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Reviews in Endocrine and Metabolic Disorders

, Volume 18, Issue 4, pp 433–442 | Cite as

Management of pulmonary neuroendocrine tumors

  • Robert A. Ramirez
  • Aman Chauhan
  • Juan Gimenez
  • Katharine E. H. Thomas
  • Ioni Kokodis
  • Brianne A. Voros
Article

Abstract

Neuroendocrine tumors (NETs) of the lung are divided into 4 major types: small cell lung cancer (SCLC), large cell neuroendocrine carcinoma (LCNEC), atypical carcinoid (AC) or typical carcinoid (TC). Each classification has distinctly different treatment paradigms, making an accurate initial diagnosis essential. The inconsistent clinical presentation of this disease, however, makes this difficult. The objective of this manuscript is to detail the diagnosis and management of the well differentiated pulmonary carcinoid (PC) tumors. A multidisciplinary approach to work up and treatment should be utilized for each patient. A multimodal radiological work-up is used for diagnosis, with contrast enhanced CT predominantly utilized and functional imaging techniques. A definitive diagnosis is based on tissue findings. Surgical management remains the mainstay of therapy and can be curative. In those with advanced disease, medical treatments consist of somatostatin analog (SSA) therapy, targeted therapy, chemotherapy or peptide receptor radionuclide therapy. SSAs are the standard of care in those with metastatic NETs, using either Octreotide long acting repeatable (LAR) or lanreotide as reasonable options, despite a scarcity of prospective data in PCs. Targeted therapies consist of everolimus which is approved for use in PCs, with various studies showing mixed results with other targeted agents. Additionally, radionuclide therapy may be used and has been shown to increase survival and to reduce symptoms in some studies. Prospective trials are needed to determine other strategies that may be beneficial in PCs as well as sequencing of therapy. Successful diagnosis and optimal treatment relies on a multidisciplinary approach in patients with lung NETs. Clinical trials should be used in appropriate patients.

Keywords

Bronchial carcinoid Neuroendocrine tumor Lung carcinoid 

Notes

Funding

None.

Compliance with ethical standards

Conflict of interest

Robert A. Ramirez, DO serves as a consultant for Ipsen Biophamaceuticals Inc. and Bio Theranostics Inc. as well as a speaker for Merck & Co. Inc., Genetech, Astra Zeneca and Ipsen Biopharmaceuticals. No other authors have conflicts of interest to disclose.

Human and animal studies

No humans or animals were used in this study.

Financial support

None to disclose.

References

  1. 1.
    Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26(18):3063–72.CrossRefPubMedGoogle Scholar
  2. 2.
    Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM. Bronchopulmonary neuroendocrine tumors. Cancer. 2008;113(1):5–21.CrossRefPubMedGoogle Scholar
  3. 3.
    Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC. Risk factors associated with neuroendocrine tumors: a US-based case–control study. Int J Cancer. 2008;123(4):867–73.CrossRefPubMedGoogle Scholar
  4. 4.
    Taal BG, Visser O. Epidemiology of neuroendocrine tumours. Neuroendocrinology. 2004;80(suppl 1):3–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Pelosi G, Sonzogni A, Veronesi G, et al. Pathologic and molecular features of screening low-dose computed tomography (LDCT)-detected lung cancer: a baseline and 2-year repeat study. Lung Cancer. 2008;62(2):202–14.CrossRefPubMedGoogle Scholar
  6. 6.
    Travis WD. Advances in neuroendocrine lung tumors. Ann Oncol. 2010;21(suppl_7):vii65–71.CrossRefPubMedGoogle Scholar
  7. 7.
    Hannah-Shmouni F, Stratakis CA, Koch CA. Flushing in (neuro) endocrinology. Rev Endocr Metab Disord. 2016;17(3):373–80.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Trantakis C, Koch C, Tannapfel A, Meixensberger J, Drynda K, Führer D. Acromegaly caused by a thoracic neuroendocrine tumor. Exp Clin Endocrinol Diabetes. 2005;113(S 1):158.  https://doi.org/10.1055/s-2005-863017.CrossRefGoogle Scholar
  9. 9.
    Dynkevich Y, Rother KI, Whitford I, et al. Tumors, IGF-2, and hypoglycemia: insights from the clinic, the laboratory, and the historical archive. Endocr Rev. 2013;34(6):798–826.  https://doi.org/10.1210/er.2012-1033.CrossRefPubMedGoogle Scholar
  10. 10.
    Shames JM, Dhurandhar NR, Blackard WG. Insulin-secreting bronchial carcinoid tumor with widespread metastases. Am J Med. 1968;44(4):632–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med. 2010;134(11):1628–38.PubMedGoogle Scholar
  12. 12.
    Kos-Kudla B, O'Toole D, Falconi M, et al. ENETS consensus guidelines for the management of bone and lung metastases from neuroendocrine tumors. Neuroendocrinology. 2010;91(4):341–50.CrossRefPubMedGoogle Scholar
  13. 13.
    Baxi AJ, Chintapalli K, Katkar A, Restrepo CS, Betancourt SL, Sunnapwar A. Multimodality imaging findings in carcinoid tumors: a head-to-toe spectrum. Radiographics. 2017;37(2):516–36.CrossRefPubMedGoogle Scholar
  14. 14.
    Benson RE, Rosado-de-Christenson ML, Martínez-Jiménez S, Kunin JR, Pettavel PP. Spectrum of pulmonary neuroendocrine proliferations and neoplasms. Radiographics. 2013;33(6):1631–49.CrossRefPubMedGoogle Scholar
  15. 15.
    Davies SJ, Gosney JR, Hansell DM, et al. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and the associated lung neuroendocrine tumors. Thorax. 2007;62(3):248–52.CrossRefPubMedGoogle Scholar
  16. 16.
    Miller RR, Müller NL. Neuroendocrine cell hyperplasia and obliterative bronchiolitis in patients with peripheral carcinoid tumors. Am J Surg Pathol. 1995;19(6):653–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Rosado de Christenson ML, Abbott GF, Kirejczyk WM, Galvin JR, Travis WD. Thoracic carcinoids: radiologic-pathologic correlation. Radiographics. 1999;19(3):707–36.CrossRefPubMedGoogle Scholar
  18. 18.
    Soga J, Yakuwa Y. Bronchopulmonary carcinoids: an analysis of 1,875 reported cases with special reference to a comparison between typical carcinoids and atypical varieties. Ann Thorac Cardiovasc Surg. 1999;5(4):211–9.PubMedGoogle Scholar
  19. 19.
    Jung K, Lee KS, Han J, et al. Large cell neuroendocrine carcinoma of the lung: clinical, CT, and pathologic findings in 11 patients. J Thorac Imaging. 2001;16(3):156–62.CrossRefPubMedGoogle Scholar
  20. 20.
    Shin AR, Shin BK, Choi J, Oh Y, Kim HK, Kang E. Large cell neuroendocrine carcinoma of the lung: radiologic and pathologic findings. J Comput Assist Tomogr. 2000;24(4):567–73.CrossRefPubMedGoogle Scholar
  21. 21.
    Chong S, Lee KS, Kim B, et al. Integrated PET/CT of pulmonary neuroendocrine tumors: diagnostic and prognostic implications. Am J Roentgenol. 2007;188(5):1223–31.CrossRefGoogle Scholar
  22. 22.
    Wolin EM. Challenges in the diagnosis and management of well-differentiated neuroendocrine tumors of the lung (typical and atypical carcinoid): current status and future considerations. Oncologist. 2015;20(10):1123–31.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Jeung M, Gasser B, Gangi A, et al. Bronchial carcinoid tumors of the thorax: Spectrum of radiologic findings. Radiographics. 2002;22(2):351–65.CrossRefPubMedGoogle Scholar
  24. 24.
    Meijer WG, van der Veer E, Jager PL, et al. Bone metastases in carcinoid tumors: clinical features, imaging characteristics, and markers of bone metabolism. J Nucl Med. 2003;44(2):184–91.PubMedGoogle Scholar
  25. 25.
    Granberg D, Sundin A, Janson ET, Öberg K, Skogseid B, Westlin J. Octreoscan in patients with bronchial carcinoid tumours. Clin Endocrinol. 2003;59(6):793–9.CrossRefGoogle Scholar
  26. 26.
    Kaifi JT, Kayser G, Ruf J, Passlick B. The diagnosis and treatment of bronchopulmonary carcinoid. Dtsch Arztebl Int. 2015;112(27–28):479–85.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Krausz Y, Freedman N, Rubinstein R, et al. 68Ga-DOTA-NOC PET/CT imaging of neuroendocrine tumors: comparison with 111In-DTPA-octreotide (OctreoScan®). Mol Imaging Biol. 2011;13(3):583–93.CrossRefPubMedGoogle Scholar
  28. 28.
    Phan AT, Oberg K, Choi J, et al. NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the thorax (includes lung and thymus). Pancreas. 2010;39(6):784–98.CrossRefPubMedGoogle Scholar
  29. 29.
    Horsch D, Schmid KW, Anlauf M, 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. Oncol Res Treat. 2014;37(5):266–76.CrossRefPubMedGoogle Scholar
  30. 30.
    Detterbeck FC. Management of carcinoid tumors. Ann Thorac Surg. 2010;89(3):998–1005.CrossRefPubMedGoogle Scholar
  31. 31.
    Travis WD, Brambilla W, Muller-Hermelink HK, Harris CC. World health organization classification of tumours. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004.Google Scholar
  32. 32.
    Chauhan A, Ramirez RA. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) and the role of somatostatin analogs: a case series. Lung. 2015;193(5):653–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Strosberg J, Nasir A, Coppola D, Wick M, Kvols L. Correlation between grade and prognosis in metastatic gastroenteropancreatic neuroendocrine tumors. Hum Pathol. 2009;40(9):1262–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Pelosi G, Rindi G, Travis WD, Papotti M. Ki-67 antigen in lung neuroendocrine tumors: unraveling a role in clinical practice. J Thorac Oncol. 2014;9(3):273–84.CrossRefPubMedGoogle Scholar
  35. 35.
    Walts AE, Ines D, Marchevsky AM. Limited role of ki-67 proliferative index in predicting overall short-term survival in patients with typical and atypical pulmonary carcinoid tumors. Mod Pathol. 2012;25(9):1258–64.CrossRefPubMedGoogle Scholar
  36. 36.
    Ramirez RA, Beyer DT, Diebold AE, et al. Clinical and pathologic characteristics of bronchial carcinoid tumors: a single institution review. J Thorac Oncol. 2015;10(9):S749–50.Google Scholar
  37. 37.
    Bhosale P, Shah A, Wei W, et al. Carcinoid tumours: predicting the location of the primary neoplasm based on the sites of metastases. Eur Radiol. 2013;23(2):400–7.CrossRefPubMedGoogle Scholar
  38. 38.
    Yang J, Kan Y, Ge BH, Yuan L, Li C, Zhao W. Diagnostic role of gallium-68 DOTATOC and gallium-68 DOTATATE PET in patients with neuroendocrine tumors: a meta-analysis. Acta Radiol. 2014;55(4):389–98.CrossRefPubMedGoogle Scholar
  39. 39.
    Edge SB, Compton CC. The American joint committee on cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–4.CrossRefPubMedGoogle Scholar
  40. 40.
    Volante M, Gatti G, Papotti M. Classification of lung neuroendocrine tumors: lights and shadows. Endocrine. 2015;50(2):315–9.CrossRefPubMedGoogle Scholar
  41. 41.
    Johnson R, Trocha S, McLawhorn M, et al. Histology, not lymph node involvement, predicts long-term survival in bronchopulmonary carcinoids. Am Surg. 2011;77(12):1669–74.PubMedGoogle Scholar
  42. 42.
    Filosso PL, Oliaro A, Ruffini E, et al. Outcome and prognostic factors in bronchial carcinoids: a single-center experience. J Thorac Oncol. 2013;8(10):1282–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Ferolla P, Daddi N, Urbani M, et al. Tumorlets, multicentric carcinoids, lymph-nodal metastases, and long-term behavior in bronchial carcinoids. J Thorac Oncol. 2009;4(3):383–7.CrossRefPubMedGoogle Scholar
  44. 44.
    Caplin ME, Baudin E, Ferolla P, et al. Pulmonary neuroendocrine (carcinoid) tumors: European neuroendocrine tumor society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26(8):1604–20.CrossRefPubMedGoogle Scholar
  45. 45.
    National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology neuroendocrine tumors. National Comprehensive Cancer Network Web site. https://www.nccn.org/professionals/physician_gls/PDF/neuroendocrine.pdf. Updated Version 2.2017. Accessed 11 May 2017.
  46. 46.
    McCaughan BC, Martini N, Bains MS. Bronchial carcinoids. Review of 124 cases. J Thorac Cardiovasc Surg. 1985;89(1):8–17.PubMedGoogle Scholar
  47. 47.
    Harpole DH, Feldman JM, Buchanan S, Young WG, Wolfe WG. Bronchial carcinoid tumors: a retrospective analysis of 126 patients. Ann Thorac Surg. 1992;54(1):50–5.CrossRefPubMedGoogle Scholar
  48. 48.
    Gonzalez-Rivas D, Marin JC, Granados JPO, et al. Uniportal video-assisted thoracoscopic right upper sleeve lobectomy and tracheoplasty in a 10-year-old patient. J Thorac Dis. 2016;8(9):E966–9.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Chughtai TS, Morin JE, Sheiner NM, Wilson JA, Mulder DS. Bronchial carcinoid—twenty years' experience defines a selective surgical approach. Surgery. 1997;122(4):801–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Yendamuri S, Gold D, Jayaprakash V, Dexter E, Nwogu C, Demmy T. Is sublobar resection sufficient for carcinoid tumors? Ann Thorac Surg. 2011;92(5):1774–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Davini F, Gonfiotti A, Comin C, Caldarella A, Mannini F, Janni A. Typical and atypical carcinoid tumours: 20-year experience with 89 patients. J Cardiovasc Surg. 2009;50(6):807.Google Scholar
  52. 52.
    Mineo TC, Guggino G, Mineo D, Vanni G, Ambrogi V. Relevance of lymph node micrometastases in radically resected endobronchial carcinoid tumors. Ann Thorac Surg. 2005;80(2):428–32.CrossRefPubMedGoogle Scholar
  53. 53.
    Thomas CF, Tazelaar HD, Jett JR. Typical and atypical pulmonary carcinoids: outcome in patients presenting with regional lymph node involvement. Chest. 2001;119(4):1143–50.CrossRefPubMedGoogle Scholar
  54. 54.
    Cardillo G, Sera F, Di Martino M, et al. Bronchial carcinoid tumors: nodal status and long-term survival after resection. Ann Thorac Surg. 2004;77(5):1781–5.CrossRefPubMedGoogle Scholar
  55. 55.
    Wurtz A, Benhamed L, Conti M, Bouchindhomme B, Porte H. Results of systematic nodal dissection in typical and atypical carcinoid tumors of the lung. J Thorac Oncol. 2009;4(3):388–94.CrossRefPubMedGoogle Scholar
  56. 56.
    Marty-Ané C, Costes V, Pujol J, Alauzen M, Baldet P, Mary H. Carcinoid tumors of the lung: do atypical features require aggressive management? Ann Thorac Surg. 1995;59(1):78–83.CrossRefPubMedGoogle Scholar
  57. 57.
    Filosso PL, Guerrera F, Evangelista A, 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. Eur J Cardiothorac Surg. 2015;48(3):441–7.CrossRefPubMedGoogle Scholar
  58. 58.
    Gosney JR. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia as a precursor to pulmonary neuroendocrine tumors. Chest. 2004;125(5_suppl):108S.CrossRefPubMedGoogle Scholar
  59. 59.
    Al-Ayoubi AM, Ralston JS, Richardson SR, Denlinger CE. Diffuse pulmonary neuroendocrine cell hyperplasia involving the chest wall. Ann Thorac Surg. 2014;97(1):333–5.CrossRefPubMedGoogle Scholar
  60. 60.
    Aubry MC, Thomas CF, Jett JR, Swensen SJ, Myers JL. Significance of multiple carcinoid tumors and tumorlets in surgical lung specimens: analysis of 28 patients. Chest. 2007;131(6):1635–43.CrossRefPubMedGoogle Scholar
  61. 61.
    Zhou H, Ge Y, Janssen B, et al. Double lung transplantation for diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. J Bronchology Interv Pulmonol. 2014;21(4):342–5.CrossRefPubMedGoogle Scholar
  62. 62.
    Wirtschafter E, Walts AE, Liu ST, Marchevsky AM. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia of the lung (DIPNECH): current best evidence. Lung. 2015;193(5):659–67.CrossRefPubMedGoogle Scholar
  63. 63.
    Ferolla P. Medical treatment of advanced thoracic neuroendocrine tumors. Thorac Surg Clin. 2014;24(3):351–5.CrossRefPubMedGoogle Scholar
  64. 64.
    Rinke A, Muller HH, Schade-Brittinger C, 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. J Clin Oncol. 2009;27(28):4656–63.CrossRefPubMedGoogle Scholar
  65. 65.
    Caplin ME, Pavel M, Ruszniewski P. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(16):1556–7.PubMedGoogle Scholar
  66. 66.
    Bongiovanni A, Recine F, Riva N, et al. Outcome analysis of first-line somatostatin analog treatment in metastatic pulmonary neuroendocrine tumors and prognostic significance of 18FDG-PET/CT. Clin Lung Cancer. 2016;  https://doi.org/10.1016/j.cllc.2016.11.004.
  67. 67.
    Sullivan I, Le Teuff G, Guigay J, et al. Antitumour activity of somatostatin analogues in sporadic, progressive, metastatic pulmonary carcinoids. Eur J Cancer. 2017;75:259–67.CrossRefPubMedGoogle Scholar
  68. 68.
    Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514–23.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Pavel ME, Hainsworth JD, Baudin E, 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. Lancet. 2011;378(9808):2005–12.CrossRefPubMedGoogle Scholar
  70. 70.
    Fazio N, Granberg D, Grossman A, et al. Everolimus plus octreotide long-acting repeatable in patients with advanced lung neuroendocrine tumors: analysis of the phase 3, randomized, placebo-controlled RADIANT-2 study. Chest. 2013;143(4):955–62.CrossRefPubMedGoogle Scholar
  71. 71.
    Yao JC, Fazio N, Singh S, 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. Lancet. 2016;387(10022):968–77.CrossRefPubMedGoogle Scholar
  72. 72.
    Fazio N, Buzzoni R, Delle Fave G, et al. Efficacy and safety of everolimus in advanced, progressive, nonfunctional neuroendocrine tumors (NET) of the lung: a subgroup analysis of the phase 3 RADIANT-4 study. Presented at the 2016 North American Neuroendocrine Tumor Society Annual Symposium.Google Scholar
  73. 73.
    Ferolla P, Brizzi MP, Meyer T, et al. Efficacy and safety of pasireotide LAR or everolimus alone, or in combination in patients with advanced carcinoids (NET) of the lung/thymus: results from the randomized, phase 2 LUNA study. Ann Oncol. 2016;27(suppl 6):416O.Google Scholar
  74. 74.
    Zhang J, Jia Z, Li Q, et al. Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer. 2007;109(8):1478–86.CrossRefPubMedGoogle Scholar
  75. 75.
    Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501–13.CrossRefPubMedGoogle Scholar
  76. 76.
    Gagliano T, Gennari G, Tassinari M, et al. The cytotoxic effect of sunitinib on human bronchial carcinoid cell lines and primary cultures is counteracted by EGF and IGF-1 but not by VEGF. Presented at the 16th European Congress of Endocrinology 2014, Poland, Wroclaw Endocrine Abstracts 2014 35:OC10 2.Google Scholar
  77. 77.
    Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26(20):3403–10.CrossRefPubMedGoogle Scholar
  78. 78.
    Castellano D, Capdevila J, Sastre J, et al. Sorafenib and bevacizumab combination targeted therapy in advanced neuroendocrine tumour: a phase II study of spanish neuroendocrine tumour group (GETNE0801). Eur J Cancer. 2013;49(18):3780–7.CrossRefPubMedGoogle Scholar
  79. 79.
    Moertel CG, Kvols LK, O’Connell MJ, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Cancer. 1991;68(2):227–32.CrossRefPubMedGoogle Scholar
  80. 80.
    Fjällskog MH, Granberg D, Welin SL, et al. Treatment with cisplatin and etoposide in patients with neuroendocrine tumors. Cancer. 2001;92(5):1101–7.CrossRefPubMedGoogle Scholar
  81. 81.
    Wirth LJ, Carter MR, Jänne PA, Johnson BE. Outcome of patients with pulmonary carcinoid tumors receiving chemotherapy or chemoradiotherapy. Lung Cancer. 2004;44(2):213–20.CrossRefPubMedGoogle Scholar
  82. 82.
    Mitry E, Baudin E, Ducreux M, et al. Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin. Br J Cancer. 1999;81(8):1351–5.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Kulke MH, Wu B, Ryan DP, et al. A phase II trial of irinotecan and cisplatin in patients with metastatic neuroendocrine tumors. Dig Dis Sci. 2006;51(6):1033–8.CrossRefPubMedGoogle Scholar
  84. 84.
    Crona J, Fanola I, Lindholm DP, et al. Effect of temozolomide in patients with metastatic bronchial carcinoids. Neuroendocrinology. 2013;98(2):151–5.CrossRefPubMedGoogle Scholar
  85. 85.
    Chan JA, Stuart K, Earle CC, et al. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol. 2012;30(24):2963–8.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Ramirez RA, Beyer DT, Chauhan A, Boudreaux JP, Wang YZ, Woltering EA. The role of Capecitabine/Temozolomide in metastatic neuroendocrine tumors. Oncologist. 2016;21(6):671–5.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Spada F, Antonuzzo L, Marconcini R, et al. Chemotherapy with capecitabine plus temozolomide (CAP-TEM) in patients with advanced neuroendocrine neoplasms (NENs): an italian multicenter retrospective analysis. J Clin Oncol. 2015;33(15):e15174.Google Scholar
  88. 88.
    Papaxoinis G, McCallum L, Nasralla M, Nonaka D. Efficacy of the combination of capecitabine and temozolomide in patients with advanced pulmonary carcinoid tumours. Neuroendocrinology. 2016;103:71–71.Google Scholar
  89. 89.
    Fine RL, Gulati AP, Tsushima D, et al. Prospective phase II study of capecitabine and temozolomide (CAPTEM) for progressive, moderately, and well-differentiated metastatic neuroendocrine tumors. J Clin Oncol. 2014;32(3):179.  https://doi.org/10.1200/jco.2014.32.3_suppl.179. CrossRefGoogle Scholar
  90. 90.
    Walter T, Planchard D, Bouledrak K, et al. Evaluation of the combination of oxaliplatin and 5-fluorouracil or gemcitabine in patients with sporadic metastatic pulmonary carcinoid tumors. Lung Cancer. 2016;96:68–73.CrossRefPubMedGoogle Scholar
  91. 91.
    Chan JA, Kulke MH. Emerging therapies for the treatment of patients with advanced neuroendocrine tumors. Expert Opin Emerg Drugs. 2007;12(2):253–70.CrossRefPubMedGoogle Scholar
  92. 92.
    Imhof A, Brunner P, Marincek N, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol. 2011;29(17):2416–23.CrossRefPubMedGoogle Scholar
  93. 93.
    Waldherr C, Pless M, Maecke HR, Haldemann A, Mueller-Brand J. The clinical value of [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study. Ann Oncol. 2001;12(7):941–5.CrossRefPubMedGoogle Scholar
  94. 94.
    Naraev B, Sharma N, Engelman ES, Bushnell DL, O'Dorisio TM, Halfdanarson TR. The outcome of peptide receptor radionuclide therapy (PRRT) in north american patients with advanced well-differentiated neuroendocrine tumors (WD-NETs). J Clin Oncol. 2012;30(15):e14600.Google Scholar
  95. 95.
    Mariniello A, Bodei L, Tinelli C, et al. Long-term results of PRRT in advanced bronchopulmonary carcinoid. Eur J Nucl Med Mol I. 2016;43(3):441–52.CrossRefGoogle Scholar
  96. 96.
    US National Institutes of Health. Safety of lanreotide 120 mg ATG in combination with metformin in patients with progressive advanced well-differentiated gastro-intestinal (GI) or lung carcinoids: A pilot, one-arm, open-label, prospective study: The MetNET-2 trial. https://clinicaltrials.gov/ct2/show/NCT02823691. Accessed 12 May 2017.
  97. 97.
    US National Institutes of Health. A phase II study of durvalumab (MEDI4736) plus tremelimumab for the treatment of patients with advanced neuroendocrine neoplasms of gastroenteropancreatic or Lung Origin (the DUNE trial). https://clinicaltrials.gov/ct2/show/NCT03095274. Accessed 12 May 2017.
  98. 98.
    US National Institutes of Health. DART: Dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors. https://clinicaltrials.gov/ct2/show/NCT02834013. Accessed 12 May 2017.
  99. 99.
    US National Institutes of Health. Phase II study of ibrutinib in advanced carcinoid and pancreatic neuroendocrine tumors. https://clinicaltrials.gov/ct2/show/NCT02575300. Accessed 12 May 2017.
  100. 100.
    US National Institutes of Health. A phase 3, prospective, randomized, double-blind, multi-center study of the efficacy and safety of lanreotide Autogel/Depot 120 mg plus BSC vs. placebo plus BSC for tumor control in subjects with well differentiated, metastatic and/or unresectable, typical or atypical, lung Neuroendocrine tumors. https://clinicaltrials.gov/ct2/show/NCT02683941. Accessed 12 May 2017.
  101. 101.
    US National Institutes of Health. Efficacy and safety of lanreotide ATG 120 mg in combination with temozolomide in subjects with progressive well differentiated thoracic neuroendocrine tumors. A phase II, multicentre, single arm, open-label trial. https://clinicaltrials.gov/ct2/show/NCT02698410. Accessed 12 May 2017.
  102. 102.
    US National Institutes of Health. Phase II study of single agent regorafenib in patients with Advanced/Metastatic neuroendocrine tumors. https://clinicaltrials.gov/ct2/show/NCT02259725. Accessed 12 May 2017.
  103. 103.
    US National Institutes of Health. An open label phase II study to evaluate the efficacy and safety of PDR001 in patients with advanced or metastatic, well-differentiated, non-functional neuroendocrine tumors of pancreatic, gastrointestinal (GI), or thoracic origin or poorly-differentiated gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC), that have progressed on prior treatment EUDRACT. https://clinicaltrials.gov/ct2/show/NCT02259725. Accessed12 May 2017.

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Robert A. Ramirez
    • 1
  • Aman Chauhan
    • 2
  • Juan Gimenez
    • 1
  • Katharine E. H. Thomas
    • 1
  • Ioni Kokodis
    • 3
  • Brianne A. Voros
    • 4
  1. 1.Ochsner Medical Center – KennerKennerUSA
  2. 2.University of Kentucky Medical CenterLexingtonUSA
  3. 3.Ochsner Clinical SchoolThe University of Queensland School of MedicineNew OrleansUSA
  4. 4.Louisiana State University Health Sciences CenterNew OrleansUSA

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