Management of Neuroendocrine Tumors: Current and Future Therapies

Kjell E Öberg

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

Management of NETs: Other Medical Therapies

Interferon Therapy

Interferon therapy is generally recommended as a second-line approach in patients with functioning NETs and low proliferation.^[12] The effect of interferons on symptom control is similar to that of somatostatin analogues and they may have greater antiproliferative activity;^[66] however, they do not act as rapidly and have a less favorable safety profile (fever, fatigue, anorexia and weight loss are commonly reported).^[11] IFN-α is the most widely studied and a pooled analysis of trials investigating this agent in patients with NETs demonstrated that approximately 40% had biochemical responses (which is comparable to that observed with octreotide and lanreotide) whilst approximately 10% had objective tumor responses.^[11] Although the number of trials is small and studies may be underpowered, combination of IFN-α with somatostatin analogues might have a synergistic effect.^[14,67–69]

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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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