Neuroendocrine neoplasms (NENs) once called carcinoid tumors, endocrine tumors or neuroendocrine tumors (NETs) are a group of pathologically and clinically heterogeneous tumors. These tumors mostly occurred in lung and gastroenteropancreatic (GEP) tract (1). In the past several decades, the incidence has been increasing in both east and west nations, partly due to the wide application of modern imaging and endoscopic technologies (2-10). According to whether these tumors can secrete hormones and amines, causing carcinoid syndrome and other clinical syndromes, they can be classified to functional NENs (F-NENs) and non-functional NENs (NF-NENs). And all the NENs have malignant potential and the malignant potential further depends on tumor site, degree of differentiation and extension of the tumors (11). The 5-year survival rate was 30–80% for all patients, 60–100% for localized disease, 40–55% for regional disease, 19–30% for distant metastases (8,12).
Pancreatic neuroendocrine neoplasms (P-NENs), commonly be called pancreatic endocrine tumors, insulinoma, gastrinoma or glucagonoma, comprise <2% of all pancreatic tumors (8,13). They may produce hormones, such as insulin, gastrin, glucagon, vasoactive intestinal peptide (VIP) and so on, causing special symptoms called carcinoid syndrome. And about half of the P-NENs present clinical symptoms (14). Of all these functional p-NENs, gastrinomas and insulinomas are the two most common, while the others are always considered together as a group called rare functional P-NENs (RFTs) (14-16).
In 1907, Oberndorfer first differentiated NENs as carcinoid from carcinomas. And because of the rareness and lacked knowledge of these tumors, people tended to lump them together in classification assessment and treatment for one hundred years (17,18). During this period, there was no published unified nomenclatures and classifications that can be accepted by both clinicians and pathologists (19,20).
In order to standardize the stratification and management procedures, in 2010, the WHO adopted the classification originally proposed by the European Neuroendocrine Tumor Society (ENET) from 2004 and 2007 (12,21-24), and presented a new classification. According to this new classification system, all tumors with a neuroendocrine differentiation called NENs (25). And all GEP-NENs can be subdivided into the well-differentiated NETs and the poorly-differentiated neuroendocrine carcinomas (NECs). Furthermore, according to different definitions of proliferation by the mitotic count and/or the Ki-67 index, NENs can be graded into three types, low grade (grade 1, G1), intermediate grade (grade 2, G2) and high-grade (grade 3, G3). In general, both G1 and G2 NENs a1re considered as NETs, and G3 NENs are considered as NECs. According to this classification, tumors with Ki-67 index more than 20% or mitotic rate more than 20 per 10 high power fields are defined as G3. Meanwhile, specific TNM classification was also introduced.
However, in recent years, several studies highlighted heterogeneity that the 2010 WHO G3 category might be composed of two different entities, according to their cellular histomorphology, nuclear mitotic rate, Ki67 index, somatostatin receptor expression, plasma CGA (chromogranin) and NSE (neuron specific enolase) levels, response to platinum-based chemotherapy and prognosis (26-31). Therefore, in 2017, the new WHO classification introduced a new category of well-differentiated pancreatic NETs (WD-pNETs) G3, different from poorly differentiated pancreatic NECs (PD-pNECs) G3 (32-34).
The 5-year survival rate of P-NENs was 80% for all stages, 60–100% for localized disease, 40% for regional disease and 29% for distant metastases (12,35). The long-term disease-specific survival (DSS) of surgical resected P-NENs is greater than 50% at 20 years (36).
As a kind of rare and special tumors, the treatment of both WD-pNETs and PD-pNECs depending on the symptoms, stage of disease, degree of uptake of radionuclide, and histological features of these tumors.
Surgery has been the focus of therapy and remains the primary and most important treatment for P-NENs, and is also the only possible curative procedure. And indications for surgery depend on clinical symptoms, tumor size and location, malignancy and metastatic spread (12,37-41). The first TNM staging system for P-NENs was proposed in the year 2006 by the European Neuroendocrine Tumor Society (ENETS) (23). Currently, two different staging systems proposed by the ENETS and AJCC (American Joint Committee on Cancer) are widely used in managing P-NENs (23,42), and tumors with superior mesenteric artery and/or celiac axis and/or common hepatic artery encasement as well as those with superior mesenteric vein occlusion are considered unresectable (41).
All resectable functional or non-functional P-NENs are recommended for surgery. The type of surgical procedure including pancreaticoduodenectomy, distal pancreatic resection, tumor enucleation and enucleation in combination with resection depending on the location of the tumor. As to whether this surgery is performed by the traditional open or laparoscopic route depending on the discretion of each designated specialist pancreatic surgery centre (38). Meanwhile lymph node dissection is recommended for malignant P-NENs, for example tumors with pancreatic membrane invasion or lymph node metastasis
Insulinomas comprise approximately 35–40% of functional P-NENs (13), and malignant insulinomas account for only about 5–10% of all insulinomas (43). Therefore, all resectable insulinomas should be removed surgically in spite of the tumor size, and 85–90% patients could be cured with surgery (44).
In the past decade, whether surgery should be applied in patients with localized small asymptomatic P-NETs is controversial. Recently, several studies have reported that nonfunctional P-NETs with diameter less than 2 cm were more likely to grow slowly over many years, with low malignancy, less or no node and liver metastasis, fewer vascular or peripancreatic invasion and satisfactory prognosis, so nonoperative management is enough (45-47). Meanwhile, there were also analyses indicated that those small tumors can display aggressive behavior, such as late metastases or recurrence, and resection was recommend to get better survival (48-53). And in 2017, a consensus statement published by the Chinese Study Group for Neuroendocrine Tumors (CSNET) except for some selected patients with NF-pNETs <1 cm, incidentally discovered and unacceptable surgical risks, all others with NF-pNETs ≤2 cm should undergo tumor resection and careful postoperative surveillance (54). Recently, by the 2018 NCCN guideline, observation can be considered for <1 cm, low-grade asymptomatic nonfunctional P-NETs base on the study by Sadot et al. in 2016 (55,56).
For the metastatic P-NENs, surgery should also be considered in both functioning and non-functioning tumors. It has been reported that primary tumor resection is associated with prolonged survival for all metastatic GEP-NENs, including P-NENs (57).
For GEP-NENs and P-NENs, liver was the most common site of distant metastases (11/14, 78.57%) (58). And when metastasis is limited to the liver, curative surgery should be applied if complete resection of both primary and metastases is available. Meanwhile, when 90% liver metastatic mass can be successfully removed, surgery should also be undertaken, with the purpose to control clinic symptom and to promote survival (12,38). However, surgical resection for liver-metastatic lesions should be avoided for non-functional liver-metastatic p-NENs with unresectable primary tumor (invading the celiac axis, the superior mesenteric artery, or adjacent organs, such as stomach, spleen, colon and adrenal gland) (59).
Depending on the slow-growing feature of these tumors, patients often survived for a long period despite having metastases. Therefore, for patients who are not suitable for surgery, somatostatin analogues, targeted therapy, radionuclides, ablation therapies, (chemo)embolisation and chemotherapy should be considered to improve and maintain a good quality of life. When possible, liver transplantation may be considered in some special patients with no extrahepatic metastases.
One special and important feature of GEP-NENs is the expression of somatostatin (SST) receptors. Totally, five SST receptors were expressed in these tumors and the order of expression has been assessed as follows: SST2, SST5, SST1, SST3, SST4 (60). The use of SST analogues to control clinical symptoms by inhibiting the secretion of tumor products has been more than thirty years (61,62). At the same time, the function of inhibiting tumor growth was also demonstrated (63,64).
Native SST an inhibitory hormone with a half-life of just 2–3 min, inhibits the release of hormones, including those causing carcinoid syndrome (65). However, the short half-life of native SST limited its use and led to the development of synthetic analogue of SST, including short-acting analogues (octreotide, lanreotide or vapreotide, long-acting analogues [octreotide long-acting release (LAR), and lanreotide autogel].
The short-acting analogues, such as octreotide with the half-life of approximately 1.5 h, need to be administered thrice daily by subcutaneous or intravenous injection. And the long-acting analogues, such as octreotide LAR, can be given once every four weeks (66,67).
In recent years, basic researches have demonstrated the antiproliferative activity of tumor cell in vitro (68,69). Meanwhile, several retrospective or prospective large clinic trials have also demonstrated the efficacy and safety of long-acting SST analogues in the treatment of well-differentiated GEP-NET, including well-differentiated PNETs (70-73). And based on minimal adverse effects of somatostatin analogs, combinations of somatostatin analogs with other biotherapies or molecular targeted therapies, and peptide receptor-targeted radionuclide therapy were introduced to get ideal efficacy (74,75). For example, 90Y-edotreotide was used to treat patients’ refractory to octreotide (76).
NENs exhibited the nature of highly vascular (77), and vascular endothelial growth factor (VEGF) is crucial to angiogenesis in pancreatic NETs (78,79), therefore angiogenesis inhibition has been considered as a treatment modality in this disease. Sunitinib which has been identified as a potent inhibitor of VEGFR-1 and VEGFR-2, is a novel oral multitargeted tyrosine kinase inhibitor with antiangiogenic and antitumor activities. Finally, the phase 1, 2 and 3 study all proved the antitumor activities of this drug in advanced P-NENs (80-83).
In 2007, Zitzmann et al. demonstrated the antiproliferative and apoptotic effects of RAD001 (everolimus) in NET cells in vitro (84). The following phase 2 and phase 3 studies subsequently confirmed the single-agent activity of the mammalian target of rapamycin (mTOR) inhibitor everolimus in patients with P-NET (85-87). By the final overall survival (OS) data of the RADIANT-3 phase 3 study, for those advanced, progressive, low or intermediate-grade pancreatic NET patients, everolimus showed a median OS of 44 months, the longest OS reported in a phase III study for this population (87).
More recently, with minimal adverse effects of new drags, combination of two or more agents have been applied to get better result for those advanced P-NETs, such as everolimus and octreotide LAR (88-92), everolimus and sunitinib (93), combination of bevacizumab, pertuzumab, and octreotide LAR (94), combination of fluorouracil, doxorubicin, and streptozocin (95,96).
Temozolomide an alkylating agent once used in metastatic melanoma and glioma, has been applied as monotherapy or combined with other agent in the treatment of advanced GEP-NENs for more than decade (97-99). More recently, the combination of Temozolomide and Capecitabine, a precursor of fluorouracil, has been proved effective in treat metastatic, well or moderately differentiated P-NENTs (100-103). And this CAPTEM regimen is well tolerated and relatively safe. In 2018, a meta-analysis including fifteen studies with 384 individuals reported that this regimen can get similar or slightly higher PFS (progression-free survival) compared with other regimens in treating NENs, with disease control rate of 72.89% (104). While, the reported overall response rates of single-agent temozolomide was 8% to 25% by retrospective studies (97,99).
The poorly differentiated GEP-NEC accounting about 35–55% of all NEC originating from the lung. This frequency might differ by organ in the tract, with only about 7% of the P-NENs have were NEC (105-107).
In recent years, most molecular discoveries and therapeutic advances have been based on studies of well differentiated low-grade NETs, but less is known about high-grade NEC (108). And, the treatment strategies for extrapulmonary NEC are often extrapolated from the treatment paradigm for small cell lung cancer (109,110).
For localized P-NECs, curative surgery is usually recommended (111). However, even for those with apparently localized disease surgery alone is rarely curative (112). Additional systemic chemotherapy has been reported to improve the survival of resected or unresectable advanced NECs (108). Etoposide and cisplatin (EP) regimen has always been considered the first line treatment for poorly differentiated NECs, since Moertel et al. reported the favorable response in treating GEP-NECs in 1991 (113).
However, the response-time of the EP regimen in treating NECs is short. So several other different chemotherapeutics have been explored in the past few years, such as IP regimen (cisplatin plus irinotecan) (114), FOLFIRI regimen (irinotecan, folinic acid and fluorouracil) (115), three-drug regimen of paclitaxel, carboplatin and etoposide (116,117).
More than one hundred years has passed since termed, and there is a general consensus that NENs are going mainstream (18). In recent years, more and more molecule mechanism about P-NENs have been discovered, and in 2017 whole-genome sequencing of 102 primary P-NENs was performed (118). With the addition of several new agents, survival improved over the time in recent years (2,8). All this made P-NENs great promise.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Modlin IM, Oberg K, Chung DC, et al. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008;9:61-72. [Crossref] [PubMed]
- 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;26:3063-72. [Crossref] [PubMed]
- 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;3:1335-42. [Crossref] [PubMed]
- Capelli P, Fassan M, Scarpa A. Pathology - grading and staging of GEP-NETs. Best Pract Res Clin Gastroenterol 2012;26:705-17. [Crossref] [PubMed]
- Gastrointestinal Pathology Study Group of Korean Society of Pathologists. Current Trends of the Incidence and Pathological Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) in Korea 2000-2009: Multicenter Study. Cancer Res Treat 2012;44:157-65. [Crossref] [PubMed]
- Tsai HJ, Wu CC, Tsai CR, et al. The epidemiology of neuroendocrine tumors in Taiwan: a nation-wide cancer registry-based study. PLoS One 2013;8:e62487. [Crossref] [PubMed]
- Scherübl H, Streller B, Stabenow R, et al. Clinically detected gastroenteropancreatic neuroendocrine tumors are on the rise: epidemiological changes in Germany. World J Gastroenterol 2013;19:9012-9. [Crossref] [PubMed]
- Halfdanarson TR, Rabe KG, Rubin J, et al. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Ann Oncol 2008;19:1727-33. [Crossref] [PubMed]
- Ito T, Igarashi H, Nakamura K, et al. Epidemiological trends of pancreatic and gastrointestinal neuroendocrine tumors in Japan: a nationwide survey analysis. J Gastroenterol 2015;50:58-64. [Crossref] [PubMed]
- Korse CM, Taal BG, van Velthuysen ML, et al. Incidence and survival of neuroendocrine tumours in the Netherlands according to histological grade: experience of two decades of cancer registry. Eur J Cancer 2013;49:1975-83. [Crossref] [PubMed]
- Uppin MS, Uppin SG, Sunil CS, et al. Clinicopathologic study of neuroendocrine tumors of gastroenteropancreatic tract: a single institutional experience. J Gastrointest Oncol 2017;8:139-47. [Crossref] [PubMed]
- Plöckinger U, Rindi G, Arnold R, et al. Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology 2004;80:394-424. [Crossref] [PubMed]
- Vortmeyer AO, Huang S, Lubensky I, et al. Non-islet origin of pancreatic islet cell tumors. J Clin Endocrinol Metab 2004;89:1934-8. [Crossref] [PubMed]
- Öberg K. Pancreatic endocrine tumors. Semin Oncol 2010;37:594-618. [Crossref] [PubMed]
- Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology 2008;135:1469-92. [Crossref] [PubMed]
- Kulke MH, Anthony LB, Bushnell DL, et al. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas 2010;39:735-52. [Crossref] [PubMed]
- Klöppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci 2004;1014:13-27. [Crossref] [PubMed]
- Kulke MH. Are neuroendocrine tumors going mainstream? J Clin Oncol 2013;31:404-5. [Crossref] [PubMed]
- Pape UF, Jann H, Muller-Nordhorn J, et al. Prognostic relevance of a novel TNM classification system for upper gastroenteropancreatic neuroendocrine tumors. Cancer 2008;113:256-65. [Crossref] [PubMed]
- Klöppel G, Rindi G, Perren A, et al. The ENETS and AJCC/UICC TNM classifications of the neuroendocrine tumors of the gastrointestinal tract and the pancreas: a statement. Virchows Arch 2010;456:595-7. [Crossref] [PubMed]
- Nilsson O, Van Cutsem E, Delle Fave G, et al. Poorly differentiated carcinomas of the foregut (gastric, duodenal and pancreatic). Neuroendocrinology 2006;84:212-5. [Crossref] [PubMed]
- Jensen RT, Niederle B, Mitry E, et al. Gastrinoma (duodenal and pancreatic). Neuroendocrinology 2006;84:173-82. [Crossref] [PubMed]
- Rindi G, Kloppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006;449:395-401. [Crossref] [PubMed]
- Rindi G, Kloppel G, Couvelard A, et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2007;451:757-62. [Crossref] [PubMed]
- Bosman FT, Carneiro F, Hruban RH, et al. WHO classification of tumours of the digestive system. International Agency for Research on Cancer, 2010:1089.
- Vélayoudom-Céphise FL, Duvillard P, Foucan L, et al. Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr Relat Cancer 2013;20:649-57. [Crossref] [PubMed]
- 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;39:683-90. [Crossref] [PubMed]
- 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;22:1011-7. [Crossref] [PubMed]
- Basturk O, Tang L, Hruban RH, et al. Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol 2014;38:437-47. [Crossref] [PubMed]
- 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;24:152-60. [Crossref] [PubMed]
- Heetfeld M, Chougnet CN, Olsen IH, et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer 2015;22:657-64. [Crossref] [PubMed]
- Lloyd RV, Osamura RY, Klöppel G, et al. WHO Classification of Tumours of Endocrine Organs. International Agency for Research on Cancer, 2017.
- Han X, Xu X, Ma H, et al. Clinical relevance of different WHO grade 3 pancreatic neuroendocrine neoplasms based on morphology. Endocr Connect 2018;7:355-63. [Crossref] [PubMed]
- Klöppel G. Neuroendocrine Neoplasms: Dichotomy, Origin and Classifications. Visc Med 2017;33:324-30. [Crossref] [PubMed]
- Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003;97:934-59. [Crossref] [PubMed]
- Chi W, Warner RR, Chan DL, et al. Long-term Outcomes of Gastroenteropancreatic Neuroendocrine Tumors. Pancreas 2018;47:321-5. [PubMed]
- Ramage JK, Davies AH, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut 2005;54 Suppl 4:iv1-16. [Crossref] [PubMed]
- Ramage JK, Ahmed A, Ardill J, et al. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). Gut 2012;61:6-32. [Crossref] [PubMed]
- Jensen RT, Cadiot G, Brandi ML, et al. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology 2012;95:98-119. [Crossref] [PubMed]
- Falconi M, Bartsch DK, Eriksson B, et al. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors. Neuroendocrinology 2012;95:120-34. [Crossref] [PubMed]
- 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;105:255-65. [Crossref] [PubMed]
- 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;35:274-80. [Crossref] [PubMed]
- de Herder WW, Niederle B, Scoazec JY, et al. Well-differentiated pancreatic tumor/carcinoma: insulinoma. Neuroendocrinology 2006;84:183-8. [Crossref] [PubMed]
- Turaga KK, Kvols LK. Recent progress in the understanding, diagnosis, and treatment of gastroenteropancreatic neuroendocrine tumors. CA Cancer J Clin 2011;61:113-32. [Crossref] [PubMed]
- Bettini R, Partelli S, Boninsegna L, et al. Tumor size correlates with malignancy in nonfunctioning pancreatic endocrine tumor. Surgery 2011;150:75-82. [Crossref] [PubMed]
- Lee LC, Grant CS, Salomao DR, et al. Small, nonfunctioning, asymptomatic pancreatic neuroendocrine tumors (PNETs): role for nonoperative management. Surgery 2012;152:965-74. [Crossref] [PubMed]
- Gaujoux S, Partelli S, Maire F, et al. Observational study of natural history of small sporadic nonfunctioning pancreatic neuroendocrine tumors. J Clin Endocrinol Metab 2013;98:4784-9. [Crossref] [PubMed]
- Haynes AB, Deshpande V, Ingkakul T, et al. Implications of incidentally discovered, nonfunctioning pancreatic endocrine tumors: short-term and long-term patient outcomes. Arch Surg 2011;146:534-8. [Crossref] [PubMed]
- Cherenfant J, Stocker SJ, Gage MK, et al. Predicting aggressive behavior in nonfunctioning pancreatic neuroendocrine tumors. Surgery 2013;154:785-91; discussion 791-3. [Crossref] [PubMed]
- Kuo EJ, Salem RR. Population-level analysis of pancreatic neuroendocrine tumors 2 cm or less in size. Ann Surg Oncol 2013;20:2815-21. [Crossref] [PubMed]
- Lombardi M, De Lio N, Funel N, et al. Prognostic factors for pancreatic neuroendocrine neoplasms (pNET) and the risk of small non-functioning pNET. J Endocrinol Invest 2015;38:605-13. [Crossref] [PubMed]
- Sallinen V, Haglund C, Seppanen H. Outcomes of resected nonfunctional pancreatic neuroendocrine tumors: Do size and symptoms matter? Surgery 2015;158:1556-63. [Crossref] [PubMed]
- Sharpe SM, In H, Winchester DJ, et al. Surgical resection provides an overall survival benefit for patients with small pancreatic neuroendocrine tumors. J Gastrointest Surg 2015;19:117-23; discussion 123. [Crossref] [PubMed]
- Yang G, Ji M, Chen J, et al. Surgery management for sporadic small (</=2 cm), non-functioning pancreatic neuroendocrine tumors: a consensus statement by the Chinese Study Group for Neuroendocrine Tumors (CSNET). Int J Oncol 2017;50:567-74. [Crossref] [PubMed]
- Sadot E, Reidy-Lagunes DL, Tang LH, et al. Observation versus Resection for Small Asymptomatic Pancreatic Neuroendocrine Tumors: A Matched Case-Control Study. Ann Surg Oncol 2016;23:1361-70. [Crossref] [PubMed]
- Shah MH, Goldner WS, Halfdanarson TR, et al. NCCN Guidelines Insights: Neuroendocrine and Adrenal Tumors, Version 2.2018. J Natl Compr Canc Netw 2018;16:693-702. [Crossref] [PubMed]
- Tierney JF, Chivukula SV, Wang X, et al. Resection of primary tumor may prolong survival in metastatic gastroenteropancreatic neuroendocrine tumors. Surgery 2019;165:644-51. [Crossref] [PubMed]
- Zhang X, Ma L, Bao H, et al. Clinical, pathological and prognostic characteristics of gastroenteropancreatic neuroendocrine neoplasms in China: a retrospective study. BMC Endocr Disord 2014;14:54. [Crossref] [PubMed]
- Jin K, Xu J, Chen J, et al. Surgical management for non-functional pancreatic neuroendocrine neoplasms with synchronous liver metastasis: A consensus from the Chinese Study Group for Neuroendocrine Tumors (CSNET). Int J Oncol 2016;49:1991-2000. [Crossref] [PubMed]
- Reubi JC, Hacki WH, Lamberts SW. Hormone-producing gastrointestinal tumors contain a high density of somatostatin receptors. J Clin Endocrinol Metab 1987;65:1127-34. [Crossref] [PubMed]
- Kvols LK, Moertel CG, O'Connell MJ, et al. Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue. N Engl J Med 1986;315:663-6. [Crossref] [PubMed]
- Wängberg B, Nilsson O, Theodorsson E, et al. The effect of a somatostatin analogue on the release of hormones from human midgut carcinoid tumour cells. Br J Cancer 1991;64:23-8. [Crossref] [PubMed]
- Saltz L, Trochanowski B, Buckley M, et al. Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors. Cancer 1993;72:244-8. [Crossref] [PubMed]
- Arnold R, Trautmann ME, Creutzfeldt W, et al. Somatostatin analogue octreotide and inhibition of tumour growth in metastatic endocrine gastroenteropancreatic tumours. Gut 1996;38:430-8. [Crossref] [PubMed]
- Garland J, Buscombe JR, Bouvier C, et al. Sandostatin LAR (long-acting octreotide acetate) for malignant carcinoid syndrome: a 3-year experience. Aliment Pharmacol Ther 2003;17:437-44. [Crossref] [PubMed]
- Harris AG. Octreotide in the treatment of disorders of the gastrointestinal tract. Drug Invest 1992;4:1-54. [Crossref]
- Grozinsky-Glasberg S, Grossman AB, Korbonits M. The role of somatostatin analogues in the treatment of neuroendocrine tumours. Mol Cell Endocrinol 2008;286:238-50. [Crossref] [PubMed]
- Theodoropoulou M, Zhang J, Laupheimer S, et al. Octreotide, a somatostatin analogue, mediates its antiproliferative action in pituitary tumor cells by altering phosphatidylinositol 3-kinase signaling and inducing Zac1 expression. Cancer Res 2006;66:1576-82. [Crossref] [PubMed]
- Florio T. Molecular mechanisms of the antiproliferative activity of somatostatin receptors (SSTRs) in neuroendocrine tumors. Front Biosci 2008;13:822-40. [Crossref] [PubMed]
- 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;27:4656-63. [Crossref] [PubMed]
- Anthony L, Vinik AI. Evaluating the characteristics and the management of patients with neuroendocrine tumors receiving octreotide LAR during a 6-year period. Pancreas 2011;40:987-94. [Crossref] [PubMed]
- Jann H, Denecke T, Koch M, et al. Impact of octreotide long-acting release on tumour growth control as a first-line treatment in neuroendocrine tumours of pancreatic origin. Neuroendocrinology 2013;98:137-43. [Crossref] [PubMed]
- Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014;371:224-33. [Crossref] [PubMed]
- Culler MD, Oberg K, Arnold R, et al. Somatostatin analogs for the treatment of neuroendocrine tumors. Cancer Metastasis Rev 2011;30 Suppl 1:9-17. [Crossref] [PubMed]
- Mazziotti G, Mosca A, Frara S, et al. Somatostatin analogs in the treatment of neuroendocrine tumors: current and emerging aspects. Expert Opin Pharmacother 2017;18:1679-89. [Crossref] [PubMed]
- Bushnell DL Jr, O'Dorisio TM, O'Dorisio MS, et al. 90Y-edotreotide for metastatic carcinoid refractory to octreotide. J Clin Oncol 2010;28:1652-9. [Crossref] [PubMed]
- Turner HE, Harris AL, Melmed S, et al. Angiogenesis in endocrine tumors. Endocr Rev 2003;24:600-32. [Crossref] [PubMed]
- Casanovas O, Hicklin DJ, Bergers G, et al. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005;8:299-309. [Crossref] [PubMed]
- Inoue M, Hager JH, Ferrara N, et al. VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell 2002;1:193-202. [Crossref] [PubMed]
- Faivre S, Delbaldo C, Vera K, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006;24:25-35. [Crossref] [PubMed]
- Kulke MH, Lenz HJ, Meropol NJ, et al. Activity of sunitinib in patients with advanced neuroendocrine tumors. J Clin Oncol 2008;26:3403-10. [Crossref] [PubMed]
- Strosberg JR, Weber JM, Choi J, et al. A phase II clinical trial of sunitinib following hepatic transarterial embolization for metastatic neuroendocrine tumors. Ann Oncol 2012;23:2335-41. [Crossref] [PubMed]
- Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011;364:501-13. [Crossref] [PubMed]
- Zitzmann K, De Toni EN, Brand S, et al. The novel mTOR inhibitor RAD001 (everolimus) induces antiproliferative effects in human pancreatic neuroendocrine tumor cells. Neuroendocrinology 2007;85:54-60. [Crossref] [PubMed]
- 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. [Crossref] [PubMed]
- Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011;364:514-23. [Crossref] [PubMed]
- 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;34:3906-13. [Crossref] [PubMed]
- 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;26:4311-8. [Crossref] [PubMed]
- Bajetta E, Catena L, Pusceddu S, et al. Everolimus in Combination with Octreotide Long-Acting Repeatable in a First-Line Setting for Patients with Neuroendocrine Tumors: A 5-Year Update. Neuroendocrinology 2018;106:307-11. [Crossref] [PubMed]
- 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;378:2005-12. [Crossref] [PubMed]
- 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;28:1569-75. [Crossref] [PubMed]
- Capdevila J, Teule A, Barriuso J, et al. Phase II Study of Everolimus and Octreotide LAR in Patients with Nonfunctioning Gastrointestinal Neuroendocrine Tumors: The GETNE1003_EVERLAR Study. Oncologist 2019;24:38-46. [Crossref] [PubMed]
- 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;79:139-46. [Crossref] [PubMed]
- Bendell JC, Zakari A, Lang E, et al. A Phase II Study of the Combination of Bevacizumab, Pertuzumab, and Octreotide LAR for Patients with Advanced Neuroendocrine Cancers. Cancer Invest 2016;34:213-9. [Crossref] [PubMed]
- Prakash L, Bhosale P, Cloyd J, et al. Role of Fluorouracil, Doxorubicin, and Streptozocin Therapy in the Preoperative Treatment of Localized Pancreatic Neuroendocrine Tumors. J Gastrointest Surg 2017;21:155-63. [Crossref] [PubMed]
- Cloyd JM, Omichi K, Mizuno T, et al. Preoperative Fluorouracil, Doxorubicin, and Streptozocin for the Treatment of Pancreatic Neuroendocrine Liver Metastases. Ann Surg Oncol 2018;25:1709-15. [Crossref] [PubMed]
- Ekeblad S, Sundin A, Janson ET, et al. Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors. Clin Cancer Res 2007;13:2986-91. [Crossref] [PubMed]
- 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;24:401-6. [Crossref] [PubMed]
- Maire F, Hammel P, Faivre S, et al. Temozolomide: a safe and effective treatment for malignant digestive endocrine tumors. Neuroendocrinology 2009;90:67-72. [Crossref] [PubMed]
- Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer 2011;117:268-75. [Crossref] [PubMed]
- Fine RL, Gulati AP, Krantz BA, et al. Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience. Cancer Chemother Pharmacol 2013;71:663-70. [Crossref] [PubMed]
- Peixoto RD, Noonan KL, Pavlovich P, et al. Outcomes of patients treated with capecitabine and temozolamide for advanced pancreatic neuroendocrine tumors (PNETs) and non-PNETs. J Gastrointest Oncol 2014;5:247-52. [PubMed]
- Crespo G, Jimenez-Fonseca P, Custodio A, et al. Capecitabine and temozolomide in grade 1/2 neuroendocrine tumors: a Spanish multicenter experience. Future Oncol 2017;13:615-24. [Crossref] [PubMed]
- Lu Y, Zhao Z, Wang J, et al. Safety and efficacy of combining capecitabine and temozolomide (CAPTEM) to treat advanced neuroendocrine neoplasms: A meta-analysis. Medicine (Baltimore) 2018;97:e12784. [Crossref] [PubMed]
- 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;104:764-77. [Crossref] [PubMed]
- Ikeda M, Okuyama H, Takahashi H, et al. Chemotherapy for advanced poorly differentiated pancreatic neuroendocrine carcinoma. J Hepatobiliary Pancreat Sci 2015;22:623-7. [Crossref] [PubMed]
- Ito T, Sasano H, Tanaka M, et al. Epidemiological study of gastroenteropancreatic neuroendocrine tumors in Japan. J Gastroenterol 2010;45:234-43. [Crossref] [PubMed]
- Sorbye H, Strosberg J, Baudin E, et al. Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer 2014;120:2814-23. [Crossref] [PubMed]
- Walenkamp AM, Sonke GS, Sleijfer DT. Clinical and therapeutic aspects of extrapulmonary small cell carcinoma. Cancer Treat Rev 2009;35:228-36. [Crossref] [PubMed]
- Brennan SM, Gregory DL, Stillie A, et al. Should extrapulmonary small cell cancer be managed like small cell lung cancer? Cancer 2010;116:888-95. [Crossref] [PubMed]
- Garcia-Carbonero R, Sorbye H, Baudin E, et al. ENETS Consensus Guidelines for High-Grade Gastroenteropancreatic Neuroendocrine Tumors and Neuroendocrine Carcinomas. Neuroendocrinology 2016;103:186-94. [Crossref] [PubMed]
- Brenner B, Tang LH, Klimstra DS, et al. Small-cell carcinomas of the gastrointestinal tract: a review. J Clin Oncol 2004;22:2730-9. [Crossref] [PubMed]
- Moertel CG, Kvols LK, O'Connell MJ, et al. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 1991;68:227-32. [Crossref] [PubMed]
- Lu ZH, Li J, Lu M, et al. Feasibility and efficacy of combined cisplatin plus irinotecan chemotherapy for gastroenteropancreatic neuroendocrine carcinomas. Med Oncol 2013;30:664. [Crossref] [PubMed]
- Hentic O, Hammel P, Couvelard A, 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;19:751-7. [Crossref] [PubMed]
- Hainsworth JD, Spigel DR, Litchy S, et al. Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: a Minnie Pearl Cancer Research Network Study. J Clin Oncol 2006;24:3548-54. [Crossref] [PubMed]
- Gupta A, Duque M, Saif MW. Treatment of poorly differentiated neuroendocrine carcinoma of the pancreas. JOP 2013;14:381-3. [PubMed]
- Scarpa A, Chang DK, Nones K, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 2017;543:65-71. [Crossref] [PubMed]