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The estimated annual incidence of R-NENs is 1.04 per 100,000 persons although the real incidence may be underestimated, as not all R-NEN are systematically reported in registers. Also the prevalence has increased substantially, reflecting the rising incidence and indolent nature of R-NENs, showing the highest prevalence increase among all site of origin of NENs. The size of the tumor reveals the behavior of R-NENs where the risk for metastatic spread increases for lesions > 10 mm. Applying the WHO 2010 grading system to whole NENs originating in the gastroenteropancreatic system, R-NENs are classified as Well-Differentiated Neuroendocrine Tumors (WD-NET), which contain NET G1 and NET G2, and Poorly-Differentiated Carcinomas (PD-NEC) enclosing only G3 neoplasms for which the term carcinoma is applied. The treatment is endoscopic resection in most cases: conventional polypectomy or endoscopic mucosal resection (EMR) for smaller lesions or endoscopic submucosal resection with a ligation device (ESMR-L), cap-assisted EMR (EMR-C) and endoscopic submucosal dissection (ESD). However it is important to know when the endoscopic treatment is not enough, and surgical treatment is indicated, or when the latter could be unnecessary. For PD-NECs, it has recently been demonstrated that chemoradiotherapy is associated with a similar long-term survival to that obtained with surgery. As well, new targeted-agents chemotherapy may be indicated for metastatic WD-NETs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Metronomic therapy is characterized by the administration of regular low doses of certain drugs with very low toxicity. There have been numerous debates over the empirical approach of this regimen, but fewest side effects are always something to consider in order to improve patients' quality of life. Neuroendocrine tumors (NETs) are rare malignancies relatively slow-growing; therefore their treatment is often chronic, involving several different therapies for tumor growth control. Knowing that these tumors are highly vascularized, the anti-angiogenic aspect is highly regarded as something to be targeted in all patients harboring NETs. Additionally the metronomic schedule has proved to be effective on an immunological level, rendering this approach as a multi-targeted therapy. Rationalizing that advanced NETs are in many cases a chronic disease, with which patients can live for as long as possible, a systemic therapy with regular low doses and a very low toxicity is in many cases a judicious manner of pursuing stabilization. Metronomic schedule is usually correlated with chemotherapy in oncology, but other therapies, such as radiotherapy and biotherapy can be delivered in a metronomic like manner. This review describes clinical trials and case series involving metronomic therapies alone or in combination in patients with advanced NETs. Nowadays level of evidence about metronomic therapy in NETs is quite low, therefore future prospective clinical studies are needed to validate the metronomic approach in specific clinical settings., (Copyright © 2017 Elsevier Ltd. All rights reserved.)