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Chan JA, Geyer S, Zemla T, Knopp MV, Behr S, Pulsipher S, Ou FS, Dueck AC, Acoba J, Shergill A, Wolin EM, Halfdanarson TR, Konda B, Trikalinos NA, Tawfik B, Raj N, Shaheen S, Vijayvergia N, Dasari A, Strosberg JR, Kohn EC, Kulke MH, O’Reilly EM, Meyerhardt JA. Phase 3 Trial of Cabozantinib to Treat Advanced Neuroendocrine Tumors. N Engl J Med 2025; 392:653-665. [PMID: 39282913 PMCID: PMC11821447 DOI: 10.1056/nejmoa2403991] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
BACKGROUND Treatment options for patients with advanced neuroendocrine tumors are limited. The efficacy of cabozantinib in the treatment of previously treated, progressive extrapancreatic or pancreatic neuroendocrine tumors is unclear. METHODS We enrolled two independent cohorts of patients - those with extrapancreatic neuroendocrine tumors and those with pancreatic neuroendocrine tumors - who had received peptide receptor radionuclide therapy or targeted therapy or both. Patients were randomly assigned in a 2:1 ratio to receive cabozantinib at a dose of 60 mg daily or placebo. The primary end point was progression-free survival as assessed by blinded independent central review. Key secondary end points included objective response, overall survival, and safety. RESULTS In the cohort of 203 patients with extrapancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 8.4 months, as compared with 3.9 months with placebo (stratified hazard ratio for progression or death, 0.38; 95% confidence interval [CI], 0.25 to 0.59; P<0.001). In the cohort of 95 patients with pancreatic neuroendocrine tumors, the median progression-free survival with cabozantinib was 13.8 months, as compared with 4.4 months with placebo (stratified hazard ratio, 0.23; 95% CI, 0.12 to 0.42; P<0.001). The incidence of confirmed objective response with cabozantinib was 5% and 19% among patients with extrapancreatic and pancreatic neuroendocrine tumors, respectively, as compared with 0% with placebo. Grade 3 or higher adverse events were noted in 62 to 65% of the patients treated with cabozantinib, as compared with 23 to 27% of the patients who received placebo. Common treatment-related adverse events of grade 3 or higher included hypertension, fatigue, diarrhea, and thromboembolic events. CONCLUSIONS Cabozantinib, as compared with placebo, significantly improved progression-free survival in patients with previously treated, progressive advanced extrapancreatic or pancreatic neuroendocrine tumors. Adverse events were consistent with the known safety profile of cabozantinib. (Funded by the National Cancer Institute and others; CABINET ClinicalTrials.gov number, NCT03375320.).
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Affiliation(s)
| | - Susan Geyer
- Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN
| | - Tyler Zemla
- Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN
| | - Michael V. Knopp
- Wright Center of Innovation & IROC, University of Cincinnati, Cincinnati, OH
| | - Spencer Behr
- University of California, San Francisco, San Francisco, CA
| | - Sydney Pulsipher
- Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN
| | - Fang-Shu Ou
- Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN
| | - Amylou C. Dueck
- Alliance Statistics and Data Management Center, Mayo Clinic, Scottsdale, AZ
| | - Jared Acoba
- University of Hawaii Cancer Center, Honolulu, HI
| | - Ardaman Shergill
- Alliance Protocol Operations Office, University of Chicago, Chicago, IL
| | | | | | - Bhavana Konda
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | | | - Bernard Tawfik
- University of New Mexico Comprehensive Cancer Center, Albuquerque, NM
| | - Nitya Raj
- Memorial Sloan Kettering Cancer Center, New York, NY
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Melhorn P, Raderer M, Kiesewetter B. Selecting systemic treatment for metastatic neuroendocrine tumors of the lung-current evidence and clinical implications. Cancer Treat Rev 2025; 133:102878. [PMID: 39787793 DOI: 10.1016/j.ctrv.2024.102878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 12/15/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025]
Abstract
Neuroendocrine tumors (NET) of the lung are a slowly growing subtype of lung cancer that has a different treatment paradigm than aggressive and more common forms of lung neuroendocrine neoplasms (NEN) like small cell lung cancer (SCLC). Current guidelines for metastatic lung NET advocate a handful of treatment options, including somatostatin analogs (SSA), everolimus, temozolomide- or platin-based chemotherapy, and peptide receptor radionuclide therapy (PRRT). However, there is no clear treatment sequence, and the therapy of choice may depend on several factors such as tumor grade / growth rate, tumor burden / symptoms, disease progression status, and somatostatin receptor (SSTR) expression. In order to tailor treatment to each individual patient, the latest scientific findings and patient-specific clinical features must be considered together. This review critically evaluates the available evidence with regards to relevant patient characteristics, inclusion and exclusion criteria, and outcome metrics of clinical trials given the presumed natural disease course. Specific patient subgroups with an unmet therapeutic need are identified and discussed in the context of ongoing clinical trials.
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Affiliation(s)
- Philipp Melhorn
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Austria
| | - Markus Raderer
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Austria
| | - Barbara Kiesewetter
- Department of Medicine I, Division of Oncology, Medical University of Vienna, Austria.
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3
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Perez K, Kulke MH, Zheng H, Allen J, Clark J, Enzinger AC, Enzinger PC, Johnson BE, McCleary NJ, Parikh A, Patel A, Rubinson D, Yurgelun MB, Ramsey K, Johnson E, Graham C, Chan JA. A phase II study of ramucirumab and somatostatin analog therapy in patients with advanced neuroendocrine tumors. Oncologist 2025; 30:oyae364. [PMID: 39834129 PMCID: PMC11753395 DOI: 10.1093/oncolo/oyae364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 12/07/2024] [Indexed: 01/22/2025] Open
Abstract
OBJECTIVES Well-differentiated neuroendocrine tumors (NET) are highly vascular tumors characterized by their expression of vascular endothelial growth factor (VEGF). This trial investigated the activity of ramucirumab, a monoclonal antibody that targets VEGF receptor-2 (VEGFR-2) and inhibits activity of VEGF, in combination with somatostatin analog therapy in patients (pts) with advanced extra-pancreatic NET. METHODS We conducted a single-arm phase II trial enrolling pts with advanced, progressive extra-pancreatic NET. Patients were treated with ramucirumab 8 mg/kg intravenously on days 1 and 15 of each 28-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints toxicity, radiographic and biochemical tumor response rate, and overall survival (OS). RESULTS The trial enrolled 43 patients. Primary tumor sites included small intestine 20 (46%), lung 10 (23%), thymus 3 (7%), rectum 1(2%), kidney 1(2%), and unknown primary 8(18%). Median PFS was 14.2 months (95% CI, 9.0-25.6 months), and median OS was 24.9 months (95% CI, 20.7-43.1 months). Best response by RECIST 1.1: partial response 5% (95% CI, 0.6%-15.8%). Chromogranin A levels dropped by at least 50% in 10% of the 37 patients who had elevated levels at baseline. Most common all-grade adverse events included fatigue (84%) and hypertension (84%). CONCLUSION Ramucirumab demonstrated efficacy and safety in this single-arm phase II trial. These findings support the continued evaluation of angiogenesis inhibitors in the treatment of NET. CLINICAL TRIAL REGISTRATION NCT02795858.
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Affiliation(s)
- Kimberly Perez
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States
- Harvard Medical School, Boston, MA 02115, United States
| | - Matthew H Kulke
- Section of Hematology and Oncology, Boston University and Boston Medical Center, Boston, MA 02118, United States
| | - Hui Zheng
- Biostatistics Center, Massachusetts General Hospital, Boston, MA 02114, United States
| | - Jill Allen
- Harvard Medical School, Boston, MA 02115, United States
- Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, United States
| | - Jeffrey Clark
- Harvard Medical School, Boston, MA 02115, United States
- Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, United States
| | - Andrea C Enzinger
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States
- Harvard Medical School, Boston, MA 02115, United States
| | - Peter C Enzinger
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States
- Harvard Medical School, Boston, MA 02115, United States
| | - Bruce E Johnson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States
- Harvard Medical School, Boston, MA 02115, United States
| | - Nadine J McCleary
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States
- Harvard Medical School, Boston, MA 02115, United States
| | - Aparna Parikh
- Harvard Medical School, Boston, MA 02115, United States
- Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, United States
| | - Anuj Patel
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States
- Harvard Medical School, Boston, MA 02115, United States
| | - Douglas Rubinson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States
- Harvard Medical School, Boston, MA 02115, United States
| | - Matthew B Yurgelun
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States
- Harvard Medical School, Boston, MA 02115, United States
| | - Kaitlyn Ramsey
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States
| | - Emma Johnson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States
| | - Christopher Graham
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States
| | - Jennifer A Chan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, United States
- Harvard Medical School, Boston, MA 02115, United States
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4
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Ye S, Li J, Xu J. Treatment strategies for advanced neuroendocrine neoplasms: current status and future prospects. Cancer Biol Med 2025; 22:j.issn.2095-3941.2024.0507. [PMID: 39749725 PMCID: PMC11795266 DOI: 10.20892/j.issn.2095-3941.2024.0507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 12/16/2024] [Indexed: 01/04/2025] Open
Affiliation(s)
- Sisi Ye
- Department of Oncology, Fifth Medical Center of the Chinese PLA General Hospital, Beijing 100071, China
| | - Juan Li
- Department of Oncology, First Medical Center of the Chinese PLA General Hospital, Beijing 100853, China
| | - Jianming Xu
- Department of Oncology, Fifth Medical Center of the Chinese PLA General Hospital, Beijing 100071, China
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5
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Othus M, Freidlin B, Korn EL. Avoiding Delays in Reporting Time-to-Event Randomized Trials: Calendar Backstops and Other Approaches. J Clin Oncol 2024; 42:3753-3760. [PMID: 38759123 PMCID: PMC11521763 DOI: 10.1200/jco.24.00025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 02/12/2024] [Accepted: 03/13/2024] [Indexed: 05/19/2024] Open
Abstract
New oncology therapies that extend patients' lives beyond initial expectations and improving later-line treatments can lead to complications in clinical trial design and conduct. In particular, for trials with event-based analyses, the time to observe all the protocol-specified events can exceed the finite follow-up of a clinical trial or can lead to much delayed release of outcome data. With the advent of multiple classes of oncology therapies leading to much longer survival than in the past, this issue in clinical trial design and conduct has become increasingly important in recent years. We propose a straightforward prespecified backstop rule for trials with a time-to-event analysis and evaluate the impact of the rule with both simulated and real-world trial data. We then provide recommendations for implementing the rule across a range of oncology clinical trial settings.
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Affiliation(s)
- Megan Othus
- SWOG Cancer Research Network and Fred Hutchinson Cancer Research Center, Seattle WA
| | - Boris Freidlin
- Biometric Research Program, National Cancer Institute, Bethesda MD
| | - Edward L. Korn
- Biometric Research Program, National Cancer Institute, Bethesda MD
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6
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Hounschell CA, Higginbotham S, Al-Kasspooles M, Selby LV. Gastroenteropancreatic Neuroendocrine Tumor with Peritoneal Metastasis: A Review of Current Management. Cancers (Basel) 2024; 16:3472. [PMID: 39456565 PMCID: PMC11506451 DOI: 10.3390/cancers16203472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 10/07/2024] [Accepted: 10/10/2024] [Indexed: 10/28/2024] Open
Abstract
Peritoneal metastasis in gastroenteropancreatic neuroendocrine tumors poses a significant clinical challenge, with limited data guiding management strategies. We review the existing literature on surgical and systemic treatment modalities for peritoneal metastasis from gastroenteropancreatic neuroendocrine tumors. Surgical interventions, including cytoreductive surgery, have shown promise in improving symptom control and overall survival-particularly in cases in which 70% cytoreduction can be achieved. Hyperthermic intraperitoneal chemotherapy remains controversial due to a paucity of high-level evidence and a lack of consensus for routine use. The use of systemic therapy in the setting of peritoneal metastasis from gastroenteropancreatic neuroendocrine tumors is extrapolated from high-quality evidence for its use in the setting of the solid organ metastasis of this disease. The use of somatostatin analogs for symptom control and some antiproliferative effects is supported by large clinical trials. Additional strong evidence exists for the use of interferon-alpha, everolimus, and sunitinib, particularly in pancreatic neuroendocrine tumors. Cytotoxic chemotherapy and peptide receptor radionuclide therapy may be used in select cases, though as an emerging treatment modality, the optimal sequence of peptide receptor radionuclide therapy within the existing algorithms is unknown. Significant gaps in understanding and standardized management exist, particularly for those patients presenting with peritoneal metastasis, and targeted research to optimize outcomes in this population is needed.
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Affiliation(s)
- Corey A. Hounschell
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66103, USA; (C.A.H.); (M.A.-K.)
| | | | - Mazin Al-Kasspooles
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66103, USA; (C.A.H.); (M.A.-K.)
| | - Luke V. Selby
- Department of Surgery, University of Kansas Medical Center, Kansas City, KS 66103, USA; (C.A.H.); (M.A.-K.)
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7
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Tan B, Zhang B, Chen H. Gastroenteropancreatic neuroendocrine neoplasms: epidemiology, genetics, and treatment. Front Endocrinol (Lausanne) 2024; 15:1424839. [PMID: 39411312 PMCID: PMC11474919 DOI: 10.3389/fendo.2024.1424839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Accepted: 09/10/2024] [Indexed: 10/19/2024] Open
Abstract
The incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) is increasing at a rapid pace and is becoming an increasingly important consideration in clinical care. Epidemiological data from multiple countries indicate that the incidence of gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) exhibits regional, site-specific, and gender-based variations. While the genetics and pathogenesis of some GEP NEN, particularly pancreatic NENs, have been investigated, there are still many mechanisms that require further investigation. The management of GEP NEN is diverse, but surgery remains the primary option for most cases. Peptide receptor radionuclide therapy (PRRT) is an effective treatment, and several clinical trials are exploring the potential of immunotherapy and targeted therapy, as well as combination therapy.
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Affiliation(s)
- Baizhou Tan
- Department of Histology and Embryology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Beiyu Zhang
- Department of Histology and Embryology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Hongping Chen
- Department of Histology and Embryology, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
- Jiangxi Key Laboratory of Experimental Animals, Nanchang University, Nanchang, China
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8
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Lamarca A, Bartsch DK, Caplin M, Kos-Kudla B, Kjaer A, Partelli S, Rinke A, Janson ET, Thirlwell C, van Velthuysen MLF, Vullierme MP, Pavel M. European Neuroendocrine Tumor Society (ENETS) 2024 guidance paper for the management of well-differentiated small intestine neuroendocrine tumours. J Neuroendocrinol 2024; 36:e13423. [PMID: 38977327 DOI: 10.1111/jne.13423] [Citation(s) in RCA: 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: 04/25/2024] [Revised: 05/28/2024] [Accepted: 06/02/2024] [Indexed: 07/10/2024]
Abstract
Both the incidence and prevalence of well-differentiated neuroendocrine tumours from the small intestine (Si-NET) are gradually increasing. Most patients have non-functioning tumours with subtle GI symptoms and tumours are often discovered incidentally by endoscopy or at advanced disease stages by imaging depicting mesenteric lymph node and /or liver metastases while around 30% of the patients present with symptoms of the carcinoid syndrome. Adequate biochemical assessment and staging including functional imaging is crucial for treatment-related decision-making that should take place in an expert multidisciplinary team setting. Preferably, patients should be referred to specialised ENETS Centres of Excellence or centres of high expertise in the field. This guidance paper provides the current evidence and best knowledge for the management of Si-NET grade (G) 1-3 following 10 key questions of practical relevance for the diagnostic and therapeutic decision making.
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Affiliation(s)
- Angela Lamarca
- Department of Oncology - Onco Health Institute, Fundación Jiménez Díaz University Hospital, Madrid, Spain
- Department of Medical Oncology, The Christie NHS Foundation, Manchester, Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Detlef K Bartsch
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Martyn Caplin
- Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK
| | - Beata Kos-Kudla
- Department of Endocrinology and Neuroendocrine Tumors, ENETS Center of Excellence, Department of Pathophysiology and Endocrinology, Medical University of Silesia, Katowice, Poland
| | - Andreas Kjaer
- Department of Clinical Physiology and Nuclear Medicine and Cluster for Molecular Imaging, Copenhagen University of Copenhagen-Rigshospitalet, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stefano Partelli
- Pancreas Translational and Clinical Research Centre, Pancreatic and Transplant Surgery Unit, Vita-Salute San Raffaele University, Milan, Italy
| | - Anja Rinke
- Department of Gastroenterology, University Hospital Marburg and Philipps University Marburg, Marburg, Germany
| | - Eva Tiensuu Janson
- Department of Medical Sciences, Endocrine Oncology Unit, Uppsala University, Uppsala, Sweden
| | - Christina Thirlwell
- Department of Medical Oncology, University of Exeter Medical School, Exeter, UK
| | | | - Marie-Pierre Vullierme
- Department of Radiology, Paul Brousse University Hospital, AP-HP-University Paris Saclay, Villejuif, France
| | - Marianne Pavel
- Department of Medicine 1, Friedrich-Alexander University Erlangen-Nürnberg, ENETS Center of Excellence Erlangen, CCC Erlangen- EMN, and Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Germany
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9
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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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10
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Ünal Ç, Sağlam S. Metronomic Temozolomide (mTMZ) and Bevacizumab-The Safe and Effective Frontier for Treating Metastatic Neuroendocrine Tumors (NETs): A Single-Center Experience. Cancers (Basel) 2023; 15:5688. [PMID: 38067391 PMCID: PMC10705735 DOI: 10.3390/cancers15235688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 11/18/2023] [Accepted: 11/29/2023] [Indexed: 10/16/2024] Open
Abstract
Addressing the persistent challenges in treating metastatic neuroendocrine tumors (NETs) demands ongoing refinement and innovation in therapeutic strategies. This study investigates the potential advantages of combining metronomic temozolomide (mTMZ) with bevacizumab for patients diagnosed with metastatic NETs, particularly focusing on those with a Ki-67 index under 55%. Data from 30 patients were analyzed, using key performance indicators such as progression-free survival (PFS), overall survival (OS), and response rates to therapy, to gauge the treatment's efficacy. The results were encouraging: the median PFS recorded was 16.3 months, and the OS was 25.9 months. The disease control rate (DCR) reached an impressive 86.7%, and the objective response rate (ORR) stood at 63.3%. The treatment regimen was well-tolerated, with no reported instances of grade 4 toxicities. Such a safety profile indicates that this regimen may be particularly advantageous for older, fragile patients who might struggle with conventional dosage levels. These initial findings suggest that the mTMZ and bevacizumab combination could potentially rival the conventional temozolomide-capecitabine therapy in managing metastatic NETs. We aimed to meticulously assess the efficacy of the mTMZ and bevacizumab combination in treating metastatic NETs. Given the initial promising results, a more conclusive understanding of its efficacy will require further research through larger, multicenter prospective clinical trials.
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Affiliation(s)
- Çağlar Ünal
- Division of Medical Oncology, Department of Internal Medicine, Kartal Dr. Lütfi Kırdar City Hospital, İstanbul 34870, Turkey
| | - Sezer Sağlam
- Division of Medical Oncology, Department of Internal Medicine, Demiroglu Bilim University, İstanbul 34870, Turkey;
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11
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Abuzakhm SM, Sukrithan V, Fruth B, Qin R, Strosberg J, Hobday TJ, Semrad T, Reidy-Lagunes D, Kindler HL, Kim GP, Knox JJ, Kaubisch A, Villalona-Calero M, Chen H, Erlichman C, Shah MH. A phase II study of bevacizumab and temsirolimus in advanced extra-pancreatic neuroendocrine tumors. Endocr Relat Cancer 2023; 30:e220301. [PMID: 37702588 PMCID: PMC10585708 DOI: 10.1530/erc-22-0301] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 08/21/2023] [Indexed: 09/14/2023]
Abstract
We assessed the efficacy and safety of combining bevacizumab with temsirolimus in patients with advanced extra-pancreatic neuroendocrine tumors. This NCI-sponsored multicenter, open-label, phase II study (NCT01010126) enrolled patients with advanced, recurrent, or metastatic extra-pancreatic neuroendocrine tumors. All patients were treated with temsirolimus and bevacizumab until disease progression or unacceptable toxicity. Temsirolimus 25 mg was administered i.v. on days 1, 8, 15, and 22 and bevacizumab 10 mg/kg i.v. on days 1 and 15 of a 4-week cycle. Discontinuation of temsirolimus or bevacizumab did not require discontinuation of the other agent. The primary endpoints were objective response rate and 6-month progression-free survival rate. Fifty-nine patients were enrolled in this study, and 54 were evaluated for efficacy and adverse events. While median progression-free survival was 7.1 months, the median duration of treatment with temsirolimus was 3.9 months and that with bevacizumab was 3.5 months. The objective response rate of combination therapy was 2%, and 6-month progression-free survival was 48%. The most frequently reported grade 3-4 adverse events included fatigue (13%), hypertension (13%), and bleeding (13%). Close to 54% of the patients discontinued treatment due to adverse events, refusal of further treatment, or treatment delays. Three deaths occurred in the study, of which two were due to treatment-related bowel perforations. Given the minimal efficacy and increased toxicity seen with the combination of bevacizumab and temsirolimus, we do not recommend the use of this regimen in patients with advanced extra-pancreatic neuroendocrine tumors.
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Affiliation(s)
| | | | | | - Rui Qin
- Janssen Pharmaceuticals, Raritan, NJ
| | | | | | | | | | | | - George P. Kim
- George Washington University Cancer Center, Washington, DC
| | | | | | | | - Helen Chen
- CTEP National Cancer Institute, Bethesda, MD
| | | | - Manisha H. Shah
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
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12
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Singh S, Hope TA, Bergsland EB, Bodei L, Bushnell DL, Chan JA, Chasen BR, Chauhan A, Das S, Dasari A, Del Rivero J, El-Haddad G, Goodman KA, Halperin DM, Lewis MA, Lindwasser OW, Myrehaug S, Raj NP, Reidy-Lagunes DL, Soares HP, Strosberg JR, Kohn EC, Kunz PL. Consensus report of the 2021 National Cancer Institute neuroendocrine tumor clinical trials planning meeting. J Natl Cancer Inst 2023; 115:1001-1010. [PMID: 37255328 PMCID: PMC10483264 DOI: 10.1093/jnci/djad096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 05/01/2023] [Accepted: 05/11/2023] [Indexed: 06/01/2023] Open
Abstract
Important progress has been made over the last decade in the classification, imaging, and treatment of neuroendocrine neoplasm (NENs), with several new agents approved for use. Although the treatment options available for patients with well-differentiated neuroendocrine tumors (NETs) have greatly expanded, the rapidly changing landscape has presented several unanswered questions about how best to optimize, sequence, and individualize therapy. Perhaps the most important development over the last decade has been the approval of 177Lu-DOTATATE for treatment of gastroenteropancreatic-NETs, raising questions around optimal sequencing of peptide receptor radionuclide therapy (PRRT) relative to other therapeutic options, the role of re-treatment with PRRT, and whether PRRT can be further optimized through use of dosimetry among other approaches. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trial planning meeting in 2021 with multidisciplinary experts from academia, the federal government, industry, and patient advocates to develop NET clinical trials in the era of PRRT. Key clinical trial recommendations for development included 1) PRRT re-treatment, 2) PRRT and immunotherapy combinations, 3) PRRT and DNA damage repair inhibitor combinations, 4) treatment for liver-dominant disease, 5) treatment for PRRT-resistant disease, and 6) dosimetry-modified PRRT.
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Affiliation(s)
- Simron Singh
- Department of Medicine, Sunnybrook Health Sciences Centre, Odette Cancer Center, University of Toronto, Toronto, ON, Canada
| | - Thomas A Hope
- Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA
| | - Emily B Bergsland
- Department of Medicine, University of California, San Francisco, CA, USA
| | - Lisa Bodei
- Department of Radiology, Memorial Sloan Kettering Cancer Center, Molecular Imaging and Therapy Service, New York, NY, USA
| | | | - Jennifer A Chan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Beth R Chasen
- Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Aman Chauhan
- Department of Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Satya Das
- Late-Stage Development, Oncology R&D AstraZeneca, Gaithersburg, MD, USA
| | - Arvind Dasari
- Department of GI Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jaydira Del Rivero
- Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ghassan El-Haddad
- Department of Diagnostic Imaging and Interventional Radiology, Moffitt Cancer Center, Tampa, FL, USA
| | - Karyn A Goodman
- Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY, USA
| | - Daniel M Halperin
- Department of GI Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mark A Lewis
- Department of Medicine, Intermountain Health, Salt Lake City, UT, USA
| | - O Wolf Lindwasser
- Coordinating Center for Clinical Trials, National Cancer Institute, Bethesda, MD, USA
| | - Sten Myrehaug
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Center, Toronto, ON, Canada
| | - Nitya P Raj
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Heloisa P Soares
- Department of Medicine, Huntsman Cancer Institute at University of Utah, Salt Lake City, UT, USA
| | | | | | - Pamela L Kunz
- Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
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13
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Castillón JC, Gordoa TA, Bayonas AC, Carretero AC, García-Carbonero R, Pulido EG, Fonseca PJ, Lete AL, Huerta AS, Plazas JG. SEOM-GETNE clinical guidelines for the diagnosis and treatment of gastroenteropancreatic and bronchial neuroendocrine neoplasms (NENs) (2022). Clin Transl Oncol 2023; 25:2692-2706. [PMID: 37204633 PMCID: PMC10425298 DOI: 10.1007/s12094-023-03205-6] [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: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 05/20/2023]
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous family of tumors of challenging diagnosis and clinical management. Their incidence and prevalence continue to rise mainly due to an improvement on diagnostic techniques and awareness. Earlier detection, along with steadfast improvements in therapy, has led to better prognosis over time for advanced gastrointestinal and pancreatic neuroendocrine tumors. The aim of this guideline is to update evidence-based recommendations for the diagnosis and treatment of gastroenteropancreatic and lung NENs. Diagnostic procedures, histological classification, and therapeutic options, including surgery, liver-directed therapy, peptide receptor radionuclide therapy, and systemic hormonal, cytotoxic or targeted therapy, are reviewed and discussed, and treatment algorithms to guide therapeutic decisions are provided.
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Affiliation(s)
- Jaume Capdevila Castillón
- Servicio de Oncología Médica, Hospital Universitario Vall D’Hebron, Ps Vall d’Hebron, 119-129, 08035 Barcelona, Spain
| | - Teresa Alonso Gordoa
- Servicio de Oncología Médica, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | | | | | | | | | - Paula Jiménez Fonseca
- Servicio de Oncología Médica, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Angela Lamarca Lete
- Servicio de Oncología Médica, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain
| | - Angel Segura Huerta
- Servicio de Oncología Médica, Hospital Universitari I Politècnic la Fe, Valencia, Spain
| | - Javier Gallego Plazas
- Servicio de Oncología Médica, Hospital General Universitario de Elche, Alicante, Spain
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14
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Mosalem O, Sonbol MB, Halfdanarson TR, Starr JS. Tyrosine Kinase Inhibitors and Immunotherapy Updates in Neuroendocrine Neoplasms. Best Pract Res Clin Endocrinol Metab 2023; 37:101796. [PMID: 37414652 DOI: 10.1016/j.beem.2023.101796] [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] [Indexed: 07/08/2023]
Abstract
Neuroendocrine tumors (NETs) represent a heterogeneous group of malignancies that arise from neuroendocrine cells dispersed throughout the organs/tissues of the body. Treatment of advanced/metastatic disease varies depending on tumor origin and grade. Somatostatin analogs (SSA) have been the mainstay first-line treatment in the advanced/metastatic setting for tumor control and managing hormonal syndromes. Treatments beyond SSAs have expanded to include everolimus (mTOR inhibitor), tyrosine kinase inhibitors (TKI) (e.g., sunitinib), and peptide receptor radionuclide therapy (PRRT) with the choice of therapy to some extent dictated by the anatomic origin of the NETs. This review will focus on emerging systemic treatments for advanced/metastatic NETs, particularly TKIs, and immunotherapy.
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Affiliation(s)
- Osama Mosalem
- Division of Hematology and Oncology, Mayo Clinic Cancer Center, Jacksonville, FL, USA.
| | | | | | - Jason S Starr
- Division of Hematology and Oncology, Mayo Clinic Cancer Center, Jacksonville, FL, USA.
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15
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Diamantopoulos LN, Kalligeros M, Halfdanarson TR, Diamantis N, Toumpanakis C. Combination Systemic Therapies in Advanced Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): A Comprehensive Review of Clinical Trials and Prospective Studies. BIOLOGY 2023; 12:1069. [PMID: 37626955 PMCID: PMC10452098 DOI: 10.3390/biology12081069] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 07/04/2023] [Accepted: 07/05/2023] [Indexed: 08/27/2023]
Abstract
There is an evolving landscape of systemic combination regimens for patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In this review, we provide a comprehensive outline of the existing clinical trials/prospective studies investigating these combinations. PubMed was searched using key relevant terms to identify articles referring to GEP-NETs and combination treatments. No systematic search of the literature or metanalysis of the data was performed, and we focused on the most recent literature results. Primarily, phase 1 and 2 clinical trials were available, with a smaller number of phase 3 trials, reporting results from combination treatments across a wide range of antiproliferative agents. We identified significant variability in the anti-tumor activity of the reported combinations, with occasional promising results, but only a very small number of practice-changing phase 3 clinical trials. Overall, the peptide receptor radionuclide therapy (PRRT)-based combinations (with chemotherapy, dual PPRT, and targeted agents) and anti-vascular endothelial growth factor (VEGF) agent combinations with standard chemotherapy were found to have favorable results and may be worth investigating in future, larger-scale trials. In contrast, the immune-checkpoint inhibitor-based combinations were found to have limited applicability in advanced, well-differentiated GEP-NETs.
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Affiliation(s)
- Leonidas N. Diamantopoulos
- Department of Medicine, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA;
| | - Markos Kalligeros
- Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA;
| | | | - Nikolaos Diamantis
- Department of Medical Oncology, Royal Free London NHS Foundation Trust and University College London, London WC1E 6BT, UK;
| | - Christos Toumpanakis
- Neuroendocrine Tumor Unit, Centre for Gastroenterology, ENETS Centre of Excellence, Royal Free London NHS Foundation Trust and University College London, London WC1E 6BT, UK
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16
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Capdevila J, Hernando J, Teule A, Lopez C, Garcia-Carbonero R, Benavent M, Custodio A, Garcia-Alvarez A, Cubillo A, Alonso V, Carmona-Bayonas A, Alonso-Gordoa T, Crespo G, Jimenez-Fonseca P, Blanco M, Viudez A, La Casta A, Sevilla I, Segura A, Llanos M, Landolfi S, Nuciforo P, Manzano JL. Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin. Nat Commun 2023; 14:2973. [PMID: 37221181 DOI: 10.1038/s41467-023-38611-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 05/10/2023] [Indexed: 05/25/2023] Open
Abstract
Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.
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Affiliation(s)
- J Capdevila
- Medical Oncology Department, Vall Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain.
- Medical Oncology Department, IOB-Quiron-Teknon, Barcelona, Spain.
| | - J Hernando
- Medical Oncology Department, Vall Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - A Teule
- Medical Oncology Department, Institut Català d'Oncologia (ICO) - IDIBELL L'Hospitalet del Llobregat, L'Hospitalet de Llobregat, Spain
| | - C Lopez
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - R Garcia-Carbonero
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Imas12, UCM, CNIO, Madrid, Spain
| | - M Benavent
- Medical Oncology Department, University Hospital Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), Seville, Spain
| | - A Custodio
- Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain
| | - A Garcia-Alvarez
- Medical Oncology Department, Vall Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - A Cubillo
- Medical Oncology Department, Hospital Universitario HM Sanchinarro, Madrid, Spain
| | - V Alonso
- Medical Oncology Department, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria de Aragón (IISA), Zaragoza, Spain
| | - A Carmona-Bayonas
- Hematology and Medical Oncology Department, Hospital Universitario Morales Meseguer, UMU, IMIB, Murcia, Spain
| | - T Alonso-Gordoa
- Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - G Crespo
- Medical Oncology Department, Complejo Asistencial Universitario de Burgos, Burgos, Spain
| | - P Jimenez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | - M Blanco
- Medical Oncology Department, Hospital Universitario Gregorio Marañon, Madrid, Spain
| | - A Viudez
- Medical Oncology Department, Hospital Universitario de Navarra, Pamplona, Spain
| | - A La Casta
- Medical Oncology Department, Hospital Universitario Donostia, San Sebastián, Spain
| | - I Sevilla
- Medical Oncology Department, Investigación Clínica y Traslacional en Cáncer/Instituto de Investigaciones Biomédicas de Málaga (IBIMA)/Hospitales Universitarios Regional y Virgen de la Victoria de Málaga, Málaga, Spain
| | - A Segura
- Medical Oncology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - M Llanos
- Medical Oncology Department, Hospital Universitario de Canarias, San Cristobal de la Laguna, Spain
| | - S Landolfi
- Pathology Department, Vall Hebron University Hospital, CIBERONC, Barcelona, Spain
| | - P Nuciforo
- Molecular Oncology Group. Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - J L Manzano
- Medical Oncology Department, Institut Català d'Oncologia (ICO) - Badalona, Hospital Germans Trias i Pujol, Badalona, Spain
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17
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Perrier M, Scoazec JY, Walter T. A practical proposal on treatment sequencing of metastatic well-differentiated neuroendocrine tumours. Ther Adv Med Oncol 2023; 15:17588359231171041. [PMID: 37152421 PMCID: PMC10155015 DOI: 10.1177/17588359231171041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 04/04/2023] [Indexed: 05/09/2023] Open
Abstract
According to the neuroendocrine tumour (NET) characteristics, 3 to 7 different treatment options are available, corresponding to 6 to 5,040 theoretical different sequences. Even though each patient is unique and despite a large heterogeneity in NET characteristics, the present review aims to discuss the main sequences and addresses how one can propose the best sequence to treat metastatic NET (mNET) on a case-by-case basis. Each treatment must be discussed during dedicated multi-disciplinary meetings, and inclusions in clinical trials should be favoured. After a thorough characterization of patients and their mNET, and taking into account the availability of drugs, the first-line treatment should be chosen according to the treatment aim. The latter is determined based on three main topics (efficacy, safety, and patient preferences) that do not necessarily converge and must be defined a priori. At baseline, physicians should design an a priori full therapeutic sequence, which may evolve at each step depending on the response to previous treatment, the occurrence of chronic toxicities, and the patients' perception of the prior treatment. To improve knowledge in terms of effectiveness and risk of cumulative toxicities regarding the different sequences, real-world data using long follow-up durations are necessary; such issues will not be resolved by randomized clinical trials.
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Affiliation(s)
- Marine Perrier
- Université Reims Champagne-Ardenne, Department
of Gastroenterology and Digestive Oncology, Reims University Hospital,
Reims, France
| | - Jean-Yves Scoazec
- Department of Surgical and Molecular Pathology,
Gustave Roussy, Villejuif, France
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18
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Targeting OPA1-Mediated Mitochondrial Fusion Contributed to Celastrol's Anti-Tumor Angiogenesis Effect. Pharmaceutics 2022; 15:pharmaceutics15010048. [PMID: 36678677 PMCID: PMC9866574 DOI: 10.3390/pharmaceutics15010048] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 12/15/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
Celastrol, an active triterpenoid extracted from one of the most famous traditional Chinese medicines (TCMs), Tripterygium wilfordii Hook.f., is a novel anti-cancer drug with significant anti-angiogenesis activity. However, the exact molecular mechanisms underlying its anti-tumor angiogenesis effect remain unclear. The process of angiogenesis needs lots of energy supply, which mostly derives from mitochondria, the "energy factory" in our body. This study shows that celastrol exerts visible suppression on tumor growth and angiogenesis in a cell-derived xenograft (CDX). Likewise, it reduced the tube formation and migration of human umbilical vein endothelial cells (HUVECs), suppressed the energy metabolism of mitochondria in the Seahorse XF Mito Stress Test, and triggered mitochondrial fragmentation and NF-κB activation. Mechanically, celastrol downregulated the expression of mitochondrial-sharping protein optic atrophy protein 1 (OPA1), which was further estimated by the OPA1 knockdown model of HUVECs. Specifically, celastrol directly suppressed OPA1 at the mRNA level by inhibiting the phosphorylation of STAT3, and stattic (STAT3 inhibitor) showed the same effects on OPA1 suppression and anti-angiogenesis activity. Overall, this study indicates that celastrol inhibits tumor angiogenesis by suppressing mitochondrial function and morphology via the STAT3/OPA1/P65 pathway and provides new insight for mitochondrion-targeted cancer therapy.
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19
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Gubbi S, Vijayvergia N, Yu JQ, Klubo-Gwiezdzinska J, Koch CA. Immune Checkpoint Inhibitor Therapy in Neuroendocrine Tumors. Horm Metab Res 2022; 54:795-812. [PMID: 35878617 PMCID: PMC9731788 DOI: 10.1055/a-1908-7790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Neuroendocrine tumors (NETs) occur in various regions of the body and present with complex clinical and biochemical phenotypes. The molecular underpinnings that give rise to such varied manifestations have not been completely deciphered. The management of neuroendocrine tumors (NETs) involves surgery, locoregional therapy, and/or systemic therapy. Several forms of systemic therapy, including platinum-based chemotherapy, temozolomide/capecitabine, tyrosine kinase inhibitors, mTOR inhibitors, and peptide receptor radionuclide therapy have been extensively studied and implemented in the treatment of NETs. However, the potential of immune checkpoint inhibitor (ICI) therapy as an option in the management of NETs has only recently garnered attention. Till date, it is not clear whether ICI therapy holds any distinctive advantage in terms of efficacy or safety when compared to other available systemic therapies for NETs. Identifying the characteristics of NETs that would make them (better) respond to ICIs has been challenging. This review provides a summary of the current evidence on the value of ICI therapy in the management of ICIs and discusses the potential areas for future research.
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Affiliation(s)
- Sriram Gubbi
- Endocrinology, National Institutes of Health Clinical Center, Bethesda,
United States
| | | | - Jian Q Yu
- Nuclear Medicine, Fox Chase Cancer Center, Philadelphia, United
States
| | - Joanna Klubo-Gwiezdzinska
- National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, United States
| | - Christian A. Koch
- Medicine/Endocrinology, The University of Tennessee Health
Science Center, Memphis, United States
- Medicine, Fox Chase Cancer Center, Philadelphia, United
States
- Correspondence Prof. Christian A. Koch, FACP,
MACE Fox Chase Cancer
CenterMedicine, 333 Cottman
AvePhiladelphia19111-2497United
States215 728 2713
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20
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Eng L, Brual J, Nagee A, Mok S, Fazelzad R, Chaiton M, Saunders DP, Mittmann N, Truscott R, Liu G, Bradbury PA, Evans WK, Papadakos J, Giuliani ME. Reporting of tobacco use and tobacco-related analyses in cancer cooperative group clinical trials: a systematic scoping review. ESMO Open 2022; 7:100605. [PMID: 36356412 PMCID: PMC9646674 DOI: 10.1016/j.esmoop.2022.100605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 09/21/2022] [Accepted: 09/23/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Continued smoking after a diagnosis of cancer negatively impacts cancer outcomes, but the impact of tobacco on newer treatments options is not well established. Collecting and evaluating tobacco use in clinical trials may advance understanding of the consequences of tobacco use on treatment modalities, but little is known about the frequency of reporting and analysis of tobacco use in cancer cooperative clinical trial groups. PATIENTS AND METHODS A comprehensive literature search was conducted to identify cancer cooperative group clinical trials published from January 2017-October 2019. Eligible studies evaluated either systemic and/or radiation therapies, included ≥100 adult patients, and reported on at least one of: overall survival, disease/progression-free survival, response rates, toxicities/adverse events, or quality-of-life. RESULTS A total of 91 studies representing 90 trials met inclusion criteria with trial start dates ranging from 1995 to 2015 with 14% involving lung and 5% head and neck cancer patients. A total of 19 studies reported baseline tobacco use; 2 reported collecting follow-up tobacco use. Seven studies reported analysis of the impact of baseline tobacco use on clinical outcomes. There was significant heterogeneity in the reporting of baseline tobacco use: 7 reported never/ever status, 10 reported never/ex-smoker/current smoker status, and 4 reported measuring smoking intensity. None reported verifying smoking status or second-hand smoke exposure. Trials of lung and head and neck cancers were more likely to report baseline tobacco use than other disease sites (83% versus 6%, P < 0.001). CONCLUSIONS Few cancer cooperative group clinical trials report and analyze trial participants' tobacco use. Significant heterogeneity exists in reporting tobacco use. Routine standardized collection and reporting of tobacco use at baseline and follow-up in clinical trials should be implemented to enable investigators to evaluate the impact of tobacco use on new cancer therapies.
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Affiliation(s)
- L Eng
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre/University Health Network and University of Toronto, Toronto, Canada.
| | - J Brual
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada
| | - A Nagee
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada
| | - S Mok
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada
| | - R Fazelzad
- Library and Information Services, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
| | - M Chaiton
- Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada
| | - D P Saunders
- Northeast Cancer Centre of Health Sciences North, Northern Ontario School of Medicine, Sudbury, Canada
| | - N Mittmann
- Canadian Agency for Drugs and Technologies in Health, Toronto, Canada
| | - R Truscott
- Division of Prevention Policy and Stakeholder Engagement, Ontario Health (Cancer Care Ontario), Toronto, Canada
| | - G Liu
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre/University Health Network and University of Toronto, Toronto, Canada
| | - P A Bradbury
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre/University Health Network and University of Toronto, Toronto, Canada
| | - W K Evans
- Department of Oncology, McMaster University, Hamilton, Canada
| | - J Papadakos
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada; Patient Education, Ontario Health (Cancer Care Ontario), Toronto, Canada
| | - M E Giuliani
- Cancer Education Program, Princess Margaret Cancer Centre, Toronto, Canada; Department of Radiation Oncology, Princess Margaret Cancer Centre, Toronto, Canada.
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21
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Lauricella E, Mandriani B, Cavallo F, Pezzicoli G, Chaoul N, Porta C, Cives M. Angiogenesis in NENs, with a focus on gastroenteropancreatic NENs: from biology to current and future therapeutic implications. Front Oncol 2022; 12:957068. [PMID: 36059642 PMCID: PMC9428554 DOI: 10.3389/fonc.2022.957068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/28/2022] [Indexed: 11/17/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are highly vascularized malignancies arising from cells of the diffuse neuroendocrine system. An intricated cross-talk exists between NEN cells and the tumor microenvironment, and three main molecular circuits (VEGF/VEGFR pathway, FGF-dependent signaling and PDGF/PDGFR axis) have been shown to regulate angiogenesis in these neoplasms. Multiple randomized trials have investigated antiangiogenic agents over the past two decades, and sunitinib is currently approved for the treatment of advanced, progressive, G1/G2 pancreatic NENs. In recent years, two phase III clinical trials have demonstrated the efficacy and safety of surufatinib, a multi-tyrosine kinase angioimmune inhibitor, in patients with well-differentiated pancreatic and extrapancreatic NENs, and two studies of this agent are currently underway in Europe and US. The HIF-2α inhibitor belzutifan has recently received regulatory approval for the treatment of tumors arising in the context of Von-Hippel Lindau syndrome including pancreatic NENs, and a study of this drug in patients with sporadic tumors is presently ongoing. Combinations of antiangiogenic agents with chemotherapeutics and targeted drugs have been tested, with accumulating toxicities being a matter of concern. The potential of antiangiogenic agents in fine-tuning the immune microenvironment of NENs to enhance the activity of immune checkpoint inhibitors has been only partially elucidated, and further research should be carried out at this regard. Here, we review the current understanding of the biology of angiogenesis in NENs and provide a summary of the latest clinical investigations on antiangiogenic drugs in this malignancy.
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Affiliation(s)
- Eleonora Lauricella
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Barbara Mandriani
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Federica Cavallo
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Gaetano Pezzicoli
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Nada Chaoul
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Camillo Porta
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
| | - Mauro Cives
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
- *Correspondence: Mauro Cives,
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22
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Abstract
OBJECTIVES Neuroendocrine tumors (NETs) are characterized by their expression of vascular endothelial growth factor (VEGF). This trial investigated the activity of Ziv-aflibercept, a recombinant protein that binds to and inhibits the activity of VEGF, in patients with advanced NETs (NCT01782443). METHODS A single-arm, phase II trial enrolling patients with advanced, progressive extrapancreatic NET. Patients were treated with Ziv-aflibercept 4 mg/kg intravenously on day 1 and 15 of a 28-day cycle; the starting dose was reduced to 2 mg/kg on days 1 and 15 of a 28-day cycle because of hypertension-related events. The primary end point was progression-free survival. RESULTS The trial enrolled 19 patients (13 male:6 female). Patients received a median of 7 cycles (range, 1-18 cycles). The median progression free survival was 11.8 months (95% confidence interval, 3.2-16.1 months), and the median overall survival was 36.4 months (95% confidence interval, 16.1-not reached). Best responses by Response Evaluation Criteria in Solid Tumors 1.1 are as follows: 1 (5%) partial response, 13 (68%) stable disease, 2 (10%) with progressive disease, and 3 (15%) unevaluable. Hypertension occurred in 18 patients (95%), including grade 3-4 hypertension in 12 patients (63%). CONCLUSIONS Although the progression free survival is similar to other VEGF inhibitors in NET, toxicity may preclude further investigation.
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23
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Ali MA, Shah SS, Tahir N, Rehman S, Saeed M, Bajwa SF, Ali R, Aiman W, Anwar MY. Efficacy and toxicity of surufatinib in neuroendocrine tumors: A systematic review and meta-analysis. J Neuroendocrinol 2022; 34:e13149. [PMID: 35665971 DOI: 10.1111/jne.13149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 12/12/2021] [Accepted: 04/15/2022] [Indexed: 02/05/2023]
Abstract
The incidence and prevalence of neuroendocrine neoplasms (NENs) has increased in the US in recent decades. These are well-vascularized tumors, but no antiangiogenic drug has been approved for treatment of extra-pancreatic NENs. The aim is to assess efficacy and safety of surufatinib in pancreatic and extra-pancreatic NETs. We searched PubMed, Embase, Cochrane Library, Web of Science and Clinicaltrials.gov. Clinical trials and observational studies that provided safety and efficacy data in clinical terms were included. Characteristics of the study, baseline characteristics of participants, treatment drugs, measures of efficacy, and toxicity (≥grade 3 adverse effects) were extracted. The meta-analysis was performed using the "R" programming language. Risk ratio (RR) of objective response (OR)/partial response (PR) was 8.55 (95% CI: 1.68-43.66, I2 = 0) in favor of surufatinib. The hazard ratio (HR) of progression-free survival (PFS) was 0.48 (95% CI: 0.25-0.92, I2 = 77%) in favor of surufatinib. The risk of ≥grade 3 adverse effects: diarrhea, hypertension, hypertriglyceridemia, proteinuria, and vomiting were high with the use of surufatinib. Quality of life (QoL) was similar in surufatinib and placebo groups except for the diarrhea that was high with surufatinib. Lack of randomized clinical trials in non-Chinese population. Surufatinib is well tolerated and is more effective than placebo in both pancreatic and extra-pancreatic NETs. More multicenter randomized, double-blinded clinical trials are needed to confirm these results.
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Affiliation(s)
- Muhammad Ashar Ali
- Beth Israel Deconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Syed S Shah
- University of Kentucky, Lexington, Kentucky, USA
| | - Nayha Tahir
- Rosalind Franklin University of Medical Sciences/Chicago Medical School, North Chicago, Illinois, USA
| | - Sana Rehman
- Shaikh Khalifa Bin Zayed Al Nahyan Medical and Dental College, Lahore, Pakistan
| | | | | | - Rimsha Ali
- Rawalpindi Medical College, Rawalpindi, Pakistan
| | - Wajeeha Aiman
- Beth Israel Deconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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24
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Koumarianou A, Daskalakis K, Tsoli M, Kaltsas G, Pavel M. Efficacy, safety and unmet needs of evolving medical treatments for carcinoid syndrome. J Neuroendocrinol 2022; 34:e13174. [PMID: 35794780 DOI: 10.1111/jne.13174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/06/2022] [Accepted: 05/31/2022] [Indexed: 11/25/2022]
Abstract
This review reports on the currently available medical treatment options for the control of symptoms due to carcinoid syndrome in patients with neuroendocrine tumors. The efficacy and adverse events (AEs) of approved drugs such as somatostatin analogues (SSA), telotristat ethyl (TE) and interferon-alpha, are reviewed. Somatostatin analogues remain the standard treatment of carcinoid syndrome based on the high expression of somatostatin receptors and the resulting inhibition of secretion of bioactive compounds; their use is associated with relatively mild AEs, involving mainly the gastrointestinal system, and being usually transient. Although dose escalation of SSA remains an unapproved option, it is clinically implemented to alleviate symptoms in refractory carcinoid syndrome and supported by the most recent guidelines. The side effects associated with the increased dose are in general mild and consistent with standard dose of SSA. Telotristat ethyl, an oral inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis, represents a rather novel innovative treatment option in patients with carcinoid syndrome suffering from diarrhea and complements the standard therapy of SSA. Given the low toxicity profile, TE may be considered an early add-on treatment to SSA in patients with uncontrolled carcinoid syndrome. However, further prolonged follow-up of patients treated with TE may be needed to exclude potential AEs, such as liver toxicity or depressed mood, in patients with long-term treatment. Interferon alpha is a cytokine with direct inhibitory effect on hormone secretion and tumor cell proliferation and an approved therapy in carcinoid syndrome but is associated with significant AEs in the majority of the patients requiring frequently dose reduction. The finding of a more favorable tolerability of pegylated interferon needs to be confirmed in a prospective study.
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Affiliation(s)
- Anna Koumarianou
- Hematology-Oncology Unit, Fourth Department of Internal Medicine, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Kosmas Daskalakis
- Department of Surgery, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- 2nd Department of Surgery, "Korgialenio-Benakio", Red Cross General Hospital, Athens, Greece
| | - Marina Tsoli
- 1st Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Gregory Kaltsas
- 1st Propaedeutic Department of Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Marianne Pavel
- Department of Endocrinology, Universitatsklinikum Erlangen, Erlangen, Germany
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25
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Dai M, Mullins CS, Lu L, Alsfasser G, Linnebacher M. Recent advances in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. World J Gastrointest Surg 2022; 14:383-396. [PMID: 35734622 PMCID: PMC9160679 DOI: 10.4240/wjgs.v14.i5.383] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 01/17/2022] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare group of tumors originating from neuroendocrine cells of the digestive system. Their incidence has increased over the last decades. The specific pathogenetic mechanisms underlying GEP-NEN development have not been completely revealed. Unfunctional GEP-NENs are usually asymptomatic; some grow slowly and thus impede early diagnosis, which ultimately results in a high rate of misdiagnosis. Therefore, many GEP-NEN patients present with later staged tumors. Motivated hereby, research attention for diagnosis and treatment for GEP-NENs increased in recent years. The result of which is great progress in clinical diagnosis and treatment. According to the most recent clinical guidelines, improved grading standards can accurately define poorly differentiated grade 3 neuroendocrine tumors and neuroendocrine carcinomas (NECs), which are subclassified into large and small cell NECs. Combining different functional imaging methods facilitates precise diagnosis. The expression of somatostatin receptors helps to predict prognosis. Genetic analyses of mutations affecting death domain associated protein (DAXX), multiple endocrine neoplasia type 1 (MEN 1), alpha thalassemia/intellectual disability syndrome X-linked (ATRX), retinoblastoma transcriptional corepressor 1 (RB 1), and mothers against decapentaplegic homolog 4 (SMAD 4) help distinguishing grade 3 NENs from poorly differentiated NECs. The aim of this review is to summarize the latest research progress on diagnosis and treatment of GEP-NENs.
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Affiliation(s)
- Meng Dai
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Christina S Mullins
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Lili Lu
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
| | - Guido Alsfasser
- Clinic of General Surgery, Rostock University Medical Center, 18057 Rostock, Germany
| | - Michael Linnebacher
- Clinic of General Surgery, Molecular Oncology and Immunotherapy, Rostock University Medical Center, 18057 Rostock, Germany
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26
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Kulke MH, Ou FS, Niedzwiecki D, Huebner L, Kunz P, Kennecke HF, Wolin EM, Chan JA, O’Reilly EM, Meyerhardt JA, Venook A. Everolimus with or without bevacizumab in advanced pNET: CALGB 80701 (Alliance). Endocr Relat Cancer 2022; 29:335-344. [PMID: 35324465 PMCID: PMC9257687 DOI: 10.1530/erc-21-0239] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 03/23/2022] [Indexed: 12/23/2022]
Abstract
Treatment with the MTOR inhibitor everolimus improves progression-free survival (PFS) in pancreatic neuroendocrine tumors (pNETs), but it is not known if the addition of a VEGF pathway inhibitor to an MTOR inhibitor enhances antitumor activity. We performed a randomized phase II study evaluating everolimus with or without bevacizumab in patients with advanced pNETs. One hundred and fifty patients were randomized to receive everolimus 10 mg daily with or without bevacizumab 10 mg/kg i.v. every 2 weeks. Patients also received standard dose of octreotide in both arms. The primary endpoint was PFS, based on local investigator review. Treatment with the combination of everolimus and bevacizumab resulted in improved progression-free survival compared to everolimus (16.7 months compared to 14.0 months; one-sided stratified log-rank P = 0.1028; hazard ratio (HR) 0.80 (95% CI 0.56-1.13)), meeting the predefined primary endpoint. Confirmed tumor responses were observed in 31% (95% CI 20%, 41%) of patients receiving combination therapy, as compared to only 12% (95% CI 5%, 19%) of patients receiving treatment with everolimus (P = 0.0053). Median overall survival duration was similar in the everolimus and combination arm (42.5 and 42.1 months, respectively). Treatment-related toxicities were more common in the combination arm. In summary, treatment with everolimus and bevacizumab led to superior PFS and higher response rates compared to everolimus in patients with advanced pNETs. Although the higher rate of treatment-related adverse events may limit the use of this combination, our results support the continued evaluation of VEGF pathway inhibitors in pNETs.
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Affiliation(s)
- Matthew H. Kulke
- Section of Hematology and Medical Oncology, Boston University and Boston Medical Center, 820 Harrison Ave, Boston, MA, 02118
| | - Fang-Shu Ou
- Alliance Statistics and Data Management Center and Mayo Clinic Cancer Center, 200 First Street SW Rochester, MN 55905
| | - Donna Niedzwiecki
- Department of Biostatistics, Duke Cancer Center, 200 Duke Medicine Circle Durham, NC 22710
| | - Lucas Huebner
- Alliance Statistics and Data Management Center Mayo Clinic Cancer Center, 200 First Street SW Rochester, MN 55905
| | - Pamela Kunz
- Yale Cancer Center, 333 Cedar Street, New Haven, CT 06510
| | | | - Edward M. Wolin
- Tisch Cancer Institute. 1470 Madison Ave, New York, NY, 10029
| | - Jennifer A Chan
- Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215
| | - Eileen M. O’Reilly
- Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065
| | | | - Alan Venook
- UCSF Helen Diller Family Comprehensive Cancer Center, Box 1705 UCSF San Francisco, CA, 94143
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27
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Kaliszewski K, Ludwig M, Greniuk M, Mikuła A, Zagórski K, Rudnicki J. Advances in the Diagnosis and Therapeutic Management of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs). Cancers (Basel) 2022; 14:2028. [PMID: 35454934 PMCID: PMC9030061 DOI: 10.3390/cancers14082028] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/10/2022] [Accepted: 04/14/2022] [Indexed: 02/07/2023] Open
Abstract
Neuroendocrine neoplasms (NENs) are an increasingly common cause of neoplastic diseases. One of the largest groups of NENs are neoplasms localized to the gastroenteropancreatic system, which are known as gastroenteropancreatic NENs (GEP-NENs). Because of nonspecific clinical symptoms, GEP-NEN patient diagnosis and, consequently, their treatment, might be difficult and delayed. This situation has forced researchers all over the world to continue progress in the diagnosis and treatment of patients with GEP-NENs. Our review is designed to present the latest reports on the laboratory diagnostic techniques, imaging tests and surgical and nonsurgical treatment strategies used for patients with these rare neoplasms. We paid particular attention to the nuclear approach, the use of which has been applied to GEP-NEN patient diagnosis, and to nonsurgical and radionuclide treatment strategies. Recent publications were reviewed in search of reports on new strategies for effective disease management. Attention was also paid to those studies still in progress, but with successful results. A total of 248 papers were analyzed, from which 141 papers most relevant to the aim of the study were selected. Using these papers, we highlight the progress in the development of diagnostic and treatment strategies for patients with GEP-NENs.
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Affiliation(s)
- Krzysztof Kaliszewski
- Department of General, Minimally Invasive and Endocrine Surgery, Wroclaw Medical University, Borowska Street 213, 50-556 Wroclaw, Poland; (M.L.); (M.G.); (A.M.); (K.Z.); (J.R.)
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28
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Halperin DM, Liu S, Dasari A, Fogelman D, Bhosale P, Mahvash A, Estrella JS, Rubin L, Morani AC, Knafl M, Overeem TA, Fu SC, Solis LM, Parra Cuentas E, Verma A, Chen HL, Gite S, Subashchandrabose P, Dervin S, Schulze K, Darbonne WC, Yun C, Wistuba II, Futreal PA, Woodman SE, Yao JC. Assessment of Clinical Response Following Atezolizumab and Bevacizumab Treatment in Patients With Neuroendocrine Tumors: A Nonrandomized Clinical Trial. JAMA Oncol 2022; 8:904-909. [PMID: 35389428 PMCID: PMC8990358 DOI: 10.1001/jamaoncol.2022.0212] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Importance Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in NET have been disappointing. Objective To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs. Design, Setting, and Participants This single-arm, open-label nonrandomized clinical study in patients with rare cancers included 40 patients with advanced, progressive grade 1 to 2 NETs (20 with pancreatic NETs [pNETs] and 20 with extrapancreatic NETs [epNETs]) treated at a tertiary care referral cancer center between March 31, 2017, and February 19, 2019. Data were analyzed from June to September 2021. Interventions Patients received intravenous bevacizumab and atezolizumab at standard doses every 3 weeks until progression, death, or withdrawal. Main Outcomes and Measures The primary end point was objective radiographic response using Response Evaluation Criteria in Solid Tumors, version 1.1, with progression-free survival (PFS) as a key secondary end point. Results Following treatment of the 40 study patients with bevacizumab and atezolizumab, objective response was observed in 4 patients with pNETs (20%; 95% CI, 5.7%-43.7%) and 3 patients with epNETs (15%; 95% CI, 3.2%-37.9%). The PFS was 14.9 (95% CI, 4.4-32.0) months and 14.2 (95% CI, 10.2-19.6) months in these cohorts, respectively. Conclusions and Relevance In this nonrandomized clinical trial, findings suggest that clinical responses in patients with NET may follow treatment with the combination of bevacizumab and atezolizumab, with a PFS consistent with effective therapies. Trial Registration ClinicalTrials.gov Identifier: NCT03074513.
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Affiliation(s)
- Daniel M Halperin
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
| | - Suyu Liu
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
| | - David Fogelman
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
| | - Priya Bhosale
- Department of Radiology, University of Texas MD Anderson Cancer Center, Houston
| | - Armeen Mahvash
- Department of Interventional Radiology, University of Texas MD Anderson Cancer Center, Houston
| | | | - Laura Rubin
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston
| | - Ajaykumar C Morani
- Department of Radiology, University of Texas MD Anderson Cancer Center, Houston
| | - Mark Knafl
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston
| | - Tim A Overeem
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston
| | - Szu-Chin Fu
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston
| | - Luisa M Solis
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston
| | - Edwin Parra Cuentas
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston
| | - Anuj Verma
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston
| | - Hong-Lei Chen
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston
| | - Swati Gite
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston
| | - Priya Subashchandrabose
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston
| | | | | | | | - Cindy Yun
- Genentech, Inc, South San Francisco, California
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston
| | - P Andrew Futreal
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston
| | - Scott E Woodman
- Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston
| | - James C Yao
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
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29
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Puliani G, Sesti F, Anastasi E, Verrico M, Tarsitano MG, Feola T, Campolo F, Di Gioia CRT, Venneri MA, Angeloni A, Appetecchia M, Lenzi A, Isidori AM, Faggiano A, Giannetta E. Angiogenic factors as prognostic markers in neuroendocrine neoplasms. Endocrine 2022; 76:208-217. [PMID: 35088292 DOI: 10.1007/s12020-021-02942-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 11/07/2021] [Indexed: 12/18/2022]
Abstract
PURPOSE Angiogenic markers in neuroendocrine neoplasms (NENs) have recently received increasing attention, but their clinical role remains unclear. The aim of this study was to evaluate the role of angiogenic markers in NEN aggressiveness and prognosis. METHODS We performed a prospective observational study including 46 consecutive patients with proven NENs of pulmonary (45.65%) and gastro-entero-pancreatic (GEP) (54.35%) origin and 29 healthy controls. Circulating pro-angiogenic factors were measured by ELISA assay. ANG2 tissue expression was evaluated in a subgroup of ten patients by immunohistochemistry. RESULTS The study demonstrated a significantly higher level of ANG2, ANG1, sTIE2, and PROK2 in patients affected by NENs compared to controls. In the NENs' group we measured that: (i) ANG2 levels were higher in poorly vs well-differentiated NENs: 4.85 (2.75-7.42) vs 3.16 (1.66-6.36) ng/ml, p = 0.046 and in tumor stage 3-4 compared to stage 1-2: 4.24 (2.66-8.72) vs 2.73 (1.53-5.70), p = 0.044; (ii) ANG2 and PROK2 were significantly higher in patents with progressive disease compared to stable disease: ANG2 = 6.26 (3.98-10.99) vs 2.73 (1.65-4.36) pg/ml, p = 0.001; PROK2 = 29.19 (28.42-32.25) vs 28.37 (28.14-28.91) pg/ml, p = 0.035. Immunohistochemistry confirmed ANG2 expression in tumor specimens. CONCLUSIONS We documented higher levels of angiogenic markers in NENs, with an association between ANG2 serum levels and NENs morphology and staging. In both GEP and lung NENs, ANG2 and PROK2 are higher in case of tumor progression, suggesting a potential role as prognostic markers in NENs patients.
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Affiliation(s)
- Giulia Puliani
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Franz Sesti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Emanuela Anastasi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Monica Verrico
- Medical Oncology Unit A, Department of Radiological, Oncological and Pathological Sciences, Sapienza University of Rome, Rome, Italy
| | | | - Tiziana Feola
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Neuroendocrinology, Neuromed Institute, IRCCS, Pozzilli, Italy
| | - Federica Campolo
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Mary Anna Venneri
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Antonio Angeloni
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Marialuisa Appetecchia
- Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Andrea Lenzi
- 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
| | - Elisa Giannetta
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
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30
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Perez K, Chan J. Medical management of gastrointestinal neuroendocrine tumors. Curr Opin Endocrinol Diabetes Obes 2022; 29:219-224. [PMID: 35045527 DOI: 10.1097/med.0000000000000711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW To summarize the recent developments in the medical treatment of gastrointestinal neuroendocrine neoplasms. RECENT FINDINGS The medical management of gastrointestinal neuroendocrine tumors (GI-NETs) continues to evolve with advances in the management of symptoms related to hormone hypersecretion and therapeutic control of disease progression. Systemic therapy options include somatostatin analogs (SSAs), radiolabeled SSAs, molecularly targeted agents, and cytotoxic therapy. Recent progress has focused on new targeted therapies, the sequencing of therapy and the role of immunotherapy. SUMMARY This review will focus on treatment of GI-NETs and highlight new developments published over the last year.
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Affiliation(s)
- Kimberly Perez
- Harvard Medical School, Program in Carcinoid and Neuroendocrine Tumors, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
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31
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Gallo C, Rossi RE, Cavalcoli F, Barbaro F, Boškoski I, Invernizzi P, Massironi S. Rectal neuroendocrine tumors: Current advances in management, treatment, and surveillance. World J Gastroenterol 2022; 28:1123-1138. [PMID: 35431507 PMCID: PMC8985485 DOI: 10.3748/wjg.v28.i11.1123] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 12/24/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
Rectal neuroendocrine neoplasms (r-NENs) are considered among the most frequent digestive NENs, together with small bowel NENs. Their incidence has increased over the past few years, and this is probably due to the widespread use of endoscopic screening for colorectal cancer and the advanced endoscopic procedures available nowadays. According to the current European Neuroendocrine Tumor Society (ENETS) guidelines, well-differentiated r-NENs smaller than 10 mm should be endoscopically removed in view of their low risk of local and distant invasion. R-NENs larger than 20 mm are candidates for surgical resection because of their high risk of distant spreading and the involvement of the muscularis propria. There is an area of uncertainty regarding tumors between 10 and 20 mm, in which the metastatic risk is intermediate and the endoscopic treatment can be challenging. Once removed, the indications for surveillance are scarce and poorly codified by international guidelines, therefore in this paper, a possible algorithm is proposed.
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Affiliation(s)
- Camilla Gallo
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza 20900, Italy
| | - Roberta Elisa Rossi
- Division of HPB Surgery, Hepatology and Liver Transplantation, Department of Pathophysiology and Transplantation, University of Milan, ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale Tumori (INT, National Cancer Institute), Milan 20133, Italy
| | - Federica Cavalcoli
- Diagnostic and Therapeutic Endoscopy Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan 20133, Italy
| | - Federico Barbaro
- Digestive Endoscopy Unit, Università Cattolica del Sacro Cuore di Roma, Center for Endoscopic Research Therapeutics and Training, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome 00168, Italy
| | - Ivo Boškoski
- Digestive Endoscopy Unit, Università Cattolica del Sacro Cuore di Roma, Center for Endoscopic Research Therapeutics and Training, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome 00168, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza 20900, Italy
| | - Sara Massironi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, European Reference Network on Hepatological Diseases, San Gerardo Hospital, Monza 20900, Italy
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32
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Neuroendocrine Tumors: a Relevant Clinical Update. Curr Oncol Rep 2022; 24:703-714. [PMID: 35254612 DOI: 10.1007/s11912-022-01217-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2021] [Indexed: 11/03/2022]
Abstract
PURPOSE OF REVIEW The field of neuroendocrine oncology has changed much since the time of Oberndorfer first described and coined the term carcinoid. The purpose of this review is to summarize recent findings and highlight clinically relevant updates in the management of NENs, particularly those that are practice changing. RECENT FINDINGS Neuroendocrine tumors (NETs) have replaced carcinoid tumor, for the most part. The classification of neuroendocrine neoplasms (NENs) improved, and the epidemiological understanding of this disease group also expanded with global collaborations and maturation of large tumor registries. Clarity in the utility of some NET biomarkers continues to be evolving. Knowledge of molecular drivers of tumorigenesis increases, and scientific/technological advancements lead the way to multiple drug approvals for the treatment of advanced NETs. The incidence and prevalence of NENs continue to increase, and patients are living longer. Better understanding of molecular drivers and further understanding of the role of immunotherapy in NENs will further elevate the level of care and transform care for all patients with NENs.
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Araujo-Castro M, Pascual-Corrales E, Molina-Cerrillo J, Moreno Mata N, Alonso-Gordoa T. Bronchial Carcinoids: From Molecular Background to Treatment Approach. Cancers (Basel) 2022; 14:520. [PMID: 35158788 PMCID: PMC8833538 DOI: 10.3390/cancers14030520] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/19/2022] [Accepted: 01/19/2022] [Indexed: 02/05/2023] Open
Abstract
A better understanding of the genetic and molecular background of bronchial carcinoids (BCs) would allow a better estimation of the risk of disease progression and the personalization of treatment in cases of advanced disease. Molecular studies confirmed that lungs neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are different entities; thus, no progression of NET to NEC is expected. In BCs, MEN1 gene mutations and deletions and decreased gene expression have been associated with a poor prognosis. ATRX mutation has also been linked to a shorter disease-specific survival. In terms of therapeutic targets, PI3K/AKT/mTOR pathway mutations have been described in 13% of typical carcinoids (TCs) and 39% of atypical carcinoids (ACs), representing a targetable mutation with kinase inhibitors. Regarding treatment, surgical resection is usually curative in localized BCs and adjuvant treatment is not routinely recommended. Multiple options for systemic therapy exist for patients with advanced BCs, although limited by a heterogeneity in the scientific evidence behind their use recommendation. These options include somatostatin analogues, everolimus, peptide receptor radionuclide therapy, chemotherapy, radiotherapy, antiangiogenic agents, and immunotherapy. In this article, we provide a comprehensive review about the molecular and genetic background of BCs, and about the treatment of local and metastatic disease, as well as the main paraneoplastic syndromes that have been associated with this tumor.
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Affiliation(s)
- Marta Araujo-Castro
- Neuroendocrinology Unit, Endocrinology and Nutrition Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain;
- Instituto de Investigación Biomédica Ramón y Cajal (IRICYS), 28034 Madrid, Spain;
- Universidad de Alcalá, 28801 Madrid, Spain
| | - Eider Pascual-Corrales
- Neuroendocrinology Unit, Endocrinology and Nutrition Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain;
- Instituto de Investigación Biomédica Ramón y Cajal (IRICYS), 28034 Madrid, Spain;
| | - Javier Molina-Cerrillo
- Instituto de Investigación Biomédica Ramón y Cajal (IRICYS), 28034 Madrid, Spain;
- Universidad de Alcalá, 28801 Madrid, Spain
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Nicolás Moreno Mata
- Thoracic Surgery Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain;
| | - Teresa Alonso-Gordoa
- Instituto de Investigación Biomédica Ramón y Cajal (IRICYS), 28034 Madrid, Spain;
- Universidad de Alcalá, 28801 Madrid, Spain
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
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Nagel I, Herrmann K, Lahner H, Rischpler C, Weber F. Combined medical therapy, nuclear medicine therapy and other therapies in metastatic neuroendocrine tumor. Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00156-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
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Walter MA, Nesti C, Spanjol M, Kollár A, Bütikofer L, Gloy VL, Dumont RA, Seiler CA, Christ ER, Radojewski P, Briel M, Kaderli RM. Treatment for gastrointestinal and pancreatic neuroendocrine tumours: a network meta-analysis. Cochrane Database Syst Rev 2021; 11:CD013700. [PMID: 34822169 PMCID: PMC8614639 DOI: 10.1002/14651858.cd013700.pub2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Several available therapies for neuroendocrine tumours (NETs) have demonstrated efficacy in randomised controlled trials. However, translation of these results into improved care faces several challenges, as a direct comparison of the most pertinent therapies is incomplete. OBJECTIVES To evaluate the safety and efficacy of therapies for NETs, to guide clinical decision-making, and to provide estimates of relative efficiency of the different treatment options (including placebo) and rank the treatments according to their efficiency based on a network meta-analysis. SEARCH METHODS We identified studies through systematic searches of the following bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (Ovid); and Embase from January 1947 to December 2020. In addition, we checked trial registries for ongoing or unpublished eligible trials and manually searched for abstracts from scientific and clinical meetings. SELECTION CRITERIA We evaluated randomised controlled trials (RCTs) comparing two or more therapies in people with NETs (primarily gastrointestinal and pancreatic). DATA COLLECTION AND ANALYSIS Two review authors independently selected studies and extracted data to a pre-designed data extraction form. Multi-arm studies were included in the network meta-analysis using the R-package netmeta. We separately analysed two different outcomes (disease control and progression-free survival) and two types of NET (gastrointestinal and pancreatic NET) in four network meta-analyses. A frequentist approach was used to compare the efficacy of therapies. MAIN RESULTS We identified 55 studies in 90 records in the qualitative analysis, reporting 39 primary RCTs and 16 subgroup analyses. We included 22 RCTs, with 4299 participants, that reported disease control and/or progression-free survival in the network meta-analysis. Precision-of-treatment estimates and estimated heterogeneity were limited, although the risk of bias was predominantly low. The network meta-analysis of progression-free survival found nine therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.36 [95% CI, 0.28 to 0.46]), interferon plus somatostatin analogue (HR, 0.34 [95% CI, 0.14 to 0.80]), everolimus plus somatostatin analogue (HR, 0.38 [95% CI, 0.26 to 0.57]), bevacizumab plus somatostatin analogue (HR, 0.36 [95% CI, 0.15 to 0.89]), interferon (HR, 0.41 [95% CI, 0.18 to 0.94]), sunitinib (HR, 0.42 [95% CI, 0.26 to 0.67]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.48 [95% CI, 0.28 to 0.83]), surufatinib (HR, 0.49 [95% CI, 0.32 to 0.76]), and somatostatin analogue (HR, 0.51 [95% CI, 0.34 to 0.77]); and six therapies for gastrointestinal NETs: 177-Lu-DOTATATE plus somatostatin analogue (HR, 0.07 [95% CI, 0.02 to 0.26]), everolimus plus somatostatin analogue (HR, 0.12 [95%CI, 0.03 to 0.54]), bevacizumab plus somatostatin analogue (HR, 0.18 [95% CI, 0.04 to 0.94]), interferon plus somatostatin analogue (HR, 0.23 [95% CI, 0.06 to 0.93]), surufatinib (HR, 0.33 [95%CI, 0.12 to 0.88]), and somatostatin analogue (HR, 0.34 [95% CI, 0.16 to 0.76]), with higher efficacy than placebo. Besides everolimus for pancreatic NETs, the results suggested an overall superiority of combination therapies, including somatostatin analogues. The results indicate that NET therapies have a broad range of risk for adverse events and effects on quality of life, but these were reported inconsistently. Evidence from this network meta-analysis (and underlying RCTs) does not support any particular therapy (or combinations of therapies) with respect to patient-centred outcomes (e.g. overall survival and quality of life). AUTHORS' CONCLUSIONS The findings from this study suggest that a range of efficient therapies with different safety profiles is available for people with NETs.
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Affiliation(s)
- Martin A Walter
- Nuclear Medicine Division, Diagnostic Department, University Hospitals Geneva (HUG), Geneva, Switzerland
| | - Cédric Nesti
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Marko Spanjol
- Nuclear Medicine Division, Diagnostic Department, University Hospitals Geneva (HUG), Geneva, Switzerland
| | - Attila Kollár
- Department of Medical Oncology, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Lukas Bütikofer
- Clinical Trials Unit, Bern, University of Bern, Bern, Switzerland
| | - Viktoria L Gloy
- Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Rebecca A Dumont
- Nuclear Medicine Division, Diagnostic Department, University Hospitals Geneva (HUG), Geneva, Switzerland
| | - Christian A Seiler
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Emanuel R Christ
- Department of Endocrinology, Diabetes, and Metabolism, Basel University Hospital, University of Basel, Basel, Switzerland
| | - Piotr Radojewski
- Nuclear Medicine Division, Diagnostic Department, University Hospitals Geneva (HUG), Geneva, Switzerland
| | - Matthias Briel
- Department of Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Reto M Kaderli
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
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Jacob A, Gabriel G, Ramirez RA, Wang YZ, Anthony L, Chauhan A. How I Treat Neuroendocrine Tumors. Indian J Med Paediatr Oncol 2021. [DOI: 10.1055/s-0041-1732833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Affiliation(s)
- Aasems Jacob
- Division of Medical Oncology, University of Kentucky, Lexington, Kentucky, United States
| | - Gaby Gabriel
- Department of Radiology, Division of Interventional Radiology, University of Kentucky, Lexington, Kentucky, United States
- Division of Medical Oncology, Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States
| | - Robert A. Ramirez
- Department of Hematology and Oncology, Ochsner Health New Orleans, New Orleans, Louisiana, United States
| | - Yi-Zarn Wang
- Department of Surgery, Louisiana State University Health Science Center, New Orleans, Louisiana, United States
| | - Lowell Anthony
- Division of Medical Oncology, University of Kentucky, Lexington, Kentucky, United States
- Division of Medical Oncology, Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States
| | - Aman Chauhan
- Division of Medical Oncology, University of Kentucky, Lexington, Kentucky, United States
- Division of Medical Oncology, Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States
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Frequency of Neuroendocrine Tumor Studies: Using Latent Dirichlet Allocation and HJ-Biplot Statistical Methods. MATHEMATICS 2021. [DOI: 10.3390/math9182281] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Background: Neuroendocrine tumors (NETs) are severe and relatively rare and may affect any organ of the human body. The prevalence of NETs has increased in recent years; however, there seem to be more data on particular types, even though, despite the efforts of different guidelines, there is no consensus on how to identify different types of NETs. In this review, we investigated the countries that published the most articles about NETs, the most frequent organs affected, and the most common related topics. Methods: This work used the Latent Dirichlet Allocation (LDA) method to identify and interpret scientific information in relation to the categories in a set of documents. The HJ-Biplot method was also used to determine the relationship between the analyzed topics, by taking into consideration the years under study. Results: In this study, a literature review was conducted, from which a total of 7658 abstracts of scientific articles published between 1981 and 2020 were extracted. The United States, Germany, United Kingdom, France, and Italy published the majority of studies on NETs, of which pancreatic tumors were the most studied. The five most frequent topics were t_21 (clinical benefit), t_11 (pancreatic neuroendocrine tumors), t_13 (patients one year after treatment), t_17 (prognosis of survival before and after resection), and t_3 (markers for carcinomas). Finally, the results were put through a two-way multivariate analysis (HJ-Biplot), which generated a new interpretation: we grouped topics by year and discovered which NETs were the most relevant for which years. Conclusions: The most frequent topics found in our review highlighted the severity of NETs: patients have a poor prognosis of survival and a high probability of tumor recurrence.
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Rinke A, Auernhammer CJ, Bodei L, Kidd M, Krug S, Lawlor R, Marinoni I, Perren A, Scarpa A, Sorbye H, Pavel ME, Weber MM, Modlin I, Gress TM. Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine? Gut 2021; 70:1768-1781. [PMID: 33692095 DOI: 10.1136/gutjnl-2020-321300] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 12/14/2022]
Abstract
Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognostically diverse tumour entities often diagnosed at late stage. Current classification provides a uniform terminology and a Ki67-based grading system, thereby facilitating management. Advances in the study of genomic and epigenetic landscapes have amplified knowledge of tumour biology and enhanced identification of prognostic and potentially predictive treatment subgroups. Translation of this genomic and mechanistic biology into advanced GEPNEN management is limited. 'Targeted' treatments such as somatostatin analogues, peptide receptor radiotherapy, tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are treatment options but predictive tools are lacking. The inability to identify clonal heterogeneity and define critical oncoregulatory pathways prior to therapy, restrict therapeutic efficacy as does the inability to monitor disease status in real time. Chemotherapy in the poor prognosis NEN G3 group, though associated with acceptable response rates, only leads to short-term tumour control and their molecular biology requires delineation to provide new and more specific treatment options.The future requires an exploration of the NEN tumour genome, its microenvironment and an identification of critical oncologic checkpoints for precise drug targeting. In the advance to personalised medical treatment of patients with GEPNEN, clinical trials need to be based on mechanistic and multidimensional characterisation of each tumour in order to identify the therapeutic agent effective for the individual tumour.This review surveys advances in NEN research and delineates the current status of translation with a view to laying the basis for a genome-based personalised medicine management of advanced GEPNEN.
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Affiliation(s)
- Anja Rinke
- Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg and Philipps University, Marburg, Germany
| | - Christoph J Auernhammer
- Department of Internal Medicine IV and Interdisciplinary Center of Neuroendocrine Tumors of the GastroEnteroPancreatic System (GEPNET-KUM), Ludwig Maximilian University, LMU Klinikum, Munich, Germany
| | - Lisa Bodei
- Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Mark Kidd
- Wren Laboratories, Branford, Connecticut, USA
| | - Sebastian Krug
- Clinic for Internal Medicine I, Martin Luther University, Halle, Germany
| | - Rita Lawlor
- Applied Research on Cancer Centre, Department of Pathology and Diagnostics, University of Verona, Verona, Italy
| | - Ilaria Marinoni
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Aurel Perren
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Aldo Scarpa
- Applied Research on Cancer Centre, Department of Pathology and Diagnostics, University of Verona, Verona, Italy
| | - Halfdan Sorbye
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Marianne Ellen Pavel
- Department of Internal Medicine I, Endocrinology, University of Erlangen, Erlangen, Germany
| | - Matthias M Weber
- Department of Internal Medicine I, Endocrinology, Johannes Gutenberg University Hospital Mainz, Mainz, Germany
| | - Irvin Modlin
- Gastroenterological and Endoscopic Surgery, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Thomas M Gress
- Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg and Philipps University, Marburg, Germany
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Yin G, Zhao L. Risk of hypertension with anti-VEGF monoclonal antibodies in cancer patients: a systematic review and meta-analysis of 105 phase II/III randomized controlled trials. J Chemother 2021; 34:221-234. [PMID: 34229563 DOI: 10.1080/1120009x.2021.1947022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
We performed a meta-analysis to fully investigate the hypertension of anti-VEGF mAbs in cancer patients. Databases were searched for randomized controlled trials (RCTs) treated with anti-VEGF mAbs till January 2021. The relevant RCTs in cancer patients treated with anti-VEGF mAbs were retrieved and the systematic evaluation was conducted. One hundred and five RCTs and 65358 patients were included. Our study suggests that anti-VEGF mAbs significantly increased the risks of all-grade (RR, 3.22; 95%CI, 2.83-3.65; p < 0.00001; I2=71%) and high-grade (RR, 6.15; 95%CI, 5.58-6.78; p < 0.00001; I2=48%) hypertension in cancer patients. Those risks may be dependent on drug type. Icrucumab did not association with an increased risk of hypertension. The RR of hypertension did not vary significantly according to the type of cancer, line of therapy, and treatment duration. The available data suggested that the use of anti-VEGF mAbs were associated with a significantly increased risk of hypertension.
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Affiliation(s)
- Gang Yin
- Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, P.R. China.,Engineering Research Center for Pharmaceuticals and Equipments of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of pharmacy, Chengdu University, Chengdu, Sichuan, P.R. China
| | - Ling Zhao
- Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, P.R. China
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Jungels C, Deleporte A. State of the art and future directions in the systemic treatment of neuroendocrine neoplasms. Curr Opin Oncol 2021; 33:378-385. [PMID: 33973550 DOI: 10.1097/cco.0000000000000740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Neuroendocrine neoplasms (NENs) are rare and heterogeneous malignancies whose natural evolution may be defined according to various prognostic factors, including localization of the primitive tumour, hormone secretory status, histological grade, tumour burden, tumour growth rate, expression of somatostatin receptors and fluorodeoxyglucose-avidity. The treatment of these tumours in an advanced setting is based on relatively little robust data. RECENT FINDINGS A recent pathological classification introduced a new category of high-grade but well differentiated neuroendocrine tumours (NET G3), with markedly different behaviour from neuroendocrine carcinomas (NECs). Yet, the optimal treatment of those tumours is still uncertain. Advances are needed in molecular subtyping of NENs to understand better their heterogeneity and inform personalized therapies. SUMMARY The current review summarizes the current knowledge, indicates some exciting future directions and outlines the most interesting ongoing clinical trials likely to impact current practice.
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Affiliation(s)
- Christiane Jungels
- Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
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Dawod M, Gordoa TA, Cives M, De Mestier L, Crona J, Spada F, Oberg K, Pavel M, Lamarca A. Antiproliferative Systemic Therapies for Metastatic Small Bowel Neuroendocrine Tumours. Curr Treat Options Oncol 2021; 22:73. [PMID: 34185197 DOI: 10.1007/s11864-021-00863-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/30/2021] [Indexed: 12/16/2022]
Abstract
OPINION STATEMENT Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies with rising incidence and prevalence. Outcome and therapy of small bowel neuroendocrine tumours (SBNETs) is variable, depending on the grade, differentiation, tumour burden, as well as the site of the tumour origin. Because of this, multidisciplinary approach is essential. Large randomized clinical trials, with somatostatin analogues (PROMID, CLARINET) or with peptide receptor radionuclide therapy (PRRT) with 177-lutetium (NETTER-1 trial) as well as the mammalian target of rapamycin inhibitor (mTOR) everolimus (RADIANT trials), represent milestones for the medical management of unresectable grade 1 and 2 SBNETS over the last decade. Novel therapies, such as tyrosine kinase inhibitors (TKI), are on the cutting edge. However, multiple unsolved questions remain. This review provides a comprehensive review of the main systemic therapeutic options for advanced SBNETs and discusses the latest guideline recommendations for palliative treatment.
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Affiliation(s)
- Mohammed Dawod
- Department of Medical Oncology, ENETs, Centre of Excellence, The Christie NHS Foundation Trust, Manchester, UK
| | - Teresa Alonso Gordoa
- Department of Medical Oncology, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | - Mauro Cives
- Department of Medical Oncology, University of Bari, Bari, Italy
| | - Louis De Mestier
- Department of Gastroenterology, Beaujon Hospital, Université de Paris, Clichy, France
| | - Joakim Crona
- Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden
| | - Francesca Spada
- Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit, European Institute of Oncology, Milan, Italy
| | - Kjel Oberg
- Department of Endocrinology, Universitatsklinikum Erlangen, Erlangen, Germany
| | - Marianne Pavel
- Department of Medical Oncology, ENETs, Centre of Excellence, The Christie NHS Foundation Trust, Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Angela Lamarca
- The Christie NHS Foundation Trust, Wilmslow Road, M20 4BX, Manchester, UK.
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de Herder WW, Feelders RA, Hofland J. Medical treatment of neuroendocrine neoplasms. CURRENT OPINION IN ENDOCRINE AND METABOLIC RESEARCH 2021; 18:139-144. [DOI: 10.1016/j.coemr.2021.03.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Papantoniou D, Grönberg M, Landerholm K, Welin S, Ziolkowska B, Nordvall D, Janson ET. Assessment of hormonal levels as prognostic markers and of their optimal cut-offs in small intestinal neuroendocrine tumours grade 2. Endocrine 2021; 72:893-904. [PMID: 33244704 PMCID: PMC8159831 DOI: 10.1007/s12020-020-02534-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 10/24/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE Small intestinal neuroendocrine tumours (siNETs) with a Ki-67 proliferation index between 3 and 20% belong to WHO grade 2. Response to treatment may be monitored by blood chromogranin A (CgA) and urine 5-hydroxyindoleacetic acid (5HIAA). The aim of this retrospective study was to investigate the prognostic value of baseline CgA and 5HIAA and of the early biochemical response to treatment, and to compare different cut-off values used in the literature. METHODS A retrospective cohort study of 184 patients with siNET Grade 2 treated with somatostatin analogues (SSA), interferon-alpha (IFN) or peptide receptor radionuclide therapy (PRRT). RESULTS Baseline CgA was a statistically significant prognostic marker for both cancer-specific survival (CSS) and progression-free survival (PFS). A cut-off of 5 × ULN (upper limit of normal) was best discriminative in most cases, but 2 × ULN discriminated better for SSA. Baseline 5HIAA was a prognostic marker for CSS in treatment with IFN and PRRT, but not for single SSA. Early changes of CgA and 5HIAA correlated well with CSS (HR 3.18, 95% CI 1.82-5.56 and HR 1.47, 95% CI 1.16-1.86) and PFS (HR 3.08, 95% CI 1.86-5.10 and HR 1.37, 95% CI 1.11-1.68) for SSA, but not for PRRT. CONCLUSIONS Baseline CgA and to a lesser extent 5HIAA are associated with CSS irrespective of treatment used, and with PFS after PRRT, and 5 × ULN provides best discrimination in many, but not all, cases. Early reductions of CgA and 5HIAA are prognostic for treatment with SSA, but not PRRT.
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Affiliation(s)
- Dimitrios Papantoniou
- Department of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden.
- Department of Oncology, Ryhov County Hospital, Jönköping, Sweden.
| | - Malin Grönberg
- Department of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden
| | | | - Staffan Welin
- Department of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden
| | - Barbara Ziolkowska
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland
| | | | - Eva Tiensuu Janson
- Department of Medical Sciences, Endocrine Oncology, Uppsala University, Uppsala, Sweden
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Winer I, Kim C, Gehrig P. Neuroendocrine tumors of the gynecologic tract update. Gynecol Oncol 2021; 162:210-219. [PMID: 34023130 DOI: 10.1016/j.ygyno.2021.04.039] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 04/29/2021] [Indexed: 10/21/2022]
Affiliation(s)
- I Winer
- Division of Gynecologic Oncology, Department of Oncology, Wayne State University, Detroit, MI, USA.
| | - C Kim
- New York Cancer Blood Specialists, Patchogue, NY, USA; Division of Hematology/Oncology, Department of Medicine, Stony Brook University Hospital, Stony Brook, NY, USA
| | - P Gehrig
- Department of Obstetrics & Gynecology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
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Targeted Cancer Therapy: What's New in the Field of Neuroendocrine Neoplasms? Cancers (Basel) 2021; 13:cancers13071701. [PMID: 33916707 PMCID: PMC8038369 DOI: 10.3390/cancers13071701] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 12/18/2022] Open
Abstract
Neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms of increasing incidence and high prevalence due to their relatively indolent nature. Their wide anatomic distribution and their characteristic ability to secrete hormonally active substances pose unique challenges for clinical management. They are also characterized by the common expression of somatostatin receptors, a target that has been extremely useful for diagnosis and treatment (i.e., somatostatin analogues (SSAs) and peptide-receptor radionuclide therapy (PRRT)). Chemotherapy is of limited use for NETs of non-pancreatic origin, and the only approved targeted agents for advanced progressive NETs are sunitinib for those of pancreatic origin, and everolimus for lung, gastrointestinal and pancreatic primaries. Despite recent therapeutic achievements, thus, systemic treatment options remain limited. In this review we will discuss the state-of-the-art targeted therapies in the field of NETs, and also future perspectives of novel therapeutic drugs or strategies in clinical development, including recently presented results from randomized trials of yet unapproved antiangiogenic agents (i.e., pazopanib, surufatinib and axitinib), PRRT including both approved radiopharmaceuticals (177Lu-Oxodotreotide) and others in development (177Lu-Edotreotide, 177Lu-Satoreotide Tetraxetan), immunotherapy and other innovative targeted strategies (antibody-drug conjugates, bites,…) that shall soon improve the landscape of personalized treatment options in NET patients.
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Rinzivillo M, De Felice I, Magi L, Annibale B, Panzuto F. Octreotide long-acting release (LAR) in combination with other therapies for treatment of neuroendocrine neoplasia: a systematic review. J Gastrointest Oncol 2021; 12:845-855. [PMID: 34012671 PMCID: PMC8107603 DOI: 10.21037/jgo-20-292] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND In the last decades, the incidence of neuroendocrine neoplasia (NEN) increased from 1 to 5 new diagnoses/100,000 persons/year. The synthetic somatostatin analogues (SSAs) represent the first-choice treatment for both functionally active and inactive gastro-enteric-pancreatic NEN. This systematic review examines the role of octreotide long-acting release (LAR) in combination with other therapies for NEN management. METHODS Primary outcomes were the disease control rate and the progression free survival (PFS), defined as the time between treatment initiation and progression of disease. Secondary outcomes were overall survival (OS) and safety. RESULTS This systematic review identified 13 studies, concerning the use of octreotide LAR in association with other therapies in advanced NENs and included 1,206 patients. Patients were treated with octreotide LAR in combination with other drugs, mainly with everolimus (404 patients, 35%), but even with Peptide Receptor Radionuclide Therapy, bevacizumab, interferon or fluoride-derivatives. Disease control was observed in 85% cases with SSAs in combination with other therapies; PFS ranged from 15 to 16.4 months and OS from 25 to 61.9 months. SSAs are very well tolerated drugs, with few side effects which are usually mild, not requiring drug withdrawn. CONCLUSIONS The review summarizes the effectiveness and available safety data on octreotide LAR in combination with other therapies in patients with NEN and may provide suggestions to address the therapeutic strategy. Further comparative head-to-head studies are needed to understand which is the best combination treatment for patients with progressive NEN after failure of first-line therapy.
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Affiliation(s)
- Maria Rinzivillo
- Digestive Disease Unit, Sant’ Andrea University Hospital, ENETS Center of Excellence, Rome, Italy
| | - Ilaria De Felice
- Digestive Disease Unit, Sant’ Andrea University Hospital, ENETS Center of Excellence, Rome, Italy
| | - Ludovica Magi
- Digestive Disease Unit, Sant’ Andrea University Hospital, ENETS Center of Excellence, Rome, Italy
| | - Bruno Annibale
- Digestive Disease Unit, Sant’ Andrea University Hospital, Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, ENETS Center of Excellence, Rome, Italy
| | - Francesco Panzuto
- Digestive Disease Unit, Sant’ Andrea University Hospital, ENETS Center of Excellence, Rome, Italy
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Baudin E, Caplin M, Garcia-Carbonero R, Fazio N, Ferolla P, Filosso PL, Frilling A, de Herder WW, Hörsch D, Knigge U, Korse CM, Lim E, Lombard-Bohas C, Pavel M, Scoazec JY, Sundin A, Berruti A. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up ☆. Ann Oncol 2021; 32:439-451. [PMID: 33482246 DOI: 10.1016/j.annonc.2021.01.003] [Citation(s) in RCA: 120] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 12/23/2020] [Accepted: 01/07/2021] [Indexed: 12/24/2022] Open
Affiliation(s)
- E Baudin
- Endocrine Oncology and Nuclear Medicine Unit, Gustave Roussy, Villejuif, France
| | - M Caplin
- Centre for Gastroenterology, Neuroendocrine Tumour Unit, Royal Free Hospital, London, UK
| | - R Garcia-Carbonero
- Oncology Department, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Madrid, Spain
| | - N Fazio
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology IEO, IRCCS, Milan, Italy
| | - P Ferolla
- Multidisciplinary NET Group, Department of Medical Oncology, Umbria Regional Cancer Network and University of Perugia, Perugia, Italy
| | - P L Filosso
- Department of Surgical Sciences Unit of Thoracic Surgery Corso Dogliotti, University of Torino, Torino, Italy
| | - A Frilling
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - W W de Herder
- Department of Internal Medicine, Sector of Endocrinology, Erasmus MC, ENETS Centre of Excellence, Rotterdam, The Netherlands
| | - D Hörsch
- ENETS Centre of Excellence Zentralklinik Bad Berka, Bad Berka, Germany
| | - U Knigge
- Department of Surgery and Department of Endocrinology, ENETS Centre of Excellence, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - C M Korse
- Department of Laboratory Medicine, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - E Lim
- Imperial College and the Academic Division of Thoracic Surgery, The Royal Brompton Hospital, London, UK
| | - C Lombard-Bohas
- Cancer Institute Hospices Civils de Lyon, Hôpital E Herriot, Lyon, France
| | - M Pavel
- Department of Medicine 1, Endocrinology, Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
| | - J Y Scoazec
- Department of Pathology, Gustave Roussy, Villejuif, France
| | - A Sundin
- Department of Radiology and Nuclear Medicine, Department of Surgical Sciences (IKV), Uppsala University, Uppsala, Sweden
| | - A Berruti
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Medical Oncology Unit, University of Brescia, Brescia, Italy
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Lamarca A, Cives M, de Mestier L, Crona J, Spada F, Öberg K, Pavel M, Alonso-Gordoa T. Advanced small-bowel well-differentiated neuroendocrine tumours: An international survey of practice on 3 rd-line treatment. World J Gastroenterol 2021; 27:976-989. [PMID: 33776367 PMCID: PMC7968134 DOI: 10.3748/wjg.v27.i10.976] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 01/12/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Somatostatin analogues are an established first-line therapy for well differentiated small bowel neuroendocrine tumours (Wd-SBNETs), while and peptide receptor radionuclide therapy (PRRT) is frequently used as a second-line therapy. Adequate treatment selection of third-line treatment remains challenging due to the limited prospective data currently available on the best therapeutic sequence.
AIM To understand current practice and rationale for decision-making by physicians in the 3rd-line setting by building an online survey.
METHODS Weighted average (WA) of likelihood of usage between responders (1 very unlikely; 4 very likely) was used to reflect the relevance of factors explored.
RESULTS Replies from representatives of 28 centers were received (5/8/2020-21/9/2020); medical oncologist (53.6%), gastroenterologist (17.9%); United Kingdom (21.4%), Spain (17.9%), Italy (14.3%). Majority from European Neuroendocrine Tumor Society (ENETS) Centres of Excellence (57.1%), who followed ENETS guidelines (82.1%). Generally speaking, 3rd-line treatment for Wd-SBNETs was: everolimus (EVE) (66.7%), PRRT (18.5%), liver embolization (LE) (7.4%) and interferon-alpha (IFN) (3.7%); chemotherapy (0%); decision was based on clinical trial data (59.3%), or personal experience (22.2%). EVE was most likely used if Ki-67 < 10% (WA 3.27/4) or age < 70 years (WA 3.23/4), in the 3rd-line setting (WA 3.23/4); regardless of presence/absence of carcinoid syndrome (CS), rate of progression or extent of disease. Chemotherapy was mainly utilised only if rapid progression (within 6 mo) (WA 3.35/4), Ki-67 10%-20% (WA 2.77/4), negative somatostatin receptor imaging (WA 2.65/4) or high tumour burden (WA 2.77/4); temozolomide or streptozocin was used with capecitabine or 5-fluorouracil (5-FU) (57.7%), FOLFOX (5-FU combined with oxaliplatin) (23.1%). LE was selected if presence of CS (WA 3.24/4) or Ki-67 < 10% (WA 2.8/4), after progression to other treatments (WA 2.8/4). IFN was rarely used (WA 1.3/4).
CONCLUSION Everolimus was the most frequently used therapeutic option in the third-line setting. The most important factors for decision-making included Ki-67, rate of progression, functionality and tumour burden; since this decision is based on multiple factors, it highlights the need for a multidisciplinary assessment.
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Affiliation(s)
- Angela Lamarca
- Department of Medical Oncology, European Neuroendocrine Tumor Society Centre of Excellence, The Christie NHS Foundation Trust, University of Manchester, Manchester M20 4BX, United Kingdom
| | - Mauro Cives
- Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari 70121, Italy
| | - Louis de Mestier
- Department of Gastroenterology and Pancreatology, European Neuroendocrine Tumor Society Center of Excellence, Paris-Diderot University, Clichy 75006, France
| | - Joakim Crona
- Department of Medical Sciences, Uppsala University, Uppsala SE-751 85, Sweden
| | - Francesca Spada
- Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit, European Institute of Oncology, Milan 20141, Italy
| | - Kjell Öberg
- Department of Endocrine Oncology, Uppsala University Hospital, Uppsala SE-751 85, Sweden
| | - Marianne Pavel
- Department of Endocrinology, Universitatsklinikum Erlangen, Erlangen 91054, Germany
| | - Teresa Alonso-Gordoa
- Medical Oncology Department, The Ramón y Cajal Health Research Institute, Alcalá University, University Hospital Ramon y Cajal, Madrid 28034, Spain
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Asa SL, La Rosa S, Basturk O, Adsay V, Minnetti M, Grossman AB. Molecular Pathology of Well-Differentiated Gastro-entero-pancreatic Neuroendocrine Tumors. Endocr Pathol 2021; 32:169-191. [PMID: 33459926 DOI: 10.1007/s12022-021-09662-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/03/2021] [Indexed: 12/17/2022]
Abstract
Well differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal and pancreaticobiliary system are the most common neuroendocrine neoplasms. Studies of the molecular basis of these lesions have identified genetic mutations that predispose to familial endocrine neoplasia syndromes and occur both as germline events and in sporadic tumors. The mutations often involve epigenetic regulators rather than the oncogenes and tumor suppressors that are affected in other malignancies. Somatic copy number alterations and miRNAs have also been implicated in the development and progression of some of these tumors. The molecular profiles differ by location, but many are shared by tumors in other sites, including those outside the gastroenteropancreatic system. The approach to therapy relies on both the neuroendocrine nature of these tumors and the identification of specific alterations that can serve as targets for precision oncologic approaches.
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Affiliation(s)
- Sylvia L Asa
- Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA.
| | - Stefano La Rosa
- Institute of Pathology, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Olca Basturk
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Volkan Adsay
- Department of Pathology and Research Center for Translational Medicine (KUTTAM), Koç University Hospital, Istanbul, Turkey
| | - Marianna Minnetti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Ashley B Grossman
- Green Templeton College, University of Oxford and ENETS Centre of Excellence, Royal Free Hospital, London, UK
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Neuroendocrine Neoplasms: Identification of Novel Metabolic Circuits of Potential Diagnostic Utility. Cancers (Basel) 2021; 13:cancers13030374. [PMID: 33498434 PMCID: PMC7864182 DOI: 10.3390/cancers13030374] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 01/01/2021] [Accepted: 01/14/2021] [Indexed: 01/14/2023] Open
Abstract
The incidence of neuroendocrine neoplasms (NEN) is increasing, but established biomarkers have poor diagnostic and prognostic accuracy. Here, we aim to define the systemic metabolic consequences of NEN and to establish the diagnostic utility of proton nuclear magnetic resonance spectroscopy (1H-NMR) for NEN in a prospective cohort of patients through a single-centre, prospective controlled observational study. Urine samples of 34 treatment-naïve NEN patients (median age: 59.3 years, range: 36-85): 18 had pancreatic (Pan) NEN, of which seven were functioning; 16 had small bowel (SB) NEN; 20 age- and sex-matched healthy control individuals were analysed using a 600 MHz Bruker 1H-NMR spectrometer. Orthogonal partial-least-squares-discriminant analysis models were able to discriminate both PanNEN and SBNEN patients from healthy control (Healthy vs. PanNEN: AUC = 0.90, Healthy vs. SBNEN: AUC = 0.90). Secondary metabolites of tryptophan, such as trigonelline and a niacin-related metabolite were also identified to be universally decreased in NEN patients, while upstream metabolites, such as kynurenine, were elevated in SBNEN. Hippurate, a gut-derived metabolite, was reduced in all patients, whereas other gut microbial co-metabolites, trimethylamine-N-oxide, 4-hydroxyphenylacetate and phenylacetylglutamine, were elevated in those with SBNEN. These findings suggest the existence of a new systems-based neuroendocrine circuit, regulated in part by cancer metabolism, neuroendocrine signalling molecules and gut microbial co-metabolism. Metabonomic profiling of NEN has diagnostic potential and could be used for discovering biomarkers for these tumours. These preliminary data require confirmation in a larger cohort.
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