Everolimus in the treatment of neuroendocrine tumors: efficacy, side-effects, resistance, and factors affecting its place in the treatment sequence

References

• Ito T, Hijioka S, Masui T, et al. Advances in the diagnosis and treatment of pancreatic neuroendocrine neoplasms in Japan. J Gastroenterol. 2017;52:9–18.
   PubMed Web of Science ®Google Scholar
• Dasari A, Shen C, Halperin D, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3:1335–1342.
   PubMed Web of Science ®Google Scholar
• 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;26:3063–3072.
   PubMed Web of Science ®Google Scholar
• Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer. 2003;97:934–959.
   PubMed Web of Science ®Google Scholar
• Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149:274–293.
   PubMed Web of Science ®Google Scholar
• Wolin EM. PI3K/Akt/mTOR pathway inhibitors in the therapy of pancreatic neuroendocrine tumors. Cancer Lett. 2013;335:1–8.
   PubMed Web of Science ®Google Scholar
• Shida T, Kishimoto T, Furuya M, et al. Expression of an activated mammalian target of rapamycin (mTOR) in gastroenteropancreatic neuroendocrine tumors. Cancer Chemother Pharmacol. 2010;65:889–893.
   PubMed Web of Science ®Google Scholar
• Righi L, Volante M, Rapa I, et al. Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung. Endocr Relat Cancer. 2010;17:977–987.
   PubMed Web of Science ®Google Scholar
• Qian ZR, Ter-Minassian M, Chan JA, et al. Prognostic significance of MTOR pathway component expression in neuroendocrine tumors. J Clin Oncol. 2013;31:3418–3425.
   PubMed Web of Science ®Google Scholar
• Kasajima A, Pavel M, Darb-Esfahani S, et al. mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer. 2011;18:181–192.
   PubMed Web of Science ®Google Scholar
• Komori Y, Yada K, Ohta M, et al. Mammalian target of rapamycin signaling activation patterns in pancreatic neuroendocrine tumors. J Hepatobiliary Pancreat Sci. 2014;21:288–295.
   PubMed Web of Science ®Google Scholar
• Missiaglia E, Dalai I, Barbi S, et al. Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol. 2010;28:245–255.
   PubMed Web of Science ®Google Scholar
• Casciano R, Chulikavit M, Perrin A, et al. Cost-effectiveness of everolimus vs sunitinib in treating patients with advanced, progressive pancreatic neuroendocrine tumors in the United States. J Med Econ. 2012;15(Suppl 1):55–64.
   PubMedGoogle Scholar
• Perren A, Komminoth P, Saremaslani P, et al. Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells. Am J Pathol. 2000;157:1097–1103.
   PubMed Web of Science ®Google Scholar
• Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331:1199–1203.
   PubMed Web of Science ®Google Scholar
• Scarpa A, Chang DK, Nones K, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543:65–71.
   PubMed Web of Science ®Google Scholar
• Grozinsky-Glasberg S, Franchi G, Teng M, et al. Octreotide and the mTOR inhibitor RAD001 (everolimus) block proliferation and interact with the Akt-mTOR-p70S6K pathway in a neuro-endocrine tumour cell Line. Neuroendocrinology. 2008;87:168–181.
   PubMed Web of Science ®Google Scholar
• Chan J, Kulke M. Targeting the mTOR signaling pathway in neuroendocrine tumors. Curr Treat Options Oncol. 2014;15:365–379.
   PubMed Web of Science ®Google Scholar
• Yang H, Rudge DG, Koos JD, et al. mTOR kinase structure, mechanism and regulation. Nature. 2013;497:217–223.
   PubMed Web of Science ®Google Scholar
• Yao JC, Phan AT, Chang DZ, 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;26:4311–4318.
   PubMed Web of Science ®Google Scholar
• 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;378:2005–2012.
   PubMed Web of Science ®Google Scholar
• Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:514–523.
   PubMed Web of Science ®Google Scholar
• 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;387:968–977.
   PubMed Web of Science ®Google Scholar
• Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011;364:501–513.
   PubMed Web of Science ®Google Scholar
• Caplin ME, Pavel M, Cwikla J, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med. 2014;371:224–233.
   PubMed Web of Science ®Google Scholar
• Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of (177)Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376:125–135.
   PubMed Web of Science ®Google Scholar
• Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–2130.
   PubMed Web of Science ®Google Scholar
• Fidelman N, Kerlan RK Jr., Hawkins RA, et al. Radioembolization with (90)Y glass microspheres for the treatment of unresectable metastatic liver disease from chemotherapy-refractory gastrointestinal cancers: final report of a prospective pilot study. J Gastrointest Oncol. 2016;7:860–874.
   PubMed Web of Science ®Google Scholar
• Benson AB III, Geschwind JF, Mulcahy MF, et al. Radioembolisation for liver metastases: results from a prospective 151 patient multi-institutional phase II study. Eur J Cancer. 2013;49:3122–3130.
   PubMed Web of Science ®Google Scholar
• Kulke MH, Horsch D, Caplin ME, et al. Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome. J Clin Oncol. 2017;35:14–23.
   PubMed Web of Science ®Google Scholar
• Vinik AI, Wolin EM, Liyanage N, et al. Evaluation of lanreotide depot/autogel efficacy and safety as a carcinoid syndrome treatment(ELECT): A randomized, double-blind, placebo-controlled trial. Endocr Pract. 2016;22:1068–1080.
   PubMed Web of Science ®Google Scholar
• Bosman FT, Carneiro F, Hruban RH, et al. WHO World Health Organization classification of tumors and genetics of the digestive system. Lyon, France: IARC press; 2010.
   Google Scholar
• WHO classification of tumours of the lung, pleura, thymus and heart. Lyon, France: International Agency for Research on Cancer; 2015.
   Google Scholar
• Rindi G, Falconi M, Klersy C, et al. TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst. 2012;104:764–777.
   PubMedGoogle Scholar
• Luo G, Javed A, Strosberg JR, et al. Modified staging classification for pancreatic neuroendocrine tumors on the basis of the American Joint Committee on Cancer and European Neuroendocrine Tumor Society Systems. J Clin Oncol. 2017;35:274–280.
   PubMed Web of Science ®Google Scholar
• Morin E, Cheng S, Mete O, et al. Hormone profiling, WHO 2010 grading, and AJCC/UICC staging in pancreatic neuroendocrine tumor behavior. Cancer Med. 2013;2:701–711.
   PubMed Web of Science ®Google Scholar
• Sorbye H, Welin S, Langer SW, 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):152–260.
   Web of Science ®Google Scholar
• Milione M, Maisonneuve P, Spada F, et al. The clinicopathologic heterogeneity of Grade 3 gastroenteropancreatic neuroendocrine neoplasms: morphological differentiation and proliferation identify different prognostic categories. Neuroendocrinology. 2017;104(1):84–93.
   Web of Science ®Google Scholar
• Heetfeld M, Chougnet CN, Olsen IH, et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2015;22:657–664.
   PubMed Web of Science ®Google Scholar
• Hijioka S, Hosoda W, Matsuo K, et al. Rb Loss and KRAS mutation are predictors of the response to platinum-based chemotherapy in pancreatic neuroendocrine neoplasm with Grade 3: A Japanese multicenter pancreatic NEN-G3 study. Clin Cancer Res. 2017;23:4625–4632.
   PubMed Web of Science ®Google Scholar
• Cho MY, Kim JM, Sohn JH, et al. Current trends of the incidence and pathological diagnosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Korea 2000–2009: multicenter study. Cancer Res Treat. 2012;44:157–165.
   PubMed Web of Science ®Google Scholar
• Hijioka S, Hosoda W, Mizuno N, et al. Does the WHO 2010 classification of pancreatic neuroendocrine neoplasms accurately characterize pancreatic neuroendocrine carcinomas? J Gastroenterol. 2015;50:564–572.
   PubMed Web of Science ®Google Scholar
• Tang LH, Basturk O, Sue JJ, et al. A 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;40:1192–1202.
   PubMed Web of Science ®Google Scholar
• Tang LH, Untch BR, Reidy DL, et al. Well-differentiated neuroendocrine tumors with a morphologically apparent high-grade component: a pathway distinct from poorly differentiated neuroendocrine carcinomas. Clin Cancer Res. 2016;22:1011–1017.
   PubMed Web of Science ®Google Scholar
• Basturk O, Yang Z, Tang LH, et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol. 2015;39:683–690.
   PubMed Web of Science ®Google Scholar
• WHO classification of tumours of endocrine organs. 4th ed. Vol. 10, Lloyd RV, Osamura RY, Kloppel G, Rosai J, editors. Lyon, France: Agency for Research on Cancer; 2017.
   Google Scholar
• Haug AR, Cindea-Drimus R, Auernhammer CJ, et al. The role of 68Ga-DOTATATE PET/CT in suspected neuroendocrine tumors. J Nucl Med. 2012;53:1686–1692.
   PubMed Web of Science ®Google Scholar
• Haug AR, Cindea-Drimus R, Auernhammer CJ, et al. Neuroendocrine tumor recurrence: diagnosis with 68Ga-DOTATATE PET/CT. Radiology. 2014;270:517–525.
   PubMed Web of Science ®Google Scholar
• Deppen SA, Liu E, Blume JD, et al. Safety and efficacy of 68Ga-DOTATATE PET/CT for diagnosis, staging, and treatment management of neuroendocrine tumors. J Nucl Med. 2016;57:708–714.
   PubMed Web of Science ®Google Scholar
• Has Simsek D, Kuyumcu S, Turkmen C, et al. Can complementary 68Ga-DOTATATE and 18F-FDG PET/CT establish the missing link between histopathology and therapeutic approach in gastroenteropancreatic neuroendocrine tumors? J Nucl Med. 2014;55:1811–1817.
   PubMed Web of Science ®Google Scholar
• Bahri H, Laurence L, Edeline J, et al. High prognostic value of 18F-FDG PET for metastatic gastroenteropancreatic neuroendocrine tumors: a long-term evaluation. J Nucl Med. 2014;55:1786–1790.
   PubMed Web of Science ®Google Scholar
• Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 2009;10:307–318.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449–456.
   PubMed Web of Science ®Google Scholar
• Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010;363:1801–1811.
   PubMed Web of Science ®Google Scholar
• Dantal J. Everolimus: preventing organ rejection in adult kidney transplant recipients. Expert Opin Pharmacother. 2012;13:767–778.
   PubMed Web of Science ®Google Scholar
• Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–529.
   PubMed Web of Science ®Google Scholar
• Kirchner GI, Meier-Wiedenbach I, Manns MP. Clinical pharmacokinetics of everolimus. Clin Pharmacokinet. 2004;43:83–95.
   PubMed Web of Science ®Google Scholar
• O’Donnell A, Faivre S, Burris HA III, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol. 2008;26:1588–1595.
   PubMed Web of Science ®Google Scholar
• Pavel ME, Baudin E, Oberg KE, et al. Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study. Ann Oncol. 2017;28(7):1569–1575.
   Web of Science ®Google Scholar
• 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;143:955–962.
   PubMed Web of Science ®Google Scholar
• Castellano D, Bajetta E, Panneerselvam A, et al. Everolimus plus octreotide long-acting repeatable in patients with colorectal neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-2 study. Oncologist. 2013;18:46–53.
   PubMed Web of Science ®Google Scholar
• Anthony LB, Pavel ME, Hainsworth JD, et al. Impact of previous somatostatin analogue use on the activity of everolimus in patients with advanced neuroendocrine tumors: analysis from the Phase III RADIANT-2 trial. Neuroendocrinology. 2015;102:18–25.
   PubMed Web of Science ®Google Scholar
• Strosberg JR, Yao JC, Bajetta E, et al. Efficacy of octreotide long-acting repeatable in neuroendocrine tumors: RADIANT-2 placebo arm post hoc analysis. Endocr Relat Cancer. 2015;22:933–940.
   PubMed Web of Science ®Google Scholar
• Pavel ME, Becerra C, Grosch K, et al. Effect of everolimus on the pharmacokinetics of octreotide long-acting repeatable in patients with advanced neuroendocrine tumors: an analysis of the randomized phase III RADIANT-2 trial. Clin Pharmacol Ther. 2017;101:462–468.
   PubMed Web of Science ®Google Scholar
• Yao JC, Pavel M, Lombard-Bohas C, et al. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: overall survival and circulating biomarkers from the randomized, Phase III RADIANT-3 study. J Clin Oncol. 2016;34:3906–3913.
   PubMed Web of Science ®Google Scholar
• Ito T, Okusaka T, Ikeda M, et al. Everolimus for advanced pancreatic neuroendocrine tumours: a subgroup analysis evaluating Japanese patients in the RADIANT-3 trial. Jpn J Clin Oncol. 2012;42:903–911.
   PubMed Web of Science ®Google Scholar
• Lombard-Bohas C, Yao JC, Hobday T, et al. Impact of prior chemotherapy use on the efficacy of everolimus in patients with advanced pancreatic neuroendocrine tumors: a subgroup analysis of the phase III RADIANT-3 trial. Pancreas. 2015;44:181–189.
   PubMed Web of Science ®Google Scholar
• Singh S, Carnaghi C, Buzzoni R, et al. Everolimus in neuroendocrine tumors of the gastrointestinal tract and unknown primary. Neuroendocrinology. 2018;106(3):211–220.
   Web of Science ®Google Scholar
• Fazio N, Buzzoni R, Delle Fave G, et al. Everolimus in advanced, progressive, well-differentiated, non-functional neuroendocrine tumors: RADIANT-4 lung subgroup analysis. Cancer Sci. 2018;109:174–181.
   PubMed Web of Science ®Google Scholar
• Buzzoni R, Carnaghi C, Strosberg J, et al. Impact of prior therapies on everolimus activity: an exploratory analysis of RADIANT-4. Onco Targets Ther. 2017;10:5013–5030.
   PubMed Web of Science ®Google Scholar
• Pavel ME, Singh S, Strosberg JR, et al. Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1411–1422.
   PubMed Web of Science ®Google Scholar
• Yao JC, Lombard-Bohas C, Baudin E, 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;28:69–76.
   PubMed Web of Science ®Google Scholar
• Bajetta E, Catena L, Fazio N, et al. Everolimus in combination with octreotide long-acting repeatable in a first-line setting for patients with neuroendocrine tumors: an ITMO group study. Cancer. 2014;120:2457–2463.
   PubMed Web of Science ®Google Scholar
• Bajetta E, Catena L, Pusceddu S, et al. Everolimus in combination with Octreotide LAR in first line setting for patients with neuroendocrine tumors: a 5-years update. Neuroendocrinology. 2017. In press.
   PubMed Web of Science ®Google Scholar
• Kulke MH, Ruszniewski P, Van Cutsem E, et al. A randomized, open-label, phase 2 study of everolimus in combination with pasireotide LAR or everolimus alone in advanced, well-differentiated, progressive pancreatic neuroendocrine tumors: COOPERATE-2 trial. Ann Oncol. 2017;28:1309–1315.
   PubMed Web of Science ®Google Scholar
• Ferolla P, Brizzi MP, Meyer T, et al. Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2017;18:1652–1664.
   PubMed Web of Science ®Google Scholar
• Chan JA, Ryan DP, Zhu AX, et al. Phase I study of pasireotide (SOM 230) and everolimus (RAD001) in advanced neuroendocrine tumors. Endocr Relat Cancer. 2012;19:615–623.
   PubMed Web of Science ®Google Scholar
• Dasari A, Phan A, Gupta S, et al. Phase I study of the anti-IGF1R antibody cixutumumab with everolimus and octreotide in advanced well-differentiated neuroendocrine tumors. Endocr Relat Cancer. 2015;22:431–441.
   PubMed Web of Science ®Google Scholar
• Kim HS, Shaib WL, Zhang C, et al. Phase 1b study of pasireotide, everolimus, and selective internal radioembolization therapy for unresectable neuroendocrine tumors with hepatic metastases. Cancer. 2018;124(9):1992–2000.
   Web of Science ®Google Scholar
• O’Reilly T, McSheehy PM. Biomarker development for the clinical activity of the mTOR inhibitor Everolimus (RAD001): processes, limitations, and further proposals. Transl Oncol. 2010;3:65–79.
   PubMed Web of Science ®Google Scholar
• von Wichert G, Jehle PM, Hoeflich A, et al. Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. Cancer Res. 2000;60:4573–4581.
   PubMed Web of Science ®Google Scholar
• Weckbecker G, Briner U, Lewis I, et al. SOM230: a new somatostatin peptidomimetic with potent inhibitory effects on the growth hormone/insulin-like growth factor-I axis in rats, primates, and dogs. Endocrinology. 2002;143:4123–4130.
   PubMed Web of Science ®Google Scholar
• Chan JA, Blaszkowsky L, Stuart K, et al. A prospective, phase 1/2 study of everolimus and temozolomide in patients with advanced pancreatic neuroendocrine tumor. Cancer. 2013;119(17):3212–3218.
   Web of Science ®Google Scholar
• Chan JA, Mayer RJ, Jackson N, et al. Phase I study of sorafenib in combination with everolimus (RAD001) in patients with advanced neuroendocrine tumors. Cancer Chemother Pharmacol. 2013;71:1241–1246.
   PubMed Web of Science ®Google Scholar
• Claringbold PG, Turner JH. NeuroEndocrine tumor therapy with Lutetium-177-octreotate and Everolimus (NETTLE): a phase I study. Cancer Biother Radiopharm. 2015;30:261–269.
   PubMed Web of Science ®Google Scholar
• Salazar R, Garcia-Carbonero R, Libutti SK, et al. Phase II study of BEZ235 versus Everolimus in patients with mammalian target of Rapamycin inhibitor-naive advanced pancreatic neuroendocrine tumors. Oncologist. 2017. In press.
   Web of Science ®Google Scholar
• Oh DY, Kim TW, Park YS, et al. Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas. Cancer. 2012;118:6162–6170.
   PubMed Web of Science ®Google Scholar
• Hobday TJ, Qin R, Reidy-Lagunes D, et al. Multicenter phase II Trial of Temsirolimus and Bevacizumab in pancreatic neuroendocrine tumors. J Clin Oncol. 2015;33:1551–1556.
   PubMed Web of Science ®Google Scholar
• Berruti A, Fazio N, Ferrero A, et al. Bevacizumab plus octreotide and metronomic capecitabine in patients with metastatic well-to-moderately differentiated neuroendocrine tumors: the XELBEVOCT study. BMC Cancer. 2014;14:184.
   PubMed Web of Science ®Google Scholar
• Chan JA, Stuart K, Earle CC, et al. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol. 2012;30:2963–2968.
   PubMed Web of Science ®Google Scholar
• Panzuto F, Rinzivillo M, Fazio N, et al. Real-world study of everolimus in advanced progressive neuroendocrine tumors. Oncologist. 2014;19:966–974.
   PubMed Web of Science ®Google Scholar
• Berardi R, Torniai M, Pusceddu S, et al. Prognostic impact of the cumulative dose and dose intensity of everolimus in patients with pancreatic neuroendocrine tumors. Cancer Med. 2017;6:1493–1499.
   PubMed Web of Science ®Google Scholar
• Liu CT, Chen MH, Chen JS, et al. The efficacy and safety of everolimus for the treatment of progressive gastroenteropancreatic neuroendocrine tumors: a multi-institution observational study in Taiwan. Asia Pac J Clin Oncol. 2016;12:396–402.
   PubMed Web of Science ®Google Scholar
• Lee L, Ito T, Igarashi H, et al. Impact of everolimus on Japanese patients with advanced pancreatic neuroendocrine neoplasms. J Hepatobiliary Pancreat Sci. 2017;24:95–102.
   PubMed Web of Science ®Google Scholar
• Lee KJ, Cho JH, Lee SH, et al. Clinical outcomes of everolimus in patients with advanced, nonfunctioning pancreatic neuroendocrine tumors: a multicenter study in Korea. Cancer Chemother Pharmacol. 2017;80:799–805.
   PubMed Web of Science ®Google Scholar
• Yao JC, Phan AT, Hess K, et al. Perfusion computed tomography as functional biomarker in randomized run-in study of bevacizumab and everolimus in well-differentiated neuroendocrine tumors. Pancreas. 2015;44:190–197.
   PubMed Web of Science ®Google Scholar
• Kamp K, Gumz B, Feelders RA, et al. Safety and efficacy of everolimus in gastrointestinal and pancreatic neuroendocrine tumors after (177)Lu-octreotate. Endocr Relat Cancer. 2013;20:825–831.
   PubMed Web of Science ®Google Scholar
• Angelousi A, Kamp K, Kaltsatou M, et al. Sequential Everolimus and Sunitinib treatment in pancreatic metastatic well-differentiated neuroendocrine tumours resistant to prior treatments. Neuroendocrinology. 2017;105:394–402.
   PubMed Web of Science ®Google Scholar
• Yoo C, Cho H, Song MJ, et al. Efficacy and safety of everolimus and sunitinib in patients with gastroenteropancreatic neuroendocrine tumor. Cancer Chemother Pharmacol. 2017;79:139–146.
   PubMed Web of Science ®Google Scholar
• Capdevila J, Sevilla I, Alonso V, et al. Evaluation of the efficacy and safety of lanreotide in combination with targeted therapies in patients with neuroendocrine tumours in clinical practice: a retrospective cross-sectional analysis. BMC Cancer. 2015;15:495.
   PubMed Web of Science ®Google Scholar
• Wolin EM. Long-term everolimus treatment of patients with pancreatic neuroendocrine tumors. Chemotherapy. 2014;60:143–150.
   PubMed Web of Science ®Google Scholar
• Ter-Minassian M, Zhang S, Brooks NV, et al. Association between tumor progression endpoints and overall survival in patients with advanced neuroendocrine tumors. Oncologist. 2017;22:165–172.
   PubMed Web of Science ®Google Scholar
• Ito T, Lee L, Jensen RT. Treatment of symptomatic neuroendocrine tumor syndromes: recent advances and controversies. Expert Opin Pharmacother. 2016;17:2191–2205.
   PubMed Web of Science ®Google Scholar
• Ito T, Lee L, Jensen RT. Carcinoid-syndrome: recent advances, current status and controversies. Curr Opin Endocrinol Diabetes Obes. 2018;25:22–35.
   PubMed Web of Science ®Google Scholar
• Falconi M, Eriksson B, Kaltsas G, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103:153–171.
   PubMed Web of Science ®Google Scholar
• Strosberg JR, Halfdanarson TR, Bellizzi AM, et al. The north american neuroendocrine tumor society consensus guidelines for surveillance and medical management of midgut neuroendocrine tumors. Pancreas. 2017;46:707–714.
   PubMed Web of Science ®Google Scholar
• Roy PK, Venzon DJ, Feigenbaum KM, et al. Gastric secretion in Zollinger-Ellison syndrome: correlation with clinical expression, tumor extent and role in diagnosis - a prospective NIH study of 235 patients and review of the literature in 984 cases. Medicine. 2001;80:189–222, (Baltimore)
   PubMed Web of Science ®Google Scholar
• Berna MJ, Hoffmann KM, Serrano J, et al. Serum gastrin in Zollinger-Ellison syndrome: I. prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. Medicine. 2006;85:295–330, (Baltimore)
   PubMed Web of Science ®Google Scholar
• Berna MJ, Hoffmann KM, Long SH, et al. Serum gastrin in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. evaluation of diagnostic criteria, proposal of new criteria, and correlations with clinical and tumoral features. Medicine. 2006;85:331–364, (Baltimore)
   PubMed Web of Science ®Google Scholar
• Ito T, Igarashi H, Jensen RT. Zollinger-Ellison syndrome: recent advances and controversies. Curr Opin Gastroenterol. 2013;29:650–661.
   PubMed Web of Science ®Google Scholar
• Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135:1469–1492.
   PubMed Web of Science ®Google Scholar
• Collen MJ, Howard JM, McArthur KE, et al. Comparison of ranitidine and cimetidine in the treatment of gastric hypersecretion. Ann Intern Med. 1984;100:52–58.
   PubMed Web of Science ®Google Scholar
• Ito T, Igarashi H, Uehara H, et al. Pharmacotherapy of Zollinger-Ellison syndrome. Expert Pharmacother. 2013;14:307–321.
   PubMed Web of Science ®Google Scholar
• Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances. Best Pract Res Clin Gastroenterol. 2012;26:737–753.
   PubMed Web of Science ®Google Scholar
• Ito T, Igarashi H, Jensen RT. Therapy of metastatic pancreatic neuroendocrine tumors (pNETs): recent insights and advances. J Gastroenterol. 2012;47:941–960.
   PubMed Web of Science ®Google Scholar
• Stehouwer CD, Lems WF, Fischer HR, et al. Aggravation of hypoglycemia in insulinoma patients by the long-acting somatostatin analogue octreotide (Sandostatin). Acta Endocrinol (Copenh). 1989;121:34–40.
   PubMedGoogle Scholar
• Pavel ME, Chen D, He W, et al. Everolimus effect on gastrin and glucagon in pancreatic neuroendocrine tumors. Pancreas. 2017;46:751–757.
   PubMed Web of Science ®Google Scholar
• Capdevila J, Diez Miranda I, Obiols G, et al. Control of carcinoid syndrome with everolimus. Ann Oncol. 2011;22:237–239.
   PubMed Web of Science ®Google Scholar
• Bainbridge HE, Larbi E, Middleton G. Symptomatic control of neuroendocrine tumours with everolimus. Horm Cancer. 2015;6:254–259.
   PubMed Web of Science ®Google Scholar
• Houde VP, Brule S, Festuccia WT, et al. Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes. 2010;59:1338–1348.
   PubMed Web of Science ®Google Scholar
• Bernard V, Lombard-Bohas C, Taquet MC, et al. Efficacy of Everolimus in patients with metastatic insulinoma and refractory Hypoglycemia. Eur J Endocrinol. 2013;168:665–674.
   PubMed Web of Science ®Google Scholar
• Bozkirli E, Bakiner O, Abali H, et al. A case of inoperable malignant insulinoma with resistant hypoglycemia who experienced the most significant clinical improvement with everolimus. Case Rep Endocrinol. 2013;2013:636175.
   PubMedGoogle Scholar
• Asayama M, Yamada-Murano T, Hara H, et al. Everolimus dramatically improves glycemic control in unresectable metastatic insulinoma: a case report. Jpn J Clin Oncol. 2014;44:186–190.
   PubMed Web of Science ®Google Scholar
• Kulke MH, Bergsland EK, Yao JC. Glycemic control in patients with insulinoma treated with everolimus. N Engl J Med. 2009;360:195–197.
   PubMed Web of Science ®Google Scholar
• Fiebrich HB, Siemerink EJ, Brouwers AH, et al. Everolimus induces rapid plasma glucose normalization in insulinoma patients by effects on tumor as well as normal tissues. Oncologist. 2011;16:783–787.
   PubMed Web of Science ®Google Scholar
• Thomas NJ, Brooke AM, Besser GM. Long-term maintenance of normoglycaemia using everolimus in a patient with disseminated insulinoma and severe hypoglycaemia. Clin Endocrinol (Oxf). 2013;78:799–800.
   PubMed Web of Science ®Google Scholar
• Scharf M, Mueller D, Koenig U, et al. Management of a metastasized high grade insulinoma (G3) with refractory hypoglycemia: case report and review of the literature. Pancreatology. 2014;14:542–545.
   PubMed Web of Science ®Google Scholar
• Garcia-Carbonero R, Sorbye H, Baudin E, et al. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology. 2016;103:186–194.
   PubMed Web of Science ®Google Scholar
• Panzuto F, Rinzivillo M, Spada F, et al. Everolimus in pancreatic neuroendocrine carcinomas G3. Pancreas. 2017;46:302–305.
   PubMed Web of Science ®Google Scholar
• Genc CG, Klumpen HJ, Denecke T, et al. Successful treatment of high-grade pancreatic neuroendocrine neoplasms with everolimus. Acta Oncol. 2018;57(5):686–688.
   PubMed Web of Science ®Google Scholar
• Fonseca PJ, Uriol E, Galvan JA, et al. Prolonged clinical benefit of everolimus therapy in the management of high-grade pancreatic neuroendocrine carcinoma. Case Rep Oncol. 2013;6:441–449.
   PubMedGoogle Scholar
• Tanaka H, Matsusaki S, Baba Y, et al. Neuroendocrine tumor G3: a pancreatic well-differentiated neuroendocrine tumor with a high proliferative rate. Clin J Gastroenterol. 2015;8:414–420.
   PubMed Web of Science ®Google Scholar
• Chung DC, Brown SB, Graeme-Cook F, et al. Localization of putative tumor suppressor loci by genome-wide allelotyping in human pancreatic endocrine tumors. Cancer Res. 1998;58:3706–3711.
   PubMed Web of Science ®Google Scholar
• Bollard J, Couderc C, Blanc M, et al. Antitumor effect of everolimus in preclinical models of high-grade gastroenteropancreatic neuroendocrine carcinomas. Neuroendocrinology. 2013;97:331–340.
   PubMed Web of Science ®Google Scholar
• Gilabert M, Rho YS, Kavan P. Targeted therapies provide treatment options for poorly differentiated pancreatic neuroendocrine carcinomas. Oncology. 2017;92:170–172.
   PubMed Web of Science ®Google Scholar
• Tarhini A, Kotsakis A, Gooding W, et al. Phase II study of everolimus (RAD001) in previously treated small cell lung cancer. Clin Cancer Res. 2010;16:5900–5907.
   PubMed Web of Science ®Google Scholar
• Sun JM, Kim JR, Do IG, et al. A phase-1b study of everolimus plus paclitaxel in patients with small-cell lung cancer. Br J Cancer. 2013;109:1482–1487.
   PubMed Web of Science ®Google Scholar
• Christopoulos P, Engel-Riedel W, Grohe C, et al. Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial. Ann Oncol. 2017;28:1898–1902.
   PubMed Web of Science ®Google Scholar
• Dasari A, Mehta K, Byers LA, et al. Comparative study of lung and extrapulmonary poorly differentiated neuroendocrine carcinomas: A SEER database analysis of 162,983 cases. Cancer. 2018;124:807–815.
   PubMed Web of Science ®Google Scholar
• Martins D, Spada F, Lambrescu I, et al. Predictive markers of response to everolimus and sunitinib in neuroendocrine tumors. Target Oncol. 2017;12:611–622.
   PubMed Web of Science ®Google Scholar
• Yao JC, Pavel M, Phan AT, et al. Chromogranin A and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus. J Clin Endocrinol Metab. 2011;96:3741–3749.
   PubMed Web of Science ®Google Scholar
• Serra S, Zheng L, Hassan M, et al. The FGFR4-G388R single-nucleotide polymorphism alters pancreatic neuroendocrine tumor progression and response to mTOR inhibition therapy. Cancer Res. 2012;72:5683–5691.
   PubMed Web of Science ®Google Scholar
• Cros J, Moati E, Raffenne J, et al. Gly388Arg FGFR4 polymorphism is not predictive of everolimus efficacy in well-differentiated digestive neuroendocrine tumors. Neuroendocrinology. 2016;103:495–499.
   PubMed Web of Science ®Google Scholar
• Meric-Bernstam F, Akcakanat A, Chen H, et al. PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors. Clin Cancer Res. 2012;18:1777–1789.
   PubMed Web of Science ®Google Scholar
• Gagliano T, Bellio M, Gentilin E, et al. mTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids. Endocr Relat Cancer. 2013;20:463–475.
   PubMed Web of Science ®Google Scholar
• Benslama N, Bollard J, Vercherat C, et al. Prediction of response to everolimus in neuroendocrine tumors: evaluation of clinical, biological and histological factors. Invest New Drugs. 2016;34:654–662.
   PubMed Web of Science ®Google Scholar
• Boulay A, Zumstein-Mecker S, Stephan C, et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res. 2004;64:252–261.
   PubMed Web of Science ®Google Scholar
• Tanaka C, O’Reilly T, Kovarik JM, et al. Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol. 2008;26:1596–1602.
   PubMedGoogle Scholar
• van Asselt SJ, Oosting SF, Brouwers AH, et al. Everolimus reduces (89)Zr-Bevacizumab tumor uptake in patients with neuroendocrine tumors. J Nucl Med. 2014;55:1087–1092.
   PubMed Web of Science ®Google Scholar
• Rugo HS, Hortobagyi GN, Yao J, et al. Meta-analysis of stomatitis in clinical studies of everolimus: incidence and relationship with efficacy. Ann Oncol. 2016;27:519–525.
   PubMed Web of Science ®Google Scholar
• Abdel-Rahman O, Fouad M. Risk of mucocutaneous toxicities in patients with solid tumors treated with everolimus; a systematic review and meta-analysis. Expert Rev Anticancer Ther. 2014;14:1529–1536.
   PubMed Web of Science ®Google Scholar
• Ravaud A, Urva SR, Grosch K, et al. Relationship between everolimus exposure and safety and efficacy: meta-analysis of clinical trials in oncology. Eur J Cancer. 2014;50:486–495.
   PubMed Web of Science ®Google Scholar
• Shameem R, Lacouture M, Wu S. Incidence and risk of rash to mTOR inhibitors in cancer patients–a meta-analysis of randomized controlled trials. Acta Oncol. 2015;54:124–132.
   PubMed Web of Science ®Google Scholar
• Ramirez-Fort MK, Case EC, Rosen AC, et al. Rash to the mTOR inhibitor everolimus: systematic review and meta-analysis. Am J Clin Oncol. 2014;37:266–271.
   PubMed Web of Science ®Google Scholar
• Abdel-Rahman O, Fouad M. Risk of fatigue and hepatic and metabolic toxicities in patients with solid tumors treated with everolimus: a meta-analysis. Future Oncol. 2015;11:79–90.
   PubMed Web of Science ®Google Scholar
• Garcia CA, Wu S. Attributable risk of infection to mTOR inhibitors Everolimus and Temsirolimus in the treatment of cancer. Cancer Invest. 2016;34:521–530.
   PubMed Web of Science ®Google Scholar
• Iacovelli R, Palazzo A, Mezi S, et al. Incidence and risk of pulmonary toxicity in patients treated with mTOR inhibitors for malignancy. A meta-analysis of published trials. Acta Oncol. 2012;51:873–879.
   PubMed Web of Science ®Google Scholar
• Noguchi S, Shinohara N, Ito T, et al. Relationship between pulmonary adverse events and Everolimus exposure in Japanese and non-japanese patients: a meta-analysis of oncology trials. Oncology. 2017;92:243–254.
   PubMed Web of Science ®Google Scholar
• Xu KY, Shameem R, Wu S. Risk of hyperglycemia attributable to everolimus in cancer patients: A meta-analysis. Acta Oncol. 2016;55:1196–1203.
   PubMed Web of Science ®Google Scholar
• Xu J, Tian D. Hematologic toxicities associated with mTOR inhibitors temsirolimus and everolimus in cancer patients: a systematic review and meta-analysis. Curr Med Res Opin. 2014;30:67–74.
   PubMed Web of Science ®Google Scholar
• Shameem R, Hamid MS, Wu S. Risk of anemia attributable to everolimus in patients with cancer: a meta-analysis of randomized controlled trials. Anticancer Res. 2015;35:2333–2340.
   PubMed Web of Science ®Google Scholar
• Qi WX, Huang YJ, Yao Y, et al. Incidence and risk of treatment-related mortality with mTOR inhibitors everolimus and temsirolimus in cancer patients: a meta-analysis. PLoS One. 2013;8:e65166.
   PubMed Web of Science ®Google Scholar
• Rogers SC, Garcia CA, Wu S. Discontinuation of Everolimus due to related and unrelated adverse events in cancer patients: a meta-analysis. Cancer Invest. 2017;35:552–561.
   PubMed Web of Science ®Google Scholar
• Choueiri TK, Je Y, Sonpavde G, et al. Incidence and risk of treatment-related mortality in cancer patients treated with the mammalian target of rapamycin inhibitors. Ann Oncol. 2013;24:2092–2097.
   PubMed Web of Science ®Google Scholar
• Plante A, Baudin E, Do Cao C, et al. Patient-reported tolerance in treatments approved in neuroendocrine tumors: a national survey from the French Group of Endocrine Tumors. Clin Res Hepatol Gastroenterol. 2018;42(2):153–159.
   PubMed Web of Science ®Google Scholar
• Pavel M, Unger N, Borbath I, et al. Safety and QOL in patients with advanced NET in a Phase 3b expanded access study of Everolimus. Target Oncol. 2016;11:667–675.
   PubMed Web of Science ®Google Scholar
• Deppenweiler M, Falkowski S, Saint-Marcoux F, et al. Towards therapeutic drug monitoring of everolimus in cancer? Results of an exploratory study of exposure-effect relationship. Pharmacol Res. 2017;121:138–144.
   PubMed Web of Science ®Google Scholar
• Aapro M, Andre F, Blackwell K, et al. Adverse event management in patients with advanced cancer receiving oral everolimus: focus on breast cancer. Ann Oncol. 2014;25:763–773.
   PubMed Web of Science ®Google Scholar
• Hsieh AC, Costa M, Zollo O, et al. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP-eIF4E. Cancer Cell. 2010;17:249–261.
   PubMed Web of Science ®Google Scholar
• Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471–484.
   PubMed Web of Science ®Google Scholar
• Houghton PJ. Everolimus. Clin Cancer Res. 2010;16:1368–1372.
   PubMed Web of Science ®Google Scholar
• Tamburini J, Chapuis N, Bardet V, et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood. 2008;111:379–382.
   PubMed Web of Science ®Google Scholar
• Kuo SH, Hsu CH, Chen LT, et al. Lack of compensatory pAKT activation and eIF4E phosphorylation of lymphoma cells towards mTOR inhibitor, RAD001. Eur J Cancer. 2011;47:1244–1257.
   PubMed Web of Science ®Google Scholar
• Svejda B, Kidd M, Kazberouk A, et al. Limitations in small intestinal neuroendocrine tumor therapy by mTor kinase inhibition reflect growth factor-mediated PI3K feedback loop activation via ERK1/2 and AKT. Cancer. 2011;117:4141–4154.
   PubMed Web of Science ®Google Scholar
• Wang X, Yue P, Kim YA, et al. Enhancing mammalian target of rapamycin (mTOR)-targeted cancer therapy by preventing mTOR/raptor inhibition-initiated, mTOR/rictor-independent Akt activation. Cancer Res. 2008;68:7409–7418.
   PubMed Web of Science ®Google Scholar
• Choo AY, Yoon SO, Kim SG, et al. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. Proc Natl Acad Sci U S A. 2008;105:17414–17419.
   PubMed Web of Science ®Google Scholar
• Kang SA, Pacold ME, Cervantes CL, et al. mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science. 2013;341:1236566.
   PubMed Web of Science ®Google Scholar
• Gupta M, Ansell SM, Novak AJ, et al. Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2. Blood. 2009;114:2926–2935.
   PubMed Web of Science ®Google Scholar
• Sarbassov DD, Guertin DA, Ali SM, et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307:1098–1101.
   PubMed Web of Science ®Google Scholar
• Stan R, McLaughlin MM, Cafferkey R, et al. Interaction between FKBP12-rapamycin and TOR involves a conserved serine residue. J Biol Chem. 1994;269:32027–32030.
   PubMed Web of Science ®Google Scholar
• Carracedo A, Ma L, Teruya-Feldstein J, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest. 2008;118:3065–3074.
   PubMed Web of Science ®Google Scholar
• Di Nicolantonio F, Arena S, Tabernero J, et al. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest. 2010;120:2858–2866.
   PubMed Web of Science ®Google Scholar
• Vandamme T, Beyens M, de Beeck KO, et al. Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors. Br J Cancer. 2016;114:650–658.
   PubMed Web of Science ®Google Scholar
• Antonuzzo L, Del RM, Barucca V, et al. Critical focus on mechanisms of resistance and toxicity of m-TOR inhibitors in pancreatic neuroendocrine tumors. Cancer Treat Rev. 2017;57:28–35.
   PubMed Web of Science ®Google Scholar
• Freitag H, Christen F, Lewens F, et al. Inhibition of mTOR’s catalytic site by PKI-587 is a promising therapeutic option for gastroenteropancreatic neuroendocrine tumor disease. Neuroendocrinology. 2017;105:90–104.
   PubMed Web of Science ®Google Scholar
• Passacantilli I, Capurso G, Archibugi L, et al. Combined therapy with RAD001 e BEZ235 overcomes resistance of PET immortalized cell lines to mTOR inhibition. Oncotarget. 2014;5:5381–5391.
   PubMedGoogle Scholar
• Zitzmann K, Ruden J, Brand S, et al. Compensatory activation of Akt in response to mTOR and Raf inhibitors - a rationale for dual-targeted therapy approaches in neuroendocrine tumor disease. Cancer Lett. 2010;295:100–109.
   PubMed Web of Science ®Google Scholar
• Bendell JC, Kurkjian C, Infante JR, et al. A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors. Invest New Drugs. 2015;33:463–471.
   PubMed Web of Science ®Google Scholar
• Fazio N, Buzzoni R, Baudin E, et al. A phase II study of BEZ235 in patients with everolimus-resistant, advanced pancreatic neuroendocrine tumours. Anticancer Res. 2016;36:713–719.
   PubMed Web of Science ®Google Scholar
• 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;27:4656–4663.
   PubMed Web of Science ®Google Scholar
• Faivre S, Niccoli P, Castellano D, et al. Sunitinib in pancreatic neuroendocrine tumors: updated progression-free survival and final overall survival from a phase III randomized study. Ann Oncol. 2017;28(2):339–343.
   PubMed Web of Science ®Google Scholar
• Dilz LM, Denecke T, Steffen IG, et al. Streptozocin/5-fluorouracil chemotherapy is associated with durable response in patients with advanced pancreatic neuroendocrine tumours. Eur J Cancer. 2015;51:1253–1262.
   PubMed Web of Science ®Google Scholar
• Clewemar Antonodimitrakis P, Sundin A, Wassberg C, et al. Streptozocin and 5-Fluorouracil for the treatment of pancreatic neuroendocrine tumors: efficacy, prognostic factors and toxicity. Neuroendocrinology. 2016;103:345–353.
   PubMed Web of Science ®Google Scholar
• Cives M, Ghayouri M, Morse B, et al. Analysis of potential response predictors to capecitabine/temozolomide in metastatic pancreatic neuroendocrine tumors. Endocr Relat Cancer. 2016;23:759–767.
   PubMed Web of Science ®Google Scholar
• von Schrenck T, Howard JM, Doppman JL, et al. Prospective study of chemotherapy in patients with metastatic gastrinoma. Gastroenterology. 1988;94:1326–1334.
   PubMed Web of Science ®Google Scholar
• Crona J, Fanola I, Lindholm DP, et al. Effect of temozolomide in patients with metastatic bronchial carcinoids. Neuroendocrinology. 2013;98:151–155.
   PubMed Web of Science ®Google Scholar
• Crona J, Bjorklund P, Welin S, et al. Treatment, prognostic markers and survival in thymic neuroendocrine tumours. Lung Cancer. 2013;79:289–293.
   PubMed Web of Science ®Google Scholar
• Kulke MH, Stuart K, Enzinger PC, et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol. 2006;24:401–406.
   PubMed Web of Science ®Google Scholar
• Krug S, Gress TM, Michl P, et al. The role of cytotoxic chemotherapy in advanced pancreatic neuroendocrine tumors. Digestion. 2017;96:67–75.
   PubMed Web of Science ®Google Scholar
• Partelli S, Bartsch DK, Capdevila J, et al. ENETS consensus guidelines for standard of care in neuroendocrine tumours: surgery for small intestinal and pancreatic neuroendocrine tumours. Neuroendocrinology. 2017;105:255–265.
   PubMed Web of Science ®Google Scholar
• Howe JR, Cardona K, Fraker DL, et al. The surgical management of small bowel neuroendocrine tumors: consensus guidelines of the North American Neuroendocrine Tumor Society. Pancreas. 2017;46:715–731.
   PubMed Web of Science ®Google Scholar
• Singh S, Dey C, Kennecke H, et al. Consensus recommendations for the diagnosis and management of pancreatic neuroendocrine tumors: guidelines from a Canadian national expert group. Ann Surg Oncol. 2015;22:2685–2699.
   PubMed Web of Science ®Google Scholar
• Oberg K, Knigge U, Kwekkeboom D, et al. Neuroendocrine gastro-entero-pancreatic tumors: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(Suppl 7):vii124–vii130.
   PubMed Web of Science ®Google Scholar
• 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;26:1604–1620.
   PubMed Web of Science ®Google Scholar
• Vinik A, Bottomley A, Korytowsky B, et al. Patient-reported outcomes and quality of life with sunitinib versus placebo for pancreatic neuroendocrine tumors: results from an international phase III trial. Target Oncol. 2016;11:815–824.
   PubMed Web of Science ®Google Scholar
• Marinova M, Mucke M, Mahlberg L, et al. Improving quality of life in patients with pancreatic neuroendocrine tumor following peptide receptor radionuclide therapy assessed by EORTC QLQ-C30. Eur J Nucl Med Mol Imaging. 2018;45:38–46.
   PubMed Web of Science ®Google Scholar
• Pavel M, O’Toole D, Costa F, 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;103:172–185.
   PubMed Web of Science ®Google Scholar
• Kulke MH, Shah MH, Benson AB, et al. Neuroendocrine tumors: version 3.2017: NCCN clinical practice guidelines in oncology. NCCN Clin Pract Guidel Oncol. 2017;1–116.
   Google Scholar
• Janson ET, Sorbye H, Welin S, et al. Nordic guidelines 2014 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. Acta Oncol. 2014;53:1284–1297.
   PubMed Web of Science ®Google Scholar
• Kulke MH, Anthony LB, Bushnell DL, et al. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010;39:735–752.
   PubMed Web of Science ®Google Scholar
• Strosberg JR, Coppola D, Klimstra DS, et al. The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas. 2010;39:799–800.
   PubMed Web of Science ®Google Scholar
• Hicks RJ, Kwekkeboom DJ, Krenning E, et al. ENETS consensus guidelines for the standards of care in neuroendocrine neoplasia: peptide receptor radionuclide therapy with radiolabeled somatostatin analogues. Neuroendocrinology. 2017;105:295–309.
   PubMed Web of Science ®Google Scholar
• Bodei L, Kidd M, Paganelli G, et al. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical factors. Eur J Nucl Med Mol Imaging. 2015;42:5–19.
   PubMed Web of Science ®Google Scholar
• Shipkova M, Hesselink DA, Holt DW, et al. Therapeutic drug monitoring of everolimus: a consensus report. Ther Drug Monit. 2016;38:143–169.
   PubMed Web of Science ®Google Scholar