars-Inge Larsson and Jens Rehfeld, and of Om Ganda reported the first cases of somatostatinoma. But only in 2013, Jens Rehfeld and colleagues described the CCK-oma syndrome. The most recently updated WHO classification for gastrointestinal neuroendocrine tumours dates from 2010.
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Affiliation(s)
- Wouter W de Herder
- Department of Internal Medicine, Section of Endocrinology, Erasmus MC, Rotterdam, The Netherlands.
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, The National University Hospital (Rigshospitalet), Copenhagen, Denmark
| | - Mark Kidd
- Wren Laboratories LLC, Branford, CT, USA
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36
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Abstract
Somatostatin analogues (SSA) are well established antisecretory drugs that have been used as first line treatment for symptomatic control in hormonally active neuroendocrine tumours (NET) for three decades. Both available depot formulations of SSA, long-acting repeatable (LAR) octreotide and lanreotide autogel, seem similarly effective and well tolerated, although comparative trials in NET have not been performed. The importance of SSA as antiproliferative treatment has been increasingly recognized during recent years. Two placebo-controlled trials demonstrated significant prolongation of progression free survival under SSA treatment. However, objective response as assessed by imaging is rare. Interferon-α (IFNα) also has antisecretory and antiproliferative efficacy in NET. Due to the less favourable toxicity profile it mainly has a role as add-on option in the refractory setting, especially in carcinoid syndrome patients. Further studies are needed to evaluate the antiproliferative efficacy of the multiligand SSA pasireotide and the role of pegylated IFNα.
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Affiliation(s)
- Anja Rinke
- Department of Gastroenterology, Philipps University Marburg, Germany.
| | - Sebastian Krug
- Department of Internal Medicine I, Martin Luther University Halle, Germany
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37
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Abstract
PURPOSE OF REVIEW Pancreatic neuroendocrine tumors (pNETs) are a rare and heterogeneous group of neoplasia. Presentation of these tumors can vary widely. Current treatment modalities range from potentially curative surgical interventions in localized disease to the use of varied hormonal analogues, cytotoxic agents and targeted therapy for the management of locally advanced and metastatic disease. With such a wide variety of therapeutic modalities, clinicians are faced with the task of building an effective and comprehensive treatment strategy for their patients. RECENT FINDINGS Targeted therapy for pNET is limited to sunitinib and everolimus. There have been a number of important studies assessing the efficacy of other targeted agents, in addition to the conjugation of these agents in the management of advanced pNET. This review will stand to highlight currently available targeted therapies for the treatment of advanced pNET. SUMMARY The use of targeted agents in the management of advanced pNET has significant potential to change the current standard of care. In addition to the use of long-acting somatostatin analogues, targeting the mammalian target of rapamycin and vascular endothelial growth factor pathways can be well tolerated and may lead to long periods of disease control in a wide variety of neuroendocrine tumors involving the pancreas.
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Öberg K. Neuroendocrine gastro-enteropancreatic tumors - from eminence based to evidence-based medicine - A Scandinavian view. Scand J Gastroenterol 2015; 50:727-39. [PMID: 25855088 DOI: 10.3109/00365521.2015.1033001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Neuroendocrine tumors (NETs) comprise a heterogenous group of neoplasms with variable clinical expression and progression. The primary tumors most frequently occur in the lungs, intestine and the pancreas. The NET incidence is approximately 6.1/100,000 per year with a prevalence higher than 35/100,000 per year. A NET may be functioning with symptoms related to hormone overproduction or non-functioning, not presenting any hormone-related symptoms. From the early 1980s and onwards, Uppsala University Hospital has contributed significantly to diagnosis, just to mention immunohistochemistry, radio-immunoassays for hormones and peptides and molecular imaging. On the therapeutic side, treatments with cytotoxics as well as biologicals such as, somatostatin analogs and interferons have been evaluated. We have furthermore been involved in important phase III trials for registration of so called, new targeted agents such as, RADIANT-3 and RADIANT-2. Our group were also the first to localize the gene for MEN I on chromosome 11 locus q13. Most recent developments have been the establishments of new biomarkers such as, olfactory receptor E51E1 as well as micro-RNAs in carcinoid tumors of the intestine and lung. A new oncolytic virus, Ad-Vince, for treatment of most NETs has been developed and is ready for the clinic. Furthermore, we have been involved in establishing Nordic and international collaborations. Today, NETs is an area with rapid development and recognized by international organizations at conferences, with large attendance. The Nordic countries continue to be significant contributors to the field.
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Affiliation(s)
- Kjell Öberg
- Department of Endocrine Oncology, Uppsala University Hospital , Entrance 40, 5th floor, SE-751 85 Uppsala , Sweden
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39
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Abstract
This paper summarizes the current understanding of the biology of somatostatin receptor (sst), role of immunotherapy in neuroendocrine tumor (NET), new agents for PPRT, and methods to assess response and clinical benefit in NET. One of the most interesting aspects of sst biology is the recent discovery of truncated variants of the sst5 receptor subtype with unique tissue distribution and response to somatostatin (SST). These truncated receptors are associated with bad patient prognosis, decreased response to SST analogs, and may be new targets for diagnoses and treatment. IFN remains a cost-effective agent, particularly in classic mid gut carcinoids, and there is interest to continue examining immunotherapy's in this disease. PRRT remains a key strategy for treatment and imaging. In addition to the classic agents, there are a series of new agents targeting other receptors such as the incretin receptors (GLP-1R; GIPR) and other G-protein coupled receptors with great potential. With regards to therapy monitoring, the most commonly used criteria are Response Criteria Evaluation in Solid Tumors (RECIST). However, for different reasons, these criteria are not very useful in NET. Incorporation of other criteria such as Choi as well as functional imaging assessment with PET would be of great interest in this area.
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40
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Walenkamp A, Crespo G, Fierro Maya F, Fossmark R, Igaz P, Rinke A, Tamagno G, Vitale G, Öberg K, Meyer T. Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment. Endocr Relat Cancer 2014; 21:R445-60. [PMID: 25296914 DOI: 10.1530/erc-14-0106] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In the past few years, there have been advances in the treatment of neuroendocrine tumours (NETs) and improvements in our understanding of NET biology. However, the benefits to patients have been relatively modest and much remains yet to be done. The 'Hallmarks of Cancer', as defined by Hanahan and Weinberg, provide a conceptual framework for understanding the aberrations that underlie tumourigenesis and to help identify potential targets for therapy. In this study, our objective is to review the major molecular characteristics of NETs, based on the recently modified 'Hallmarks of Cancer', and highlight areas that require further research.
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Affiliation(s)
- Annemiek Walenkamp
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Guillermo Crespo
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Felipe Fierro Maya
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Reidar Fossmark
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Peter Igaz
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Anja Rinke
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Gianluca Tamagno
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Giovanni Vitale
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Au
| | - Kjell Öberg
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
| | - Tim Meyer
- Department of Medical OncologyUniversity Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The NetherlandsDepartment of Medical OncologyHospital Universitario de Burgos, Avenida Islas Baleares 3, 09006 Burgos, SpainDepartment of Endocrine OncologyNational Cancer Institute, Bogotá, ColombiaDepartment of Cancer Research and Molecular MedicineNorwegian University of Science and Technology, 7491 Trondheim, Norway2nd Department of MedicineSemmelweis University, 46, Szentkiralyi Street, H-1088 Budapest, HungaryDepartment of GastroenterologyUniversity Hospital Marburg, Baldinger Strasse, Marburg D-35043, GermanyDepartment of General Internal MedicineSt Columcille's Hospital, Loughlinstown - Co., Dublin, IrelandDepartment of Clinical Sciences and Community Health (DISCCO)University of Milan, Milan, ItalyLaboratory of Endocrine and Metabolic ResearchIstituto Auxologico Italiano IRCCS, Via Zucchi 18, Cusano Milanino (MI) 20095, ItalyDepartment of Endocrine OncologyUniversity Hospital, Uppsala, SwedenUCL Cancer InstituteUCL, Huntley Street, London WC1E 6BT, UK
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Jacob J, Chargari C, Helissey C, Ferrand FR, Ceccaldi B, Le Moulec S, Bauduceau O, Fayolle M, Védrine L. [Neuroendocrine carcinoma of the digestive tract: a literature review]. Rev Med Interne 2013; 34:700-5. [PMID: 23871177 DOI: 10.1016/j.revmed.2013.02.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Revised: 06/12/2012] [Accepted: 02/08/2013] [Indexed: 01/10/2023]
Abstract
Neuroendocrine carcinoma is a rare and agressive malignant tumor, mainly developing at the expense of the respiratory and of the digestive tract. Among the digestive tract, appendix, small bowel, and pancreas are the preferential sites of involvement, other locations have been more rarely reported. Neuroendocrine digestive tumors may present with various symptoms in relationship with their localization and a complex pathophysiology. Diagnosis is often made at an advanced stage, explaining partly the bad prognosis of these tumors. The optimal management of digestive neuroendocrine tumors is rendered difficult by their rarity and by a low number of randomized trials. We review the literature regarding epidemiologic and prognostic features of these rare tumors, their diagnostic and therapeutic care. Potential complications are also discussed.
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Affiliation(s)
- J Jacob
- Service d'oncologie-radiothérapie, hôpital d'instruction des armées du Val-de-Grâce, 74, boulevard de Port-Royal, 75005 Paris, France.
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Abstract
The field of epigenetics has evolved rapidly over recent years providing insight into the tumorigenesis of many solid and haematological malignancies. Determination of epigenetic modifications in neuroendocrine tumour (NET) development is imperative if we are to improve our understanding of the biology of this heterogenous group of tumours. Epigenetic marks such as DNA methylation at RASSF1A are frequent findings in NETs of all origins and may be associated with worse prognosis. MicroRNA signatures and histone modifications have been identified which can differentiate subtypes of NET and distinguish NET from adenocarcinoma in cases of diagnostic uncertainty. Historically, candidate gene-driven approaches have yielded limited insight into the epigenetics of NET. Recent progress has been facilitated by development of high-throughput tools including second-generation sequencing and arrays for analysis of the 'epigenome' of tumour and normal tissue, permitting unbiased approaches such as exome sequencing that identified mutations of chromatin-remodelling genes ATRX/DAXX in 44% of pancreatic NETs. Epigenetic changes are reversible and therefore represent an attractive therapeutic target; to date, clinical outcomes of epigenetic therapies in solid tumours have been disappointing; however, in vitro studies on NETs are promising and further clinical trials are required to determine utility of this class of novel agents. In this review, we perform a comprehensive evaluation of epigenetic changes found in NETs to date, including rare NETs such as phaeochromocytoma and adrenocortical tumours. We suggest priorities for future research and discuss potential clinical applications and novel therapies.
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Affiliation(s)
- A Karpathakis
- University College London Cancer Institute, 72 Huntley Street, London WC1E 6BT, UK
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43
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Abstract
Neuroendocrine tumors (NETs) occur throughout the body, and share similar histologic characteristics. However, it has become increasingly evident that pancreatic NETs tend to respond differently to therapeutic agents than do other NET subtypes. In most cases, systemic therapy has been more effective in NETs of pancreatic origin than in NETs arising from other locations. Traditional systemic treatment options for pancreatic NETs include somatostatin analogs or cytotoxic chemotherapy. Recently, the biologically targeted agents everolimus and sunitinib were approved for use in patients with metastatic disease. Novel agents, as well as novel drug combinations, are currently under investigation.
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Affiliation(s)
- Matthew H Kulke
- Program in Neuroendocrine and Carcinoid Tumors, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.
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44
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Systemic treatment in unresectable metastatic well-differentiated carcinoid tumors: consensus results from a modified delphi process. Pancreas 2013; 42:397-404. [PMID: 23211372 DOI: 10.1097/mpa.0b013e31826d3a17] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVES This study aimed to develop expert consensus for the use of systemic treatments for unresectable metastatic well-differentiated (grade 1-2) carcinoid tumors using the RAND/UCLA modified Delphi process. METHODS After a comprehensive literature review, 404 patient scenarios addressing the use of systemic treatments for carcinoid tumors were constructed. A multidisciplinary panel of 10 physicians assessed the scenarios as appropriate, inappropriate, or uncertain (on a 1-9 scale) or as an area of disagreement before and after an extended discussion of the evidence. RESULTS Experts were medical and surgical oncologists, interventional radiologists, and gastroenterologists. Among rated scenarios, disagreement decreased from 14% before the meeting to 4% after. Consensus statements about midgut carcinoids included the following: (1) Somatostatin analogs are appropriate as first-line therapy for all patients; (2) In patients with uncontrolled secretory symptoms, it is appropriate to increase the dose/frequency of octreotide long-acting repeatable up to 60 mg every 4 weeks or up to 40 mg every 3 weeks as second-line therapy for refractory carcinoid syndrome. Other options may also be appropriate. Consensus was similar for non-midgut carcinoids. CONCLUSIONS The Delphi process provided a structured methodological approach to assist clinician experts in reaching consensus on the appropriateness of specific medical therapies for the treatment of advanced carcinoid tumors.
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45
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Strosberg J. Neuroendocrine tumours of the small intestine. Best Pract Res Clin Gastroenterol 2012; 26:755-73. [PMID: 23582917 DOI: 10.1016/j.bpg.2012.12.002] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 12/27/2012] [Indexed: 01/31/2023]
Abstract
The prevalence of intestinal neuroendocrine tumours, also known as carcinoid tumours, has increased significantly over the past three decades. Tumours of the distal small intestine (midgut) are often indolent, but are characterized by a high potential to metastasize to the small-bowel mesentery and liver. Patients with distant metastases are prone to development of the carcinoid syndrome, a constellation of symptoms which includes flushing, diarrhoea, and valvular heart disease. The carcinoid syndrome is caused by secretion of serotonin and other vasoactive substances into the systemic circulation. Treatment options for metastatic intestinal NETs have expanded in recent years. Of particular importance has been the development of somatostatin-analogue therapies. Somatostatin analogues were originally introduced for palliation of the carcinoid syndrome; however recent clinical trials have demonstrated that they can exert an inhibitory effect on tumour growth. Other novel agents targeting the VEGF and mTOR pathways have recently been evaluated in phase III trials, however their role in the management of small-intestinal NETs remains controversial. This article examines the biological characteristics of small intestinal NETs, summarizes current guidelines on classification, staging and grading, and reviews developments in locoregional and systemic therapy.
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Affiliation(s)
- Jonathan Strosberg
- H. Lee Moffitt Cancer Center and Research Institute, Dept. of GI Oncology, 12902 Magnolia Dr., Tampa, FL 33612, USA.
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46
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Karpathakis A, Caplin M, Thirlwell C. Hitting the target: where do molecularly targeted therapies fit in the treatment scheduling of neuroendocrine tumours? Endocr Relat Cancer 2012; 19:R73-92. [PMID: 22474226 DOI: 10.1530/erc-12-0050] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Neuroendocrine tumours (NETs) are a rare and heterogeneous group of tumours whose incidence is increasing and their prevalence is now greater than that of any other upper gastrointestinal tumour. Diagnosis can be challenging, and up to 25% of patients present with metastatic disease. Following the recent FDA approval of two new molecularly targeted therapies for the treatment of advanced pancreatic NETs (pNETs), the first in 25 years, we review all systemic therapies and suggest where these newer targeted therapies fit in the treatment schedule for these challenging tumours. Clinical trial data relating to the routine use of sunitinib and everolimus in low-intermediate-grade pNETs are summarised alongside newer molecularly targeted agents undergoing clinical assessment in NETs. We particularly focus on the challenge of optimal scheduling of molecularly targeted treatments around existing systemic and localised treatment such as chemotherapy or radiotargeted therapy. We also discuss application of current evidence to subgroups of patients who have not so far been directly addressed such as those with poorer performance status or patients receiving radical surgery who may benefit from adjuvant treatment.
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Affiliation(s)
- Anna Karpathakis
- University College London Cancer Institute, Paul O'Gorman Building, Huntley Street, London WC1E 6BT, UK
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47
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Ganetsky A, Bhatt V. Gastroenteropancreatic neuroendocrine tumors: update on therapeutics. Ann Pharmacother 2012; 46:851-62. [PMID: 22589450 DOI: 10.1345/aph.1q729] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE To review the available literature addressing the treatment of pancreatic neuroendocrine tumors (PNETs) and carcinoid tumors. DATA SOURCES Relevant literature was identified by a PubMed search (January 1977-December 2011) of English-language literature using the terms gastroenteropancreatic neuroendocrine tumor, pancreatic neuroendocrine, carcinoid, and pancreatic islet cell tumor. STUDY SELECTION AND DATA EXTRACTION All published studies and abstracts, as well as relevant consensus guidelines, evaluating the current literature about PNETs and carcinoid tumors were included. DATA SYNTHESIS Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a genetically diverse group of complex malignancies with varying biological and clinical courses. Historically believed to be rare, recent epidemiologic data suggest their incidence is rising. Two of the most commonly diagnosed GEP-NETs are PNETs and carcinoid tumors. Both subtypes are well-differentiated tumors and present as low or intermediate grade. The systemic manifestations of PNETs and carcinoid tumors are diverse and are related to the secretion of affected hormones and biogenic amines. Surgical resection of localized disease remains the only curative option. However, the utility of this approach is limited because most patients are diagnosed with advanced disease. Recent advances have led to an improvement in outcomes in patients with PNETs and carcinoid tumors. This review describes traditional therapies as well as emerging strategies being investigated to help manage these cancers. Treatment of poorly differentiated GEP-NETs is beyond the scope of this review. CONCLUSIONS The advent of new therapies for PNETs and carcinoid tumors has introduced a paradigm shift in the management of this heterogeneous malignancy.
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Affiliation(s)
- Alex Ganetsky
- Pharmacy Department, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
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48
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Eads JR, Meropol NJ. A new era for the systemic therapy of neuroendocrine tumors. Oncologist 2012; 17:326-38. [PMID: 22357730 PMCID: PMC3316918 DOI: 10.1634/theoncologist.2011-0356] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2011] [Accepted: 01/03/2012] [Indexed: 12/16/2022] Open
Abstract
Carcinoids and pancreatic neuroendocrine tumors are becoming increasingly common, with the majority of patients presenting with either lymph node involvement or metastatic disease. An improved understanding of the molecular mechanisms involved in these tumors has implicated several pathways that have led to new therapeutic approaches. In this manuscript, we describe the biology of neuroendocrine tumors and approaches to systemic therapy. We review early data regarding the use of cytotoxics and several recent studies employing more targeted approaches that promise to change the standard of care. Specifically, phase III studies indicate that pharmacologic inhibition of the vascular endothelial growth factor pathway with sunitinib, and of the mammalian target of rapamycin pathway with everolimus, appears to have altered the natural history of these diseases. These successes set the stage for further advances in the management of patients with neuroendocrine tumors.
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Affiliation(s)
- Jennifer R. Eads
- University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA
| | - Neal J. Meropol
- University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA
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49
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Rönnblom L. The type I interferon system in the etiopathogenesis of autoimmune diseases. Ups J Med Sci 2011; 116:227-37. [PMID: 22066971 PMCID: PMC3207297 DOI: 10.3109/03009734.2011.624649] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2011] [Accepted: 09/14/2011] [Indexed: 12/30/2022] Open
Abstract
Many patients with systemic autoimmune diseases have signs of a continuous production of type I interferon (IFN) and display an increased expression of IFN-α-regulated genes. The reason for the on-going IFN-α synthesis in these patients seems to be an activation of plasmacytoid dendritic cells (pDCs) by immune complexes (ICs), consisting of autoantibodies in combination with DNA or RNA-containing autoantigens. Such interferogenic ICs are internalized via the FcγRIIa expressed on pDCs, reach the endosome, and stimulate Toll-like receptor (TLR)-7 or -9, which subsequently leads to IFN-α gene transcription. Variants of genes involved in both the IFN-α synthesis and response have been linked to an increased risk to develop systemic lupus erythematosus (SLE) and other autoimmune diseases. Among these autoimmunity risk genes are IFN regulatory factor 5 (IRF5), which is involved in TLR signaling, and the signal transducer and activator of transcription 4 (STAT4) that interacts with the type I IFN receptor. Several other gene variants in the IFN signaling pathway also confer an increased risk to develop an autoimmune disease. The observations that IFN-α therapy can induce autoimmunity and that many autoimmune conditions have an on-going type I IFN production suggest that the type I IFN system has a pivotal role in the etiopathogenesis of these diseases. Possible mechanisms behind the dysregulated type IFNsystem in autoimmune diseases and how the IFN-α produced can contribute to the development of an autoimmune process will be reviewed.
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Affiliation(s)
- Lars Rönnblom
- Department of Medical Sciences, Section of Rheumatology, Uppsala University, Uppsala, Sweden.
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50
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Gupta S, Engstrom PF, Cohen SJ. Emerging therapies for advanced gastroenteropancreatic neuroendocrine tumors. Clin Colorectal Cancer 2011; 10:298-309. [PMID: 21813338 DOI: 10.1016/j.clcc.2011.06.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Revised: 12/21/2010] [Accepted: 01/24/2011] [Indexed: 01/17/2023]
Abstract
Neuroendocrine tumors comprise a heterogeneous group of neoplasms derived from peptide- and amine-producing cells of the neuroendocrine system. Gastroenteropancreatic NET are differentiated into tumors and carcinomas based on their malignant potential and subdivided into those arising from the pancreas (islet cell tumors or pancreatic NET) and the more classical gut "carcinoids". Moderate to well differentiated NET have historically been considered rare tumors but recent epidemiological statistics suggest that their frequency has increased substantially over the past three decades. While the incidence of NET is increasing, data from both the US and UK demonstrate no improvement in outcomes over a similar time period. Due to the generally indolent biology of NET, most patients present with advanced disease before symptoms become apparent. In patients with localized NET, the 5-year survival rates after resection range from 60 to 90%, while regional lymph node involvement decreases the 5-year survival rates after surgery to 50-75%. Patients with distant metastases have a 5 year survival rate of approximately 25-40%. Conventional cytotoxic chemotherapy is of unclear benefit in patients with these generally slow growing tumors. Multiple agents have been tested in Phase 2 and Phase 3 trials. In general, the lack of major objective responses with significant toxicities has limited routine use of traditional chemotherapy agents and has emphasized the need to develop new agents in these diseases. This review will focus on emerging molecularly-targeted treatments with an emphasis on their underlying biologic and preclinical rationale.
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Affiliation(s)
- Sameer Gupta
- Fox Chase Cancer Center, Philadelphia, PA 19111, USA
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