New drugs that inhibit blood vessel formation appear to be promising for well vascularized neuroendocrine tumors. Initial reports evaluated bevacizumab, a neutralizing VEGF antibody (Vascular Endothelial Growth Factor). A small initial study showed that bevacizumab plus octreotide was superior to the treatment with interferon plus octreotide.

The growth signal of VEGF can also be inhibited by drugs available in capsules. Sunitinib is such a drug. A controlled prospective phase III-study on the safety and effectiveness of sunitinib was terminated early in 2009, when the interim analysis showed a significant (progression-free) survival benefit for patients with neuroendocrine pancreatic tumors who took capsules containing sunitinib (37.5 mg/d) every day. In the meantime sunitinib has been approved for the treatment of patients with advanced, G1- or G2-differentiated neuroendocrine tumors of the pancreas.

The so-called mTOR inhibitors are another fascinating new type of drugs. mTOR is a very important intracellular protein that can control both growth and death of tumor cells. The mTOR-inhibitor everolimus has been studied in prospective phase III trials for its safety and efficacy in neuroendocrine tumor disease. The so-called Radiant 3-trial was terminated in 2010. This prospective controlled phase III-trial demonstrated a significant (progression-free) survival benefit for those patients with G1- or G2-differentiated, neuroendocrine pancreatic tumors who took a tablet of everolimus a day. Almost at the same time as sunitinib did, everolimus received accelerated approval for the treatment of patients with advanced, G1- or G2-differentiated neuroendocrine tumors of the pancreas. Thus, sunitinib and everolimus are the first drugs to be approved for the treatment of neuroendocrine pancreatic tumors after 25 years. The approvals of both sunitinib and everolimus are important steps forward for physicians treating neuroendocrine tumors of the pancreas. Both sunitinib and everolimus provide new hope to patients living with this often difficult-to-treat disease.

In another prospective controlled trial (Radiant 2-trial) everolimus in combination with octreotide has been evaluated for its safety and efficacy for the treatment of advanced carcinoids, mostly of the small bowels (midgut carcinoids). In the Radiant 2-, phase III-trial everolimus plus octreotide lengthened median progression-free survival in patients with advanced non-pancreatic neuroendocrine tumors compared to placebo plus octreotide. The final evaluation of the survival data of the Radiant 2-trial is still awaited for the subgroups. It will be important to know which subgroups of patients benefit most from the combination therapy of everolimus plus octreotide LAR.

Figure 14:
Overview of phase III-studies on new treatment approaches for intestinal carcinoids and islet cell tumors of the pancreas.



Modified according to Kulke & Scherübl, Gastrointestinal Cancer Res 2009; 5: S62-66

Contact

Center of Neuroendocrine Tumors
Prof. Dr. med. Hans Scherübl
Vivantes Klinikum Am Urban
Academic Teaching Hospital of Charité-University Medicine, Berlin
Dieffenbachstraße 1
10967 Berlin, Germany
Tel: + 49 30 130 225201
Fax: + 49 30 130 225205
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