Pancreatic
neuroendocrine tumors (
pNETs) are relatively rare
malignancies. With secretory
tumors such as
insulinomas, vasoactive intestinal peptideomas, and
gastrinomas, the
hormone produced causes the symptom complex (e.g.
hypoglycemia,
peptic ulcer disease). With nonsecretory NETs, the clinical condition is determined by tumoral growth and
metastasis. The course of metastatic
pNETs may be indolent for several years but progression is often more rapid at later stages, leading to significant disability and a markedly negative impact on quality of life. Until recently, there were few effective systemic treatments for
pNETs. Standard
chemotherapy produces limited responses and has considerable toxicity.
Somatostatin analogues control symptoms in some types of
pNETs, but have not yet demonstrated antitumor activity. The recent introduction of targeted
therapies, including the
tyrosine kinase inhibitor sunitinib and the
mammalian target of rapamycin inhibitor
everolimus, yielded new opportunities for patients with advanced/metastatic
pNETs. These drugs, which target key pathways in
tumor proliferation and angiogenesis, provided clear clinical benefits in phase III clinical trials, including delayed
tumor progression. The pivotal
sunitinib phase III trial was discontinued prematurely due to higher rates of death and serious adverse events with placebo and greater progression-free survival (PFS) with
sunitinib. In this trial,
sunitinib demonstrated encouraging long-term responses as well as PFS and overall survival benefits, and an acceptable safety profile that allowed patients to preserve their quality of life. In every patient subgroup, including secretory and nonsecretory
tumors, the hazard ratio for progression or death favored
sunitinib. Circulating
biomarkers are being investigated for the prediction and monitoring of responses to
sunitinib. Although not fully evaluated in
pNETs,
biomarkers associated with response to
sunitinib in several
tumor types include soluble
vascular endothelial growth factor receptor 2 and 3,
interleukin 8, and stromal cell-derived factor 1α. Based on recent data, treatment algorithms have been updated for advanced and metastatic
pNETs.