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Table 1a: SSAs approved for NETs treatment
Author/trials Regimen Patients enrolled Results Adverse reactions
(grade > 3)
[49]
Rinke et al. Arnold et al. [28] Octreotide vs. placebo Advanced GEP or NETs mTTP: 14.3 vs. 6 Diarrhea
PROMID (Phase III) of unknown origin months; SD: 64% vs.
37.2%
Caplin et al. [50] Clarinet (Phase Lanreotide vs. placebo Advanced GEP or NETs mPFS: NR vs. 18 Diarrhea
III) of unknown origin months
Filosso et al. [57] Octreotide Metastatic atypical RR = 60% None
bronchial carcinoid with
carcinoid syndrome
(diarrhea)
GEP: gastro-entero-pancreatic; NETs: neuroendocrine tumors; mTTP: median time to progression; mPFS: median progression free
survival; SD: stable disease; NR: not reached; RR: response rate

Table 1b: SSAs not yet approved for NETs treatment
Adverse reactions
Author/trials Regimen Patients enrolled Results
(grade > 3)
Wolin et al. (Phase III) Pasireotide vs. octreotide Advanced GEP- NETs mPFS: 11.8 vs. 6.8 Hyperglycemia, diarrhea
[53]
months; SD: 60.8% vs.
42.3%
SSAs: short synthetic analogues of somatostatin; NETs: neuroendocrine tumors; GEP-NETs: gastro-entero-pancreatic neuroendocrine
tumors; mPFS: median progression free survival; SD: stable disease

Table 1c: Drug not yet approved for the treatment of refractory carcinoid syndrome
Author/trials Regimen Patients enrolled Results Adverse reactions (grade >3)
Kulke et al. [54] Telotristat Metastatic GEP-NETs with Reduction of BMs: 30% Gastrointestinal symptoms: nausea,
carcinoid syndrome vomiting, or abdominal discomfort
Pavel et al. [55] Telotristat Metastatic well-differentiated Reduction of BMs: Gastrointestinal symptoms: nausea,
NETs with carcinoid syndrome 43.5% vomiting, or abdominal discomfort
(diarrhea)
GEP-NETs: gastro-entero-pancreatic neuroendocrine tumors; mTTP: median time to progression; mPFS: median progression free
survival; BMs: bowel movements; RR: response rate
glucagonomas, and VIPomas (80-100%). [27,28] However, SSTR functioning appears different and dependent on
insulinomas express SSTR in 50-70% of cases, showing a the presence in several types of cancer cell, various
prevalence of SSTR5 mRNA expression that is positively distributions on cellular surface, and intrinsic features
correlated with aggressive pathological characteristics. [29] (ability of desensitization, internalization, and cross
talk). [26,38] However, their activity causes a blockage
SSTR2 is usually expressed in NENs, and its loss could of cellular survival, proliferation, differentiation, and
be highly correlated with the dysregulation of tumor hormone secretion, except for SSTR4, promoting cell
proliferation, consequently promoting tumor growth. [30,31] mitosis through overregulation of Mitogen-activated
protein kinase/extracellular signal-regulated kinase 1/2
SSTR1 and SSTR5 are less expressed in NENs and (MAPK/ERK1/2) pathway.
correlate with a major risk of angioinvasion and distant
metastasis. SSTR3 is even less present, and SSTR4 is In fact SSTR1 acts on starting MAPK pathway; SSTR2
almost absent. [32-34] augments Src homology region 2 domain-containing
phosphatase-1 and epidermal growth factor receptor
Reductions of receptor density, changes in their subtype (EGFR) activity, over-regulates p21 and Rb, reducing
MAPK activity and blocking cellular proliferation. p53
pattern, and probably also their downregulation seem to and Bax, involved in apoptosis, are induced by SSTR3.
be a consequence of tumor dedifferentiation. Thus, the It also blocks vascular endothelial growth factor receptor
presence of SSTRs might also be useful as a specific (VEGFR). Finally, protein tyrosine phosphatases are
predictor of prognosis. [16] However, any significant targeted by SSTR5. [18,39]
association between the expressed receptors subtypes and
the primary tumor site at onset is observed in relation The role of SSAs, as mentioned, is to reduce active
to high and heterogeneous expression of SSTRs, or to a symptoms and to have an antiproliferative effect in
specific hormone secretion. [35-37] secreting and nonsecreting neuroendocrine tumors.

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ August 31, 2016 ¦ 331