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Pancreatic neuroendocrine tumors are a group of endocrine tumors that constitute 7% of all pancreatic neoplasms. They can be benign or malignant. Their presentation can vary from slow growing, non infiltrative, indolent masses to rapidly progressing, highly aggressive, metastasizing tumors. In the past, there was paucity of scientific data available about the diagnosis and treatment strategy of these neoplasms but in recent years, ongoing research has inferred much data regarding classification, prognostic stratification and therapy of pancreatic neuroendocrine tumors. In this chapter we will discuss epidemiology, clinical presentation and classification, diagnosis and management of these tumors. We will also deliberate about the latest developments in treatment of pancreatic neuroendocrine tumors with focus on recent studies done on this topic.
Department of Radiation Oncology, Lady Hardinge Medical College and Associated SSK and KSC Hospital, India
Deepti Sharma
Department of Radiation Oncology, Institute of Liver and Biliary Science, India
*Address all correspondence to: mailnehash@gmail.com
1. Introduction
Neuro-endocrine tumors constitute 0.5% of all malignancies [1]. Gastro-entero-pancreatic neuro-endocrine tumors (GEP-NET) originate from neuro-endocrine cells of the embryological gut and they constitute a group of heterogeneous tumors that demonstrate divergent tumor biology, different diagnostic behavior, management principles and tumor-patient outcomes [2].
GEP-NET comprises 2% of all gastrointestinal tumors [3]. Pancreatic neuroendocrine tumors (PNETs) are one of the most common neuroendocrine tumors [4]. But they are relatively rare tumors and comprise about 7% of all cancers that occur in the pancreas [5]. According to The American Cancer Society’s estimates for 2020, about 4,032 people in the United States will be diagnosed with pancreatic NET.8
With better imaging modalities coming into play, the incidence of pancreatic NETs is increasing over the years as they are often found incidentally when radiological tests such as CT or MRI scans are done for other diseases. There has also been increased sensitivity of lab tests that have escalated the ability to distinguish these tumors from other malignancies. The increased prevalence over the past few decades, is attributed to multifactorial causes mainly as a consequence of increased awareness and improved diagnostic technique [6]. It is estimated that nowadays almost 50% of PNET diagnoses are incidentalomas [7]. An aging population and heightened awareness of the disease have also contributed to an increase in the detection of incidentalomas [8].
Majority of pNET are sporadic, i.e. non inherited while 10–30% pNET are associated with a genetic syndrome like multiple endocrine neoplasia (MEN) type 1, which is most commonly associated with it [9]. Other rare genetic conditions include MEN4, Von Hippel–Lindau disease, neurofibromatosis 1 (von Recklinghausen’s syndrome), and tuberous sclerosis, which are linked to genetic type pNET [10].
There is no gender predilection for pNET although some studies have suggested a slight preponderance for men. These tumors can present at any age but the incidence of sporadic tumors rises from fifth decade and peaks around 80s [11].
In the past NETs were classified based upon the site of origin in embryological gut as foregut, midgut and hindgut tumors. It has been rather challenging to classify these tumors due to their heterogeneity, difference in their morphology, clinical presentation, molecular biology, hormone profile and treatment response.
Clinically these tumors have been classified as functioning and non functioning tumors. In 2007 WHO introduced a new classification system for neuroendocrine tumors which categorized them according to tumor’s proliferation indices like mitotic index or Ki67 score as well differentiated tumors and poorly differentiated carcinomas [12]. In 2010 it also included histopathological features as a criteria for classification apart from proliferation indices, which lead to revision of the existing guidelines and NETs were further divided into three grades based upon ENETS classification (Table 1) [14]. Well differentiated tumors comprised of grade 1 and grade 2 NET, while poorly differentiated tumors were grade 3 NET also described as neuroendocrine carcinoma (NEC). The difference between the two has been illustrated in Table 2 [14].
The difference between NET Grade3 and NEC grade3 [15].
In 2017, the classification was re-revised to include NET grade1, 2 and 3 in the well differentiated category and the poorly differentiated category was NEC grade 3. See Table 3 [15].
European neuroendocrine society has also devised a staging for GEP-NET. American cancer society has included tumor resectability as classification criteria (Figure 1) [17].
Figure 1.
Comparison of TNM classification of pancreatic NENs according to ENETS versus UICC/AJCC (TNM classification) [16].
Mixed adenoneuroendocrine carcinoma (MANEC) of pancreas are a group of extremely rare tumors, with incidence approximately 0.2% and only a few cases are reported in literature [18]. They have both adenocarcinoma and neuroendocrine components with each component accounting for more than 30% of the tumor [19]. Due to rarity of this, tumor the clinical behavior is not studied much. It has been proposed that the treatment should depend on the aggressiveness of the cell type of the tumor [20]. In various cases studied, surgery has been considered as the first line of treatment for resectable tumors. Post operative treatment includes adjuvant chemotherapy and/or radiotherapy [21].
As such pNETs were classically thought to arise from pancreatic islet cells or the islets of Langerhans, hence the term islet cell tumors was coined [22]. Islet cells are the endocrine cells of the pancreas and they constitute 1–2% of total pancreatic mass. They are therefore distinct from the exocrine cells, from which pancreatic ductal adenocarcinomas arise. They are composed of various cell types and responsible for secretion of hormones like beta cells (insulin), alpha cells (glucagon), delta cells (somatostatin), and PP cells (pancreatic polypeptide) [23]. However, current theory says that pNETs in fact arise from the APUD (amine precursor uptake and decarboxylation) cells [24]. The presence of neurosecretory granules is the characteristic feature of APUD cells and these neurosecretory granules have autocrine, paracrine and neuromodulatory functions, in addition to the endocrine property. These cells are thought to originate in the embryologic neural crest, but more recent research suggests that they originate in the embryologic endoderm [25].
The most common genes involved in pancreatic neuroendocrine tumors are mentioned in Table 4.
Gene
Prevalence in PNET
Prevalence in PDAC
MEN1
44%
0%
ATRX/DAXX
43%
0%
mTOR
15%
0.8%
TP53
3%
85%
KRAS
0%
100%
CDKN2A
0%
25%
TGFBR1/SMAD3/SMAD4
0%
38%
Table 4.
Common genes in pancreatic neuroendocrine tumors vs. pancreatic adenocarcinoma [26, 27].
Other specific genes suggested to be implicated in the etiopathogenesis of NETs include BIN1, Serpine 10, BST2, IGFBP3, LCK, MET, fibronectin, PDGF, IGF- 1, fibroblast growth factor, TGF-alpha and–beta, EGFR, and stem cell factor receptor [27].
Multiple studies have elucidated the underlying genetic mechanism regarding molecular development and progression of these tumors but still much remains unexplored in this area. Loss of chromosomes 3q, 6pq, and 10 pq, and gains of 5q, 12a, 18q, and 20q is associated with malignant behavior in these tumors [28]. In tumors less than 2 cm in size, it has been observed that Chromosome 1 and 11q loss with gain of 9q is associated with genetic instability [29].
4.2 Olecular pathology of PNET and its role in prognosis
Most recent advancements in assessment of pancreatic NET is the development of microRNA profiling which corresponds to various proliferation indices and also propensity of tumor to cause local spread and distant metastasis [30]. MicroRNA are non-coding RNA sequences having length of 21–25 nucleotides. They regulate genes at post translational level [31]. They can act as oncogenes or tumor suppressor genes and play a significant role in proliferation of tumors or their dissemination [32]. They can act as diagnostic as well as a prognostic marker.
There is very limited data available regarding microRNA profiling of pNET. In one large study done on pancreatic NET, 28 different miRs have been shown to be differentially expressed with 18 of them being higher expressed and 10 lower expressed as compared to healthy pancreatic tissue [33]. There is a higher expression of miR-103, miR-107 and miR-193b and lower expression of let-7 miR and miR-155 in pancreatic neuroendocrine neoplasias [34]. Tumor proliferation is denoted by expression levels of miR-196a, miR-21 and miR-642 while miR-210 and miR-21 seem to correlate with metastatic disease and tumor recurrence is predicted by expression of both miR-196a and miR-27b [35, 36].
Circulating tumor cell count also plays an important role in delineating the prognostic value of pNETs, especially before and during the treatment. Liquid biopsy is emerging as a newer and more profound biomarker test which provides valid cytochemical, morphological, pathological and molecular information regarding response of anti tumor therapy for pNET [37]. Circulating tumor cells (CTC) are shed from the primary or metastatic component of the tumor and they are evaluated by liquid biopsy [38]. CTC are considered as prognosticators in many solid malignancies but their role in neuroendocrine tumors was highlighted first by Khan et al. in 2011 [39] patients with advanced NETs who were starting either systemic or local therapy were enrolled. It was found that patients with one or more circulating tumor cells (CTC) were more likely to have worse progression free and overall survival.
Further placental growth factor (PIGF) is also evaluated as a prospective biomarker in NET. pIGF is a derivative of VEGF, which shows increased expression in NETs. It was found that PlGF levels were elevated in pNET samples and serum as compared to control pancreatic tissue and control serum. It was concluded that elevated PIGF levels are seen in pNET and it has also been projected that increase PIGF levels correlate with shorter time to progression [40].
Since non functional pNET represent up to 90% of PanNETs, they present with high hormone levels without symptoms. However, upto 60% of these patients have a metastatic disease at diagnosis, while 21% present with a locally advanced disease [41].
Non specific symptoms of pNET include abdominal pain, weight loss, or mass effect related to the pancreatic tumor or to the distant spread. Less frequently it is associated with complaints of jaundice, hemorrhage from tumors, and a palpable mass. Symptoms often do not appear until metastases develop [42].
Usually endocrine tumors of the pancreas present with typical symptoms due to hormonal hypersecretion, such as insulinoma, gastrinoma, VIP-oma, glucagonoma and somatostatinoma. In upto 40%-50, cases may present as non-functioning tumors or secrete pancreatic polypeptide (PP) and neurotensin [43]. The various pancreatic NET subtypes with their incidence, clinical presentation and survival are mentioned below (Table 5).
Chromogranin A is a secretory glycoprotein present in neurosecretory granules of pancreatic NET. Majority of pNET show elevated chromogranin A levels. The sensitivity depends upon the tumor burden and the levels of chromogranin A are directly correlated with the prognosis of the patient. In insulinomas elevated chromogranin A levels are rare. Other serologic markers include neuronal serum enolase, human chorionic gonadotropin, and pancreatic polypeptide, which are elevated in 20–40% of PNETs. (See Table 6) [52].
Syndrome
Test
Result
Gastrinoma
Fasting gastrin Gastrin secretion studies
Raised basal serum gastrin, High gastric acid secretion
Insulinoma
Fasting Insulin, Glucose, C peptide (sulfonyl urea screen negative)
Raised fasting insulin/glucose ratio, proinsulin or c peptide
Glucagonoma
Fasting gut hormones, ski biopsy
Raised serum pancreatic glucagons and enteroglucagon
When any NET is suspected then fasting gut hormones such as chromogranin B, pancreatic polypeptide and urinary 5HIAA (a breakdown product of serotonin) are also useful baseline tests. False positive chromogranin A levels are caused due to treatment with a proton pump inhibitor, Parkinson’s disease, hypertension, glucocorticoids, renal failure and atrophic gastritis, while various dietary factors and drugs can cause an elevated urinary 5HIAA [53].
Additional blood tests for secreted peptides can be useful if a clinical syndrome is suspected and calcium, prolactin and parathyroid hormones should be tested in possible MEN1 cases. For Nonfunctioning pNETs, pancreatic polypeptide is a useful test. For insulinomas the gold standard diagnostic tool is supervised fasting with serial blood glucose analysis. Diagnosis requires the fulfillment of Whipple’s triad of hypoglycemia, symptoms and correction of symptoms with glucose, in the presence of non-suppressed insulin levels. Factitious hypoglycemia due to administration of insulin or sulfonylureas must be ruled out [54].
6.2 Radiological
Cross sectional imaging plays an important role in the workup of PNETs by characterizing the primary tumor and determining the extent of disease. Location of the tumor and its spread can be delineated by the use of multimodality imaging which includes computed tomography (CT), MRI and various nuclear medicine scans. Endoscopic ultrasound (EUS), digital subtraction angiography and venous sampling can also be used [55]. The sensitivity of CT and MRI is more than 80% for the detection of PNETs which is more sensitive than an octreotide-based scintigraphic scans [56].
EUS acts as an indispensable accompaniment to CT or MRI and has superior resolution. For tumors with size as small as 2 mm, EUS shows sensitivity of more than 90% and when combined with cross sectional imaging the sensitivity reaches upto 100%. Addition of EUS is recommended when cross-sectional imaging fails to define the pancreatic mass, when the location of primary cannot be delineated or biopsy is needed to confirm the diagnosis before commencing the treatment [57].
Since NETs have high levels of somatostatin receptor 2 (SSTR2) expression, Functional imaging comes into play in these tumors. For tumors lacking SSTR2, like insulinomas and poorly differentiated tumors, it is less useful [58]. It is used to detect primary tumors or metastatic disease which is not readily seen on cross-sectional imaging. Also, the uptake can predict response to octreotide analogs [59].
Indium-111 (111In) pentetreotide scan (Octreoscan) is a readily available nuclear scan that is effective at identifying nonfunctional PNETs, glucagonomas, and gastrinomas [60]. Although High-resolution positron emission tomography (PET) in combination with CT is superior in detecting small tumors and identifying occult metastases as compared to 111In pentetreotide. For identifying well-differentiated NETs, Octreoscan appears more sensitive than (18) FDG-PET, whereas (18) FDG-PET demonstrates superior sensitivity for poorly-differentiated NETs [61].
Somatostatin receptors are overexpressed in a proportion of NETs and Somatostatin receptor scintigraphy (SSRS) is useful in detecting these tumors. There are five subtypes of SSTR and 80% of pNETs, excluding insulinomas, express SSTR-2. Less than half of insulinomas express SSRT-2, therefore Single-photon emission computed tomography (SPECT) has sensitivity of 50% when combined with SSRS. In gastrinomas, VIPomas, glucagonomas and nonfunctional tumors SSRS combined with SPECT has a diagnostic sensitivity of 75% [20].
Currently both 18F-FDG PET/CT and 68Gallium (Ga)-labeled somatostatin analog PET/CTs such as 68Ga-DOTATOC or 68Ga-DOTATATE PET/CTs are used. FDGPET use is limited to poorly differentiated NETs, as well differentiated NETs are not FDG avid. It may also be used to demonstrate aggressive behavior or heterogeneity between lesions in a single patient. 68Ga-labeled somatostatin analog PETs have been shown to be superior to CT or SSRS in sensitivity and specificity, for detecting an unknown primary, staging at diagnosis, and for follow-up [62].
6.3 Histopathology
They can be classified as well differentiated and poorly differentiated NET. the major differences are elaborated further (Table 7).
Acinar cell carcinoma: It can be differentiated from pNET as it has granular PAS positive cytoplasm, BCL10, trypsin, chymotrypsin positive, Synaptophysin and chromogranin positivity <25% while pNET is PAS negative, BCL10, trypsin, chymotrypsin negative and Synaptophysin or chromogranin positivity over 25% [65].
Solid-pseudopapillary neoplasm: It has pseudopapillary architecture, Chromogranin focal to negative, Galectin 3,Vimentin, CD10, Nuclear beta catenin positive while pNET has no pseudopapillary architecture, Chromogranin strongly positive, Galectin 3,Vimentin, CD10, Nuclear beta catenin negative [65].
Pancreatoblastoma: It shows Trypsin, chymotrypsin positive, Chromogranin, synaptophysin scattered positive, Islet polypeptide markers negative or very focal while Trypsin, chymotrypsin negative, Chromogranin or synaptophysin widespread staining, Islet polypeptide markers frequently positive in pNET [65]
Insulinoma [27]: the differential diagnosis includes conditions with increased insulin levels in blood
Persistent hyperinsulinemic hypoglycemia of infancy (PHHI)
Multidisciplinary teams (MDTs) have an important role in deciding the treatment of these tumors as they are slightly rare.
Treatment options range from curative surgery to palliation with medical therapies including somatostatin analogs, chemotherapy and targeted treatments [67].
Conservative management is indicated for incidentalomas, i.e. the tumors which are small, non functional and asymptomatic [68]. Although it is a controversy whether small nonfunctional tumors of under 2 cm should be resected, when they are likely to have less metastatic potential, but a more aggressive surgical approach is recommended for tumors over 2 cm [69].
8.1 Surgery
Surgery is the only curative treatment option and should be considered in all patients with localized disease as it not only cures the mass related symptoms but also the hormone related effects. Such patients should have their surgery carried out at specialist hepatopancreatobiliary centers. Surgery can be done for curative treatment like radical excision or palliative treatment that aims for symptomatic relief. It can also be used for surgical treatment of complications. The 5-year overall survival rate of resected PNETs is significantly greater than unresected ones, ranging from 77% to 46% [70]. Unfortunately, pancreatic surgery shows significant mortality, ranging from 1% to 10% [71] and morbidity. The perioperative and long-term complications include diabetes, pancreatic exocrine impairment in up to 50–60% patients, even in high volume centers [72, 73].
Careful observation and wait and watch policy can be employed for small non functioning pNET which helps in not only avoiding the pancreatic surgery but also helps curb the operation related complications, as most of the small NF-PanNETs are indolent despite a chance of 10% of nodal involvement [74, 75].
According to the updated ENET guidelines patients having NF-PanNETs ≤2 cm can be safely managed conservatively.
Indications of non operative approach:
the presence of G1-low G2 tumor
Tumor localized to pancreatic head
no signs of malignancy at imaging.
In patients with G2 NF-PanNETs greater than or equal to 2 cm, surgery should be recommended. Other factors to be taken into consideration include patient’s age, comorbidities, surgical risk, the tumor site, and desire for surgical intervention.
In cases of surveillance, EUS and MRI should be mandatory and to be repeated every 6 months (12 months if no changes are discovered). If an increase of 0.5 cm (or more) in the size of the lesion is seen on the imaging then the patient should be reevaluated for surgery [9].
The studies comparing observation with surgery in pNET are as follows:(Table 8).
Tumor size has great impact on malignancy. he cutoff of 2 cm of malignancy used for small NF-PNETs could be decreased to 1.7 cm to select patients more accurately.
Resection of nonfunctioning PNETs over 1.5 cm is independently and significantly associated with a longer survival
Table 8.
Studies comparing observation versus surgery in small pNET.
In contrast to the ENETS guidelines, the American National Comprehensive Cancer Network (NCCN) guidelines recommend surgery to be done in a pNET bigger than 1 cm. Observation is indicated incidentally discovered, low-grade NF-PanNETs smaller than 1 cm. Additional factors for conservative management include the surgical risk, the tumor site, and the patient comorbidities, especially when dealing with small asymptomatic tumor [80]. NCCN states that more aggressive approach (routine surgery) is recommended in tumors greater than 1 cm as some small (<2 cm) high-grade tumors demonstrate frankly malignant behavior (9% to 39%) [81].
8.2 Systemic therapy
In patients with resectable PanNETs, surgery with curative intent (that is, R0 or margins that are microscopically free of tumor) remains the treatment of choice. Unfortunately, as the majority of patients with PanNETs either present with metastatic disease or have disease recurrence within 2 years of surgery, effective systemic therapies are also needed [82].
8.3 Somatostatin analogs
Somatostatin analogs remain the cornerstone in treatment of advanced neuroendocrine tumors.
Long acting octrotide, lanreotide which bind both SSTR2 and SSTR5 and pasireotide which binds to SSTR1, 3, and 5 are currently approved for clinical use [83].
Trials studying the role of somatostatin analogues (Table 9).
204 patients with advanced, G1/G2 differentiated, nonfunctioning, somatostatin receptor–positive NETs
Lanreotide(n = 101) vs. placebo(n = 103)
Better PFS with lanreotide Median PFS lanreotide(32.8 month) vs. placebo(18 month)
Table 9.
Studies showing role of somatostatin analogues in pNET.
The use of pasireotide, a somatostatin analog was evaluated in a phase III randomized trial targeting SSTR5, in octreotide-resistant patients. It demonstrated no difference in the response rate (RR) compared with long-acting octreotide. The trial was stopped prematurely [86].
Chan et al., studied 1022 patients in 18 trials using more than 30 mg octreotide or 120 mg lanreotide over 28 days in a meta-analysis in 2017 [87]. Pasireotide has shown a more potent antiproliferative effect as compared to octreotide in preclinical data from NCI-H727 cells and from pancreatic NET primary cell cultures [88].
A similar study conducted by Cives et al. recently showed that pasireotide LAR provides better tumor control efficacy (PFS 11 months), when used as first-line therapy in patients with advanced NET [89]. Further, in patients with functionally active advanced GEP-NETs, pasireotide provided an improved tumor control rate at 6 months compared to octreotide [50]. In 160 patients with progressive grade 1 through 2 pancreatic NETs, the COOPERATE-2 trial tested the combination of everolimus and pasireotide vs. everolimus. It was seen that both overall and progression-free survival were similar in both arms (16.8 months vs. 16.6 months), although response rates were higher in the experimental arm [90].
8.4 Targeted therapy
Molecular targeted therapies have emerged as a promising treatment modality for patients with well-differentiated PNETs in which disease progression is seen on a somatostatin analog or who are on best supportive care. Randomized studies have shown an improvement in PFS but not OS. Currently, sunitinib and everolimus are approved for use in PNETs (Table 10).
Median PFS was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group. objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group
Studies showing the role of targeted therapy in treatment of pNET.
8.5 Cytotoxic chemotherapies
Much of the focus on treatment over the past half century has been on the use of conventional cytotoxic agents such as streptozocin [99] and temozolomide [100]. Sunitinib and everolimus are approved for use in PNETs (Table 11).
Median PFS 23.7 months OS rate at 24 months was 88%.
Table 11.
Studies showing role of cytotoxic chemotherapy in pNET.
8.6 Peptide receptor radionuclide therapy (PRRT)
Majority of neuroendocrine tumors show increased level expression of somatostatin receptors (SSRs) 2 and 5 on the tumor cell surface and it forms the basis of not only functional imaging but also tumor directed therapies like somatostatin analogues [111]. Beyond somatostatin analogues, PRRT, which is described as peptide receptor radioligand therapy or targeted radiotherapy using radiolabeled somatostatin analogs is emerging as an effective treatment modality in metastatic, well-differentiated, grade 1 and 2 GEP-NET [112]. Yttrium, a high-energy β particle emitter and Lutetium, a β and γ particle emitter with lower tissue penetration are most commonly studied radioligands [113] (Table 12).
Various retrospective studies have been conducted on PRRT.
131I-metaiodobenzylguanidine (131I-MIBG) therapy has shown promise in in MIBG positive metastatic neuroendocrine tumors, in addition to radiolabeled somatostatin analogs [121].
The toxicities associated with PRRT include myelosuppression and nephrotoxicity, both of which are reversible, acute pain due to radiation edema and nausea and vomiting, associated with the use of amino acids to reduce the risk of nephrotoxicity and very rarely myelodysplastic syndrome.
Depends upon Metastatic spread, large tumor size, and hormonal hypersecretion as well as gender, age, and histopathological high-grade, Ki67 (Table 13).
SEER Stage
5-year Relative Survival Rate
Localized
93%
Regional
77%
Distant
27%
All SEER stages combined
54%
Table 13.
5-year relative survival rates for pancreatic NET [8].
Pancreatic neuroendocrine tumors are a distinct group of tumors from other pancreatic malignancies. They present with vastly different spectrum of clinical features ranging from asymptomatic incidentalomas to symptoms related to hormone hypersecretion or due to mass effect. Due to rarity of these tumors and as the biological potential of these tumors remain unexplored, the management is largely consensus based and is still under a lot of research. Although surgery is the main modality of treatment but conservative management is also indicated in small non functioning tumors. Advanced pNET can be treated with chemotherapy or targeted agents. In this context, prospective studies with the creation of a large multi-center trials and an international registry are future recommendations.
Conflict of interest
The authors declare no conflict of interest.
Thanks
A special thanks to Dr. Vivek Sharma for his invaluable contribution.
References
1.Taal BG, Visser O. Epidemiology of neuroendocrine tumours Vol. 80, Suppl. 1, 2004. Neuroendocrinology 2004;80:104–. doi:10.1159/000081547
2.Massironi S, Sciola V, Peracchi M, Ciafardini C, Spampatti MP, Conte D. Neuroendocrine tumors of the gastro-entero-pancreatic system. World Journal of Gastroenterology 2008;14:5377. doi:10.3748/wjg.14.5377
3.Warner RR. Enteroendocrine Tumors Other Than Carcinoid: A Review of Clinically Significant Advances. Gastroenterology 2005;128:1668-84. doi:10.1053/j.gastro.2005.03.078
4.Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One Hundred Years After “Carcinoid”: Epidemiology of and Prognostic Factors for Neuroendocrine Tumors in 35,825 Cases in the United States. Journal of Clinical Oncology 2008;26:3063-72. doi:10.1200/jco.2007.15.4377
5.B. Lawrence, B. I. Gustafsson, A. Chan, B. Svejda, M. Kidd, and I. M. Modlin, “The epidemiology of gastroenteropancreatic neuroendocrine tumors,” Endocrinology and Metabolism Clinics of North America, vol. 40, no. 1, pp. 1-18, 2011
6.Ehehalt F, Saeger HD, Schmidt CM, Grützmann R. Neuroendocrine Tumors of the Pancreas. The Oncologist 2009;14:456-67. doi:10.1634/theoncologist.2008-0259
7.Watley DC, Ly QP, Talmon G, Are C, Sasson AR. Clinical presentation and outcome of non-functional pancreatic neuroendocrine tumors in a modern cohort. Am J Surg. 2015;210(6):1192-6
8.Key Statistics for Pancreatic Neuroendocrine Tumor. American Cancer Society. https://www.cancer.org/cancer/pancreatic-neuroendocrine-tumor/about/key-statistics.html
9.Wilde RFD, Edil BH, Hruban RH, Maitra A. Well-differentiated pancreatic neuroendocrine tumors: from genetics to therapy. Nature Reviews Gastroenterology & Hepatology 2012;9:199-208. doi:10.1038/nrgastro.2012.9
10.Falconi M, Eriksson B, Kaltsas G, Bartsch D, Capdevila J, Caplin M, et al. ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors. Neuroendocrinology 2016;103:153-71. doi:10.1159/000443171
11.Halfdanarson T, Rabe K, Rubin J, Petersen G. Pancreatic neuroendocrine tumors (PNETs): incidence, prognosis and recent trend toward improved survival. Annals of Oncology 2008;19:1727-33. doi:10.1093/annonc/mdn351
12.Rindi G Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler MW, 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
13.Ueda Y, Toyama H, Fukumoto T, Ku Y. Prognosis of Patients with Neuroendocrine Neoplasms of the Pancreas According to the World Health Organization 2017 Classification. JOP Journal of the Pancreas 2017. https://pancreas.imedpub.com/prognosis-of-patients-with-neuroendocrine-neoplasms-of-the-pancreas-according-to-the-world-health-organization-2017-classification.php?aid=21167#11
14.Cavalcanti MS, Gönen M, Klimstra DS. The ENETS/WHO grading system for neuroendocrine neoplasms of the gastroenteropancreatic system: a review of the current state, limitations and proposals for modifications. Int J Endocr Oncol. 2016;3(3):203-219. doi:10.2217/ije-2016-000
15.Lloyd RV, Osamura RY, Klöppel G, Rosai J. WHO Classification of Tumours of Endocrine Organs 4th ed. Lyon: IARC, 201
16.Klöppel G, Rindi G, Perren A, Komminoth P, Klimstra DS. The ENETS and AJCC/UICC TNM classifications of the neuroendocrine tumors of the gastrointestinal tract and the pancreas: a statement. Virchows Archiv 2010;456:595-7. doi:10.1007/s00428-010-0924-6
17.Seydafkan S, Coppola D. Neuroendocrine Tumor Classification Systems: Staging. Neuroendocrine Tumors: Review of Pathology, Molecular and Therapeutic Advances 2016:21-30. doi:10.1007/978-1-4939-3426-3_2
18.Cubilla AL, Fitzgerald PJ. Cancer of the exocrine pancreas: the pathologic aspects. CA Cancer J Clin. 1985;35:2-18. doi: 10.3322/canjclin.35.1.2
19.Shimada N, Miwa S, Arai T, Kitagawa N, Akita S, Iinuma N, et al. Cystic mixed adenoneuroendocrine carcinoma of the pancreas: A case report. International Journal of Surgery Case Reports. 2018;52:1-4
20.Lee HH, Jung CK, Jung ES, Song KY, Jeon HM, Park CH. Mixed Exocrine and Endocrine Carcinoma in the Stomach: A Case Report. Journal of Gastric Cancer. 2011;11(2):122
21.Imaoka K, Fukuda S, Tazawa H, Kuga Y, Mochizuki T, Hirata Y, et al. A mixed adenoneuroendocrine carcinoma of the pancreas: a case report. Surgical Case Reports. 2016;2(1)
22.Asa S. Pancreatic endocrine tumors. Modern Pathology. 2011;24(S2):S66-S77
23.Pavlidis TE, Psarras K, Symeonidis NG, Pavlidis ET, Sakantamis AK. Current surgical management of pancreatic endocrine tumor liver metastases. Hepatobiliary Pancreat Dis Int. 2011;10(3):243-7
24.Reid MD, Balci S, Saka B, Adsay NV. Neuroendocrine Tumors of the Pancreas: Current Concepts and Controversies. Endocrine Pathology 2014;25:65-79. doi:10.1007/s12022-013-9295-2
25.Andrew A, Kramer B, Rawdon BB. The origin of gut and pancreatic neuroendocrine (APUD) cells—the last word? The Journal of Pathology 1998;186:117-8. doi:10.1002/(sici)1096-9896(1998100)186:2<117::aid-path152>3.0.co;2-j
26.Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801-6
27.Antonello D, Gobbo S, Corbo V, Sipos B, Lemoine NR, Scarpa A. Update on the molecular pathogenesis of pancreatic tumors other than common ductal adenocarcinoma. Pancreatology. 2009;9(1-2):25-33
28.Fasanella KE, McGrath KM, Sanders M, Brody D, Domsic R, Khalid A. Pancreatic endocrine tumor EUS-guided FNA DNA microsatellite loss and mortality. Gastrointest Endosc. 2009;69(6):1074-80
29.Oberg K. Genetics and molecular pathology of neuroendocrine gastrointestinal and pancreatic tumors (gastroenteropancreatic neuroendocrine tumors). Curr Opin Endocrinol Diabetes Obes. 2009;16(1):72-8
30.Zimmermann N, Knief J, Kacprowski T, Lazar-Karsten P, Keck T, Billmann F, et al. MicroRNA analysis of gastroenteropancreatic neuroendocrine tumors and metastases. Oncotarget. 2018;9(47):28379-9
31.Satapathy S, Batra J, Jeet V, Thompson EW, Punyadeera C. MicroRNAs in HPV associated cancers: small players with big consequences. Expert Review of Molecular Diagnostics. 2017;17(7):711-22
32.Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov. 2010;9:775-89. doi: 10.1038/nrd3179
33.Calin GA, Croce CM. MicroRNA signatures in human cancers. Nature Reviews Cancer. 2006;6(11):857-66
34.Meiri E, Mueller WC, Rosenwald S, Zepeniuk M, Klinke E, Edmonston TB, Werner M, Lass U, Barshack I, Feinmesser M, Huszar M, Fogt F, Ashkenazi K, et al. A second-generation microRNA-based assay for diagnosing tumor tissue origin. Oncologist. 2012;17:801-12. doi: 10.1634/theoncologist.2011-0466
35.Thorns C, Schurmann C, Gebauer N, Wallaschofski H, Kümpers C, Bernard V, Feller AC, Keck T, Habermann JK, Begum N, Lehnert H, Brabant G. Global microRNA profiling of pancreatic neuroendocrine neoplasias. Anticancer Res. 2014;34:2249-54
36.Ruebel K, Leontovich AA, Stilling GA, Zhang S, Righi A, Jin L, Lloyd RV. MicroRNA expression in ileal carcinoid tumors: downregulation of microRNA-133a with tumor progression. Mod Pathol. 2010;23:367-75. doi: 10.1038/modpathol.2009.161
37.Pantel K, Speicher MR. The biology of circulating tumor cells. Oncogene. 2015;35(10):1216-2
38.Hsieh JC-H, Chen G-Y, Jhou DD-W, Chou W-C, Yeh C-N, Hwang T-L, et al. The Prognostic Value of Circulating Tumor Cells in Asian Neuroendocrine Tumors. Scientific Reports. 2019;9(1)
39.Khan MS, Tsigani T, Rashid M, Rabouhans JS, Yu D, Luong TV, et al. Circulating Tumor Cells and EpCAM Expression in Neuroendocrine Tumors. Clinical Cancer Research. 2011;17(2):337-45
40.Fischer C, Pape U-F, Neumann T, Detjen KM, Hilfenhaus G, Hess G, et al. Prognostic relevance of circulating PIGF levels in patients with neuroendocrine tumors. Journal of Clinical Oncology. 2012;30(15_suppl):412
41.L. R. McKenna and B. H. Edil, “Update on pancreatic neuroendocrine tumors,” Gland Surgery, vol. 3, no. 4, pp. 258-275, 2014
42.Ro C, Chai W, Yu VE, Yu R. Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment. Chin J Cancer. 2013;32(6):312-324. doi:10.5732/cjc.012.1029
43.Alexakis N, Neoptolemos JP. Pancreatic neuroendocrine tumours. Best Pract Res Clin Gastroenterol. 2008;22(1):183-205. doi:10.1016/j.bpg.2007.10.00
44.Ito T, Igarashi H, Jensen RT. Pancreatic neuroendocrine tumors: Clinical features, diagnosis and medical treatment: Advances. Best Practice & Research Clinical Gastroenterology. 2012;26(6):737-53
45.Zhuo F. Insulinoma [Internet]. StatPearls [Internet]. U.S. National Library of Medicine; 2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK544299/
46.Feliberti E. Gastrinoma [Internet]. Endotext [Internet]. U.S. National Library of Medicine; 2017. Available from:https://www.ncbi.nlm.nih.gov/books/NBK279075/
47.Sandhu S. Glucagonoma Syndrome [Internet]. StatPearls [Internet]. U.S. National Library of Medicine; 2020. Available from: https://www. ncbi.nlm.nih.gov/books/NBK519500
48.Sandhu S. ViPoma [Internet]. StatPearls [Internet]. U.S. National Library of Medicine; 2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507698/
49.Williamson JM, Thorn CC, Spalding D, Williamson RC. Pancreatic and peripancreatic somatostatinomas. Ann R Coll Surg Engl. 2011;93(5):356-360. doi:10.1308/003588411X58268
50.Park YS. Less Common Types of Pancreatic Neuroendocrine Tumors. Neuroendocrine Tumours. 2015;:271-4
51.Lee DW, Kim MK, Kim HG. Diagnosis of Pancreatic Neuroendocrine Tumors. Clinical Endoscopy. 2017;50(6):537-45
52.Viudez A, De Jesus-Acosta A, Carbalho FL, Vera R, Martin-Algarra S, Ramirez N. Pancreatic neuroendocrine tumors: challenges in an underestimated disease. Crit Rev Oncol Hematol. 2016;101:193-206
53.Jun E, Kim SC, Song KB, et al. Diagnostic value of chromogranin A in pancreatic neuroendocrine tumors depends on tumor size: A prospective observational study from a single institute. Surgery. 2017;162(1):120-130. doi:10.1016/j.surg.2017.01.01
54.Ramage JK. Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours. Gut 2005;54:iv1–iv16. doi:10.1136/gut.2004.053314
55.Khashab MA, Yong E, Lennon AM, et al. EUS is still superior to multidetector computerized tomography for detection of pancreatic neuroendocrine tumors. Gastrointest Endosc. 2011;73:691-6
56.Reidy-Lagunes DL, Gollub MJ, Saltz LB. Addition of Octreotide Functional Imaging to Cross-Sectional Computed Tomography or Magnetic Resonance Imaging for the Detection of Neuroendocrine Tumors: Added Value or an Anachronism? Journal of Clinical Oncology 2011;29. doi:10.1200/jco.2010.32.8559
57.James PD, Tsolakis AV, Zhang M, Belletrutti PJ, Mohamed R, Roberts DJ, et al. Incremental benefit of preoperative EUS for the detection of pancreatic neuroendocrine tumors: a meta-analysis. Gastrointestinal Endoscopy 2015;81. doi:10.1016/j.gie.2014.12.031
58.Zimmer T, Stolzel U, Bader M, Koppenhagen K, Hamm B, Buhr H, et al. Endoscopic ultrasonography and somatostatin receptor scintigraphy in the preoperative localisation of insulinomas and gastrinomas. Gut 1996;39:562-8. doi:10.1136/gut.39.4.562
59.Westlin J-E, Janson ET, Arnberg H, Ahlström H, Öberg K, Nilsson S. Somatostatin Receptor Scintigraphy of Carcinoid Tumours Using the [111In-Dtpa-D-Phe1]-Octreotide. Acta Oncologica 1993;32:783-6. doi:10.3109/02841869309096136
60.Papotti M, Bongiovanni M, Volante M, et al. Expression of somatostatin receptor types 1-5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. Virchows Arch. 2002;440:461-7
61.Jabiev AA, Lew JI. In Reply: Surgeon-Performed Ultrasound and Prediction of Differentiated Thyroid Cancer. Annals of Surgical Oncology 2010;18:301–. doi:10.1245/s10434-010-1312-9
62.Raj N, Reidy-Lagunes D. The Role of 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography in Well-Differentiated Neuroendocrine Tumors. Pancreas 2018;47:1-5. Doi: 10.1097/MPA.000000000000094
63.Heitz PU KP, Perren A, Klimstra D, et al. Tumors of the endocrine pancreas. In: DeLellis RA LR, Heitz PU, Eng C, eds. Pathology and Genetics of Tumours of Endocrine Organs. Lyon: France IARC Press, 2004:175-208
64.Sopha S. Neuroendocrine neoplasms - general. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/pancreaspen.html. Accessed May 5th, 2020
65.Well Differentiated Pancreatic Neuroendocrine Tumor / Islet Cell Tumor [Internet]. Differential Diagnosis - Well Differentiated Pancreatic Endocrine Neoplasm (Islet Cell Tumor) - Surgical Pathology Criteria - Stanford University School of Medicine. Available from: http://surgpathcriteria.stanford.edu/pancreas/well-differentiated-pancreatic-neuroendocrine-neoplasm-tumor-islet-cell/differentialdiagnosis.html#t5
66.Glucagonoma Differential Diagnoses. 2020. Available from:https://emedicine.medscape.com/article/118899-differential
67.Teh SH, Deveney C, Sheppard BC. Aggressive pancreatic resection for primary pancreatic neuroendocrine tumor: is it justifiable? Am J Surg. 2007;193:610-3
68.Hashim YM, Trinkaus KM, Linehan DC, Strasberg SS, Fields RC, Cao D, et al. Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs). Ann Surg. 2014;259(2):197-203
69.Pathak S, Dash I, Taylor MR et al The surgical management of neuroendocrine tumour hepatic metastases. Eur. J. Surg. Oncol. 39, 224-228 (2013)
70.Pancreatic Neuroendocrine Tumors in the 21st Century –An Update [Internet]. Clinicsinsurgery.com. 2020 [cited 9 May 2020]. Available from: http://www.clinicsinsurgery.com/full-text/cis-v2-id1662.php
71.V. Sallinen, T. Y. S. le Large, S. Galeev et al., “Surveillance strategy for small asymptomatic non-functional pancreatic neuroendocrine tumors – a systematic review and meta-analysis,” HPB: The Official Journal of the International Hepato Pancreato Biliary Association, vol. 19, no. 4, pp. 310-320, 2017
72.J. Chabot, “Editorial: pancreatic neuroendocrine tumors: primum non nocere,” Surgery, vol. 159, no. 1, pp. 348-349, 2016
73.F. J. Hüttner, J. Koessler-Ebs, T. Hackert, A. Ulrich, M. W. Büchler, and M. K. Diener, “Meta-analysis of surgical outcome after enucleation versus standard resection for pancreatic neoplasms,” British Journal of Surgery, vol. 102, no. 9, pp. 1026-1036, 2015
74.S. Gaujoux, S. Partelli, F. Maire et al., “Observational study of natural history of small sporadic nonfunctioning pancreatic neuroendocrine tumors,” The Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 12, pp. 4784-4789, 2013
75.L. C. Lee, C. S. Grant, D. R. Salomao et al., “Small, nonfunctioning, asymptomatic pancreatic neuroendocrine tumors (PNETs): role for nonoperative management,” Surgery, vol. 152, no. 6, pp. 965-974, 2012
76.E. Sadot, D. L. Reidy-Lagunes, L. H. Tang et al., “Observation versus resection for small asymptomatic pancreatic neuroendocrine tumors: a matched case-control study,” Annals of Surgical Oncology, vol. 23, no. 4, pp. 1361-1370, 2016
77.Rosenberg AM, Friedmann P, Rivero JD, Libutti SK, Laird AM. Resection versus expectant management of small incidentally discovered nonfunctional pancreatic neuroendocrine tumors. Surgery 2016;159:302-10. doi:10.1016/j.surg.2015.10.013
78.Regenet N, Carrere N, Boulanger G, Calan LD, Humeau M, Arnault V, et al. Is the 2-cm size cutoff relevant for small nonfunctioning pancreatic neuroendocrine tumors: A French multicenter study. Surgery 2016;159:901-7. doi:10.1016/j.surg.2015.10.003
79.Zhang, I.Y., Zhao, J., Fernandez-del Castillo, C. et al. Operative Versus Nonoperative Management of Nonfunctioning Pancreatic Neuroendocrine Tumors. J Gastrointest Surg 20, 277-283 (2016). https://doi.org/10.1007/s11605-015-3043-5
80.Shah MH, Goldner WS, Halfdanarson TR, Bergsland E, Berlin JD, Halperin D, et al. NCCN Guidelines Insights: Neuroendocrine and Adrenal Tumors, Version 2.2018. Journal of the National Comprehensive Cancer Network 2018;16:693-702. doi:10.6004/jnccn.2018.0056
81.Cherenfant J, Stocker SJ, Gage MK, Du H, Thurow TA, Odeleye M, et al. Predicting aggressive behavior in nonfunctioning pancreatic neuroendocrine tumors. Surgery 2013;154:785-93. doi:10.1016/j.surg.2013.07.00
82.Panzuto F, Boninsegna L, Fazio N, Campana D, Brizzi MP, Capurso G, et al. Metastatic and Locally Advanced Pancreatic Endocrine Carcinomas: Analysis of Factors Associated With Disease Progression. Journal of Clinical Oncology 2011;29:2372-7. doi:10.1200/jco.2010.33.0688
83.Eriksson B. New drugs in neuroendocrine tumors: rising of new therapeutic philosophies? Current Opinion in Oncology 2010;22:381-6. doi:10.1097/cco.0b013e32833adee2
84.Rinke A, Müller H-H, Schade-Brittinger C, Klose K-J, Barth P, Wied M, et al. Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients With Metastatic Neuroendocrine Midgut Tumors: A Report From the PROMID Study Group. Journal of Clinical Oncology 2009;27:4656-63. doi:10.1200/jco.2009.22.8510
85.Caplin ME, Pavel M, Ćwikła JB, Phan AT, Raderer M, Sedláčková E, et al. Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors. New England Journal of Medicine 2014;371:224-33. doi:10.1056/nejmoa1316158
86.Wolin E, Jarzab B, Eriksson B, Walter T, Toumpanakis C, Morse MA, et al. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Design, Development and Therapy 2015:5075. doi:10.2147/dddt.s84177
87.Chan D.L., Ferone D., Albertelli M., Pavlakis N., Segelov E., Singh S. Escalated-dose somatostatin analogues for antiproliferative effect in GEPNETS: A systematic review. Endocrine. 2017;57:366-375. doi: 10.1007/s12020-017-1360-z
88.Mohamed A., Blanchard M.P., Albertelli M., Barbieri F., Brue T., Niccoli P., Delpero J.R., Monges G., Garcia S., Ferone D., et al. Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures. Endocr. Relat. Cancer. 2014;21:691-704. doi: 10.1530/ERC-14-0086
89.Cives M., Kunz P.L., Morse B., Coppola D., Schell M.J., Campos T., Nguyen P.T., Nandoskar P., Khandelwal V., Strosberg J.R. Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors. Endocr. Relat. Cancer. 2015;22:1-9. doi: 10.1530/ERC-14-0360
90.Kulke M.H., Ruszniewski P., Van Cutsem E., Lombard-Bohas C., Valle J.W., De Herder W.W., Pavel M., Degtyarev E., Brase J.C., Bubuteishvili-Pacaud L., 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. doi: 10.1093/annonc/mdx078
91.1. Kulke M, Lenz H, Meropol N, Posey J, Ryan D, Picus J et al. Activity of Sunitinib in Patients With Advanced Neuroendocrine Tumors. Journal of Clinical Oncology. 2008;26(20):3403-3410
92.2. Raymond E, Dahan L, Raoul J, Bang Y, Borbath I, Lombard-Bohas C et al. Sunitinib Malate for the Treatment of Pancreatic Neuroendocrine Tumors. New England Journal of Medicine. 2011;364(6):501-513
93.Yao J, Lombard-Bohas C, Baudin E, Kvols L, Rougier P, Ruszniewski P et al. Daily Oral Everolimus Activity in Patients With Metastatic Pancreatic Neuroendocrine Tumors After Failure of Cytotoxic Chemotherapy: A Phase II Trial. Journal of Clinical Oncology. 2010;28(1):69-76
94.Yao J, Phan A, Chang D, Wolff R, Hess K, Gupta S et al. Efficacy of RAD001 (Everolimus) and Octreotide LAR in Advanced Low- to Intermediate-Grade Neuroendocrine Tumors: Results of a Phase II Study. Journal of Clinical Oncology. 2008;26(26):4311-4318
95.Yao J, Shah M, Ito T, Bohas C, Wolin E, Van Cutsem E et al. Everolimus for Advanced Pancreatic Neuroendocrine Tumors. New England Journal of Medicine. 2011;364(6):514-523
96.Duran I, Kortmansky J, Singh D, Hirte H, Kocha W, Goss G et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. British Journal of Cancer. 2006;95(9):1148-
97.Hobday TJ, Rubin J, Holen K, et al. MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study. J Clin Oncol. 2007;25:18s. (Suppl; abstr 4504)
98.Phan AT, Yao JC, Fogelman DR, et al. A prospective, multi-institutional phase II study of GW786034 (pazopanib) and depot octreotide (sandostatin LAR) in advanced low-grade neuroendocrine carcinoma (LGNEC) J Clin Oncol. 2010;28:15s. (Suppl; abstr 4001
99.Broder, L. E. & Carter, S. K. Pancreatic islet cell carcinoma. II. Results of therapy with streptozotocin in 52 patients. Ann. Intern. Med. 79, 108-118 (1973
100.Kulke, M. H. et al. Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J. Clin. Oncol. 24, 401-406 (2006
101.Moertel C, Hanley J, Johnson L. Streptozocin Alone Compared with Streptozocin plus Fluorouracil in the Treatment of Advanced Islet-Cell Carcinoma. New England Journal of Medicine. 1980;303(21):1189-1194
102.Moertel C, Lefkopoulo M, Lipsitz S, Hahn R, Klaassen D. Streptozocin–Doxorubicin, Streptozocin–Fluorouracil, or Chlorozotocin in the Treatment of Advanced Islet-Cell Carcinoma. New England Journal of Medicine. 1992;326(8):519-523
103.Moertel C, Kvols L, O'Connell M, Rubin J. Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer. 1991;68(2):227-232
104.Turner N, Strauss S, Sarker D, Gillmore R, Kirkwood A, Hackshaw A et al. Chemotherapy with 5-fluorouracil, cisplatin and streptozocin for neuroendocrine tumours. British Journal of Cancer. 2010;102(7):1106-1112
105.Ramanathan R, Cnaan A, Hahn R, Carbone P, Haller D. Phase II trial of dacarbazine (DTIC) in advanced pancreatic islet cell carcinoma. Study of the Eastern Cooperative Oncology Group-E6282. Annals of Oncology. 2001;12(8):1139-1143
106.Bajetta E, Catena L, Procopio G, De Dosso S, Bichisao E, Ferrari L et al. Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours?. Cancer Chemotherapy and Pharmacology. 2006;59(5):637-642
107.Kulke M, Stuart K, Enzinger P, Ryan D, Clark J, Muzikansky A et al. Phase II Study of Temozolomide and Thalidomide in Patients With Metastatic Neuroendocrine Tumors. Journal of Clinical Oncology. 2006;24(3):401-406
108.Chan JA, Stuart K, Earle CC, et al. Prospective study of bevacizumab plus temozolomide in patients with advanced neuroendocrine tumors. J Clin Oncol. 2012;30(24):2963-2968. doi:10.1200/JCO.2011.40.314
109.Chan J, Blaszkowsky L, Stuart K, Zhu A, Allen J, Wadlow R et al. A prospective, phase 1/2 study of everolimus and temozolomide in patients with advanced pancreatic neuroendocrine tumor. Cancer. 2013;119(17):3212-3218
110.Ducreux M, Dahan L, Smith D, O’Toole D, Lepère C, Dromain C et al. Bevacizumab combined with 5-FU/streptozocin in patients with progressive metastatic well-differentiated pancreatic endocrine tumours (BETTER trial) – A phase II non-randomised trial. European Journal of Cancer. 2014;50(18):3098-3106
111.Fani M, Maecke H, Okarvi S. Radiolabeled Peptides: Valuable Tools for the Detection and Treatment of Cancer. Theranostics. 2012;2(5):481-501
112.Van Essen M, Krenning E, De Jong M, Valkema R, Kwekkeboom D. Peptide Receptor Radionuclide Therapy with radiolabelled somatostatin analogues in patients with somatostatin receptor positive tumours. Acta Oncologica. 2007;46(6):723-734
113.Imhof A, Brunner P, Marincek N, Briel M, Schindler C, Rasch H, et al. Response, survival, and long-term toxicity after therapy with the radiolabeled somatostatin analogue [90Y-DOTA]-TOC in metastasized neuroendocrine cancers. J Clin Oncol. 2011;29(17):2416
114.Valkema R., Pauwels S., Kvols L.K., Barone R., Jamar F., Bakker W.H., Kwekkeboom D.J., Bouterfa H., Krenning E.P. Survival and Response after Peptide Receptor Radionuclide Therapy with [90Y-DOTA0, Tyr3] Octreotide in Patients with Advanced Gastroenteropancreatic Neuroendocrine Tumors. Elsevier; Amsterdam, The Netherlands: 2006. pp. 147-156. Seminars in Nuclear Medicine
115.Kwekkeboom D.J., de Herder W.W., Kam B.L., van Eijck C.H., van Essen M., Kooij P.P., Feelders R.A., van Aken M.O., Krenning E.P. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0, Tyr3] octreotate: Toxicity, efficacy, and survival. J. Clin. Oncol. 2008;26:2124-2130. doi: 10.1200/JCO.2007.15.2553
116.Bushnell D.L., Jr., O’Dorisio T.M., O’Dorisio M.S., Menda Y., Hicks R.J., Van Cutsem E., Baulieu J.-L., Borson-Chazot F., Anthony L., Benson A.B. 90Y-edotreotide for metastatic carcinoid refractory to octreotide. J. Clin. Oncol. 2010;28:1652-1659. doi: 10.1200/JCO.2009.22.8585
117.Cwikla J., Sankowski A., Seklecka N., Buscombe J., Nasierowska-Guttmejer A., Jeziorski K., Mikolajczak R., Pawlak D., Stepien K., Walecki J. Efficacy of radionuclide treatment DOTATATE Y-90 in patients with progressive metastatic gastroenteropancreatic neuroendocrine carcinomas (GEP-NETs): A phase II study. Ann. Oncol. 2009;21:787-794. doi: 10.1093/annonc/mdp372
118.Pfeifer A.K., Gregersen T., Grønbæk H., Hansen C.P., Müller-Brand J., Bruun K.H., Krogh K., Kjær A., Knigge U. Peptide receptor radionuclide therapy with 90Y-DOTATOC and 177Lu-DOTATOC in advanced neuroendocrine tumors: Results from a Danish cohort treated in Switzerland. Neuroendocrinology. 2011;93:189-196. doi: 10.1159/000324096
119.Bodei L., Cremonesi M., Grana C.M., Fazio N., Iodice S., Baio S.M., Bartolomei M., Lombardo D., Ferrari M.E., Sansovini M., et al. Peptide receptor radionuclide therapy with 177Lu-DOTATATE: The IEO phase I-II study. Eur. J. Nucl. Med. Mol. Imaging. 2011;38:2125-2135. doi: 10.1007/s00259-011-1902-
120.Ezziddin S., Attassi M., Yong-Hing C.J., Ahmadzadehfar H., Willinek W., Grünwald F., Guhlke S., Biersack H.-J., Sabet A. Predictors of long-term outcome in patients with well-differentiated gastroenteropancreatic neuroendocrine tumors after peptide receptor radionuclide therapy with 177Lu-octreotate. J. Nucl. Med. 2014;55:183-190. doi: 10.2967/jnumed.113.125336
121.Nwosu AC, Jones L, Vora J, Poston GJ, Vinjamuri S, Pritchard DM. Assessment of the efficacy and toxicity of (131)I-metaiodobenzylguanidine therapy for metastatic neuroendocrine tumours. Br J Cancer. 2008;98(6):1053
Written By
Neha Sharma and Deepti Sharma
Submitted: 09 May 2020Reviewed: 27 January 2021Published: 22 December 2021
Open access peer-reviewed chapter
