Targeted Oncology

, Volume 12, Issue 6, pp 757–774 | Cite as

The Treatment Landscape and New Opportunities of Molecular Targeted Therapies in Gastroenteropancreatic Neuroendocrine Tumors

  • Fabiola Amair-Pinedo
  • Ignacio Matos
  • Tamara Saurí
  • Jorge Hernando
  • Jaume Capdevila
Review Article

Abstract

Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms that originate from neuroendocrine stem cells and express both neural and endocrine markers. They are found in almost every organ, and while NENs are mostly associated with slow growth, complications due to the uncontrolled secretion of active peptides, and metastatic disease, may significantly impair the quality of life and can ultimately lead to the death of affected individuals. Expanding knowledge of the genetic, epigenetic, and proteomic landscapes of NENs has led to a better understanding of their molecular pathology and consequently increased treatment options for patients. Here, we review the principal breakthroughs in NEN treatment management, owing largely to omics technologies over the last few years, current recommendations of systemic treatment, and ongoing research into the identification of predictive and response biomarkers based on molecular targeted therapies.

Notes

Compliance with Ethical Standards

Funding

No funding was used to prepare this article.

Conflict of Interest

The authors declare no conflicts of interest.

References

  1. 1.
    Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, 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.PubMedCrossRefGoogle Scholar
  2. 2.
    Garcia-Carbonero R, Capdevila J, Crespo-Herrero G, Diaz-Perez JA, Martinez Del Prado MP, Alonso Orduna V, et al. Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). Ann Oncol. 2010;21(9):1794–803.PubMedCrossRefGoogle Scholar
  3. 3.
    Halfdanarson TR, Rabe KG, Rubin J, Petersen GM. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol. 2008;19(10):1727–33.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Kulke MH, Shah MH, Benson AB, et al. Neuroendocrine tumors, version 1.2015. JNCCN. 2015;13(1):78–108.PubMedGoogle Scholar
  5. 5.
    Oberg K. Neuroendocrine gastrointestinal tumors - a condensed overview of diagnosis and treatment. Ann Oncol. 1999;10(Suppl 2):S3–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Cives M, Strosberg J. An update on gastroenteropancreatic neuroendocrine tumors. Oncology. 2014;28(9):749–56. 58PubMedGoogle Scholar
  7. 7.
    Williams ED, Sandler M. The classification of carcinoid tum ours. Lancet. 1963;1(7275):238–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Rindi G, Kloppel G, Couvelard A, Komminoth P, Komminoth P, Korner M, et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch. 2007;451(4):757–62.PubMedCrossRefGoogle Scholar
  9. 9.
    Edge SBBD, Carducci MA, et al., editors. American joint committee on cancer (AJCC) cancer staging manual. 7th ed. New York: Springer; 2009.Google Scholar
  10. 10.
    Bosman FT CF, Hruban RH, Theise ND. WHO Classification of Tumours of the digestive system. WHO/IARC classification of Tumours. 4th edition. 2010.Google Scholar
  11. 11.
    Lloyd RV OR, Klöppel G, Rosai J. WHO Classification of Tumours of endocrine organs. WHO/IARC classification of Tumours. 4th edition. 2017.Google Scholar
  12. 12.
    Frilling A, Modlin IM, Kidd M, Russell C, Breitenstein S, Salem R, et al. Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol. 2014;15(1):e8–21.PubMedCrossRefGoogle Scholar
  13. 13.
    Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2013;24(1):152–60.PubMedCrossRefGoogle Scholar
  14. 14.
    Milione M, Maisonneuve P, Spada F, Pellegrinelli A, Spaggiari P, Albarello L, et al. The Clinicopathologic heterogeneity of grade 3 Gastroenteropancreatic Neuroendocrine Neoplasms: morphological differentiation and proliferation identify different prognostic categories. Neuroendocrinology. 2017;104(1):85–93.PubMedCrossRefGoogle Scholar
  15. 15.
    Karpathakis A, Dibra H, Thirlwell C. Neuroendocrine tumours: cracking the epigenetic code. Endocr Relat Cancer. 2013;20(3):R65–82.PubMedCrossRefGoogle Scholar
  16. 16.
    Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin N Am. 2011;40(1):1–18.Google Scholar
  17. 17.
    Khasraw M, Gill A, Harrington T, Pavlakis N, Modlin I. Management of advanced neuroendocrine tumors with hepatic metastasis. J Clin Gastroenterol. 2009;43(9):838–47.PubMedCrossRefGoogle Scholar
  18. 18.
    Frilling A, Sotiropoulos GC, Li J, Kornasiewicz O, Plockinger U. Multimodal management of neuroendocrine liver metastases. HPB. 2010;12(6):361–79.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Kasajima A, Pavel M, Darb-Esfahani S, Noske A, Stenzinger A, Sasano H, et al. mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer. 2011;18(1):181–92.PubMedCrossRefGoogle Scholar
  20. 20.
    Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006;5(8):671–88.PubMedCrossRefGoogle Scholar
  21. 21.
    Missiaglia E, Dalai I, Barbi S, Beghelli S, Falconi M. Della Peruta M et al. pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol. 2010;28(2):245–55.PubMedCrossRefGoogle Scholar
  22. 22.
    Russell RC, Fang C, Guan KL. An emerging role for TOR signaling in mammalian tissue and stem cell physiology. Development. 2011;138(16):3343–56.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Orlova KA, Crino PB. The tuberous sclerosis complex. Ann N Y Acad Sci. 2010;1184:87–105.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331(6021):1199–203.Google Scholar
  25. 25.
    Corbo V, Dalai I, Scardoni M, Barbi S, Beghelli S, Bersani S, et al. MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases. Endocr Relat Cancer. 2010;17(3):771–83.PubMedCrossRefGoogle Scholar
  26. 26.
    Wang Y, Ozawa A, Zaman S, Prasad NB, Chandrasekharappa SC, Agarwal SK, et al. The tumor suppressor protein menin inhibits AKT activation by regulating its cellular localization. Cancer Res. 2011;71(2):371–82.PubMedCrossRefGoogle Scholar
  27. 27.
    Scarpa A, Chang DK, Nones K, Corbo V, Patch AM, Bailey P, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543(7643):65–71.PubMedCrossRefGoogle Scholar
  28. 28.
    Martins D, Spada F, Lambrescu I, Rubino M, Cella C, Gibelli B, et al. Predictive markers of response to Everolimus and Sunitinib in Neuroendocrine tumors. Target Oncol. 2017;12(5):611–22.PubMedCrossRefGoogle Scholar
  29. 29.
    Yao JC, Pavel M, Phan AT, Kulke MH, Kulke MH, Hoosen S, et al. Chromogranin a and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus. J Clin Endocrinol Metab. 2011;96(12):3741–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Baudin EWE, Castellano D. Correlation of PFS with early response of chromogranin a and 5-hydroxyindoleacetic acid levels in patients with advanced neuroendocrine tumors: phase III RADIANT-2 study results. Eur J Cancer. 2011;47(Suppl 1):S460.CrossRefGoogle Scholar
  31. 31.
    de Wilde RF, Heaphy CM, Maitra A, Meeker AK, Edil BH, Wolfgang CL, et al. Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors. Mod Pathol. 2012;25(7):1033–9.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Puto LA, Reed JC. Daxx represses RelB target promoters via DNA methyltransferase recruitment and DNA hypermethylation. Genes Dev. 2008;22(8):998–1010.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Marinoni I, Kurrer AS, Vassella E, Dettmer M, Rudolph T, Banz V, et al. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology. 2014;146(2):453–60.e5.PubMedCrossRefGoogle Scholar
  34. 34.
    Hoareau-Aveilla C, Meggetto F. Crosstalk between microRNA and DNA Methylation offers potential biomarkers and targeted therapies in ALK-positive lymphomas. Cancers (Basel). 2017;9(8).Google Scholar
  35. 35.
    Pipinikas CP, Dibra H, Karpathakis A, Feber A, Novelli M, Oukrif D, et al. Epigenetic dysregulation andpoorer prognosis in DAXX-deficient pancreatic neuroendocrine tumours. Endocr Relat Cancer. 2015;22(3):L13–8.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Kim H, Lee JE, Cho EJ, Liu JO, Youn HD. Menin, a tumor suppressor, represses JunD-mediated transcriptional activity by association with an mSin3A-histone deacetylase complex. Cancer Res. 2003;63(19):6135–9.PubMedGoogle Scholar
  37. 37.
    Yang YJ, Song TY, Park J, Lee J, Lim J, Jang H, et al. Menin mediates epigenetic regulation via histone H3 lysine 9 methylation. Cell Death Dis. 2013;4:e583.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Gurung B, Feng Z, Iwamoto DV, Thiel A, Jin G, Fan CM, et al. Menin epigenetically represses hedgehog signaling in MEN1 tumor syndrome. Cancer Res. 2013;73(8):2650–8.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Lin W, Watanabe H, Peng S, Francis JM, Kaplan N, Pedamallu CS, et al. Dynamic epigenetic regulation by menin during pancreatic islet tumor formation. Mol Cancer Res. 2015;13(4):689–98.PubMedCrossRefGoogle Scholar
  40. 40.
    Wajapeyee N, Serra RW, Zhu X, Mahalingam M, Green MR, Oncogenic BRAF. Induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell. 2008;132(3):363–74.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Francis J, Lin W, Rozenblatt-Rosen O, Meyerson M. The menin tumor suppressor protein is phosphorylated in response to DNA damage. PLoS One. 2011;6(1):e16119.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Fang M, Xia F, Mahalingam M, Virbasius CM, Wajapeyee N, Green MR. MEN1 is a melanoma tumor suppressor that preserves genomic integrity by stimulating transcription of genes that promote homologous recombination-directed DNA repair. Mol Cell Biol 2013;33(13):2635-47.Google Scholar
  43. 43.
    Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature. 2010;463(7279):360–3.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Robinson CM, Ohh M. The multifaceted von Hippel-Lindau tumour suppressor protein. FEBS Lett. 2014;588(16):2704–11.PubMedCrossRefGoogle Scholar
  45. 45.
    Winter J, Jung S, Keller S, Gregory RI, Gregory R, Diederichs S. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol. 2009;11(3):228–34.PubMedCrossRefGoogle Scholar
  46. 46.
    Roldo C, Missiaglia E, Hagan JP, Falconi M, Capelli P, Bersani S, et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol. 2006;24(29):4677–84.PubMedCrossRefGoogle Scholar
  47. 47.
    Arnold CN, Sosnowski A, Schmitt-Graff A, Arnold R, Blum HE. Analysis of molecular pathways in sporadic neuroendocrine tumors of the gastro-entero-pancreatic system. Int J Cancer. 2007;120(10):2157–64.PubMedCrossRefGoogle Scholar
  48. 48.
    Stefanoli M, La Rosa S, Sahnane N, Romualdi C, Pastorino R, Marando A, et al. Prognostic relevance of aberrant DNA methylation in g1 and g2 pancreatic neuroendocrine tumors. Neuroendocrinology. 2014;100(1):26–34.PubMedCrossRefGoogle Scholar
  49. 49.
    House MG, Herman JG, Guo MZ, Hooker CM, Schulick RD, Lillemoe KD, et al. Aberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms. Ann Surg. 2003;238(3):423–31.Google Scholar
  50. 50.
    Perri F, Longo F, Giuliano M, Sabbatino F, Favia G, Ionna F, et al. Epigenetic control of gene expression: potential implications for cancer treatment. Crit Rev Oncol Hematol. 2017;111:166–72.PubMedCrossRefGoogle Scholar
  51. 51.
    Shah MH, Binkley P, Chan K, Xiao J, Arbogast D, Collamore M, et al. Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors. Clin Cancer Res. 2006;12(13):3997–4003.PubMedCrossRefGoogle Scholar
  52. 52.
    Jin N, Lubner SJ, Mulkerin DL, Rajguru S, Carmichael L, Chen H, et al. A phase II trial of a Histone Deacetylase inhibitor Panobinostat in patients with low-grade Neuroendocrine tumors. Oncologist. 2016;21(7):785–6.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Carter CA, Degesys A, Oronsky B, Scicinski J, Caroen SZ, Oronsky AL, et al. Flushing out Carcinoid syndrome: beneficial effect of the anticancer epigenetic agent RRx-001 in a patient with a treatment-refractory Neuroendocrine tumor. Case Rep Oncol. 2015;8(3):461–5.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Banck MS, Kanwar R, Kulkarni AA, Boora GK, Metge F, Kipp BR, et al. The genomic landscape of small intestine neuroendocrine tumors. J Clin Invest. 2013;123(6):2502–8.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7.CrossRefGoogle Scholar
  56. 56.
    Lollgen RM, Hessman O, Szabo E, Westin G, Akerstrom G. Chromosome 18 deletions are common events in classical midgut carcinoid tumors. Int J Cancer. 2001;92(6):812–5.PubMedCrossRefGoogle Scholar
  57. 57.
    Kulke MH, Freed E, Chiang DY, Philips J, Zahrieh D, Glickman JN, et al. High-resolution analysis of genetic alterations in small bowel carcinoid tumors reveals areas of recurrent amplification and loss. Genes Chromosomes Cancer. 2008;47(7):591–603.PubMedCrossRefGoogle Scholar
  58. 58.
    Cunningham JL, Diaz de Stahl T, Sjoblom T, Westin G, Dumanski JP, Janson ET. Common pathogenetic mechanism involving human chromosome 18 in familial and sporadic ileal carcinoid tumors. Genes Chromosomes Cancer. 2011;50(2):82–94.PubMedCrossRefGoogle Scholar
  59. 59.
    Du Y, Ter-Minassian M, Brais L, Brooks N, Waldron A, Chan JA et al. Genetic associations with neuroendocrine tumor risk: results from a genome-wide association study. Endocr Relat Cancer 2016;23(8):587-94.Google Scholar
  60. 60.
    Zhang HY, Rumilla KM, Jin L, Nakamura N, Stilling GA, Ruebel KH, et al. Association of DNA methylation and epigenetic inactivation of RASSF1A and beta-catenin with metastasis in small bowel carcinoid tumors. Endocrine. 2006;30(3):299–306.PubMedCrossRefGoogle Scholar
  61. 61.
    Ruebel K, Leontovich AA, Stilling GA, Zhang S, Righi A, Jin L, et al. MicroRNA expression in ileal carcinoid tumors: downregulation of microRNA-133a with tumor progression. Mod Pathol. 2010;23(3):367–75.PubMedCrossRefGoogle Scholar
  62. 62.
    Li SC, Essaghir A, Martijn C, Lloyd RV, Demoulin JB, Oberg K, et al. Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors. Mod Pathol. 2013;26(5):685–96.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Karpathakis A, Dibra H, Pipinikas C, Feber A, Morris T, Francis J et al. Prognostic impact of novel molecular subtypes of small intestinal Neuroendocrine tumor. Clin Cancer Res 2016;22(1):250-8.Google Scholar
  64. 64.
    How-Kit A, Dejeux E, Dousset B, Renault V, Baudry M, Terris B, et al. DNA methylation profiles distinguish different subtypes of gastroenteropancreatic neuroendocrine tumors. Epigenomics. 2015;7(8):1245–58.PubMedCrossRefGoogle Scholar
  65. 65.
    Andersson E, Arvidsson Y, Sward C, Hofving T, Wangberg B, Kristiansson E, et al. Expression profiling of small intestinal neuroendocrine tumors identifies subgroups with clinical relevance, prognostic markers and therapeutic targets. Mod Pathol. 2016;29(6):616–29.PubMedCrossRefGoogle Scholar
  66. 66.
    Halasi M, Gartel AL. FOX(M1) news-it is cancer. Mol Cancer Ther. 2013;12(3):245–54.Google Scholar
  67. 67.
    Zona S, Bella L, Burton MJ, Nestal de Moraes G, Lam EW, Halasi M, et al. FOXM1: an emerging master regulator of DNA damage response and genotoxic agent resistance. Biochim Biophys Acta. 2014;1839(11):1316–22.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Massague J. TGFbeta signalling in context. Nature Rev Mol Cell Biol. 2012;13(10):616–30.CrossRefGoogle Scholar
  69. 69.
    Massague J. TGFbeta in cancer. Cell. 2008;134(2):215–30.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Jiang J, Dingledine R. Role of prostaglandin receptor EP2 in the regulations of cancer cell proliferation, invasion, and inflammation. J Pharmacol Exp Ther. 2013;344(2):360–7.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Hamidi T, Cano CE, Grasso D, Garcia MN, Sandi MJ, Calvo EL, et al. Nupr1-aurora kinase a pathway provides protection against metabolic stress-mediated autophagic-associated cell death. Clin Cancer Res. 2012;18(19):5234–46.PubMedCrossRefGoogle Scholar
  72. 72.
    Arvidsson Y, Johanson V, Pfragner R, Wangberg B, Nilsson O. Cytotoxic effects of Valproic acid on Neuroendocrine tumour cells. Neuroendocrinology. 2016;103(5):578–91.PubMedCrossRefGoogle Scholar
  73. 73.
    Kusunoki M, Yamamura T, Ichii S, Fujita S, Nakai T, Utsunomiya J. The effects of sodium valproate on plasma somatostatin and insulin in humans. J Clin Endocrinol Metab. 1988;67(5):1060–3.PubMedCrossRefGoogle Scholar
  74. 74.
    Mohammed TA, Holen KD, Jaskula-Sztul R, Mulkerin D, Lubner SJ, Schelman WR, et al. A pilot phase II study of valproic acid for treatment of low-grade neuroendocrine carcinoma. Oncologist. 2011;16(6):835–43.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Ilett EE, Langer SW, Olsen IH, Federspiel B, Kjaer A, Knigge U, et al. Neuroendocrine carcinomas of the Gastroenteropancreatic system: a comprehensive review. Diagnostics (Basel). 2015;5(2):119–76.CrossRefGoogle Scholar
  76. 76.
    Yachida S, Vakiani E, White CM, Zhong Y, Saunders T, Morgan R, et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol. 2012;36(2):173–84.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Hijioka S, Hosoda W, Mizuno N, Hara K, Imaoka H, Bhatia V, et al. Does the WHO 2010 classification of pancreatic neuroendocrine neoplasms accurately characterize pancreatic neuroendocrine carcinomas? J Gastroenterol. 2015;50(5):564–72.PubMedCrossRefGoogle Scholar
  78. 78.
    Tang LH, Basturk O, Sue JJ, Klimstra DSA. Practical approach to the classification of WHO grade 3 (G3) well-differentiated Neuroendocrine tumor (WD-NET) and poorly differentiated Neuroendocrine carcinoma (PD-NEC) of the pancreas. Am J Surg Pathol. 2016;40(9):1192–202.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Park C, Ha SY, Kim ST, Kim HC, Heo JS, Park YS, et al. Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors. Oncotarget. 2016;7(4):4024–35.PubMedCrossRefGoogle Scholar
  80. 80.
    Klempner SJ, Gershenhorn B, Tran P, Lee TK, Erlander MG, Gowen K, et al. BRAFV600E mutations in high-grade colorectal Neuroendocrine tumors may predict responsiveness to BRAF-MEK combination therapy. Cancer Discov. 2016;6(6):594–600.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Kondo NI, Ikeda Y. Practical management and treatment of pancreatic neuroendocrine tumors. Gland Surg. 2014;3(4):276–83.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Kaltsas GA, Besser GM, Grossman AB. The diagnosis and medical management of advanced neuroendocrine tumors. Endocr rev. 2004;25(3):458-511.Google Scholar
  83. 83.
    Ferolla P. Medical treatment of advanced thoracic neuroendocrine tumors. Thorac Surg Clin. 2014;24(3):351–5.PubMedCrossRefGoogle Scholar
  84. 84.
    Alonso-Gordoa T, Capdevila J, Grande EGEP-NET. Update: biotherapy for neuroendocrine tumours. Eur J Endocrinol. 2015;172(1):R31–46.PubMedCrossRefGoogle Scholar
  85. 85.
    Fjallskog ML, Ludvigsen E, Stridsberg M, Oberg K, Eriksson B, Janson ET. Expression of somatostatin receptor subtypes 1 to 5 in tumor tissue and intratumoral vessels in malignant endocrine pancreatic tumors. Med Oncol. 2003;20(1):59–67.PubMedCrossRefGoogle Scholar
  86. 86.
    Grozinsky-Glasberg S, Shimon I, Korbonits M, Grossman AB. Somatostatin analogues in the control of neuroendocrine tumours: efficacy and mechanisms. Endocr Relat Cancer. 2008;15(3):701–20.PubMedCrossRefGoogle Scholar
  87. 87.
    Arnold R, Trautmann ME, Creutzfeldt W, Benning R, Benning M, Neuhaus C, et al. Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours. Gut. 1996;38(3):430–8.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Oberg KE, Reubi JC, Kwekkeboom DJ, Krenning EP. Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology. 2010;139(3):742–53.Google Scholar
  89. 89.
    Viudez A. De Jesus-Acosta a, Carvalho FL, Vera R, Martin-Algarra S, Ramirez N. Pancreatic neuroendocrine tumors: challenges in an underestimated disease. Crit Rev Oncol Hematol. 2016;101:193–206.PubMedCrossRefGoogle Scholar
  90. 90.
    Baudin E, Planchard D, Scoazec JY, Guigay J, Dromain C, Hadoux J, et al. Intervention in gastro-enteropancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol. 2012;26(6):855–65.PubMedCrossRefGoogle Scholar
  91. 91.
    Narayanan S, Kunz PL. Role of Somatostatin analogues in the treatment of Neuroendocrine tumors. Hematol Oncol Clin N Am. 2016;30:163–77.CrossRefGoogle Scholar
  92. 92.
    Pavel M, O’Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R, 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. Neuroendocrinology. 2016;103(2):172–85.PubMedCrossRefGoogle Scholar
  93. 93.
    Rinke A, Muller HH, Schade-Brittinger C, Klose KJ, Barth P, Wied M, 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.PubMedCrossRefGoogle Scholar
  94. 94.
    Laskaratos FM, Walker M, Naik K, Maragkoudakis E, Oikonomopoulos N, Grant L, et al. Predictive factors of antiproliferative activity of octreotide LAR as first-line therapy for advanced neuroendocrine tumours. Br J Cancer. 2016;115(11):1321–7.Google Scholar
  95. 95.
    Caplin ME, Pavel M, Ruszniewski P. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371(16):1556–7.PubMedGoogle Scholar
  96. 96.
    Krenning EP, Bakker WH, Kooij PP, Breeman WA, Oei HY, de Jong M, et al. Somatostatin receptor scintigraphy with indium-111-DTPA-D-Phe-1-octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-octreotide. J Nucl Med. 1992;33(5):652–8.PubMedGoogle Scholar
  97. 97.
    Vezzosi D, Bennet A, Rochaix P, Courbon F, Selves J, Pradere B, et al. Octreotide in insulinoma patients: efficacy on hypoglycemia, relationships with Octreoscan scintigraphy and immunostaining with anti-sst2A and anti-sst5 antibodies. Eur J Endocrinol. 2005;152(5):757–67.PubMedCrossRefGoogle Scholar
  98. 98.
    van Essen M, Sundin A, Krenning EP, Kwekkeboom DJ. Neuroendocrine tumours: the role of imaging for diagnosis and therapy. Nature Rev Endocrinol. 2014;10(2):102–14.CrossRefGoogle Scholar
  99. 99.
    Schmid HA. Pasireotide (SOM230): development, mechanism of action and potential applications. Mol Cell Endocrinol. 2008;286(1–2):69–74.PubMedCrossRefGoogle Scholar
  100. 100.
    Kvols LK, Oberg KE, O’Dorisio TM, Mohideen P, de Herder WW, Arnold R, et al. Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistant to octreotide LAR: results from a phase II study. Endocr Relat Cancer. 2012;19(5):657–66.PubMedCrossRefGoogle Scholar
  101. 101.
    Wolin EM, Hu K, Hughes G, Bouillaud E, Giannone V, Resendiz KH. Safety, tolerability, pharmacokinetics, and pharmacodynamics of a long-acting release (LAR) formulation of pasireotide (SOM230) in patients with gastroenteropancreatic neuroendocrine tumors: results from a randomized, multicenter, open-label, phase I study. Cancer Chemother Pharmacol. 2013;72(2):387–95.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Cives M, Kunz PL, Morse B, Coppola D, Schell MJ, Campos T, et al. Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors. Endocr Relat Cancer. 2015;22(1):1–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Jann H, Denecke T, Koch M, Pape UF, Wiedenmann B, Pavel M. Impact of octreotide long-acting release on tumour growth control as a first-line treatment in neuroendocrine tumours of pancreatic origin. Neuroendocrinology. 2013;98(2):137–43.PubMedCrossRefGoogle Scholar
  104. 104.
    Meric-Bernstam F, Gonzalez-Angulo AM. Targeting the mTOR signaling network for cancer therapy. J Clin Oncol. 2009;27(13):2278–87.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Yao JC, Phan AT, Chang DZ, Wolff RA, Hess K, Gupta S, et al. Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. J Clin Oncol. 2008;26(26):4311–8.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol. 2010;28(1):69–76.PubMedCrossRefGoogle Scholar
  107. 107.
    Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514–23.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Yao JC, Pavel M, Lombard-Bohas E, Van Cutsem T, Kunz U, et al. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: final overall survivall results of a randomized, double-blind, placebo-controlled, multicenter phase III trial (RADIANT-3). Ann Oncol. 2014;25(suppl_4):iv394.Google Scholar
  109. 109.
    Pavel m, Lombard-Bohas, E., Van Cutsem, D.H., Lam, T., Kunz, U., ET AL. Everolimus in patients with advanced, progressive pancreatic neurodendocrine tumors: overall survival results form the phase III RADIANT-3 study after adjusting for crossover bias. J Clin Oncol. 2015;33(15_suppl):4091.Google Scholar
  110. 110.
    Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, 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.PubMedCrossRefGoogle Scholar
  111. 111.
    Pavel M, Valle JW, Eriksson B, Rinke A, Caplin M, Chen J, et al. ENETS consensus guidelines for the standards of Care in Neuroendocrine Neoplasms: systemic therapy - biotherapy and novel targeted agents. Neuroendocrinology. 2017;105(3):266-80.Google Scholar
  112. 112.
    Duran I, Kortmansky J, Singh D, Hirte H, Kocha W, Goss G, et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer. 2006;95(9):1148–54.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Pavel ME, Hainsworth JD, Baudin E, Peeters M, Horsch D, Winkler RE, 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.PubMedCrossRefGoogle Scholar
  114. 114.
    Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 2011;19(1):58–71.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Hobday TJ, Qin R, Reidy-Lagunes D, Moore MJ, Strosberg J, Kaubisch A, et al. Multicenter phase II trial of Temsirolimus and Bevacizumab in pancreatic Neuroendocrine tumors. J Clin Oncol. 2015;33(14):1551–6.PubMedCrossRefGoogle Scholar
  116. 116.
    Yao JC, Phan AT, Hess K, Fogelman D, Jacobs C, Dagohoy C, et al. Perfusion computed tomography as functional biomarker in randomized run-in study of bevacizumab and everolimus in well-differentiated neuroendocrine tumors. Pancreas. 2015;44(2):190–7.PubMedCrossRefGoogle Scholar
  117. 117.
    Kulke MH, Niedzwiecki D, Foster B, Fruth PL, Kennecke HF, et al. Randomized phase II study of everolius (E) versus everolimus plus bevacizumab (E+B) in patients (pts) with locally advanced or metastatic pancreatic neuroendocrine tumors (pNET), CALGB 80701 (alliance). J Clin Oncol. 2015;33(15_suppl):4005.Google Scholar
  118. 118.
    Chan JA, Mayer RJ, Jackson N, Malinowski P, Regan E, Kulke MH, et al. Study of sorafenib in combination with everolimus (RAD001) in patients with advanced neuroendocrine tumors. Cancer Chemother Pharmacol. 2013;71(5):1241–6.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Piatek CI, Raja GL, Ji L, Gitlitz BJ, Dorff TB, Quinn DI, et al. Phase I clinical trial of temsirolimus and vinorelbine in advanced solid tumors. Cancer Chemother Pharmacol. 2014;74(6):1227–34.PubMedCrossRefGoogle Scholar
  120. 120.
    Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell. 2005;8(4):299–309.Google Scholar
  121. 121.
    Zhang J, Francois R, Iyer R, Seshadri M, Zajac-Kaye M, Hochwald SN. Current understanding of the molecular biology of pancreatic neuroendocrine tumors. J Natl Cancer Inst. 2013;105(14):1005–17.PubMedCrossRefGoogle Scholar
  122. 122.
    Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol. 2008;26(20):3403–10.PubMedCrossRefGoogle Scholar
  123. 123.
    Okusaka I, Nishida T, Yamao K, Igarashi H, Morizane C, Kondo S, et al. Phase II study of sunitinib (SU) in Japanese patients with unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumor (NET). J Clin Oncol. 2012;30(4_suppl):381.Google Scholar
  124. 124.
    Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):501–13.PubMedCrossRefGoogle Scholar
  125. 125.
    Ahn HK, Choi JY, Kim KM, Kim H, Choi SH, Park SH, et al. Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours. Br J Cancer. 2013;109(6):1414–9.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Grande E, Capdevila J, Castellano D, Teule A, Duran I, Fuster J, et al. Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish task force Group for Neuroendocrine Tumors (GETNE). Ann Oncol. 2015;26(9):1987–93.PubMedCrossRefGoogle Scholar
  127. 127.
    Phan AT, Halperin DM, Chan JA, Fogelman DR, Hess KR, Malinowski P, et al. Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. Lancet Oncol. 2015;16(6):695–703.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Garcia-Carbonero R, Rinke A, Valle JW, Fazio N, Caplin M, Gorbounova V, et al. ENETS consensus guidelines for the standards of Care in Neuroendocrine Neoplasms. systemic therapy 2: chemotherapy. Neuroendocrinology. 2017;105(3):281-94.Google Scholar
  129. 129.
    Lamarca A, Elliott E, Barriuso J, Backen A, McNamara MG, Hubner R, et al. Chemotherapy for advanced non-pancreatic well-differentiated neuroendocrine tumours of the gastrointestinal tract, a systematic review and meta-analysis: a lost cause? Cancer Treat Rev. 2016;44:26–41.PubMedCrossRefGoogle Scholar
  130. 130.
    Strosberg J, Goldman J, Costa F, Pavel M. The role of chemotherapy in well-differentiated Gastroenteropancreatic Neuroendocrine tumors. Front Horm Res. 2015;44:239–47.PubMedCrossRefGoogle Scholar
  131. 131.
    Dilz LM, Denecke T, Steffen IG, Prasad V, von Weikersthal LF, Pape UF, et al. Streptozocin/5-fluorouracil chemotherapy is associated with durable response in patients with advanced pancreatic neuroendocrine tumours. Eur J Cancer. 2015;51(10):1253–62.PubMedCrossRefGoogle Scholar
  132. 132.
    Clewemar Antonodimitrakis P, Sundin A, Wassberg C, Granberg D, Skogseid B, Eriksson B. Streptozocin and 5-fluorouracil for the treatment of pancreatic Neuroendocrine tumors: efficacy, prognostic factors and toxicity. Neuroendocrinology. 2016;103(3–4):345–53.PubMedCrossRefGoogle Scholar
  133. 133.
    Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006;24(3):401–6.PubMedCrossRefGoogle Scholar
  134. 134.
    Ekeblad S, Skogseid B, Dunder K, Oberg K, Eriksson B. Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution. Clin Cancer Res. 2008;14(23):7798–80.PubMedCrossRefGoogle Scholar
  135. 135.
    Fine RL, Gulati AP, Krantz BA, Moss RA, Schreibman S, Tsushima DA, et al. Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: the pancreas Center at Columbia University experience. Cancer Chemother Pharmacol. 2013;71(3):663–70.PubMedCrossRefGoogle Scholar
  136. 136.
    Crespo G, Jimenez-Fonseca P, Custodio A, Lopez C, Carmona-Bayonas A, Alonso V, et al. Capecitabine and temozolomide in grade 1/2 neuroendocrine tumors: a Spanish multicenter experience. Future Oncol. 2017;13(7):615–24.PubMedCrossRefGoogle Scholar
  137. 137.
    Chan JA, Blaszkowsky L, Stuart K, Zhu AX, Allen J, Wadlow R, et al. A prospective, phase 1/2 study of everolimus and temozolomide in patients with advanced pancreatic neuroendocrine tumor. Cancer. 2013;119(17):3212–8.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Kulke MH, Hornick JL, Frauenhoffer C, Hooshmand S, Ryan DP, Enzinger PC, et al. O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res. 2009;15(1):338–45.PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Cives M, Ghayouri M, Morse B, Brelsford M, Black M, Rizzo A, et al. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. Endocr Relat Cancer. 2016;23(9):759–67.PubMedCrossRefGoogle Scholar
  140. 140.
    Ceppi P, Volante M, Ferrero A, Righi L, Rapa I, Rosas R, et al. Thymidylate synthase expression in gastroenteropancreatic and pulmonary neuroendocrine tumors. Clin Cancer Res. 2008;14(4):1059–64.PubMedCrossRefGoogle Scholar
  141. 141.
    Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen DT, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer. 2011;117(2):268–75.PubMedCrossRefGoogle Scholar
  142. 142.
    Welin S, Sorbye H, Sebjornsen S, Knappskog S, Busch C, Oberg K. Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy. Cancer. 2011;117(20):4617–22.PubMedCrossRefGoogle Scholar
  143. 143.
    Fazio N, Spada F, Giovannini M. Chemotherapy in gastroenteropancreatic (GEP) neuroendocrine carcinomas (NEC): a critical view. Cancer Treat Rev. 2013;39(3):270–4.PubMedCrossRefGoogle Scholar
  144. 144.
    Morizane C, Machida, N., Honma, Y., Okusaka, T., Boku, N., Kato, K., Mizusawa, J., Katayama, H., Hiraoka, N., Taniguchi, H., et al. . Randomized phase III study of etoposide plus cisplatin versus irinotecan plus cisplatin in advanced neuroendocrine carcinoma of the digestive system: A Japan clinical oncology group study (JCOG1213). J Clin Oncol. 2015;33 (Suppl.) Abstract: TPS4143.Google Scholar
  145. 145.
    Hentic O, Hammel P, Couvelard A, Rebours V, Zappa M, Palazzo M, et al. FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3. Endocr Relat Cancer. 2012;19(6):751–7.PubMedCrossRefGoogle Scholar
  146. 146.
    Hadoux J, Malka D, Planchard D, Scoazec JY, Caramella C, Guigay J, et al. Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma. Endocr Relat Cancer. 2015;22(3):289–98.PubMedCrossRefGoogle Scholar
  147. 147.
    Bushnell DL Jr, O’Dorisio TM, O’Dorisio MS, Menda Y, Hicks RJ, Van Cutsem E, et al. 90Y-edotreotide for metastatic carcinoid refractory to octreotide. J Clin Oncol. 2010;28(10):1652–9.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M, Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26(13):2124–30.PubMedCrossRefGoogle Scholar
  149. 149.
    Kwekkeboom DJ, Krenning EP. Peptide receptor radionuclide therapy in the treatment of Neuroendocrine tumors. Hematology/oncology clinics of North America. 2016;30(1):179-91. 152. Strosberg J, el-Haddad G, Wolin E, Hendifar a, Yao J, Chasen B et al. phase 3 trial of 177Lu-Dotatate for Midgut Neuroendocrine tumors. N Engl J Med. 2017;376(2):125–35.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Brabander T, Van der Zwan WA, Teunissen JJ, Kam BLR, Feelders RA, de Herder WW, et al. Long-term efficacy, survival and safety of [177Lu-DOTA0,Tyr3]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clin Cancer Res. 2017;23(16):4617–24.PubMedCrossRefGoogle Scholar
  151. 151.
    Hubble D, Kong G, Michael M, Johnson V, Ramdave S, Hicks RJ. 177Lu-octreotate, alone or with radiosensitising chemotherapy, is safe in neuroendocrine tumour patients previously treated with high-activity 111In-octreotide. Eur J Nucl Med Mol Imaging. 2010;37(10):1869–75.PubMedCrossRefGoogle Scholar
  152. 152.
    Claringbold PG, Price RA, Turner JH. Phase I-II study of radiopeptide 177Lu-octreotate in combination with capecitabine and temozolomide in advanced low-grade neuroendocrine tumors. Cancer Biother Radiopharm. 2012;27(9):561–9.PubMedCrossRefGoogle Scholar
  153. 153.
    Claringbold PG, Turner JH, Claringbold PG. Price Ra Fau - turner JH, turner JH, Hubble D et al. NeuroEndocrine tumor therapy with Lutetium-177-octreotate and Everolimus (NETTLE): a phase I study. Cancer Biother Radiopharm. 2015;30(6):261–9.PubMedCrossRefGoogle Scholar
  154. 154.
    Modlin IM, Kidd M, Bodei L, Drozdov I, Aslanian H. The clinical utility of a novel blood-based multi-transcriptome assay for the diagnosis of neuroendocrine tumors of the gastrointestinal tract. The. Am J Gastroenterol. 2015;110(8):1223–32.PubMedCrossRefGoogle Scholar
  155. 155.
    Cwikla JB, Bodei L, Kolasinska-Cwikla A, Sankowski A, Modlin IM, Kidd M. Circulating transcript analysis (NETest) in GEP-NETs treated with Somatostatin analogs defines therapy. J Clin Endocrinol Metab. 2015;100(11):E1437–45.PubMedCrossRefGoogle Scholar
  156. 156.
    Pavel M, Jann H, Prasad V, Drozdov I, Modlin IM, Kidd MNET. Blood transcript analysis defines the crossing of the clinical Rubicon: when stable disease becomes progressive. Neuroendocrinology. 2017;104(2):170–82.PubMedCrossRefGoogle Scholar
  157. 157.
    Bodei L, Kidd M, Modlin IM, Prasad V, Severi S, Ambrosini V, et al. Gene transcript analysis blood values correlate with (6)(8)Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status. Eur J Nucl Med Mol Imaging. 2015;42(9):1341–52.PubMedCrossRefGoogle Scholar
  158. 158.
    Khan MS, Kirkwood AA, Tsigani T, Lowe H, Goldstein R, Hartley JA, et al. Early changes in circulating tumor cells are associated with response and survival following treatment of metastatic Neuroendocrine Neoplasms. Clin Cancer Res. 2016;22(1):79–85.PubMedCrossRefGoogle Scholar
  159. 159.
    Roncati L, Manenti A, Farinetti A, Pusiol T. The association between tumor-infiltrating lymphocytes (TILs) and metastatic course in neuroendocrine neoplasms. Surgery. 2016;160(6):1709.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Vall d’Hebron University HospitalBarcelonaSpain
  2. 2.Vall d’Hebron Institute of Oncology (VHIO)BarcelonaSpain

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