Vascular endothelial growth factor (VEGF) pathway and neuroendocrine neoplasms (NENs): prognostic and therapeutic considerations

Neuroendocrine neoplasms (NENs) consist of a large heterogeneous group of epithelial tumors with neuroendocrine differentiation, as proved by immune reactivity for neuroendocrine markers. From the very first studies of vascular endothelial growth factor (VEGF) pathway, VEGF has been considered an important prognostic marker in NENs. Consequently, a number of preclinical experiences and clinical trials have examined the efficacy of VEGF-targeted therapeutics in NENs. Bevacizumab and sorafenib were clinically tested in NENs and they showed modest activity, while on the other hand, they present significant toxicity problems. More interesting in gastroenteropancreatic (GEP)-NENs seems to be the demonstrated efficacy of sunitinib. Preclinical as well as clinical sunitinib data in this regard provide a new hope in that direction. The use of other novel VEGF-targeted agents like aflibercept as well as VEGFR-TKI is being investigated in a number of phase II studies; the results of which are greatly awaited. Additionally, the use of potential biomarkers to select patients for VEGF-targeted therapy may be considered for further clinical evaluation. Thus, this article reviews the basic science as well as clinical data of VEGF signaling in advanced NENs with special emphasis on the different VEGF-targeting agents tested previously in this disease and the future prospective in that field.