Targeted Systemic Treatment of Neuroendocrine Tumors: Current Options and Future Perspectives

Abstract

Neuroendocrine tumors (NETs) originate from the neuroendocrine cell system in the bronchial and gastrointestinal tract and can produce hormones leading to distinct clinical syndromes. Systemic treatment of patients with unresectable NETs aims to control symptoms related to hormonal overproduction and tumor growth. In the last decades prognosis has improved as a result of increased detection of early stage disease and the introduction of somatostatin analogs (SSAs) as well as several new therapeutic options. SSAs are the first-line medical treatment of NETs and can control hormonal production and tumor growth. The development of next-generation multireceptor targeted and radiolabelled somatostatin analogs, as well as target-directed therapies (as second-line treatment options) further improve progression-free survival in NET patients. To date, however, a significant prolongation of overall survival with systemic treatment in NET has not been convincingly demonstrated. Several new medical options and treatment combinations will become available in the upcoming years, and although preliminary results of preclinical and clinical trials are encouraging, large, preferrably randomized clinical studies are required to provide definitive evidence of their effect on survival and symptom control.

Fig. 1

Current medical treatment for symptoms control in neuroendocrine tumors. Short- and long-acting and radiolabeled somatostatin analogs bind to G-protein linked receptors on the cell surface with variable affinity. Decreases in cAMP and intracellular calcium levels inhibit hormone release. Somatostatin influences hormone secretion and motility in the whole gastrointestinal tract. Serotonin production may also be decreased by telotristat, which inhibits the rate-limiting step in the serotonin secretion (the enzyme tryptophan hydroxylase). sstr somatostatin receptor, SSAs somatostatin analog, PRRT peptide receptor radionuclide therapy, cAMP cyclic adenosine monophosphate, VIP vasoactive intestinal peptide, PP pancreatic polypeptide, SST somatostatin

Fig. 2

Current and future medical options for tumor control in neuroendocrine tumors. Current therapeutic options are presented in blue, possible novel therapeutic options are presented in red. SSAs and PRRT: increase apoptosis by activating the protein tyrosine phosphatase SHP1; decrease cell proliferation and survival through the mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate (cAMP); and inhibit the signaling of the insulin-like growth factor receptor type 1 (IGFR-1); additionally, PRRT produces DNA double strand breaks induced by β-irradiation, consequently leading to apoptosis. Sunitinib is a multikinase inhibitor that modulates the phosphoinositate-3-kinase/Akt pathway (it blocks the vascular endothelial growth factor receptors (VEGFR) 1-3, the platelet-derived growth factor receptors (PDGFR) α and β, and the epidermal growth factor receptor (EGFR)). Everolimus decreases tumor cell proliferation, metabolism, survival, and angiogenesis through the mammalian target of rapamycin complex-1. The indirect inhibition of mTOR through the phosphoinositate-3-kinase/Akt produced by the SSAs seems to increase sensitivity to mTOR inhibition. Multi-receptor chimeras may bind SSTR and D2R, and may enhance the signaling of the cAMP and JNK pathways; induced SST2R internalization and SST2R/D2R heterodimerisation interference have also been hypothesized. The interaction between some receptors expressed on the surface of cytotoxic T-cells (PD-1, CTLA-4) with ligands expressed on the tumor cells (PDL-1, B7-1/B7-2) downregulates the immune response to tumor cells; novel drugs that target these specific immune checkpoints inhibit this interaction allowing the immune system to maximize an efficient antitumor response. SSAs somatostatin analogs, PRRT peptide receptor radionuclide therapy, IGF-1R insulin-growth factor receptor type 1, VEGFR vascular endothelial growth factor, EGFR epidermal growth factor receptor, PDGFR platelet-derived growth factor receptors, mTOR mammalian Target of Rapamycin, CTL4 cytotoxic T-lymphocyte antigen-4, PDL-1 Programmed death-ligand 1

Fig. 3

Peptide receptor radionuclide therapy in neuroendocrine tumors (NETs). a CT imaging of a pancreas neuroendocrine tumor grade 2 with lymphatic and liver metastasis (segment 6); in this case, four cycles of peptide receptor radionuclide therapy (cumulative dose 30 Gbq) was administered resulting in decreased size of the primary tumor (b). After 6 years of partial response and stable disease, the primary tumor increased in size accompanied by new liver and mesenteric metastasis (c). Because of an initial good treatment response, two cycles of PRRT (14.9 GBq) were administered, and a decreased size of primary tumor and liver metastasis were observed (d). Images are of an NET patient evaluated in the ENETS Center of Excellence Erasmus MC, Rotterdam. Informed consent was provided

Fig. 4

Treatment algorithms for tumor control in neuroendocrine tumors (NETs). Summary of current medical strategies for tumor control in NETs according to the primary tumor site. Legend: Blue, red and green colors represent lung, pancreas and midgut NETs respectively. SSTR somatostatin receptor expression, SSA somatostatin analog, PRRT peptide receptor radionuclide therapy. *Not registered for this indication, **PRRT has been approved in Europe for midgut NETs and in the USA for midgut and pancreatic NETs, ***streptozocin/5-fluorouracil or streptozocin/doxorubicin; temozolomide/capecitabine as an alternative regimen