Management of Typical and Atypical Pulmonary Carcinoids Based on Different Established Guidelines

Neuroendocrine tumors (NETs) are a group of malignancies that originated from neuroendocrine cells, with the most common sites being lungs and the gastrointestinal tract. Lung NETs comprise 25% of all lung malignancies. Small cell lung cancer is the most common form of lung NETs, and other rare forms include well-differentiated typical carcinoids (TCs) and poorly differentiated atypical carcinoids (ACs). Given the paucity of randomized studies, rational treatment is challenging. Therefore, it is recommended that these decisions be made using a multidisciplinary collaborative approach. Surgery remains the mainstay of treatment, when feasible. Following surgery, various guidelines offer different recommendations in the adjuvant setting. In this paper, we describe the adjuvant management of lung NETs, as recommended by different guidelines, and highlight their differences. In addition to that, we also discuss the management of metastatic lung NETS, including the use of peptide receptor radionucleotide therapy.

[1]  R. Bies,et al.  Multicenter phase 2 study of nintedanib in patients (pts) with advanced progressing carcinoid tumors. , 2018 .

[2]  J. Crabtree Clinical and Preclinical Advances in Gastroenteropancreatic Neuroendocrine Tumor Therapy , 2017, Front. Endocrinol..

[3]  M. Berry,et al.  Adjuvant Chemotherapy Does Not Confer Superior Survival in Patients With Atypical Carcinoid Tumors. , 2017, The Annals of thoracic surgery.

[4]  S. Basu,et al.  Clinical Response Profile of Metastatic/Advanced Pulmonary Neuroendocrine Tumors to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE , 2017, Clinical nuclear medicine.

[5]  J. Molina,et al.  Impact of adjuvant chemotherapy in non-metastatic node positive bronchial neuroendocrine tumors (BNET). , 2017 .

[6]  E. Krenning,et al.  Long-Term Efficacy, Survival, and Safety of [177Lu-DOTA0,Tyr3]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors , 2017, Clinical Cancer Research.

[7]  Shouhao Zhou,et al.  Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study. , 2017, The Lancet. Oncology.

[8]  D. Planchard,et al.  Antitumour activity of somatostatin analogues in sporadic, progressive, metastatic pulmonary carcinoids. , 2017, European journal of cancer.

[9]  A. Marchevsky,et al.  Neuroendocrine Tumors of the Lung: Current Challenges and Advances in the Diagnosis and Management of Well‐Differentiated Disease , 2017, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[10]  M. Zimmerman,et al.  Peptide Receptor Radionuclide Therapy Outcomes in a North American Cohort With Metastatic Well-Differentiated Neuroendocrine Tumors , 2017, Pancreas.

[11]  J. Berlin,et al.  Phase 3 Trial of 177Lu‐Dotatate for Midgut Neuroendocrine Tumors , 2017, The New England journal of medicine.

[12]  F. D. De Braud,et al.  Peptide receptor radionuclide therapy: focus on bronchial neuroendocrine tumors , 2016, Tumor Biology.

[13]  D. Jäger,et al.  Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. , 2016, The Lancet. Oncology.

[14]  James C Yao,et al.  Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study , 2016, The Lancet.

[15]  C. Tinelli,et al.  Long-term results of PRRT in advanced bronchopulmonary carcinoid , 2016, European Journal of Nuclear Medicine and Molecular Imaging.

[16]  E. Krenning,et al.  ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of Unknown Primary Site , 2016, Neuroendocrinology.

[17]  W. Travis,et al.  Prognostic model of survival for typical bronchial carcinoid tumours: analysis of 1109 patients on behalf of the European Association of Thoracic Surgeons (ESTS) Neuroendocrine Tumours Working Group. , 2015, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[18]  A. Nicholson,et al.  Introduction to The 2015 World Health Organization Classification of Tumors of the Lung, Pleura, Thymus, and Heart. , 2015, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[19]  F. Khuri,et al.  Atypical Carcinoid Tumor of the Lung: A Surveillance, Epidemiology, and End Results Database Analysis , 2015, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[20]  W. Travis,et al.  Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[21]  M. Berry,et al.  Defining the role of adjuvant chemotherapy after lobectomy for typical bronchopulmonary carcinoid tumors. , 2015, The Annals of thoracic surgery.

[22]  P. Jänne,et al.  Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors. , 2014, Lung cancer.

[23]  A. Mojtahedi,et al.  The value of (68)Ga-DOTATATE PET/CT in diagnosis and management of neuroendocrine tumors compared to current FDA approved imaging modalities: a review of literature. , 2014, American journal of nuclear medicine and molecular imaging.

[24]  W. Travis Pathology and diagnosis of neuroendocrine tumors: lung neuroendocrine. , 2014, Thoracic surgery clinics.

[25]  P. Ruszniewski,et al.  Lanreotide in metastatic enteropancreatic neuroendocrine tumors. , 2014, The New England journal of medicine.

[26]  K. Darwiche,et al.  Neuroendocrine Tumors of the Bronchopulmonary System (Typical and Atypical Carcinoid Tumors): Current Strategies in Diagnosis and Treatment. Conclusions of an Expert Meeting February 2011 in Weimar, Germany , 2014, Oncology Research and Treatment.

[27]  G. Giaccone,et al.  Systemic Therapy, Clinical Outcomes, and Overall Survival in Locally Advanced or Metastatic Pulmonary Carcinoid: A Brief Report , 2014, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[28]  D. Radice,et al.  Capecitabine plus temozolomide (CAP-TEM) in patients with advanced neuroendocrine neoplasms (NEN): An Italian multicenter retrospective analysis. , 2014 .

[29]  F. Beuschlein,et al.  Neuroendocrine tumor recurrence: diagnosis with 68Ga-DOTATATE PET/CT. , 2013, Radiology.

[30]  E. Ruffini,et al.  Outcome and Prognostic Factors in Bronchial Carcinoids: A Single-Center Experience , 2013, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[31]  K. Öberg,et al.  Effect of Temozolomide in Patients with Metastatic Bronchial Carcinoids , 2013, Neuroendocrinology.

[32]  M. Zakkar,et al.  Is sublobar resection equivalent to lobectomy for surgical management of peripheral carcinoid? , 2013, Interactive cardiovascular and thoracic surgery.

[33]  D. Metz,et al.  Consensus guidelines for the management and treatment of neuroendocrine tumors. , 2013, Pancreas.

[34]  Robert C. G. Martin,et al.  Surgical management of pulmonary carcinoid tumors: sublobar resection versus lobectomy. , 2013, American journal of surgery.

[35]  J. Chabot,et al.  Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience , 2013, Cancer Chemotherapy and Pharmacology.

[36]  G. Schmidt,et al.  The Role of 68Ga-DOTATATE PET/CT in Suspected Neuroendocrine Tumors , 2012, The Journal of Nuclear Medicine.

[37]  P. Hellman,et al.  Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[38]  E. Papini,et al.  Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian Epidemiological study: THE NET MANAGEMENT STUDY , 2012, Journal of Endocrinological Investigation.

[39]  A. Marchevsky,et al.  Limited role of Ki-67 proliferative index in predicting overall short-term survival in patients with typical and atypical pulmonary carcinoid tumors , 2012, Modern Pathology.

[40]  Jeffrey W. Clark,et al.  Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  J. Hainsworth,et al.  Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study , 2011, The Lancet.

[42]  T. Demmy,et al.  Is sublobar resection sufficient for carcinoid tumors? , 2011, The Annals of thoracic surgery.

[43]  R. Vassilopoulou-sellin,et al.  Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion , 2011, Cancer.

[44]  E. Krenning,et al.  Quality of Life in 265 Patients with Gastroenteropancreatic or Bronchial Neuroendocrine Tumors Treated with [177Lu-DOTA0,Tyr3]Octreotate , 2011, The Journal of Nuclear Medicine.

[45]  B. Glaser,et al.  68Ga-DOTA-NOC PET/CT Imaging of Neuroendocrine Tumors: Comparison with 111In-DTPA-Octreotide (OctreoScan®) , 2011, Molecular Imaging and Biology.

[46]  C. Lagrasta,et al.  Involvement of HER-2/neu and metastasis-related proteins in the development of ileal neuroendocrine tumors , 2011, Virchows Archiv.

[47]  Y. Bang,et al.  Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. , 2011, The New England journal of medicine.

[48]  Natasha Rekhtman,et al.  Neuroendocrine tumors of the lung: an update. , 2010, Archives of pathology & laboratory medicine.

[49]  W. Travis Advances in neuroendocrine lung tumors. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[50]  Manal M. Hassan,et al.  Consensus Guideline for the Diagnosis and Management of Neuroendocrine Tumors Well-Differentiated Neuroendocrine Tumors of the Thorax ( Includes Lung and Thymus ) , 2010 .

[51]  I. Kayani,et al.  The Role of 68Ga-DOTATATE PET in Patients with Neuroendocrine Tumors and Negative or Equivocal Findings on 111In-DTPA-Octreotide Scintigraphy , 2010, Journal of Nuclear Medicine.

[52]  F. Detterbeck Management of carcinoid tumors. , 2010, The Annals of thoracic surgery.

[53]  S. Bölükbas,et al.  Parenchyma-sparing bronchial sleeve resections in trauma, benign and malign diseases. , 2010, The Thoracic and cardiovascular surgeon.

[54]  C. Schade-Brittinger,et al.  Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  R. Valkema,et al.  Peptide-receptor radionuclide therapy for endocrine tumors , 2009, Nature Reviews Endocrinology.

[56]  I. Drozdov,et al.  Neuroendocrine tumor epidemiology , 2008, Cancer.

[57]  K. Hess,et al.  Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[58]  Manal M. Hassan,et al.  Risk factors associated with neuroendocrine tumors: A U.S.‐based case–control study , 2008, International journal of cancer.

[59]  J. Blaauwgeers,et al.  Pulmonary tumours in the Netherlands: focus on temporal trends in histology and stage and on rare tumours , 2008, Thorax.

[60]  Irvin M Modlin,et al.  Bronchopulmonary neuroendocrine tumors , 2008, Cancer.

[61]  Manal M. Hassan,et al.  One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[62]  J. Crowley,et al.  The Impact of Additional Prognostic Factors on Survival and their Relationship with the Anatomical Extent of Disease Expressed by the 6th Edition of the TNM Classification of Malignant Tumors and the Proposals for the 7th Edition , 2008, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[63]  E. Krenning,et al.  Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[64]  B. Skogseid,et al.  Temozolomide as Monotherapy Is Effective in Treatment of Advanced Malignant Neuroendocrine Tumors , 2007, Clinical Cancer Research.

[65]  M. Bidlingmaier,et al.  Ectopic growth hormone-releasing hormone secretion by a metastatic bronchial carcinoid tumor: a case with a non hypophysial intracranial tumor that shrank during long acting octreotide treatment , 2007, Pituitary.

[66]  F. Rea,et al.  Outcome and surgical strategy in bronchial carcinoid tumors: single institution experience with 252 patients. , 2007, European Journal of Cardio-Thoracic Surgery.

[67]  G. Rossi,et al.  Bronchial typical carcinoid tumors. , 2006, Seminars in thoracic and cardiovascular surgery.

[68]  Jeffrey W. Clark,et al.  Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[69]  S. Zwas,et al.  Experience with somatostatin receptor scintigraphy in the management of pulmonary carcinoid tumors. , 2005, The Israel Medical Association journal : IMAJ.

[70]  X. Teng [World Health Organization classification of tumours, pathology and genetics of tumours of the lung]. , 2005, Zhonghua bing li xue za zhi = Chinese journal of pathology.

[71]  B. Taal,et al.  Metastatic carcinoid tumors: a clinical review. , 2005, The oncologist.

[72]  G. Pelosi,et al.  Typical and Atypical Pulmonary Carcinoid Tumor Overdiagnosed as Small-Cell Carcinoma on Biopsy Specimens: A Major Pitfall in the Management of Lung Cancer Patients , 2005, The American journal of surgical pathology.

[73]  A. Harris,et al.  Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression , 2004, British Journal of Cancer.

[74]  P. Jänne,et al.  Outcome of patients with pulmonary carcinoid tumors receiving chemotherapy or chemoradiotherapy. , 2004, Lung cancer.

[75]  F. Sera,et al.  Bronchial carcinoid tumors: nodal status and long-term survival after resection. , 2004, The Annals of thoracic surgery.

[76]  U. Mansmann,et al.  Prospective, randomized, multicenter trial on the antiproliferative effect of lanreotide, interferon alfa, and their combination for therapy of metastatic neuroendocrine gastroenteropancreatic tumors--the International Lanreotide and Interferon Alfa Study Group. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[77]  J. Reubi,et al.  Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting , 2003, European Journal of Nuclear Medicine and Molecular Imaging.

[78]  I. Modlin,et al.  A 5‐decade analysis of 13,715 carcinoid tumors , 2003, Cancer.

[79]  E. P. Krenning,et al.  Treatment of patients with gastro-entero-pancreatic (GEP) tumours with the novel radiolabelled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate , 2003, European Journal of Nuclear Medicine and Molecular Imaging.

[80]  J. Olsen,et al.  Pulmonary neuroendocrine tumors: incidence and prognosis of histological subtypes. A population-based study in Denmark. , 2002, Lung cancer.

[81]  E. Ruffini,et al.  Bronchial carcinoid tumors: surgical management and long-term outcome. , 2002, The Journal of thoracic and cardiovascular surgery.

[82]  Xinjun Li,et al.  Incidence trends and risk factors of carcinoid tumors , 2001, Cancer.

[83]  E. Wilander,et al.  Experience in treatment of metastatic pulmonary carcinoid tumors. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[84]  M. Fjällskog,et al.  Treatment with cisplatin and etoposide in patients with neuroendocrine tumors , 2001, Cancer.

[85]  H. Tazelaar,et al.  Familial pulmonary carcinoid tumors , 2001, Cancer.

[86]  T. de Baère,et al.  Antitumour activity of somatostatin analogues in progressive metastatic neuroendocrine tumours. , 2001, European journal of cancer.

[87]  R. Jian,et al.  The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors , 2000, American Journal of Gastroenterology.

[88]  N. Altorki,et al.  Long-term outcome after resection for bronchial carcinoid tumors. , 2000, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[89]  J. Reubi,et al.  Affinity profiles for human somatostatin receptor subtypes SST1–SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use , 2000, European Journal of Nuclear Medicine.

[90]  R. Giudicelli,et al.  Operative risk and prognostic factors of typical bronchial carcinoid tumors. , 1998, The Annals of thoracic surgery.

[91]  W. Travis,et al.  Reproducibility of neuroendocrine lung tumor classification. , 1998, Human pathology.

[92]  Belghiti,et al.  Expression of vascular endothelial growth factor in digestive neuroendocrine tumours , 1998, Histopathology.

[93]  D. Hanahan,et al.  Vascular endothelial growth factor and its receptors, flt-1 and flk-1, are expressed in normal pancreatic islets and throughout islet cell tumorigenesis. , 1995, Molecular endocrinology.

[94]  P. Carpenter,et al.  The Cushing Syndrome Induced by Bronchial Carcinoid Tumors , 1992, Annals of Internal Medicine.

[95]  A. Sundin,et al.  Imaging of Neuroendocrine Tumors. , 2016, Frontiers of hormone research.

[96]  W. Travis WHO classification of tumours of the lung, pleura, thymus and heart , 2015 .

[97]  L. Tanoue,et al.  The National Comprehensive Cancer Network , 1998, Cancer.

[98]  Hisao Asamura,et al.  Neuroendocrine neoplasms of the lung: a prognostic spectrum. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[99]  W. Travis Pathology & Genetics Tumours of the lung, Pleura, Thymus and Heart , 2004 .

[100]  L. Albarello,et al.  Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features. , 2003, Human pathology.

[101]  E. Berg,et al.  World Health Organization Classification of Tumours , 2002 .

[102]  H. Stünzi,et al.  Tumours of the lung. , 1974, Bulletin of the World Health Organization.