Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs)

These guidelines update previous guidance published in 2005. They have been revised by a group who are members of the UK and Ireland Neuroendocrine Tumour Society with endorsement from the clinical committees of the British Society of Gastroenterology, the Society for Endocrinology, the Association of Surgeons of Great Britain and Ireland (and its Surgical Specialty Associations), the British Society of Gastrointestinal and Abdominal Radiology and others. The authorship represents leaders of the various groups in the UK and Ireland Neuroendocrine Tumour Society, but a large amount of work has been carried out by other specialists, many of whom attended a guidelines conference in May 2009. We have attempted to represent this work in the acknowledgements section. Over the past few years, there have been advances in the management of neuroendocrine tumours, which have included clearer characterisation, more specific and therapeutically relevant diagnosis, and improved treatments. However, there remain few randomised trials in the field and the disease is uncommon, hence all evidence must be considered weak in comparison with other more common cancers.     

Tumour biology of gastroenteropancreatic neuroendocrine tumours

Neuroendocrine tumours of the gastroenteropancreatic tract (GEP NETs) represent a rare and heterogeneous group of tumours. Based on their ontogenetic origin, GEP NETs are classified into foregut, midgut and hindgut tumours. Although they have many features in common, their molecular backgrounds are obviously different. Elucidation of the key factors determining tumour biology has been hampered by the low incidence and high variability of these tumours in terms of origin, morphology and growth. However, recent years have shed some light on molecular genetics of these tumours, revealing important genetic factors as the RET proto-oncogene and the tumour suppressor menin as well as knowledge about the role of growth factors like IGF-1, TGF-beta, VEGF and PDGF for the regulation of differentiation, growth and secretion. In the future, emerging molecular tools in rapid individual genome analysis and in proteomic and array technologies may help to delineate common patterns of NET disease.     

Selecting patients for cytotoxic therapies in gastroenteropancreatic neuroendocrine tumours

Gastroenteropancreatic neuroendocrine tumours (GEP-NET) have heterogenic clinical presentations. The majority of GEP-NET tumours have an indolent behaviour, but patients will eventually develop symptoms of tumour progression or hormone secretion that may require systemic medical interventions. Cytotoxic chemotherapy has been tested in GEP-NETs since the 80s, but treatment recommendations are controversial in many instances. Patient selection is mandatory for optimal use of chemotherapy. Important prognostic factors such as primary tumour site, tumour differentiation, tumour staging and proliferation index have been identified and validated in retrospective and prospective series. The combination of those factors and the natural history of GEP-NET provide valuable information with respect to treatment planning. In this report we provide treatment recommendations to improve systemic therapy in patients with advanced GEP-NETs based on a comprehensive review of the literature.     

Therapeutic management of patients with gastroenteropancreatic neuroendocrine tumours

Patients with neuroendocrine tumours (NETs) are best managed in a specialist centre as part of a multidisciplinary team comprising gastroenterologists, oncologists, endocrinologists, gastrointestinal and hepatopancreaticobiliary surgeons, pathologists, nuclear medicine physicians and technicians, radiologists, specialist nurses, pharmacists, biochemists and dieticians. This should ideally be led by a clinician with experience and interest in NETs. Although the number of medical treatments and clinical trials has increased in the decade, there is still a lack of prospective randomised trials; thus, management is mainly based on limited often single-centre studies, although there are now formal guidelines based on consensus expert opinion. We have outlined the current optimal management of patients with NETs. We have reviewed therapeutic options including surgery, somatostatin analogues and other biotherapies and peptide receptor-targeted therapy. We have discussed the challenge in managing hepatic metastases including hepatic artery embolisation, ablation and orthotopic liver transplant. In addition, we have briefly reviewed the emerging therapies such as the mammalian target of rapamycin and angiogenic inhibitors and the newer somatostatin analogues.     

mTOR expression and activity patterns in gastroenteropancreatic neuroendocrine tumours

Clinical trials indicate efficacy of drugs inhibiting the mammalian target of rapamycin (mTOR) in the treatment of gastroenteropancreatic neuroendocrine tumours (GEP-NET); however, information on detailed expression and activity patterns of mTOR in these tumours is sparse. We investigated the expression of mTOR and expression as well as phosphorylation of its downstream targets 4EBP1, S6K and eIF4E in a cohort of 99 human GEP-NET by immunohistochemistry. We correlated our findings with clinicopathological variables and patient prognosis. We found that 61, 93, 80, 69, 57 and 79% of GEP-NET were positive for mTOR, 4EBP1, cytoplasmic phospho-4EBP1 (p-4EBP1), nuclear p-4EBP1, phospho-S6K (p-S6K) and phospho-eIF4E (p-eIF4E) respectively. mTOR expression and activity were higher in foregut than in midgut tumours. In foregut tumours, expression of mTOR was higher when distant metastases were present (P=0.035). Strong mTOR activity was associated with higher proliferative capacity. In patients with stage IV midgut tumours, strong p-S6K expression was associated with poor disease-specific survival (P=0.048). In conclusion, mTOR shows considerable variations in expression and activity patterns in GEP-NET in dependence of tumour location and metastatic status. We hypothesise that these differences in mTOR expression and activity might possibly influence response to mTOR inhibitors.     

Radiological and nuclear medicine imaging of gastroenteropancreatic neuroendocrine tumours

Neuroendocrine tumours (NETs) comprise a heterogeneous group of neoplasms with very varying clinical expression. A functioning NET, for instance in the pancreas, may be very small and yet give rise to severe endocrine symptoms whereas a patient with a small bowel tumour may present with diffuse symptoms and disseminated disease with a palpable bulky liver. Imaging of NETs is therefore challenging and the imaging needs in the various patients are diverse. The basic modalities for NET imaging are computed tomography (CT) or magnetic resonance imaging (MRI) in combination with somatostatin receptor imaging (SMI) by scintigraphy with 111In-labelled octreotide (OctreoScan) or more recently by positron emission tomography (PET) with 68Ga-labelled somatostatin analogues. In this review these various morphological and functional imaging modalities and important methodological aspects are described. Imaging requirements for the various types of NETs are discussed and typical image findings are illustrated.     

Role of biological targeted therapies in gastroenteropancreatic neuroendocrine tumours

Approximately two-thirds of neuroendocrine tumours (NET) occur in the gastrointestinal tract and over 60% present with metastases. With greater insight into molecular pathways involved in tumour progression, opportunities are presented for the use of targeted therapies in NET. Although a wide array of targeted agents has been investigated, only a handful has emerged as forerunners from recent clinical trials. This literature review focuses on the use of anti-angiogenic monoclonal antibody bevacizumab, as well as small molecule inhibitors sunitinib and everolimus.     

Prognostic factors of long-term outcome in gastroenteropancreatic neuroendocrine tumours

Neuroendocrine tumours (NET) of the gastroenteropancreatic system comprise a malignant entity with a low incidence. Only limited information is available on long-term clinical outcome and clinically applicable prognostic factors. We performed a retrospective analysis of a large, well-characterized centre-based patient cohort of 399 patients with histologically proven NET. Data were analysed according to epidemiological, clinical and histopathological characteristics. Detailed survival analyses using the Kaplan-Meier method were performed. Prognostic factors were tested by log-rank testing and independent risk factors were analysed using a Cox regression model. In the studied cohort, primary tumours originated in the fore-, mid- and hindgut in 46.1, 37.1 and 4.5% respectively. Extra-intestinal or unknown primary tumours were present in 8.4 and 10.5% respectively. Distant metastasis was present at initial diagnosis in 69.4%. Most frequent metastatic sites were liver (85%), peritoneal cavity (18%), bones (8%), other intra-abdominal sites (6%) and lungs (4%). Overall, 5- and 10-year survival rates were 78 and 63% respectively. Time to progression after initial diagnosis was significantly shorter in pancreatic as compared with ileal NET. Survival analysis revealed significantly better clinical outcome for primary tumours smaller than 25 mm, absence of metastasis, absence of any clinical symptoms, positive immunohistochemical staining for chromogranin A and a lower Ki67 index. These results were confirmed as independent by multivariate analysis. Therefore, this large retrospective analysis of a well-documented cohort of patients with NET demonstrates several prognostic factors of clinical relevance and wide availability, which should be considered for risk stratification in the management of NET.     

Trends in diagnosis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in India: A report of multicenter data from a web-based registry

Introduction

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare tumors. We report data of 407 GEP-NET cases from a neuroendocrine tumor (NET) registry in India.

Methods

The AP-NET registry is an open-label, multicenter, longitudinal observational registry of patients with GEP-NETs in which six tertiary care oncology centers contributed data. Data was prospectively entered in a dedicated computerized database and was reviewed retrospectively. The patients were divided into three cohorts—those diagnosed from 2001 to 2005, from 2006 to 2010, and from 2011 to 2016.

Results

Of the 407 cases registered, 37 were in Cohort I, 136 in Cohort II, and 234 in Cohort III. Majority were symptomatic with only 98 patients (24.0%) asymptomatic. The most common presentation of non-functional tumors was abdominal pain (42.4%), while functional tumors presented most commonly with carcinoid syndrome. Use of DOTA-PET, introduced in 2011, has increased evaluation in 33.3% patients in Cohort III. The most common primary site was pancreas in all three cohorts. Male preponderance (58.3%) was seen. Histopathological grading was obtained in 230 (56.5%) patients—118 (29%) Grade I, 74 (18.2%) Grade II, and 36 (8.8%) Grade III NET.

Conclusion

This report highlights changing trends in the diagnosis and reporting of NETs over the last 15 years.

     

Role of endoscopy in the management of gastroenteropancreatic neuroendocrine tumours

Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) represent in clinical practice a diagnostic dilemma because they are often very small, located deeply within the retroperitoneum or in an extramucosal site in the gastrointestinal (GI) tract and, lastly, because they may be multi-sited. Modern digestive endoscopy offers a myriad of techniques, useful for localization, diagnosis and treatment (therapeutic endoscopy). The available tools include upper digestive endoscopy (esophagogastroduodenoscopy, endoscopic retrograde cholangiopancreatography), lower digestive endoscopy (ileo-colonoscopy), enteroscopy (push-type, intra-operative, capsule, double or single balloon), for examining the small intestine, diagnostic and interventional echo-endoscopy (EUS), with radial, linear and miniprobe equipment. This narrative review offers scientific support to affirm that endoscopy and EUS give imaging and diagnostic possibilities that are unbeatable in the localization of GEP-NETs both of the GI tract and the pancreas. Endoscopy is useful for localization, bioptic diagnosis and curative resection of small neuroendocrine lesions of the stomach, duodenum, colon-rectum and more recently of the jejuno-ileum. EUS associated with dedicated instruments, particularly high frequency miniprobes, is a valuable procedure in locoregional staging of lesions of the GI wall and can supply information which has a clinical impact on therapeutic options and prognostic value. EUS is still today the sole technique in a certain number of cases which provides a definitive diagnosis of pancreatic insulinoma and to detect and follow subcentimetric lesions of the pancreas in patients with MEN-1 syndrome. It should be used in all those cases where results from radiographic imaging or nuclear medicine techniques show negative or dubious.     

Tumour markers in neuroendocrine tumours

Most of the neuroendocrine tumours produce and secrete a large number of peptide hormones and amines. Each of these substances cause a specific clinical syndrome: carcinoid, Zollinger-Ellison, hyperglycaemic, glucagonoma and WDHA syndrome. Specific markers for these syndromes are basal and/or stimulated levels of: urinary-5-HIAA, serum or plasma gastrin, insulin, glucagon, and VIP, respectively. About 1/3 of neuroendocrine tumours belong to the so-called "non-functioning" tumours. Therefore, general markers such as chromogranin A, pancreatic polypeptide, serum neuronspecific enolase and subunit of glycoprotein hormones have been used for screening purposes in patients without distinct clinical hormone related syndromes. Among these general tumour markers chromogranin A, although its precise function is not yet established, has been shown to be a very sensitive and specific serum marker for various types of neuroendocrine tumours. This is because it may also be increased in many cases of less well differentiated tumours of neuroendocrine origin that do not secrete known hormones. Then chromogranin A is considered the best general neuroendocrine serum or plasma marker available at the moment and is increased in 50-100% of patients with various neuroendocrine tumours. Chromogranin A serum or plasma levels reflect tumour load and may be an independent marker of prognosis in patients with midgut carcinoids.     

Angiogenic markers endoglin and vascular endothelial growth factor in gastroenteropancreatic neuroendocrine tumors

AIM:To investigate the expression and potential prognostic role of vascular endothelial growth factor(VEGF) and endoglin in gastroenteropancreatic neuroendocrine tumors(GEP-NETs) . METHODS:Microvessel density(MVD) in GEP-NETs was evaluated using endoglin and CD31 immunohistochemistry.In addition,tissue levels of endoglin and VEGF were determined in homogenates by ELISA. RESULTS:Endoglin was highly expressed on tumor endothelial cells.CD31 MVD in GEP-NETs was significantly higher compared to endoglin MVD(P<0...     

New pharmacologic therapies for gastroenteropancreatic neuroendocrine tumors

Successful treatment of unresectable and metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs) requires the thoughtful choice of systemic therapy as a component of a multidisciplinary therapeutic approach. The role of somatostatin analogues is established in symptom relief, but the efficacy of interferon and radiopeptide targeted therapy is not clear. The utility of a variety of tyrosine kinase and antiangiogenic agents is variable and under investigation, whereas the role of cytotoxic chemotherapy in poorly differentiated GEP-NETs is accepted. Overall, the ideal treatment of more indolent tumors is less certain. Reassessments of the GEP-NET pathology classification has provided improved logic for the role of a variety of agents, whereas the precise positioning of many new agents that target molecular pathways of angiogenesis and proliferation is under examination. This article describes the current options for systemic therapy for GEP-NETs within the framework of the current World Health Organization classification system.     

Update on gastroenteropancreatic neuroendocrine tumors

The incidence gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) has dramatically risen over the last three decades, probably due to the increased detection of asymptomatic lesions. The diagnostic work-up for patients with suspected GEP-NENs is based on conventional imaging, endoscopy, pathology, and functional imaging, including ⁶⁸Gallium-DOTATATE PET and ¹⁸F-FDG PET. The choice of the best treatment strategy should be based on the evaluation of tumor-related features and patient's characteristics. A conservative management, consisting of active surveillance or endoscopic resection, has been advocated for patients with small, incidentally discovered, nonfunctioning tumors without features of aggressiveness. On the other hand, surgery with lymphadenectomy, also with a minimally invasive approach, represents the gold standard for the curative treatment of localized disease. Moreover, surgical resection plays an important role also in the context of a multimodal treatment strategy for patients with advanced GEP-NENs. Finally, a wide range of medical therapies, comprising somatostatin analogues, peptide receptor radionuclide therapy, target therapies and several chemotherapy regimens, can be offered to patients with advanced GEP-NENs not amenable of surgical resection, according to the biological and molecular features of their disease.     

Peptide receptor radionuclide therapy (PRRT) for GEP-NETs

Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues plays an increasing role in the treatment of patients with inoperable or metastasised gatroenteropancreatic neuroendocrine tumours (GEP-NETs). ⁹⁰Y-DOTATOC and ¹⁷⁷Lu-DOTATATE are the most used radiopeptides for PRRT with comparable tumour response rates (about 15–35%). The side effects of this therapy are few and mild. However, amino acids should be used for kidney protection, especially during infusion of ⁹⁰Y-DOTATOC. Options to improve PRRT may include combinations of radioactive labelled somatostatin analogues and the use of radiosensitising drugs combined with PRRT. Other therapeutic applications of PRRT may include intra-arterial administration, neo-adjuvant treatment and additional PRRT cycles in patients with progressive disease, who have benefited from initial therapy. Considering the mild side-effects, PRRT may well become the first-line therapy in patients with metastasised or inoperable GEP-NETs if more widespread use of PRRT can be accomplished.