Abstract
The ileum is one of the most common primary sites for neuroendocrine tumours and the most common site of GI NETs. Approximately half will present as locoregionally advanced or metastatic disease. Patients with ileal NETs can vary widely in terms of their clinical course, based on underlying histopathological factors and patient characteristics. Recently, large international randomised trials have reported significant progress in the treatment of ileal NETs for the following therapies: somatostatin analogues, the mTOR inhibitor everolimus and peptide receptor radionuclide therapy (PRRT). Other treatments such as debulking surgery, liver-directed therapy chemotherapy and interferon (IFN) are commonly used albeit with less evidence base. There are few randomised trials in Grade 3 NETs or neuroendocrine carcinoma (NEC), but chemotherapy is the mainstay of systemic treatment for this patient group. Issues remain in defining the optimal sequencing of therapies and detecting of changes in disease that should trigger changes in therapy. The increasing use of functional imaging gives clinicians a greater understanding of individual tumour biology and disease burden. Further research is needed to probe the molecular characteristics across the spectrum of NETs, to allow optimisation of current systemic therapies and develop even more effective approaches.
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References
Singh S, Granberg D, Wolin E, Warner R, Sissons M, Kolarova T et al (2016) Patient-reported burden of a neuroendocrine tumor (NET) diagnosis: results from the first global survey of patients with NETs. J Glob Oncol [Internet] [Cited 2016 Sep 5]. Available from: http://jgo.ascopubs.org/cgi/doi/10.1200/JGO.2015.002980
Capurso G, Rinzivillo M, Bettini R, Boninsegna L, Delle Fave G, Falconi M (2012) Systematic review of resection of primary midgut carcinoid tumour in patients with unresectable liver metastases. Br J Surg 99(11):1480–1486
Fatti LM, Scacchi M, Lavezzi E, Pecori Giraldi F, De Martin M, Toja P et al (2006) Effects of treatment with somatostatin analogues on QT interval duration in acromegalic patients. Clin Endocrinol 65(5):626–630
Kulke MH, Hörsch D, Caplin ME, Anthony LB, Bergsland E, Öberg K et al (2017) Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome. J Clin Oncol Off J Am Soc Clin Oncol 35(1):14–23
Hallet J, Law CHL, Cukier M, Saskin R, Liu N, Singh S (2015) Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer 121(4):589–597
Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE et al (2008) One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 26(18):3063–3072
Bosman FT, World Health Organization, International Agency for Research on Cancer (eds) (2010) WHO classification of tumours of the digestive system. 4th edn. International Agency for Research on Cancer, Lyon, 417 p (World Health Organization classification of tumours)
Meijer WG, Kema IP, Volmer M, Willemse PH, de Vries EG (2000) Discriminating capacity of indole markers in the diagnosis of carcinoid tumors. Clin Chem 46(10):1588–1596
Townsend A, Price T, Yeend S, Pittman K, Patterson K, Luke C (2010) Metastatic carcinoid tumor: changing patterns of care over two decades. J Clin Gastroenterol 44:195–199
Rinke A, Müller H-H, Schade-Brittinger C, Klose K-J, Barth P, Wied M et al (2009) 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 Off J Am Soc Clin Oncol 27(28):4656–4663
Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E et al (2014) Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371(3):224–233
Wolin E, Jarzab B, Eriksson B, Walter T, Toumpanakis C, Morse MA et al (2015) Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther 9:5075–5086
Pavel M, O’Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R et al (2016) 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 103(2):172–185
Oberg K, Akerstrom G, Rindi G, Jelic S (2010) Neuroendocrine gastroenteropancreatic tumours: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(Suppl 5):v223–v227
Kunz PL, Reidy-Lagunes D, Anthony LB, Bertino EM, Brendtro K, Chan JA et al (2013) Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas 42:557–577
Ito T, Tanaka M, Sasano H, Osamura YR, Sasaki I, Kimura W et al (2007) Preliminary results of a Japanese nationwide survey of neuroendocrine gastrointestinal tumors. J Gastroenterol 42(6):497–500
Marshall JB, Bodnarchuk G (1993) Carcinoid tumors of the gut. Our experience over three decades and review of the literature. J Clin Gastroenterol 16(2):123–129
Shen C, Dasari A, Zhou S, Chu Y, Xu Y, Shih Y-CT et al (2016) Functional status of neuroendocrine tumors among elderly patients: a large population-based study using SEER-Medicare data. ASCO Meet Abstr 34(15_suppl):4097
Gustafsson BI, Tømmerås K, Nordrum I, Loennechen JP, Brunsvik A, Solligård E et al (2005) Long-term serotonin administration induces heart valve disease in rats. Circulation 111(12):1517–1522
di Bartolomeo M, Bajetta E, Buzzoni R, Mariani L, Carnaghi C, Somma L et al (1996) Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian trials in medical oncology group. Cancer 77(2):402–408
Strosberg JR, Benson AB, Huynh L, Duh MS, Goldman J, Sahai V et al (2014) Clinical benefits of above-standard dose of octreotide LAR in patients with neuroendocrine tumors for control of carcinoid syndrome symptoms: a multicenter retrospective chart review study. Oncologist 19(9):930–936
Al-Efraij K, Aljama MA, Kennecke HF (2015) Association of dose escalation of octreotide long-acting release on clinical symptoms and tumor markers and response among patients with neuroendocrine tumors. Cancer Med 4(6):864–870
Faiss S, Pape U-F, Böhmig M, Dörffel Y, Mansmann U, Golder W et al (2003) 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. J Clin Oncol Off J Am Soc Clin Oncol 21(14):2689–2696
Ferolla P, Faggiano A, Grimaldi F, Ferone D, Scarpelli G, Ramundo V et al (2012) Shortened interval of long-acting octreotide administration is effective in patients with well-differentiated neuroendocrine carcinomas in progression on standard doses. J Endocrinol Investig 35(3):326–331
Anthony L, Johnson D, Hande K, Shaff M, Winn S, Krozely M et al (1993) Somatostatin analogue phase I trials in neuroendocrine neoplasms. Acta Oncol Stockh Swed 32(2):217–223
Faggiano A, Carratù AC, Guadagno E, Tafuto S, Tatangelo F, Riccardi F et al (2016) Somatostatin analogues according to Ki67 index in neuroendocrine tumours: an observational retrospective-prospective analysis from real life. Oncotarget 7(5):5538–5547
Kulke MH, Horsch D, Caplin M, Anthony L, Bergsland E, Oberg K et al (2015) 37LBA Telotristat etiprate is effective in treating patients with carcinoid syndrome that is inadequately controlled by somatostatin analog therapy (the phase 3 TELESTAR clinical trial). Eur J Cancer 51:S728
Hashemolhosseini S, Nagamine Y, Morley SJ, Desrivières S, Mercep L, Ferrari S (1998) Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J Biol Chem 273(23):14424–14429
Dufner A, Thomas G (1999) Ribosomal S6 kinase signaling and the control of translation. Exp Cell Res 253(1):100–109
Johannessen CM, Reczek EE, James MF, Brems H, Legius E, Cichowski K (2005) The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci U S A 102(24):8573–8578
Kasajima A, Pavel M, Darb-Esfahani S, Noske A, Stenzinger A, Sasano H et al (2011) mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer 18(1):181–192
Yao JC, Lombard-Bohas C, Baudin E, Kvols LK, Rougier P, Ruszniewski P et al (2010) Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol 28(1):69–76
Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE et al (2011) 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 378(9808):2005–2012
Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514–523
Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E et al (2016) 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 Lond Engl 387(10022):968–977
Yao JC, Hainsworth JD, Wolin EM, Pavel ME, Baudin E, Gross D et al (2012) Multivariate analysis including biomarkers in the phase III RADIANT-2 study of octreotide LAR plus everolimus (E+O) or placebo (P+O) among patients with advanced neuroendocrine tumors (NET). J Clin Oncol 30(suppl):Abstr 4014
Singh S, Carnaghi C, Buzzoni R, Raderer M, Lahner H, Valle JW et al (2016) Everolimus for advanced, progressive, nonfunctional neuroendocrine tumors (NET) of the gastrointestinal (GI) tract: efficacy and safety from a RADIANT-4 subgroup analysis. ENETS 2016. P. Abstr L20
Yazdani S, Kasajima A, Tamaki K, Nakamura Y, Fujishima F, Ohtsuka H et al (2014) Angiogenesis and vascular maturation in neuroendocrine tumors. Hum Pathol 45(4):866–874
Kuiper P (2011) Angiogenic markers endoglin and vascular endothelial growth factor in gastroenteropancreatic neuroendocrine tumors. World J Gastroenterol 17(2):219
Chan JA, Blaszkowsky L, Stuart K, Zhu AX, Allen J, Wadlow R et al (2013) A prospective, phase 1/2 study of everolimus and temozolomide in patients with advanced pancreatic neuroendocrine tumor. Cancer 119:3212–3218
Yao J, Guthrie K, Moran C, Strosberg JR, Kulke MH, Chan JA et al (2015) SWOG S0518: Phase III prospective randomized comparison of depot octreotide plus interferon alpha-2b versus depot octreotide plus bevacizumab (NSC #704865) in advanced, poor prognosis carcinoid patients (NCT00569127). J Clin Oncol 33(Suppl):Abstr 4004
Kulke MH, Lenz HJ, Meropol NJ, Posey J, Ryan DP, Picus J et al (2008) Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 26:3403–3410
Bello C, Deprimo SE, Friece C, Smeraglia J, Sherman L, Tye L et al (2006) Analysis of circulating biomarkers of sunitinib malate in patients with unresectable neuroendocrine tumors (NET): VEGF, IL-8, and soluble VEGF receptors 2 and 3. ASCO Meet Abstr 24(18_suppl):4045
Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C et al (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501–513
Phan AT, Halperin DM, Chan JA, Fogelman DR, Hess KR, Malinowski P et al (2015) Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. Lancet Oncol 16:695–703
Grande E, Capdevila J, Castellano D, Teulé A, Durán I, Fuster J et al (2015) Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE). Ann Oncol 26(9):1987–1993
Wong MH, Chan DL, Lee A, Li BT, Lumba S, Clarke SJ et al (2016) Systematic review and meta-analysis on the role of chemotherapy in advanced and metastatic neuroendocrine tumor (NET). Stemmer SM, editor. PLoS One 11(6):e0158140
Venook AP, Ko AH, Tempero MA, Uy J, Weber T, Korn M et al (2008) Phase II trial of FOLFOX plus bevacizumab in advanced, progressive neuroendocrine tumors. ASCO Meet Abstr 26(15_suppl):15545
Kunz PL, Kuo T, Zahn JM, Kaiser HL, Norton JA, Visser BC et al (2010) A phase II study of capecitabine, oxaliplatin, and bevacizumab for metastatic or unresectable neuroendocrine tumors. ASCO Meet Abstr 28(15_suppl):4104
Fine RL, Gulati AP, Tsushima D, Mowatt KB, Oprescu A, Bruce JN et al (2014) Prospective phase II study of capecitabine and temozolomide (CAPTEM) for progressive, moderately, and well-differentiated metastatic neuroendocrine tumors. ASCO Meet Abstr 32(3_suppl):179
Wick W, Weller M, van den Bent M, Sanson M, Weiler M, von Deimling A et al (2014) MGMT testing—the challenges for biomarker-based glioma treatment. Nat Rev Neurol 10(7):372–385
Kulke MH, Hornick JL, Frauenhoffer C, Hooshmand S, Ryan DP, Enzinger PC et al (2009) O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res 15(1):338–345
Cives M, Ghayouri M, Morse B, Brelsford M, Black M, Rizzo A et al (2016). Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. Endocr Relat Cancer 23(9):759–767
Granberg D, Eriksson B, Wilander E, Grimfjärd P, Fjällskog ML, Oberg K et al (2001) Experience in treatment of metastatic pulmonary carcinoid tumors. Ann Oncol Off J Eur Soc Med Oncol ESMO 12(10):1383–1391
Mirvis E, Mandair D, Garcia-Hernandez J, Mohmaduvesh M, Toumpanakis C, Caplin M (2014) Role of interferon-alpha in patients with neuroendocrine tumors: a retrospective study. Anticancer Res 34(11):6601–6607
Arnold R, Chen Y-J, Costa F, Falconi M, Gross D, Grossman AB et al (2009) ENETS consensus guidelines for the standards of care in neuroendocrine tumors: follow-up and documentation. Neuroendocrinology 90(2):227–233
Kolby L, Persson G, Franzen S, Ahren B (2003) Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg 90:687–693
Gulec SA, Mountcastle TS, Frey D, Cundiff JD, Mathews E, Anthony L et al (2002) Cytoreductive surgery in patients with advanced-stage carcinoid tumors. Am Surg 68(8):667. -671-672
Strosberg JR, Wolin EM, Chasen B, Kulke MH, Bushnell DL, Caplin ME et al (2016) NETTER-1 phase III: Progression-free survival, radiographic response, and preliminary overall survival results in patients with midgut neuroendocrine tumors treated with 177-Lu-Dotatate. J Clin Oncol 34(Suppl 4S):Abstr 194
Kratochwil C, Stefanova M, Mavriopoulou E, Holland-Letz T, Dimitrakopoulou-Strauss A, Afshar-Oromieh A et al (2015) SUV of [68Ga]DOTATOC-PET/CT predicts response probability of PRRT in neuroendocrine tumors. Mol Imaging Biol 17(3):313–318
Basturk O, Yang Z, Tang LH, Hruban RH, Adsay V, McCall CM et al (2015) The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogeneous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol 39(5):683–690
Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P et al (2013) Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol Off J Eur Soc Med Oncol ESMO 24(1):152–160
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We acknowledge the help of Professor Dale Bailey in providing ◘ Fig. 22.1.
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Chan, D.L., Segelov, E., Singh, S. (2018). Therapy for Metastatic Disease: Ileum. In: Colao, A., Faggiano, A., de Herder, W. (eds) Neuroendocrine Tumors in Real Life. Springer, Cham. https://doi.org/10.1007/978-3-319-59024-0_22
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