Management of Neuroendocrine Tumors: Current and Future Therapies

Kjell E Öberg

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

Five-year View

New biomarkers for early diagnosis and recurrence of disease will be developed. Molecular imaging will increase in the management of NETs. ⁶⁸Ga-DOTA octreotate will probably be preferred to Octreoscan in the near future. The novel multireceptor ligand analogue pasireotide has demonstrated efficacy in patients with NETs, including those with metastatic NETs refractory or resistant to, or inadequately controlled with, current somatostatin analogues;^[53,91] pasireotide has also shown evidence of antiproliferative effects in vitro.^[92,93] A randomized, double-blind Phase III study comparing pasireotide LAR with octreotide LAR in patients with metastatic NETs whose symptoms of carcinoid syndrome were inadequately controlled with their current somatostatin analogue therapy is currently ongoing. It seems likely that somatostatin analogues will be used more frequently in combination with other medical therapies such as mTOR as well as tyrosine kinase inhibitors; positive antiproliferative effects have been seen in patients administered both octreotide LAR and everolimus. Combination trials of everolimus with PRRT will start in Europe as well as everolimus in combination with temozolomide. Sunitinib alone or in combination with somatostatin analogs as well as mTOR inhibitors or VEGF inhibitors (bevacizumab) will be tested. The precise role of everolimus or sunitinib in the treatment algorithm of pancreatic NETs has to be established in forthcoming studies.

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Financial & competing interests disclosure
The author has been at the Speakers Bureau for Novartis, Ipsen and Pfizer and also received honoraria from these companies. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

Cite this: Management of Neuroendocrine Tumors: Current and Future Therapies - Medscape - Jan 01, 2011.

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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