NEUROENDOCRINE TUMOR: MOLECULAR-TARGETING THERAPY FOR PNET

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Abstract

Apart from symptomatic relief, there have been few treatment options for pancreatic neuroendocrine tumors (PNET). Studies examining the use of chemotherapy for these tumors have reported moderate response rates, although such treatment is associated with considerable adverse events. Several preclinical studies have noted the elevated expression of cellular growth factors and their receptors in PNET, and recent early-phase clinical studies have provided evidence that the disruption of these signaling pathways can inhibit tumor growth. Very recently, promising results have been achieved in placebo-controlled, phase III trials examining the use of the multi-targeted tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus.

The continuous administration of sunitinib at a dose of 37.5 mg per day was compared with a placebo in a phase III trial of 171 patients. In the placebo-controlled RADIANT-3 trial of 410 patients, everolimus monotherapy at a dose of 10 mg once daily was compared with best supportive care alone. Both drugs were effective, with significant improvements in progression-free survival (PFS) as the primary end point.

Several other molecular-targeted agents have demonstrated modest activities in phase II settings. Sorafenib yielded a response rate of 11% in patients with PNET. In patients who received pazopanib, which targets VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alpha, and PDGFR-beta as well as KIT, the response rate was 17%. In a phase II study of bevacizumab plus temozolomide in patients with advanced NET, 18 of the 34 patients enrolled in the study had PNET, and 4 of these patients (24%) achieved a PR. In a phase II study of the mTOR inhibitor temsirolimus, the response rate was 6% and the disease control rate was 64%. For patients treated with gefitinib, the PFS rate at 6 months was 31%.

To develop more effective therapies for this rare disease, cooperative, multinational, randomized studies are urgently needed to assess the real benefits of molecular targeting agents, which have the potential to demonstrate beneficial activities.

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