Management of Neuroendocrine Tumors: Current and Future Therapies

Kjell E Öberg

Expert Rev Endocrinol Metab. 2011;6(1):49-62.

Medical Management of NETs: Somatostatin Analogues

As curative surgery is generally not possible, many patients require chronic postoperative medical management to relieve symptoms and to suppress tumor growth and spread. Somatostatin is an endogenous inhibitor of various hormones secreted from the endocrine system. It binds with high affinity to the five somatostatin receptor subtypes (sst_1–5) on secretory endocrine cells,^[33] which have different inhibitory effects in the body (Table 4). Subtypes sst₂ and sst₅ are the most important in inhibiting hormonal secretions in functioning NETs due to their wide-ranging effects; it is thought the dual inhibition of both subtypes may have an increased inhibitory effect.^[34] The two subtypes may also mediate antiproliferative effects.

Somatostatin has limited clinical use due to its short half-life (<3 min). Therefore, specific somatostatin analogues have been developed that work as receptor agonists and block hormone release. These analogues form the first-line medical therapy for well-differentiated NETs.^[12] Octreotide (Sandostatin®, Novartis, Basel, Switzerland), the first somatostatin analogue available commercially, is a sst₂-preferring agonist that also has moderate affinity for sst₃ and sst₅. It has a different chemical structure to somatostatin and a much longer half-life of 2 h. Lanreotide (Somatuline®, Ipsen, Paris, France) was the second analogue available and has a similar binding profile to octreotide. SOM230 (Pasireotide®, Novartis, Basel, Switzerland) is a novel multireceptor ligand analogue that has high affinity for four of the five somatostatin receptor subtypes (sst₁, ₂, ₃ and sst₅);^[35,36] it has 40-fold higher affinity and 158-fold higher functional activity for sst₅ than octreotide.

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Abstract and Introduction
Diagnosis
Biochemical Markers
Imaging
Classification
Functioning NETs
Other Syndromes
Nonfunctioning NETs
Management of NETs: Surgery
Medical Management of NETs: Somatostatin Analogues
Symptomatic & Biochemical Control
Escape from Response
Antiproliferative Effects & Survival
Management of NETs: Other Medical Therapies
New Therapeutic Strategies
Management of NETs: Summary
Expert Commentary
Five-year View
References
Sidebar

Table 1. Sensitivities of imaging techniques used for neuroendocrine tumor detection.
Technique	Primary carcinoid tumor (%)	Carcinoid liver metastases (%)	Primary gastrinoma (%)	Gastrinoma liver metastases (%)	Primary insulinoma (%)^†
Ultrasound	46	83	23	50	27
CT	64	88	38–75	54–88	30
MRI	56	85	22–90	63–90	10
SRS	80	90	72	97	25
EUS	80 (gastric)		90–100		88
Angio+Ca Stim			93		95

^†Metastatic insulinoma is rare.
Angio+Ca Stim: Angiography with calcium stimulation; CT: Computed tomography; EUS: Endoscopic ultrasound; SRS: Somatostatin-receptor scintigraphy (Octreoscan®).
Data from [5]

Table 2. WHO classification of neuroendocrine tumors.
Classification	Biological behavior	Metastases	Ki-67 index (%)^†	Histological differentiation	Infiltration/angioinvasion	Tumor size (cm)
Well-differentiated NET	Benign	–^‡; ±^§	<2	Well	–	≤1
Well-differentiated neuroendocrine carcinoma	Low malignancy	±	>2	Well	+	>2^‡; >3^§
Poorly-differentiated neuroendocrine carcinoma	High malignancy	+	>30	Poor	+	Any size

^†Identical to MIB1.
^‡Gastrointestinal neuroendocrine tumor.
^§Pancreatic neuroendocrine tumor.
NET: Neuroendocrine tumor.
Data from [20,94].

Table 3. Proposal for tumor–node–metastasis classification and disease staging for endocrine tumors of the pancreas.
Classification	Criteria
*T – primary tumor*
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
T1	Tumor limited to the pancreas and size <2 cm
T2	Tumor limited to the pancreas and size 2–4 cm
T3	Tumor limited to the pancreas and size >4 cm or invading duodenum or bile duct
T4	Tumor invading other organs (stomach, spleen, colon and adrenal gland) or wall of large vessels (celiac axis or superior mesenteric artery)
*N – regional lymph nodes*
NX	Regional lymph node cannot be assessed
N0	No regional lymph node metastasis
N1	Regional lymph node metastasis
*M – distant metastases*
MX	Distant metastasis cannot be assessed
M0	No distant metastases
M1^†	Distant metastasis
*Disease stage for tumors of the pancreas*
I	T1, N0, M0
IIa	T2, N0, M0
IIb	T3, N0, M0
IIIa	T4, N0, M0
IIIb	Any T, N1, M0
IV	Any T, Any N, M1

^†M1-specific sites defined according to Sobin and Wittekind.
M: Metastasis; N: Node; T: Tumor.
Data from [21].

Table 4. Inhibitory effects of somatostatin receptor subtypes.
Inhibitory effect	Receptor subtype
Inhibitory effect	sst ₁	sst ₂	sst ₃	sst ₄	sst ₅
Hormone secretion
Growth hormone	+	+			+
Adrenocorticotropic hormone		+			+
Thyroid-stimulating hormone		+			+
Insulin		+			+
Glucagon		+
Exocrine secretion
Gastric acid		+
Amylase					+
Intestinal GI secretion	+	+
Cell proliferation
Induction of G₁ cell cycle arrest	+	+		+	+
Induction of apoptosis		+	+

GI: Gastrointestinal.
Data from [34].

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