Pancreatic neuroendocrine tumors: approach to treatment with focus on sunitinib

Abstract

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.

Pancreatic neuroendocrine tumors

“…Sunitinib malate is an oral, multitargeted tyrosine kinase inhibitor of VEGF receptors 1, 2, and 3, PDGFRs α and β, stem-cell factor (KIT) receptor, FMS-like tyrosine kinase 3, colony-stimulating factor 1 receptor, and glial cell line-derived neurotrophic factor receptor [121]. The antitumor activity of sunitinib in PNETs was shown in a phase III study.…”

Vandetanib for the treatment of thyroid cancer: an update

“…Three different oral regimens of vandetanib (A: ascending doses of 300 --1200 mg or placebo; B: crossover design of 300 mg under fed and fasting conditions and [14] C: vandetanib 800 mg), were studied in healthy volunteers in order to investigate metabolism, excretion and elimination routes in a previous study [38]. Mean t 1/2 time in all regimens was 215.8 --246.6 h (19 days on average).…”

“…The above findings indicate VEGFR-2 signaling as a key regulator in tumor pathogenesis. VEGFR-2 appears to be an eligible target for novel therapeutic approaches, and currently several new anticancer agents, including TKI targeting VEGFR-2, are already in use in daily clinical practice, while several others are being developed or tested in clinical trials [13,14].…”

Genetics of pancreatic neuroendocrine tumors: implications for the clinic

“…A trial evaluating the efficacy of sunitinib in PanNETs showed that the progression free survival in the treatment group was more than double that of the control group, demonstrating the promise of this therapeutic approach. 118, 119 . Other drugs targeting angiogenesis such as bevacizumab and pazopanib are currently under study in PanNETs.…”