Neuroendocrine neoplasms constitute a highly heterogeneous spectrum of tumors with a variety of biological and clinical behaviors. Site-specific classification systems generally recognize at one end of the spectrum highly aggressive, poorly differentiated neoplasms, termed neuroendocrine carcinoma grade 3 of the gastrointestinal tract and pancreas according to the new World Health Organization (WHO) classification 2010 , and small and large cell neuroendocrine carcinomas of the lung . At the other end is a highly heterogeneous group of well-to-moderately differentiated neuroendocrine neoplasms (WMD-NEN) comprising low-grade (G1) and intermediate grade (G2) neuroendocrine tumors of the gastrointestinal tract and pancreas , typical and atypical carcinoids of the lung and thymus , along with other cancers such as medullary thyroid carcinoma and pheochromocytoma/paraganglioma. These neoplasms are relatively rare and, despite their relatively indolent course, are frequently diagnosed in advanced stage [3, 4]. Because of their limited aggressiveness, WMD-NEN are notoriously resistant to standard chemotherapy and are usually addressed with biological target therapies .
For decades the standard therapy for both functioning and non-functioning WMD-NEN has been with somatostatin analogues [6, 7]. More recently, target drugs, such as sunitinib and everolimus, have been shown to be efficacious in the management of pancreatic WMD-NEN [8, 9]. One of the antiangiogenesis-targeted drugs that can be added to other types of chemotherapy is bevacizumab, a monoclonal antibody that blocks vascular endothelial growth factor (VEGF) by binding to its receptor. In a randomized phase 2 trial, the combination of bevacizumab and octreotide had a greater efficacy than interferon α2 and octreotide . Common toxicities of bevacizumab are hypertension and proteinuria; both these adverse events may lead to premature interruption of drug administration. Hypertension, however, has been associated with drug efficacy in breast cancer and colon cancer patients [11, 12], and proteinuria has been suggested as a potential marker of drug efficacy . In addition, VEGF polymorphisms have been found to be predictive of hypertension and associated with time to progression in advanced breast cancer treated with bevacizumab .
Hypovitaminosis D is highly prevalent in cancer patients. It has been reported to increase the risk of cardiovascular diseases and mortality in such patients  and to promote proteinuria in patients with type 2 diabetes . To our knowledge, the association of hypovitaminosis D and bevacizumab-induced proteinuria has never been explored to date nor has the prognostic role of hypovitaminosis D been tested in patients with neuroendocrine tumors.
Metronomic administration of chemotherapy inhibits angiogenesis and vasculogenesis by continuously exposing the more slowly proliferating tumor endothelial cells to the damaging action of the cytotoxic therapy . These requisites make metronomic chemotherapy a suitable approach in the management of WMD-NEN. In our previous phase 2 trial, we observed that the combination of octreotide long-acting release (LAR) therapy 20 mg every 4 weeks plus 5-fluorouracil protracted continuous infusion led to a disease control rate >90% (response + stabilization) as first-line treatment in the management of locally advanced or metastatic WMD-NEN . In contrast, the response rate obtained with octreotide LAR alone is generally <5%  and the time to progression reported in the PROMID trial with octreotide LAR 30 mg every 4 weeks was 14 months .
There is a strong rationale for combining metronomic chemotherapy with antiangiogenic drugs . Prior preclinical metronomic chemotherapy studies have shown that the combination of antiangiogenic drugs with metronomic chemotherapy can increase antitumor efficacy compared to either agent alone [19, 20]. Capecitabine is an orally administered third-generation fluoropyrimidine carbamate that mimics the tolerability and activity of protracted intravenous 5-FU infusion .
The XELBEVOCT trial, a single-arm multicenter Italian phase 2 study, was designed to test the activity of the association of metronomic capecitabine, bevacizumab, and octreotide in the treatment of advanced/metastatic WMD-NEN. The primary study aim was the assessment of activity; the secondary aims were to evaluate toxicity, time to progression, overall survival, and the relationship between common toxicities associated with bevacizumab (hypertension and proteinuria) and drug efficacy. In predefined ancillary studies we also explored the role of circulating VEGF, VEGF polymorphisms, vitamin D status, and vitamin D metabolism-related polymorphism in predicting toxicities and treatment efficacy.