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Lauricella E, Vilisova S, Chaoul N, Giglio A, D'Angelo G, Porta C, Cives M. The current status of somatostatin analogs in the treatment of neuroendocrine tumors and future perspectives. Expert Rev Neurother 2025; 25:245-258. [PMID: 39415322 DOI: 10.1080/14737175.2024.2417419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 10/13/2024] [Indexed: 10/18/2024]
Abstract
INTRODUCTION Somatostatin analogs (SSAs) were developed as antisecretory agents to palliate hormonal symptoms in patients with functioning neuroendocrine tumors (NETs). Their antiproliferative activity has been established in the phase 3 PROMID and CLARINET trials. SSAs currently represent the standard first-line therapy for the majority of well-differentiated G1/G2 gastroenteropancreatic NETs as well as for pulmonary NETs. AREAS COVERED An update on the clinical applications of established SSAs for the treatment of NETs is provided. Perspectives on emerging nonpeptide SSAs such as paltusotine and innovative formulations of octreotide (CAM2029) are included. EXPERT OPINION SSAs represent the cornerstone of treatment for both functioning and nonfunctioning NETs. While standard-dose SSAs have a defined place in the therapeutic algorithm of well-differentiated NETs, uncertainties remain on how to best integrate above-label doses of SSAs in the treatment sequence, particularly when tumor control is the goal. Octreotide and lanreotide appear to be clinically interchangeable, and no signs of superiority of one agent over the other has been observed so far. Whether SSAs may be exploited in the maintenance setting following more aggressive treatments, whether continuing SSAs beyond-progression after first-line therapy could be an effective treatment strategy, and whether new-generation SSAs such as pasireotide could overcome resistance to established SSAs are key areas of investigation.
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Affiliation(s)
- Eleonora Lauricella
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Sofija Vilisova
- Department of Oncology, Pauls Stradins Clinical University Hospital, Riga, Latvia
| | - Nada Chaoul
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Andrea Giglio
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Gabriella D'Angelo
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Camillo Porta
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
| | - Mauro Cives
- Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
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Melhorn P, Mazal P, Wolff L, Kretschmer-Chott E, Raderer M, Kiesewetter B. From biology to clinical practice: antiproliferative effects of somatostatin analogs in neuroendocrine neoplasms. Ther Adv Med Oncol 2024; 16:17588359241240316. [PMID: 38529270 PMCID: PMC10962050 DOI: 10.1177/17588359241240316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 02/27/2024] [Indexed: 03/27/2024] Open
Abstract
Somatostatin analogs (SSA), specifically octreotide and lanreotide, have demonstrated antiproliferative effects in patients with neuroendocrine tumors (NET), a group of rare malignancies of diverse origin and presentation. A prominent feature of NET cells is the expression of G protein-coupled receptors called somatostatin receptors (SSTR). Although these SSTR are not uniformly present in NET, they can be instrumental in the diagnosis and treatment of NET. Apart from their application in nuclear imaging and radionuclide therapy, SSA have proven invaluable in the treatment of hormonal syndromes associated with certain NET (antisecretory effects of SSA), but it took more than two decades to convincingly demonstrate the antiproliferative effects of SSA in metastatic NET with the two pivotal studies PROMID and CLARINET. The current review summarizes three decades of SSA treatment and provides an overview of the clinical trial landscape for SSA monotherapy and combination therapy, including clinical implications and quality of life aspects, as well as ongoing fields of research.
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Affiliation(s)
- Philipp Melhorn
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Peter Mazal
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Ladislaia Wolff
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Elisabeth Kretschmer-Chott
- Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Markus Raderer
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria
| | - Barbara Kiesewetter
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
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Faggiano A. Long-acting somatostatin analogs and well differentiated neuroendocrine tumors: a 20-year-old story. J Endocrinol Invest 2024; 47:35-46. [PMID: 37581846 PMCID: PMC10776682 DOI: 10.1007/s40618-023-02170-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 07/28/2023] [Indexed: 08/16/2023]
Abstract
PURPOSE The specific indications of somatostatin analogs (SSAs) in patients with neuroendocrine tumor (NET) emerged over the time. The objective of this review is to summarize and discuss the most relevant data concerning long-acting SSAs in NET. METHODS A narrative review was performed including publications focusing on therapy with the long-acting octreotide, lanreotide, and pasireotide in patients with NET. RESULTS Long-acting SSAs confirm to be a manageable and widely used tool in patients with NET. Both long-acting octreotide and lanreotide are safe as the short-acting formulations, while patient compliance and adherence is further improved. Together with some randomized phase-3 trials, many retrospective and prospective studies have been performed in the last 20 years revealing a variable but substantial impact on progression free survival, not only in gastroenteropancreatic but also in lung and unknown primary NETs. The most frequent tumor response to SSAs is stable disease, but an objective response can be observed, more frequently by using high-dose schedules and in MEN1-related pancreatic NETs. Low tumor burden, low tumor grade (G1 and low G2), good performance status and use as first-line therapy are the main predictive factors to SSAs in NET patients. Pasireotide has been evaluated in few studies. This compound remains a promising SSA and would deserve to be further evaluated as a potential additional indication in NET therapy. CONCLUSIONS Long-acting SSAs are an effective and safe initial therapy of patients with well differentiated NET, allowing tumor growth as well as symptoms control for long-time in selected patients.
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Affiliation(s)
- A Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sapienza University of Rome, Sant'Andrea Hospital, ENETS Center of Excellence, Via di Grottarossa 1038, 00189, Rome, Italy.
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Gabiache G, Zadro C, Rozenblum L, Vezzosi D, Mouly C, Thoulouzan M, Guimbaud R, Otal P, Dierickx L, Rousseau H, Trepanier C, Dercle L, Mokrane FZ. Image-Guided Precision Medicine in the Diagnosis and Treatment of Pheochromocytomas and Paragangliomas. Cancers (Basel) 2023; 15:4666. [PMID: 37760633 PMCID: PMC10526298 DOI: 10.3390/cancers15184666] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/11/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
In this comprehensive review, we aimed to discuss the current state-of-the-art medical imaging for pheochromocytomas and paragangliomas (PPGLs) diagnosis and treatment. Despite major medical improvements, PPGLs, as with other neuroendocrine tumors (NETs), leave clinicians facing several challenges; their inherent particularities and their diagnosis and treatment pose several challenges for clinicians due to their inherent complexity, and they require management by multidisciplinary teams. The conventional concepts of medical imaging are currently undergoing a paradigm shift, thanks to developments in radiomic and metabolic imaging. However, despite active research, clinical relevance of these new parameters remains unclear, and further multicentric studies are needed in order to validate and increase widespread use and integration in clinical routine. Use of AI in PPGLs may detect changes in tumor phenotype that precede classical medical imaging biomarkers, such as shape, texture, and size. Since PPGLs are rare, slow-growing, and heterogeneous, multicentric collaboration will be necessary to have enough data in order to develop new PPGL biomarkers. In this nonsystematic review, our aim is to present an exhaustive pedagogical tool based on real-world cases, dedicated to physicians dealing with PPGLs, augmented by perspectives of artificial intelligence and big data.
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Affiliation(s)
- Gildas Gabiache
- Department of Radiology, Rangueil University Hospital, 31400 Toulouse, France (F.-Z.M.)
| | - Charline Zadro
- Department of Radiology, Rangueil University Hospital, 31400 Toulouse, France (F.-Z.M.)
| | - Laura Rozenblum
- Department of Nuclear Medicine, Sorbonne Université, AP-HP, Hôpital La Pitié-Salpêtrière, 75013 Paris, France
| | - Delphine Vezzosi
- Department of Endocrinology, Rangueil University Hospital, 31400 Toulouse, France
| | - Céline Mouly
- Department of Endocrinology, Rangueil University Hospital, 31400 Toulouse, France
| | | | - Rosine Guimbaud
- Department of Oncology, Rangueil University Hospital, 31400 Toulouse, France
| | - Philippe Otal
- Department of Radiology, Rangueil University Hospital, 31400 Toulouse, France (F.-Z.M.)
| | - Lawrence Dierickx
- Department of Nuclear Medicine, IUCT-Oncopole, 31059 Toulouse, France;
| | - Hervé Rousseau
- Department of Radiology, Rangueil University Hospital, 31400 Toulouse, France (F.-Z.M.)
| | - Christopher Trepanier
- New York-Presbyterian Hospital/Department of Radiology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Laurent Dercle
- New York-Presbyterian Hospital/Department of Radiology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Fatima-Zohra Mokrane
- Department of Radiology, Rangueil University Hospital, 31400 Toulouse, France (F.-Z.M.)
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Cheung WY, LaForty C, Liovas A, McKechnie H, Loree JM. A Real-World Observational Study of the Use and Associated Costs of Treating Neuroendocrine Tumors With Somatostatin Analogs in Canada. Pancreas 2022; 51:1146-1152. [PMID: 37078938 PMCID: PMC10144276 DOI: 10.1097/mpa.0000000000002144] [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: 12/02/2021] [Accepted: 10/17/2022] [Indexed: 04/21/2023]
Abstract
OBJECTIVES Somatostatin analogs (SSAs; lanreotide autogel and octreotide long-acting release) are used to treat neuroendocrine tumors; however, factors that influence SSA use are unclear. METHODS This real-world, observational study collected data from private/public pharmacy claims for patients using SSAs in Canada. Data relating to dosing regimens, injection burden, treatment persistence, and costs were retrospectively analyzed for treatment-naive patients. RESULTS Overall, 1545 patients were included in the analysis of dosing regimens, 908 for injection burden, 453 for treatment persistence, and 903 for treatment-associated costs. Compared with lanreotide, treatment with octreotide long-acting release was more likely associated with treatment above the maximum recommended dose (odds ratio, 16.2; 95% confidence interval, 4.3-136.2; P < 0.0001), higher weighted average long-acting SSA injection burden (13.4 vs 12.5, P < 0.0001), and a higher number of rescue medication claims per patient (0.22 vs 0.03, P < 0.0001). Treatment with lanreotide autogel was associated with greater treatment persistence (hazard ratio, 0.58; 95% confidence interval, 0.42-0.80; P = 0.001) and lower mean annual costs of treatment than octreotide long-acting release (Canadian dollars $27,829.35 vs $31,255.49; P < 0.0001). CONCLUSIONS These findings provide valuable insight into SSA use in clinical settings and may inform treatment selection.
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Affiliation(s)
| | | | - Anna Liovas
- Ipsen Biopharmaceuticals Canada, Mississauga
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Lopes S, Alves M, Rodrigues P. Vasoactive Intestinal Peptide Tumor as the Cause of Persistent Diarrhea: A Diagnostic Challenge. Cureus 2022; 14:e29130. [PMID: 36258959 PMCID: PMC9560002 DOI: 10.7759/cureus.29130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2022] [Indexed: 11/05/2022] Open
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Ruggeri RM, Altieri B, Grossrubatcher E, Minotta R, Tarsitano MG, Zamponi V, MIsidori A, Faggiano A, Colao AM. Sex differences in carcinoid syndrome: A gap to be closed. Rev Endocr Metab Disord 2022; 23:659-669. [PMID: 35292889 DOI: 10.1007/s11154-022-09719-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/04/2022] [Indexed: 12/17/2022]
Abstract
The incidence of neuroendocrine neoplasms and related carcinoid syndrome (CS) has markedly increased over the last decades and women seem to be more at risk than men for developing CS. Nevertheless, very few studies have investigated sex differences in clinical presentation and outcomes of CS. However, as per other tumours, sex might be relevant in influencing tumour localization, delay in diagnosis, clinical outcomes, prognosis and overall survival in CS. The present review was aimed at evaluating sex differences in CS, as they emerge from an extensive search of the recent literature. It emerged that CS occurs more frequently in female than in male patients with NENs and women seem to have a better prognosis and a slight advantage in overall survival and response to therapy. Moreover, the disease likely impacts differently the quality of life of men and women, with different psychological and social consequences. Nevertheless, sex differences, even if partially known, are deeply underestimated in clinical practice and data from clinical trials are lacking. There is urgent need to increase our understanding of the sex-related differences of CS, in order to define tailored strategies of management of the disease, improving both the quality of life and the prognosis of affected patients.
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Affiliation(s)
- Rosaria M Ruggeri
- Department of Clinical and Experimental Medicine, Unit of Endocrinology, University of Messina, Messina, Italy.
| | - Barbara Altieri
- Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, Würzburg, Germany
| | | | - Roberto Minotta
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
| | | | - Virginia Zamponi
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Andrea MIsidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Antongiulio Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
| | - Anna Maria Colao
- Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy
- Cattedra Unesco "Educazione Alla Salute E Allo Sviluppo Sostenibile", University Federico II, Naples, Italy
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Gosain R, Gupta M, Roy AM, Strosberg J, Glaser KM, Iyer R. Health-Related Quality of Life (HRQoL) in Neuroendocrine Tumors: A Systematic Review. Cancers (Basel) 2022; 14:1428. [PMID: 35326587 PMCID: PMC8946839 DOI: 10.3390/cancers14061428] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/08/2022] [Accepted: 03/08/2022] [Indexed: 12/28/2022] Open
Abstract
Therapeutic advancements in neuroendocrine tumors (NETs) have improved survival outcomes. This study aims to review the impact of the current therapeutics on health-related quality of life (HRQoL) in NET patients. A literature review was performed utilizing PubMed, The Cochrane Library, and EMBASE, using the keywords "Carcinoid", "Neuroendocrine tumor", "NET", "Quality of life", "Chemotherapy", "Chemoembolization", "Radiofrequency ablation", "Peptide receptor radionucleotide therapy", "PRRT", "Surgery", "Everolimus", "Octreotide", "Lanreotide", "Sunitinib", and "Somatostatin analog". Letters, editorials, narrative reviews, case reports, and studies not in English were excluded. Out of 2375 publications, 61 studies met our inclusion criteria. The commonly used instruments were EORTC QLQ-C30, FACT G, and EORTC- QLQ GI.NET-21. HRQoL was assessed in all pivotal trials that led to approvals of systemic therapies. All systemic therapies showed no worsening in HRQoL. The NETTER-1 study was the only study to show a statistically significant improvement in HRQoL in several domains. The trial examining sunitinib versus placebo in pancreatic NETs showed no change in QoL, except for worsening of diarrhea. In addition to clinical outcomes, patient-reported outcomes are a key element in making appropriate treatment decisions. HRQoL data should be readily provided to patients to assist in shared decision-making.
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Affiliation(s)
- Rohit Gosain
- University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, UPMC Chautauqua Hospital, Jamestown, NY 14701, USA;
| | - Medhavi Gupta
- Program in Women’s Oncology, Women and Infants Hospital and Warren Alpert Medical School of Brown University, Providence, RI 02912, USA;
| | - Arya Mariam Roy
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Jonathan Strosberg
- Department of Gastro Intestinal Oncology, Moffitt Cancer Center, 12902 Magnolia Dr., Tampa, FL 33612, USA;
| | - Kathryn M. Glaser
- Department of Cancer Prevention & Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Renuka Iyer
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
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Massironi S, Cavalcoli F, Elvevi A, Quatrini M, Invernizzi P. Somatostatin analogs in patients with Zollinger Ellison syndrome (ZES): an observational study. Endocrine 2022; 75:942-948. [PMID: 34716542 DOI: 10.1007/s12020-021-02915-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 10/07/2021] [Indexed: 02/05/2023]
Abstract
PURPOSE Zollinger Ellison syndrome (ZES) is a rare syndrome caused by gastrin hypersecretion from a gastrinoma. Gastrinoma treatment has two goals: the control of acid hypersecretion and the control of tumor growth. While therapy for the syndrome is univocally based on proton pump inhibitors, the one for disease control is still debated. We here aimed at evaluating the role of somatostatin analogs (SSAs) in the control of tumor progression in a series of ZES patients. METHODS A retrospective analysis of a prospectively collected database of ZES patients, followed and managed from 1990 to 2019, was performed. The patients' clinical, pathological, treatment, and follow-up data were analyzed. Data regarding SSAs therapy start, dosage, duration, and side effects were collected. RESULTS 33 patients with ZES were diagnosed. Fourteen patients (42%) had a grade 1 (G1) neuroendocrine neoplasm (NEN), five had G2 (15%), none had G3. Fifteen patients (45%) had metastatic disease. Overall, 12 (36%) underwent SSAs therapy. The median treatment duration was 36 months. Eight patients (67%) had a sustained response to SSAs, four (33%) showed an early progression, with a significant difference in terms of PFS between the patients with early and late progression (84 vs 2 months, p = 0.004). No differences in terms of OS and PFS were observed between the treated and non-treated patients, despite the proportion of metastatic patients was greater in the SSAs-treated group (75% vs 29% in the non-treated group, p = 0.01). CONCLUSION Present data support the use of SSAs in ZES, considering that gastrinoma is mainly a well-differentiated low-grade tumor (G1 or G2), with a high expression of somatostatin receptors.
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Affiliation(s)
- Sara Massironi
- Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, San Gerardo School of Medicine, Monza, Italy.
| | - Federica Cavalcoli
- Diagnostic and Therapeutic Endoscopy Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Alessandra Elvevi
- Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, San Gerardo School of Medicine, Monza, Italy
| | - Maurizio Quatrini
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, San Gerardo School of Medicine, Monza, Italy
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Somatostatin and Somatostatin Receptors: From Signaling to Clinical Applications in Neuroendocrine Neoplasms. Biomedicines 2021; 9:biomedicines9121810. [PMID: 34944626 PMCID: PMC8699000 DOI: 10.3390/biomedicines9121810] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/23/2021] [Accepted: 11/25/2021] [Indexed: 12/26/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are heterogeneous neoplasms which arise from neuroendocrine cells that are distributed widely throughout the body. Although heterogenous, many of them share their ability to overexpress somatostatin receptors (SSTR) on their cell surface. Due to this, SSTR and somatostatin have been a large subject of interest in the discovery of potential biomarkers and treatment options for the disease. The aim of this review is to describe the molecular characteristics of somatostatin and somatostatin receptors and its application in diagnosis and therapy on patients with NENs as well as the use in the near future of somatostatin antagonists.
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Somatostatin Analogue Therapy in MEN1-Related Pancreatic Neuroendocrine Tumors from Evidence to Clinical Practice: A Systematic Review. Pharmaceuticals (Basel) 2021; 14:ph14101039. [PMID: 34681263 PMCID: PMC8538402 DOI: 10.3390/ph14101039] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 12/20/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are relatively rare and complex tumors that can be sporadic or hereditary, as in the context of multiple endocrine neoplasia type 1 (MEN1) where patients display a 70% lifelong risk of developing a pancreatic NENs (pNENs). To date, specific personalized treatment for pNENs in patients with MEN1 are lacking. The aim of this study was to systematically analyze the efficacy and safety of somatostatin analogue (SSA) treatment in patients affected by MEN1-related pNENs. We performed a systematic review of the literature, searching for peer-reviewed articles on SSA (octreotide or lanreotide) treatment in MEN1 associated with pNENs. We selected 20 studies with a pooled population of 105 MEN1 patients with pNENs. Females were 58.5%, median age was 44 years (18-73). TNM stage at diagnosis was stage I-II in 84.8% and stage IV in 15.2%. The overall response rate (SD+PR+CR) was achieved in 88.3% of cases, with stable disease in 75.6% and objective response in 12.7% of patients. The safety profile was favorable with both SSA agents. SSAs appear to be an effective and safe treatment option for MEN1-related pNEN, either at localized or advanced stages.
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Spada F, Rossi RE, Kara E, Laffi A, Massironi S, Rubino M, Grimaldi F, Bhoori S, Fazio N. Carcinoid Syndrome and Hyperinsulinemic Hypoglycemia Associated with Neuroendocrine Neoplasms: A Critical Review on Clinical and Pharmacological Management. Pharmaceuticals (Basel) 2021; 14:539. [PMID: 34199977 PMCID: PMC8228616 DOI: 10.3390/ph14060539] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/31/2021] [Accepted: 06/01/2021] [Indexed: 02/05/2023] Open
Abstract
The carcinoid syndrome (CS) and hyperinsulinemic hypoglycemia (HH) represent two of the most common clinical syndromes associated with neuroendocrine neoplasms (NENs). The former is mainly related to the serotonin secretion by a small bowel NEN, whereas the latter depends on an insulin hypersecretion by a pancreatic insulinoma. Both syndromes/conditions can affect prognosis and quality of life of patients with NENs. They are often diagnosed late when patients become strongly symptomatic. Therefore, their early detection and management are a critical step in the clinical management of NEN patients. A dedicated and experienced multidisciplinary team with appropriate therapeutic strategies is needed and should be encouraged to optimize clinical outcomes. This review aims to critically analyze clinical features, evidence and treatment options of CS and HH and therefore to improve their management.
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Affiliation(s)
- Francesca Spada
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, via G. Ripamonti 435, 20141 Milano, Italy; (F.S.); (A.L.); (M.R.)
| | - Roberta E. Rossi
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS, Istituto Nazionale Tumori (INT), via G. Venezian 1, 20133 Milano, Italy; (R.E.R.); (S.B.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, via Festa del Perdono 7, 20122 Milano, Italy
| | - Elda Kara
- Endocrinology and Metabolism Unit, University Hospital S. Maria della Misericordia, Piazzale Santa Maria della Misericordia, 15, 33100 Udine, Italy; (E.K.); (F.G.)
| | - Alice Laffi
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, via G. Ripamonti 435, 20141 Milano, Italy; (F.S.); (A.L.); (M.R.)
| | - Sara Massironi
- Division of Gastroenterology, San Gerardo Hospital, Bicocca School of Medicine, University of Milano Bicocca, 20126 Milano, Italy;
| | - Manila Rubino
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, via G. Ripamonti 435, 20141 Milano, Italy; (F.S.); (A.L.); (M.R.)
| | - Franco Grimaldi
- Endocrinology and Metabolism Unit, University Hospital S. Maria della Misericordia, Piazzale Santa Maria della Misericordia, 15, 33100 Udine, Italy; (E.K.); (F.G.)
| | - Sherrie Bhoori
- Hepatology and Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS, Istituto Nazionale Tumori (INT), via G. Venezian 1, 20133 Milano, Italy; (R.E.R.); (S.B.)
| | - Nicola Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO) IRCCS, via G. Ripamonti 435, 20141 Milano, Italy; (F.S.); (A.L.); (M.R.)
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Cella D, Evans J, Feuilly M, Neggers S, Van Genechten D, Herman J, Khan MS. Patient and Healthcare Provider Perspectives of First-Generation Somatostatin Analogs in the Management of Neuroendocrine Tumors and Acromegaly: A Systematic Literature Review. Adv Ther 2021; 38:969-993. [PMID: 33432541 PMCID: PMC7799425 DOI: 10.1007/s12325-020-01600-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 12/05/2020] [Indexed: 11/24/2022]
Abstract
Introduction Somatostatin analogs (SSAs) are used to treat neuroendocrine tumors (NETs) and acromegaly. Two first-generation SSAs, octreotide long-acting release (OCT LAR) and lanreotide autogel/depot (LAN), are available. A systematic literature review (SLR) was conducted to investigate which characteristics beyond efficacy are most important in patient and healthcare practitioner (HCP) experience of LAN and OCT when used to treat acromegaly and NETs. Methods MEDLINE, Embase, the Cochrane Library, and Database of Abstracts of Reviews of Effect were searched from database inception to January 2019 with terms for first-generation SSAs, NETs, acromegaly, preferences, decision-making, and human factors. Key congresses in 2016–2018 and SLR bibliographies were hand-searched. Two independent reviewers screened articles at title/abstract and full-text stage. Publications fulfilling pre-specified inclusion criteria reported patient or HCP perspectives of LAN or OCT, or any factors affecting treatment perspectives for NETs or acromegaly. Results A total of 1110 unique records were screened, of which 21 studies were included, reporting from the perspectives of patients (n = 18) and/or HCPs (n = 9). Perspectives were collected using shared decision-making frameworks, questionnaires, informal patient opinion, and a Delphi panel. Where patient preference was specifically reported, LAN was preferred in 4/5 studies and OCT LAR in 1/5. Common factors underlying treatment experience included technical problems with injections and associated pain, emotional quality/anxiety of injections, time and convenience of treatment administration, and independence. Immediate aspects of injections appeared most important to patients, though the possibilities of extended dosing intervals and self-/partner-injection with LAN were also notable factors. Conclusions Study outcomes favored LAN in this SLR, with factors surrounding injection administration most influential in treatment experience. The findings of this SLR provide a basis that could inform development of decision-making criteria, with patient and HCP treatment perspectives considered. Future studies should utilize a common method to report preference and associated drivers. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-020-01600-x.
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Affiliation(s)
- David Cella
- Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| | | | | | - Sebastian Neggers
- Department of Medicine, Section Endocrinology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Dirk Van Genechten
- Belgian Neuroendocrine Tumour (NET) and Multiple Endocrine Neoplasia (MEN) Association, Blankenberge, Belgium
- International Neuroendocrine Cancer Alliance (INCA), Boston, MA, USA
| | - Jackie Herman
- Canadian Neuroendocrine Tumour Society, Cornwall, ON, Canada
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14
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Patel M, Tena I, Jha A, Taieb D, Pacak K. Somatostatin Receptors and Analogs in Pheochromocytoma and Paraganglioma: Old Players in a New Precision Medicine World. Front Endocrinol (Lausanne) 2021; 12:625312. [PMID: 33854479 PMCID: PMC8039528 DOI: 10.3389/fendo.2021.625312] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 03/04/2021] [Indexed: 12/16/2022] Open
Abstract
Neuroendocrine tumors overexpress somatostatin receptors, which serve as important and unique therapeutic targets for well-differentiated advanced disease. This overexpression is a well-established finding in gastroenteropancreatic neuroendocrine tumors which has guided new medical therapies in the administration of somatostatin analogs, both "cold", particularly octreotide and lanreotide, and "hot" analogs, chelated to radiolabeled isotopes. The binding of these analogs to somatostatin receptors effectively suppresses excess hormone secretion and tumor cell proliferation, leading to stabilization, and in some cases, tumor shrinkage. Radioisotope-labeled somatostatin analogs are utilized for both tumor localization and peptide radionuclide therapy, with 68Ga-DOTATATE and 177Lu-DOTATATE respectively. Benign and malignant pheochromocytomas and paragangliomas also overexpress somatostatin receptors, irrespective of embryological origin. The pattern of somatostatin receptor overexpression is more prominent in succinate dehydrogenase subunit B gene mutation, which is more aggressive than other subgroups of this disease. While the Food and Drug Administration has approved the use of 68Ga-DOTATATE as a radiopharmaceutical for somatostatin receptor imaging, the use of its radiotherapeutic counterpart still needs approval beyond gastroenteropancreatic neuroendocrine tumors. Thus, patients with pheochromocytoma and paraganglioma, especially those with inoperable or metastatic diseases, depend on the clinical trials of somatostatin analogs. The review summarizes the advances in the utilization of somatostatin receptor for diagnostic and therapeutic approaches in the neuroendocrine tumor subset of pheochromocytoma and paraganglioma; we hope to provide a positive perspective in using these receptors as targets for treatment in this rare condition.
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Affiliation(s)
- Mayank Patel
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Isabel Tena
- Scientific Department, Medica Scientia Innovation Research (MedSIR), Barcelona, Spain
- Section of Medical Oncology, Consorcio Hospitalario Provincial of Castellon, Castellon, Spain
| | - Abhishek Jha
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - David Taieb
- Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Karel Pacak,
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15
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Watson C, Tallentire CW, Ramage JK, Srirajaskanthan R, Leeuwenkamp OR, Fountain D. Quality of life in patients with gastroenteropancreatic tumours: A systematic literature review. World J Gastroenterol 2020; 26:3686-3711. [PMID: 32742136 PMCID: PMC7366058 DOI: 10.3748/wjg.v26.i25.3686] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 06/04/2020] [Accepted: 06/16/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are slow-growing cancers that arise from diffuse endocrine cells in the gastrointestinal tract (GI-NETs) or the pancreas (P-NETs). They are relatively uncommon, accounting for 2% of all gastrointestinal malignancies. The usual treatment options in advanced GEP-NET patients with metastatic disease include chemotherapy, biological therapies, and peptide receptor radionuclide therapy. Understanding the impact of treatment on GEP-NET patients is paramount given the nature of the disease. Health-related quality of life (HRQoL) is increasingly important as a concept reflecting the patients’ perspective in conjunction with the disease presentation, severity and treatment.
AIM To conduct a systematic literature review to identify literature reporting HRQoL data in patients with GEP-NETs between January 1985 and November 2019.
METHODS The PRISMA guiding principles were applied. MEDLINE, Embase and the Cochrane library were searched. Data extracted from the publications included type of study, patient population data (mid-gut/hind-gut/GI-NET/P-NET), sample size, intervention/comparators, HRQoL instruments, average and data spread of overall and sub-scores, and follow-up time for data collection.
RESULTS Forty-three publications met the inclusion criteria. The heterogeneous nature of the different study populations was evident; the percentage of female participants ranged between 30%-60%, whilst average age ranged from 53.8 to 67.0 years. Eight studies investigated GI-NET patients only, six studies focused exclusively on P-NET patients and the remaining studies involved both patient populations or did not report the location of the primary tumour. The most commonly used instrument was the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (n = 28) with consistent results across studies; the GI-NET-specific module Quality of Life Questionnaire-GINET21 was used in six of these studies. A number of randomised trials demonstrated no HRQoL changes between active treatment and placebo arms. The Phase III NETTER-1 study provides the best data available for advanced GEP-NET patients; it shows that peptide receptor radionuclide therapy can significantly improve GEP-NET patients’ HRQoL.
CONCLUSION HRQoL instruments offer a means to monitor patients’ general disease condition, disease progression and their physical and mental well-being. Instruments including the commonly used European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and GINET21 lack, however, validation and a defined minimal clinical important difference specifically for GI-NET and P-NET patients.
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Affiliation(s)
- Catherine Watson
- PHMR Health Economics, Pricing and Reimbursement, London NW1 8XY, United Kingdom
| | | | - John K Ramage
- Kings Health Partners NET centre, Kings College Hospital London, London SE5 9RS, United Kingdom
| | | | | | - Donna Fountain
- PHMR Health Economics, Pricing and Reimbursement, London NW1 8XY, United Kingdom
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16
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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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17
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Alexandraki KI, Daskalakis K, Tsoli M, Grossman AB, Kaltsas GA. Endocrinological Toxicity Secondary to Treatment of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs). Trends Endocrinol Metab 2020. [DOI: 10.1016/j.tem.2019.11.003 [epub ahead of print]] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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18
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Alexandraki KI, Daskalakis K, Tsoli M, Grossman AB, Kaltsas GA. Endocrinological Toxicity Secondary to Treatment of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs). Trends Endocrinol Metab 2020; 31:239-255. [PMID: 31839442 DOI: 10.1016/j.tem.2019.11.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 10/16/2019] [Accepted: 11/12/2019] [Indexed: 12/18/2022]
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are increasingly recognized, characterized by prolonged survival even with metastatic disease. Their medical treatment is complex involving various specialties, necessitating awareness of treatment-related adverse effects (AEs). As GEP-NENs express somatostatin receptors (SSTRs), long-acting somatostatin analogs (SSAs) that are used for secretory syndrome and tumor control may lead to altered glucose metabolism. Everolimus and sunitinib are molecular targeted agents that affect glucose and lipid metabolism and may induce hypothyroidism or hypocalcemia, respectively. Chemotherapeutic drugs can affect the reproductive system and water homeostasis, whereas immunotherapeutic agents can cause hypophysitis and thyroiditis or other immune-mediated disorders. Treatment with radiopeptides may temporarily lead to radiation-induced hormone disturbances. As drugs targeting GEP-NENs are increasingly introduced, recognition and management of endocrine-related AEs may improve compliance and the quality of life of these patients.
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Affiliation(s)
- Krystallenia I Alexandraki
- National and Kapodistrian University of Athens, Athens, Greece; EKPA-LAIKO ENETS Center of Excellence, Athens, Greece.
| | - Kosmas Daskalakis
- National and Kapodistrian University of Athens, Athens, Greece; Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; EKPA-LAIKO ENETS Center of Excellence, Athens, Greece
| | - Marina Tsoli
- National and Kapodistrian University of Athens, Athens, Greece; EKPA-LAIKO ENETS Center of Excellence, Athens, Greece
| | - Ashley B Grossman
- University of Oxford, Oxford, UK; Green Templeton College, Oxford, UK; Royal Free London, London, UK; Barts and the London School of Medicine, London, UK
| | - Gregory A Kaltsas
- National and Kapodistrian University of Athens, Athens, Greece; EKPA-LAIKO ENETS Center of Excellence, Athens, Greece
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19
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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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20
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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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21
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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: 124] [Impact Index Per Article: 20.7] [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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22
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Ge W, Zhou D, Zhu L, Song W, Wang W. Efficacy and Safety of Everolimus plus Somatostatin Analogues in Patients with Neuroendocrine Tumors. J Cancer 2018; 9:4783-4790. [PMID: 30588264 PMCID: PMC6299392 DOI: 10.7150/jca.25908] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 09/10/2018] [Indexed: 12/14/2022] Open
Abstract
Everolimus, an oral mammalian target of rapamycin(mTOR) inhibitor, which acts upstream of the phosphoinositide 3-kinase/protein kinase B(PI3K/AKT) signaling pathway to downregulate cellular metabolism, growth, proliferation, and angiogenesis, has been shown to significantly prolong the progression-free survival of patients with advanced neuroendocrine tumors. Somatostatin analogues (SSAs) such as octreotide, lanreotide, and pasireotide, have been widely used for symptom control and antiproliferative effects in metastatic or unresectable neuroendocrine tumors. Both everolimus and SSAs have demonstrated antitumor effects in randomized controlled trials (RCTs) involving selected patients with neuroendocrine tumors, but the efficacy and safety of their combined use require further investigation. In this systematic review, we summarize the published studies that have investigated the use of everolimus and SSAs to provide a comprehensive understanding of their combined effects and better guidance for the treatment of neuroendocrine tumors.
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Affiliation(s)
- Wenhao Ge
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310003, Zhejiang, China
| | - Dongkai Zhou
- Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China
| | - Lijun Zhu
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310003, Zhejiang, China
| | - Wei Song
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310003, Zhejiang, China
| | - Weilin Wang
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310003, Zhejiang, China.,State Key Laboratory & Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310003, Zhejiang, China.,Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China
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23
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Well differentiated neuroendocrine tumors, a single center experience. JOURNAL OF ONCOLOGICAL SCIENCES 2018. [DOI: 10.1016/j.jons.2018.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Della Torre S, Procopio G, Fusi A, Catena L, Ferrari L, Nova P, Denaro A, Bichisao E, Bajetta E. Current Treatments of Neuroendocrine Tumors Role of Biotherapy and Chemotherapy. TUMORI JOURNAL 2018; 89:111-6. [PMID: 12841654 DOI: 10.1177/030089160308900201] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Neuroendocrine tumors are rare neoplasms originating from cells belonging to a diffuse or confined neuroendocrine system and characterized by a significant histopatologic and biologic heterogeneity. Timely diagnosis is delayed because they are often clinically silent for their low differentiation grade and the absence of any symptom due to abnormal hormone release. For these reasons, many neuroendocrine tumor patients are not treated medically for metastatic or inoperable disease. Medical treatments include biotherapy, with interferon-α and somatostatin analogues, and chemotherapy. Somastostatin analogues are widely used in patients with symptoms and with carcinoids of low differentiation grade. Interferon-α is used alone or in combination with somatostatin analogues. Chemotherapy is active in patients with poorly differentiated neuroendocrine tumors. The therapeutic regimen commonly used is the combination of cisplatinum and etoposide. In conclusion, no standard treatment for NET has yet been identified, and the response criteria suggested by ITMO remain a reference point. The clinical aspect of the disease and biologic features suggest the identification of neuroendocrine tumors patients suitable for the appropriate therapies. On these bases, it is recommended that diagnosis and treatment of neuroendocrine tumors be carried out at specialized oncological centers involved in clinical trials.
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25
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Guarnotta V, Martini C, Davì MV, Pizza G, Colao A, Faggiano A. The Zollinger-Ellison syndrome: is there a role for somatostatin analogues in the treatment of the gastrinoma? Endocrine 2018; 60:15-27. [PMID: 29019150 DOI: 10.1007/s12020-017-1420-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 09/02/2017] [Indexed: 12/17/2022]
Abstract
PURPOSE Analyze the role of somatostatin analogues (SSAs) in the treatment of sporadic and MEN1-related gastrinomas, trying to define whether recent trials have changed the landscape of gastrinoma therapy. METHODS We evaluate the rationale of SSA use in the treatment of gastrinomas, summarize the current literature concerning the effect of SSAs on the control of Zollinger-Ellison syndrome (ZES) and gastrinomas tumor progression and discuss their role in the most recent guidelines. RESULTS The medical treatment of gastrinoma and related ZES is aimed at controlling acid hypersecretion and tumor progression, in inoperable patients. The use of proton pump inhibitors (PPIs) to control the syndrome is a cornerstone in the ZES therapy. SSAs are not usually indicated for antisecretory purpose, because PPIs are considered the treatment of choice, due to their long lasting high efficacy and oral availability. The antiproliferative effect of SSAs has been established by two placebo-controlled trials that have clearly demonstrated a significant increase in progression free survival in patients affected by non-functioning well-differentiated advanced neuroendocrine tumors (NETs). The recent ENETS guidelines recommend the use of SSAs in advanced well differentiated NETs as antiproliferative agents. CONCLUSIONS The high sstr-expression in gastrinomas make them highly responsive to SSAs and support the use of such drugs to counteract the tumour growth in patients not amenable to surgical cure. Unfortunately, limited data, mainly case reports or small series, support the use of SSAs in advanced gastrinomas, therefore, it is difficult to quantify their ability to control tumour growth and disease progression.
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Affiliation(s)
- Valentina Guarnotta
- Biomedical Department of Internal and Specialist Medicine (DIBIMIS), Section of Endocrine-Metabolic Diseases, University of Palermo, Palermo, Italy
| | - Chiara Martini
- Clinica Medica 3^, Department of Medicine, DIMED, University of Padova, Padova, Italy.
| | - Maria Vittoria Davì
- Section of Endocrinology, Medicina Generale e Malattie Aterotrombotiche e Degenerative, Department of Medicine, University of Verona, Verona, Italy
| | - Genoveffa Pizza
- Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Naples, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Naples, Italy
| | - Antongiulio Faggiano
- Thyroid and Parathyroid Surgery Unit, Istituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy
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Abstract
Pancreatic neuroendocrine tumors (pNETs) constitute a heterogenous group of malignancies with varying clinical presentation, tumor biology and prognosis. The incidence of pNETs has steadily increased during the last decades with an estimated incidence 2012 of 4.8/100,000. Recent whole genome sequencing of pNETs has demonstrated mutations in the DNA repair genes MUTYH and point mutations and gene fusions in four main pathways from chromatin remodeling, DNA damage repair, activation of mechanistic target of rapamycin (mTOR) signaling and the telomere maintenance. This new information will be the foundation for new therapies in the near future for malignant pNETs. The functioning pNETs constitute about 30-40% of all pNETs displaying nine different clinical syndromes: insulinoma, Zollinger-Ellison, Verner-Morrison, glucagonoma, somatostatinomas, ectopic adrenocorticotropic hormone (ACTH) and parathyroid hormone related peptide (PTH-rP) syndromes. Single patients might also present carcinoid syndrome. The diagnostic work-up include histopathology with the new WHO 2017 Classification, biomarkers (CgA, NSE), radiology and molecular imaging including CT-scan, magnetic resonance imaging (MRI), ultrasound and PET-scan. A cornerstone in the treatment of pNETs is surgery which is rarely curative but can reduce the clinical symptoms by debulking which also include radiofrequency ablation, embolization of liver metastases. Medical treatment includes chemotherapy and the targeted agents such as everolimus, sunitinib and peptide receptor radiotherapy (PRRT). Somatostatin analogs has for the last decades been the main stay for management for clinical symptoms related to functioning pNETs and is often combined with new targeted agents as well as chemotherapy. Long-term management of functioning pNETs need a combination of different procedures, surgery, local ablation, targeted agents and somatostatin analogs. Future therapies might be based on the recent advances in molecular genetics and tumor biology.
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Affiliation(s)
- Kjell Öberg
- Department of Medical Sciences, Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden
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Abstract
Understanding of neuroendocrine tumors has increased greatly in the last 2 decades. Along with this, the prevalence of neuroendocrine tumors has increased because of the ubiquitous use of cross-sectional imaging, improved endoscopic screening, and the indolent nature of the disease. Up to 35% of patients have symptoms at the time of diagnosis, whereas the others have occult disease. Neuroendocrine tumors are a diverse group of malignancies with unique clinical courses. This article critically reviews the most important randomized controlled trials for neuroendocrine tumors and introduces a few awaiting completion.
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Affiliation(s)
- John C McAuliffe
- Department of Surgery, Montefiore-Einstein Center for Cancer Care, 1521 Jarrett Place, Suite 207, Bronx, NY 10461, USA
| | - Edward M Wolin
- Neuroendocrine Tumor Program, Division of Medical Oncology, Department of Medicine, Montefiore-Einstein Center for Cancer Care, 1695 Eastchester Road, 2nd Floor, Bronx, NY 10461, USA.
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Gut P, Waligórska-Stachura J, Czarnywojtek A, Sawicka-Gutaj N, Bączyk M, Ziemnicka K, Fischbach J, Woliński K, Kaznowski J, Wrotkowska E, Ruchała M. Management of the hormonal syndrome of neuroendocrine tumors. Arch Med Sci 2017; 13:515-524. [PMID: 28507564 PMCID: PMC5420621 DOI: 10.5114/aoms.2016.60311] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Accepted: 04/07/2016] [Indexed: 12/17/2022] Open
Abstract
Gastroenteropancreatic neuroendocrine tumors (GEP/NET) are unusual and rare neoplasms that present many clinical challenges. They characteristically synthesize store and secrete a variety of peptides and neuroamines which can lead to the development of distinct clinical syndrome, however many are clinically silent until late presentation with mass effects. Management strategies include surgery cure and cytoreduction with the use of somatostatin analogues. Somatostatin have a broad range of biological actions that include inhibition of exocrine and endocrine secretions, gut motility, cell proliferation, cell survival and angiogenesis. Five somatostatin receptors (SSTR1-SSTR5) have been cloned and characterized. Somatostatin analogues include octreotide and lanreotide are effective medical tools in the treatment and present selectivity for SSTR2 and SSTR5. During treatment is seen disapperance of flushing, normalization of bowel movements and reduction of serotonin and 5-hydroxyindole acetic acid (5-HIAA) secretion. Telotristat represents a novel approach by specifically inhibiting serotonin synthesis and as such, is a promising potential new treatment for patients with carcinoid syndrome. To pancreatic functionig neuroendocrine tumors belongs insulinoma, gastrinoma, glucagonoma and VIP-oma. Medical management in patients with insulinoma include diazoxide which suppresses insulin release. Also mTOR inhibitors may inhibit insulin secretion. Treatment of gastrinoma include both proton pump inhibitors (PPIs) and histamine H2 - receptor antagonists. In patients with glucagonomas hyperglycaemia can be controlled using insulin and oral blood glucose lowering drugs. In malignant glucagonomas smatostatin analogues are effective in controlling necrolytic migratory erythemia. Severe cases of the VIP-oma syndrome require supplementation of fluid losses. Octreotide reduce tumoral VIP secretion and control secretory diarrhoea.
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Affiliation(s)
- Paweł Gut
- Department of Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | | | - Agata Czarnywojtek
- Department of Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | - Nadia Sawicka-Gutaj
- Department of Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | - Maciej Bączyk
- Department of Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | - Katarzyna Ziemnicka
- Department of Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | - Jakub Fischbach
- Department of Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | - Kosma Woliński
- Department of Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | - Jarosław Kaznowski
- Department of Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | - Elżbieta Wrotkowska
- Department of Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | - Marek Ruchała
- Department of Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
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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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Michael M, Garcia-Carbonero R, Weber MM, Lombard-Bohas C, Toumpanakis C, Hicks RJ. The Antiproliferative Role of Lanreotide in Controlling Growth of Neuroendocrine Tumors: A Systematic Review. Oncologist 2017; 22:272-285. [PMID: 28220021 PMCID: PMC5344642 DOI: 10.1634/theoncologist.2016-0305] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 09/27/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Neuroendocrine tumors (NETs) are a heterogeneous group of tumors, with >50% of cases involving the gastrointestinal system or pancreas. Somatostatin analogs (SSAs) are used for treating NET-related secretory syndromes and, more recently, for their antiproliferative effects. We conducted a systematic review of published literature on the antiproliferative efficacy and safety of the SSA lanreotide Autogel in the management of NETs to gain a fuller understanding of the evidence and identify future areas of research. METHODS Searches were conducted in PubMed up to March 16, 2016, and in the proceedings of four congresses from 2013 to 2016. RESULTS Screening of 1,132 publications identified in the searches found 40 relevant publications, including 27 full-length publications and 13 congress abstracts. Twenty-four of these publications reported antiproliferative efficacy data for lanreotide Autogel. The CLARINET study showed that 120 mg lanreotide Autogel every 4 weeks improves progression-free survival (PFS) in patients with gastroenteropancreatic (GEP)-NETs, with grade 1 or grade 2 (Ki-67 <10%) disease, providing class I evidence of its antiproliferative effects. The CLARINET open-label extension study reported a median PFS of 32.8 months with lanreotide Autogel. Other smaller studies generally support CLARINET. CONCLUSION Current clinical evidence shows that lanreotide Autogel has good antiproliferative activity with favorable safety and tolerability in patients with GEP-NETs, suggesting it should be considered as an early first-line treatment in this population. Further studies are needed to assess the potential benefits of higher doses and the use of lanreotide Autogel in combination therapy and as maintenance therapy in the absence of disease progression following other therapies. The Oncologist 2017;22:272-285 IMPLICATIONS FOR PRACTICE: This review presents the current clinical evidence for the antiproliferative activity of lanreotide Autogel in patients with midgut or pancreatic neuroendocrine tumors (NETs) and shows its effectiveness, safety, and tolerability in these patient populations. By systematically presenting all the clinical evidence, the review adds to existing publications by discussing results in a broad range of settings. The review also indicates future directions for investigation of the use of lanreotide Autogel in NETs originating in other locations, in combination therapy, or as maintenance therapy in progressive disease.
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Affiliation(s)
- Michael Michael
- Neuorendocrine Service & Division of Cancer Medicine, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Australia
| | | | | | | | | | - Rodney J Hicks
- Cancer Imaging & Neuroendocrine Service & Molecular Imaging and Targeted Therapeutics Laboratory, Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Australia
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Somatostatin analogues according to Ki67 index in neuroendocrine tumours: an observational retrospective-prospective analysis from real life. Oncotarget 2016; 7:5538-47. [PMID: 26701729 PMCID: PMC4868704 DOI: 10.18632/oncotarget.6686] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 12/10/2015] [Indexed: 02/03/2023] Open
Abstract
Somatostatin analogues (SSAs) have shown limited and variable antiproliferative effects in neuroendocrine tumours (NETs). Whether tumour control by SSAs depends on grading based on the 2010 WHO NET classification is still unclear. The aim of this study is to evaluate the efficacy of long-acting SSAs in NETs according to Ki67 index. An observational Italian multicentre study was designed to collect data in patients with gastro-entero-pancreatic or thoracic NETs under SSA treatment. Both retrospective and prospective data were included and they were analysed in line with Ki67 index, immunohistochemically evaluated in tumour samples and graded according to WHO classification (G1 = Ki67 index 0-2%, G2 = Ki67 index 3-20%, G3 = Ki67 index > 20%). Among 601 patients with NET, 140 with a histologically confirmed gastro-entero-pancreatic or thoracic NET or NET with unknown primary were treated with lanreotide autogel or octreotide LAR. An objective tumour response was observed in 11%, stability in 58% and progression in 31%. Objective response and tumour stability were not significantly different between G1 and G2 NETs. Progression free survival was longer but not significantly different in G1 than G2 NETs (median: 89 vs 43 months, p = 0.15). The median PFS was significantly longer in NETs showing Ki67 < 5% than in those showing Ki67 ≥5% (89 vs 35 months, p = 0.005). SSA therapy shows significant antiproliferative effects in well differentiated low/intermediate-proliferating NETs, not only G1 but also in G2 type. A Ki67 index of 5% seems to work better than 3% to select the best candidates for SSA therapy.
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Lamarca A, Barriuso J, McNamara MG, Hubner RA, Valle JW. Telotristat ethyl: a new option for the management of carcinoid syndrome. Expert Opin Pharmacother 2016; 17:2487-2498. [PMID: 27817224 DOI: 10.1080/14656566.2016.1254191] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Many patients with neuroendocrine tumour-related carcinoid syndrome treated with somatostatin analogues (SSA) won't achieve adequate symptom relief with the SSA alone; new treatment options are required. Telotristat ethyl is a tryptophan hydroxylase inhibitor, developed for the treatment of carcinoid syndrome. Areas covered: This review summarises the evidence supporting the role of telotristat ethyl in the management of carcinoid syndrome. Rationale, pharmacodynamics, pharmacokinetics, metabolism, clinical experience, efficacy and toxicity profiles are covered. Expert opinion: The efficacy of telotristat ethyl in producing a statistically-significant and clinically-meaningful reduction in daily bowel movements has been confirmed in phase III clinical trials. Two pivotal trials, TELESTAR and TELECAST, explored the role of telotristat ethyl in the management of patients with carcinoid syndrome refractory to SSAs focusing on patients with ≥4 and <4 daily bowel movements, respectively. In addition, benefit was confirmed in patient-reported outcomes. Based on activity and safe toxicity profile, telotristat ethyl is pending regulatory agencies evaluation and is likely to add to the armamentarium used to treat carcinoid syndrome. Long-term safety and efficacy data will be available from the ongoing TELEPATH study. The impact on carcinoid heart disease, mesenteric fibrosis and other long-term complications of carcinoid syndrome as well as its role earlier in patients' pathways remain investigational.
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Affiliation(s)
- Angela Lamarca
- a Department of Medical Oncology , The Christie NHS Foundation Trust , Manchester , UK
| | - Jorge Barriuso
- a Department of Medical Oncology , The Christie NHS Foundation Trust , Manchester , UK.,b Faculty of Medical, Biological and Human Sciences , University of Manchester , Manchester , UK
| | - Mairéad G McNamara
- a Department of Medical Oncology , The Christie NHS Foundation Trust , Manchester , UK.,c Institute of Cancer Sciences , University of Manchester , Manchester , UK
| | - Richard A Hubner
- a Department of Medical Oncology , The Christie NHS Foundation Trust , Manchester , UK
| | - Juan W Valle
- a Department of Medical Oncology , The Christie NHS Foundation Trust , Manchester , UK.,c Institute of Cancer Sciences , University of Manchester , Manchester , UK
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Predictive factors of antiproliferative activity of octreotide LAR as first-line therapy for advanced neuroendocrine tumours. Br J Cancer 2016; 115:1321-1327. [PMID: 27811856 PMCID: PMC5129835 DOI: 10.1038/bjc.2016.349] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 09/08/2016] [Accepted: 10/03/2016] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND The antiproliferative activity of octreotide LAR in neuroendocrine tumours (NETs) has been demonstrated by small retrospective studies and confirmed by a prospective phase III trial (PROMID). However, there are limited data about the duration and predictors of response. The aim of our retrospective study was to determine the time to radiological progression (TTRP) of disease and the factors that were associated with better response. METHODS A total of 254 treatment naïve patients with advanced NETs and positive somatostatin receptor scintigraphy were included. Mean follow-up period was 42 months. RESULTS The location of primary was in the small bowel in 204, pancreas in 22, lungs in 14, rectum in 7 and unknown in 7 patients. Most tumours were well-differentiated, G1 (58%) and G2 (23%). The majority of patients commenced octreotide LAR due to functional symptoms (57%), radiological progression (10%) or in the presence of asymptomatic and stable disease on the basis of data from the PROMID trial (18.5%). Partial response occurred in 5%. For all patients, the median TTRP was 37 months (95% confidence interval, CI: 32-52 months). There was a statistically significant shorter TTRP in patients with pancreatic tumours, liver metastases and intermediate grade tumours. Extremely raised (>10 times the upper limit of normal) baseline chromogranin A levels were associated with an unfavourable outcome. In contrast, male sex, carcinoid heart disease and initiation of treatment in the presence of stable disease were predictive of a better response. Age, extra-hepatic metastases, presence of mesenteric desmoplasia, previous resection and functional status of the primary tumour did not affect response. CONCLUSIONS The duration of the antiproliferative effect of octreotide LAR seems to be longer than previously reported. This study has identified several predictors of response in a large cohort of patients with NETs on somatostatin analogue therapy.
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Martini C, Gamper EM, Wintner L, Nilica B, Sperner-Unterweger B, Holzner B, Virgolini I. Systematic review reveals lack of quality in reporting health-related quality of life in patients with gastroenteropancreatic neuroendocrine tumours. Health Qual Life Outcomes 2016; 14:127. [PMID: 27614762 PMCID: PMC5018190 DOI: 10.1186/s12955-016-0527-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 09/02/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine tumours (GEP-NET) are often slow-growing and patients may live for years with metastasised disease. Hence, along with increasing overall and progression-free survival, treatments aim at preserving patients' well-being and health-related quality of life (HRQoL). However, studies on systematic HRQoL assessment in patients with GEP-NET are scarce. Therefore, the purpose of the current review is to systematically evaluate the methodological quality of the identified studies. METHODS A targeted database search was performed in PubMed, EMBASE, and CENTRAL. Data extraction was conducted by two independent researchers according to predefined criteria. For study evaluation, the Minimum Standard Checklist for Evaluating HRQoL Outcomes in Cancer Clinical Trials and the CONSORT Patient-Reported Outcome extension were adapted. RESULTS The database search yielded 48 eligible studies. We found the awareness for the need of HRQoL measurement to be growing and application of cancer-specific instruments gaining acceptance. Overall, studies were too heterogeneous in terms of patient characteristics and treatment interventions to draw clear conclusions for clinical practice. More importantly, a range of methodological shortcomings has been identified which were mainly related to the assessment and statistical analysis, as well as the reporting and interpretation of HRQoL data. CONCLUSION Despite an increasing interest in HRQoL in GEP-NET patients, there is still a lack of knowledge on this issue. A transfer of HRQoL results into clinical practice is hindered not only by the scarceness of studies, but also by the often limited quality of HRQoL processing and reporting.
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Affiliation(s)
- Caroline Martini
- Department for Psychiatry, Psychotherapy and Psychosomatics, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Eva-Maria Gamper
- Department for Psychiatry, Psychotherapy and Psychosomatics, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.
- Department for Nuclear Medicine, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.
| | - Lisa Wintner
- Department for Psychiatry, Psychotherapy and Psychosomatics, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Bernhard Nilica
- Department for Nuclear Medicine, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Barbara Sperner-Unterweger
- Department for Psychiatry, Psychotherapy and Psychosomatics, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Bernhard Holzner
- Department for Psychiatry, Psychotherapy and Psychosomatics, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Irene Virgolini
- Department for Nuclear Medicine, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
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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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Ruszniewski P, Valle JW, Lombard-Bohas C, Cuthbertson DJ, Perros P, Holubec L, Delle Fave G, Smith D, Niccoli P, Maisonobe P, Atlan P, Caplin ME. Patient-reported outcomes with lanreotide Autogel/Depot for carcinoid syndrome: An international observational study. Dig Liver Dis 2016; 48:552-558. [PMID: 26917486 DOI: 10.1016/j.dld.2015.12.013] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 12/18/2015] [Accepted: 12/22/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Lanreotide Autogel/Depot effectively controls symptoms in patients with carcinoid syndrome associated with neuroendocrine tumours. Data on patient-reported outcomes are sparse. AIM To evaluate the effect of lanreotide on patient-reported outcomes (PROs) with carcinoid syndrome. METHODS This was an international, open-label, observational study of adults with neuroendocrine tumours and history of diarrhoea, receiving lanreotide for >3 months for relief of carcinoid syndrome symptoms. The primary PRO measure was satisfaction with diarrhoea control. Secondary PRO measures included severity, change in symptoms and impact on daily life of diarrhoea; and patient satisfaction with flushing control. RESULTS Of 273 patients enrolled, 76% were 'completely' or 'rather' satisfied with diarrhoea control; 79% reported improvement in diarrhoea with lanreotide. The proportion of patients with 'mild', 'minimal', or 'no diarrhoea' increased from 33% before treatment to 75% during treatment; 75% were unconcerned about the impact of diarrhoea on daily life. Satisfaction with flushing control amongst patients with significant flushing at treatment initiation was 73%. CONCLUSIONS Lanreotide treatment was associated with improvements in symptoms as well as a range of PROs in patients with neuroendocrine tumours and carcinoid syndrome (ClinicalTrials.gov: NCT01234168).
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Affiliation(s)
| | - Juan W Valle
- Institute of Cancer Studies, University of Manchester/The Christie NHS Foundation Trust, Manchester, UK
| | | | - Daniel J Cuthbertson
- Department of Obesity and Endocrinology and Liverpool ENETS Centre of Excellence, University Hospital Aintree and University of Liverpool, Liverpool, UK
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37
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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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Massironi S, Conte D, Rossi RE. Somatostatin analogues in functioning gastroenteropancreatic neuroendocrine tumours: literature review, clinical recommendations and schedules. Scand J Gastroenterol 2015; 51:513-523. [PMID: 26605828 DOI: 10.3109/00365521.2015.1115117] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Revised: 10/27/2015] [Accepted: 10/27/2015] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Neuroendocrine tumours (NETs) represent a heterogeneous group of neoplasms, which include functioning and non-functioning forms. Somatostatin analogues (SSAs) play a key role in the management of these tumours. Herein, we aimed at reviewing the current evidence about the role of SSAs in the treatment of gastro-entero-pancreatic (GEP)-NETs. MATERIAL AND METHODS An extensive bibliographical search was performed in PubMed using the following keywords: gastro-entero-pancreatic neuroendocrine tumours, somatostatin analogues, octreotide, lanreotide, in order to identify all the pertinent English-written articles published between 1990 and 2015. RESULTS SSAs have shown to help the symptomatic and biochemical improvement of patients with NETs and to exhibit a good safety profile. Recent studies have also reported a role for SSAs in tumour growth control, although the results are less impressive and the underlying mechanisms are not fully understood. CONCLUSIONS SSAs are well known as a symptomatic and, to lesser extent, anti-proliferative treatment in GEP-NETs. However, some issues, including optimal dosage, benefits and adverse events of combination with other molecules, and the role of new analogues, remain to be elucidated in further randomised studies.
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Affiliation(s)
- Sara Massironi
- a Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy
| | - Dario Conte
- a Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy
- b Department of Pathophysiology and Transplantation , Università Degli Studi Di Milano , Milan , Italy
| | - Roberta Elisa Rossi
- a Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico , Milan , Italy
- b Department of Pathophysiology and Transplantation , Università Degli Studi Di Milano , Milan , Italy
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Health-related quality of life in well-differentiated metastatic gastroenteropancreatic neuroendocrine tumors. Cancer Metastasis Rev 2015; 34:381-400. [DOI: 10.1007/s10555-015-9573-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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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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Abstract
Neuroendocrine tumours (NETs) represent a less frequent and heterogeneous group of tumours, which has experienced, in recent years, a significant increase in effective therapeutic possibilities overcoming the disappointing results from chemotherapy. Initial improvements in treatment strategies came from somatostatin analogues (SSAs) that have widely demonstrated a significant improvement in symptomatic relief and tumour control growth by a complex mechanism of action over cell survival, angiogenesis and immunomodulation. Recent investigations have pointed out novel SSAs with a wider binding profile (pasireotide), chimeric molecules against somatostatin receptors and dopamine receptors and the combination with targeted agents, such as mTOR inhibitors or antiangiogenic agents. Immunotherapy is the second cornerstone in NET treatment and has been represented with interferon alpha for a long time, with a demonstrated activity on tumour and clinical response. Its less manageable adverse events have limited its usage. However, different checkpoints in immune system regulation have been effectively targeted in different solid tumours, and novel approaches are currently arising in NETs. In conclusion, biotherapy remains an active treatment strategy for initial approach in patients with NETs. Further investigation on patients' selection, molecular profiles, treatment sequence or combination and optimisation of current and novel biotherapy agents is required.
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Affiliation(s)
- T Alonso-Gordoa
- Medical Oncology DepartmentRamón y Cajal University Hospital, Carretera de Colmenar Km 9,100, 28034 Madrid, SpainMedical Oncology DepartmentVall d'Hebrón University Hospital, Passeig de la Vall d'Hebrón, 119-129, 08035 Barcelona, Spain
| | - J Capdevila
- Medical Oncology DepartmentRamón y Cajal University Hospital, Carretera de Colmenar Km 9,100, 28034 Madrid, SpainMedical Oncology DepartmentVall d'Hebrón University Hospital, Passeig de la Vall d'Hebrón, 119-129, 08035 Barcelona, Spain
| | - E Grande
- Medical Oncology DepartmentRamón y Cajal University Hospital, Carretera de Colmenar Km 9,100, 28034 Madrid, SpainMedical Oncology DepartmentVall d'Hebrón University Hospital, Passeig de la Vall d'Hebrón, 119-129, 08035 Barcelona, Spain
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42
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Carcinoid Tumors. Surg Oncol 2015. [DOI: 10.1007/978-1-4939-1423-4_26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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43
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Expert consensus for the management of advanced or metastatic pancreatic neuroendocrine and carcinoid tumors. Cancer Chemother Pharmacol 2014; 75:1099-114. [DOI: 10.1007/s00280-014-2642-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 11/24/2014] [Indexed: 02/04/2023]
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Baudin E, Caron P, Lombard-Bohas C, Tabarin A, Mitry E, Reznick Y, Taieb D, Pattou F, Goudet P, Vezzosi D, Scoazec JY, Cadiot G, Borson-Chazot F, Do Cao C. [Malignant insulinoma: recommendations for workup and treatment]. Presse Med 2014; 43:645-59. [PMID: 24857257 DOI: 10.1016/j.lpm.2013.08.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Revised: 07/15/2013] [Accepted: 08/19/2013] [Indexed: 02/09/2023] Open
Abstract
Insulinoma are malignant in 4 to 14 % of cases. Their rarity and the sparse data available in the literature have limited publication of specific guidelines for their management. The following review aim to provide up-to-date recommendations on initial evaluation including pathologic grading, measures to control hypoglycemia, antitumor strategies and long term follow-up. Will be discussed in detail respective indications of surgery, diazoxide, somatostatin analogs, everolimus, sunitinib, liver directed treatments including arterial embolization, chemotherapy and radiometabolic therapy. A Medline search using terms "insulinoma", "neuroendocrine pancreatic tumors", "islet cell carcinoma", "malignant insulinoma" was performed limiting the selection to English language articles and adult age cases, along with cross referencing.
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Affiliation(s)
- Eric Baudin
- Institut Gustave-Roussy, service de médecine nucléaire et d'oncologie endocrinienne, 94805 Villejuif cedex, France.
| | - Philippe Caron
- CHU Rangueil-Larrey, pôle cardiovasculaire et métabolique, service d'endocrinologie et maladies métaboliques, 31059 Toulouse cedex 9, France
| | | | - Antoine Tabarin
- Hôpital Haut-Lévêque, service d'endocrinologie, 33600 Pessac, France
| | - Emmanuel Mitry
- Institut Curie, hôpital René-Huguenin, service d'onco-gastroentérologie, 92210 Saint-Cloud, France
| | - Yves Reznick
- CHU Côte-de-Nacre, unité fonctionnelle d'endocrinologie et maladies métaboliques, 14033 Caen cedex, France
| | - David Taieb
- CHU de la Timone, service central de biophysique et de médecine nucléaire, 13005 Marseille, France
| | - François Pattou
- Hôpital Claude-Huriez, service de chirurgie endocrinienne, 59000 Lille, France
| | - Pierre Goudet
- CHU de Dijon, service de chirurgie générale et endocrinienne, 21000 Dijon, France
| | - Delphine Vezzosi
- CHU Rangueil-Larrey, pôle cardiovasculaire et métabolique, service d'endocrinologie et maladies métaboliques, 31059 Toulouse cedex 9, France
| | - Jean-Yves Scoazec
- Institut Gustave-Roussy, service de biologie et de pathologie médicales, 94805 Villejuif cedex, France
| | - Guillaume Cadiot
- Hôpital Robert-Debré, service d'hépato-gastro-entérologie et de cancérologie digestive, 51100 Reims, France
| | - Françoise Borson-Chazot
- Hospices Civils de Lyon, Fédération d'endocrinologie du pole Est, Fédération d'endocrinologie et centre de médecine nucléaire, 69500 Lyon, France
| | - Christine Do Cao
- Hôpital Claude-Huriez, service d'endocrinologie et de maladies métaboliques, 59000 Lille, France
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Chalabi M, Duluc C, Caron P, Vezzosi D, Guillermet-Guibert J, Pyronnet S, Bousquet C. Somatostatin analogs: does pharmacology impact antitumor efficacy? Trends Endocrinol Metab 2014; 25:115-27. [PMID: 24405892 DOI: 10.1016/j.tem.2013.11.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 11/05/2013] [Accepted: 11/15/2013] [Indexed: 01/17/2023]
Abstract
Somatostatin is an endogenous inhibitor of secretion and cell proliferation. These features render somatostatin a logical candidate for the management of neuroendocrine tumors that express somatostatin receptors. Synthetic somatostatin analogs (SSAs) have longer half-lives than somatostatin, but have similar activities, and are used for the treatment of these types of disorders. Interest has focused on novel multireceptor analogs with broader affinity to several of the five somatostatin receptors, thereby presenting putatively higher antitumor activities. Recent evidence indicates that SSAs cannot be considered mimics of native somatostatin in regulating signaling pathways downstream of receptors. Here we review this knowledge, discuss the concept of biased agonism, and highlight what considerations need to be taken into account for the optimal clinical use of SSAs.
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Affiliation(s)
- Mounira Chalabi
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), 31432 Toulouse, France; Université Toulouse III Paul Sabatier, 31062 Toulouse, France
| | - Camille Duluc
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), 31432 Toulouse, France; Université Toulouse III Paul Sabatier, 31062 Toulouse, France
| | - Philippe Caron
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), 31432 Toulouse, France; Université Toulouse III Paul Sabatier, 31062 Toulouse, France; Service d'Endocrinologie et Maladies Métaboliques, Pôle Cardio-Vasculaire et Métabolique, Centre Hospitalier Universitaire (CHU) Larrey, 31059 Toulouse, France
| | - Delphine Vezzosi
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), 31432 Toulouse, France; Université Toulouse III Paul Sabatier, 31062 Toulouse, France; Service d'Endocrinologie et Maladies Métaboliques, Pôle Cardio-Vasculaire et Métabolique, Centre Hospitalier Universitaire (CHU) Larrey, 31059 Toulouse, France
| | - Julie Guillermet-Guibert
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), 31432 Toulouse, France; Université Toulouse III Paul Sabatier, 31062 Toulouse, France
| | - Stéphane Pyronnet
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), 31432 Toulouse, France; Université Toulouse III Paul Sabatier, 31062 Toulouse, France
| | - Corinne Bousquet
- Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR) 1037, Centre de Recherche en Cancérologie de Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), 31432 Toulouse, France; Université Toulouse III Paul Sabatier, 31062 Toulouse, France.
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Martín-Richard M, Massutí B, Pineda E, Alonso V, Marmol M, Castellano D, Fonseca E, Galán A, Llanos M, Sala MA, Pericay C, Rivera F, Sastre J, Segura A, Quindós M, Maisonobe P. Antiproliferative effects of lanreotide autogel in patients with progressive, well-differentiated neuroendocrine tumours: a Spanish, multicentre, open-label, single arm phase II study. BMC Cancer 2013; 13:427. [PMID: 24053191 PMCID: PMC3853091 DOI: 10.1186/1471-2407-13-427] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 09/11/2013] [Indexed: 01/17/2023] Open
Abstract
Background Somatostatin analogues (SSAs) are indicated to relieve carcinoid syndrome but seem to have antiproliferative effects on neuroendocrine tumours (NETs). This is the first prospective study investigating tumour stabilisation with the long-acting SSA lanreotide Autogel in patients with progressive NETs. Methods This was a multicentre, open-label, phase II trial conducted in 17 Spanish specialist centres. Patients with well-differentiated NETs and radiologically confirmed progression within the previous 6 months received lanreotide Autogel, 120 mg every 28 days over ≤92 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, tumour biomarkers, symptom control, quality of life (QoL), and safety. Radiographic imaging was assessed by a blinded central radiologist. Results Of 30 patients included in the efficacy and safety analyses, 40% had midgut tumours and 27% pancreatic tumours; 63% of tumours were functioning. Median PFS time was 12.9 (95% CI: 7.9, 16.5) months, and most patients achieved disease stabilisation (89%) or partial response (4%). No deterioration in QoL was observed. Nineteen patients (63%) experienced treatment-related adverse events, most frequently diarrhoea and asthenia; only one treatment-related adverse event (aerophagia) was severe. Conclusion Lanreotide Autogel provided effective tumour stabilisation and PFS >12 months in patients with progressive NETs ineligible for surgery or chemotherapy, with a safety profile consistent with the pharmacology of the class. Trial registration ClinicalTrials.gov Identifier NCT00326469; EU Clinical Trial Register EudraCT no 2004-002871-18.
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Affiliation(s)
- Marta Martín-Richard
- Medical Oncology Department, Hospital de la Santa Creu y Sant Pau, Av, Sant Antoni Mª Claret, 167, Barcelona 08025, Spain.
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47
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Baudin E, Caron P, Lombard-Bohas C, Tabarin A, Mitry E, Reznick Y, Taieb D, Pattou F, Goudet P, Vezzosi D, Scoazec JY, Cadiot G, Borson-Chazot F, Do Cao C. Malignant insulinoma: recommendations for characterisation and treatment. ANNALES D'ENDOCRINOLOGIE 2013; 74:523-33. [PMID: 23993836 DOI: 10.1016/j.ando.2013.07.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Accepted: 07/05/2013] [Indexed: 12/11/2022]
Affiliation(s)
- Eric Baudin
- Service de médecine nucléaire et d'oncologie endocrinienne, institut Gustave-Roussy, 94800 Villejuif, France
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48
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Theodoropoulou M, Stalla GK. Somatostatin receptors: from signaling to clinical practice. Front Neuroendocrinol 2013; 34:228-52. [PMID: 23872332 DOI: 10.1016/j.yfrne.2013.07.005] [Citation(s) in RCA: 280] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 06/13/2013] [Accepted: 07/12/2013] [Indexed: 02/08/2023]
Abstract
Somatostatin is a peptide with a potent and broad antisecretory action, which makes it an invaluable drug target for the pharmacological management of pituitary adenomas and neuroendocrine tumors. Somatostatin receptors (SSTR1, 2A and B, 3, 4 and 5) belong to the G protein coupled receptor family and have a wide expression pattern in both normal tissues and solid tumors. Investigating the function of each SSTR in several tumor types has provided a wealth of information about the common but also distinct signaling cascades that suppress tumor cell proliferation, survival and angiogenesis. This provided the rationale for developing multireceptor-targeted somatostatin analogs and combination therapies with signaling-targeted agents such as inhibitors of the mammalian (or mechanistic) target of rapamycin (mTOR). The ability of SSTR to internalize and the development of rabiolabeled somatostatin analogs have improved the diagnosis and treatment of neuroendocrine tumors.
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Affiliation(s)
- Marily Theodoropoulou
- Department of Endocrinology, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany.
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49
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Toumpanakis C, Caplin ME. Update on the role of somatostatin analogs for the treatment of patients with gastroenteropancreatic neuroendocrine tumors. Semin Oncol 2013; 40:56-68. [PMID: 23391113 DOI: 10.1053/j.seminoncol.2012.11.006] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Somatostatin analogs (SA) are the standard of care for controlling symptoms of patients with functional gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). SA control symptoms in more than 70% of patients with carcinoid syndrome. Similar results are obtained in patients with functional, hormone-secreting, pancreatic NETs. The use of SA as antiproliferative agents has been established only recently. Retrospective studies have shown stabilization of tumor growth in >50% of patients with progressive disease. The results of a recent randomized phase III trial (PROMID) demonstrated that the median time to progression in patients with midgut carcinoid tumors treated with octreotide LAR (Long-Acting-Repeatable, Novartis, Basel, Switzerland) was more than twice as long compared to that of patients treated with placebo. The results of a phase III study of lanreotide versus placebo in nonfunctional NETs are not yet available. More studies are needed to determine whether combining SA with novel targeted treatments will result in enhanced antiproliferative activity compared to treatment with a SA alone. Studies are ongoing using pan-receptor agonists (eg, pasireotide) and chimeric dimers, which possess features of somatostatin and dopamine agonists (dopastatins) and are thought to enhance symptom control by binding multiple receptors (somatostatin and dopamine receptors). Somatostatin receptor antagonists are also currently being developed for clinical use. Peptide receptor radionuclide therapy (PRRT), consisting of yttrium-90 and lutetium-177 isotopes conjugated with SA appear to be efficacious in advanced NETs. Randomized studies are needed to definitively establish the safety and efficacy of this strategy compared to other available treatments, and to determine which radiolabeled isotopes or combinations are most effective.
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Affiliation(s)
- Christos Toumpanakis
- Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
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50
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Ki67 proliferation index, hepatic tumor load, and pretreatment tumor growth predict the antitumoral efficacy of lanreotide in patients with malignant digestive neuroendocrine tumors. Eur J Gastroenterol Hepatol 2013; 25:232-8. [PMID: 23108416 DOI: 10.1097/meg.0b013e328359d1a6] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND An antiproliferative effect of somatostatin analogs was recently demonstrated. AIM To identify factors associated with tumor control in a group of patients with well-differentiated malignant digestive neuroendocrine tumors treated with lanreotide. METHODS A retrospective study was conducted in 68 patients treated with lanreotide alone, with progression-free survival as the primary endpoint. The role of the following factors was searched for by univariate and multivariate analyses: age, sex, mode of discovery, site of the primary tumor, metastatic spread, Ki67 proliferation index, uptake on somatostatin receptor scintigraphy, pretreatment tumor growth, extent of liver involvement, resection of primary tumor, previous treatments, and tumor markers. RESULTS Tumor progression was observed in 39/68 patients (57.4%). Median progression-free survival was 29 months. On multivariate analysis, a Ki67 proliferation index of up to 5% [hazard ratio (HR)=0.262, P=0.009], pretreatment stability (HR=0.241, P=0.008), and hepatic tumor load of up to 25% (HR=0.237, P=0.004) were significantly associated with disease stability under lanreotide therapy. CONCLUSION In patients with well-differentiated malignant digestive neuroendocrine tumors, Ki67 proliferation index of up to 5%, stable disease before treatment, and low-to-moderate hepatic tumor involvement (≤ 25%) are associated with tumor control during lanreotide treatment. These data if confirmed in prospective trials will help in rationalizing the use of somatostatin analogs with antiproliferative intent.
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