Biological targeted therapies in patients with advanced enteropancreatic neuroendocrine carcinomas.
Enteropancreatic (EP) neuroendocrine carcinomas (NECs) represent relatively rare and heterogeneous malignancies. They are the most common group among neuroendocrine tumors (NETs). In most cases they are advanced at diagnosis and slow-growing, therefore conditioning a better prognosis compared with non neuroendocrine carcinomas from the same sites. No standard medical therapy exists, except for somatostatin analogs in functioning tumors, and octreotide LAR in functioning or non functioning well differentiated NECs from small bowel. Several systemic therapeutic options exist, including chemotherapy, somatostatin analog, interferon, peptide receptor radionuclide therapy (PRRT), and molecular targeted drugs. Among them some therapies have specific biological tumor targets and can be defined as "biological targeted therapies". This review focuses on the status of EP NECs targeted therapies in the light of recent advances. Somatostatin receptors (SSTRs) are the first therapeutic target detected in EP NECs. Through them SS analogs and PRRT act, producing symptomatic, biochemical, and, to a lesser extent, antiproliferative effects. New SS analogs, covering a higher number of SSTR subtypes, were developed, including pasireotide (SOM230), which controls 25% of carcinoid syndromes resistant to full dose octreotide LAR. Chimeric analogs, which bind SSTR2/SSTR5 and dopamine-2 receptor subtype (D2), are in preclinical phase of development. Among the numerous molecular targeted agents investigated in NETs, mTOR inhibitors and VEGF/VEGFR/PDGFR inhibitors are in most advanced clinical phase of investigation. In particular, everolimus, sunitinib, and bevacizumab are all studied in phase III trials. Both everolimus and sunitinib produced significant survival benefit versus placebo in advanced progressing well-differentiated pancreatic NECs. Sunitinib data have been presented at the last ASCO in June 2010, and everolimus data will be presented at next ESMO in September 2010.
European Institute of Oncology, IEO NET Study Group, Via Ripamonti 435, Milan, Italy. nicola.fazio@ieo.it
Nicola
N
Fazio
Saverio
S
Cinieri
Katia
K
Lorizzo
Michela
M
Squadroni
Laura
L
Orlando
Francesca
F
Spada
Evaristo
E
Maiello
Lisa
L
Bodei
Giovanni
G
Paganelli
Gianfranco
G
Delle Fave
Filippo
F
de Braud
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000068258:Bevacizumab; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy*; D000068338:Everolimus; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011758:Pyrroles / Q000627:therapeutic use; D017481:Receptors, Somatostatin / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D013004:Somatostatin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D017481:Receptors, Somatostatin; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D013004:Somatostatin; C517782:pasireotide; D000068338:Everolimus; D000077210:Sunitinib; D020123:Sirolimus