Evolving Strategies for the Management of Neuroendocrine tumours1,2,3
Neuroendocrine tumours (NETs) are a genetically diverse group of malignant solid tumours arising from neuroendocrine cells throughout the body (including in the thymus, lung, pancreas, GI tract and less common sites). They can be either clinically symptomatic (i.e., ‘functioning’), producing peptides causing characteristic hormonal syndromes, or silent, (i.e., ‘nonfunctioning’). Functioning NETs are characterised by the hormones they produce and the symptoms they cause. The clinical symptoms of functioning NETs typically appear after the tumour has metastasised to the liver.
NETs can be broadly classified into well-differentiated tumours (more indolent) and poorly differentiated ones (far more aggressive) (see Table 1 for histological classification of NET). Well-differentiated tumours are traditionally further subdivided into either carcinoid or pancreatic NETs. Carcinoid tumours have a similar histological appearance to pancreatic NETs, but generally originate in the bronchi, small intestine, appendix or rectum.*
Neuroendocrine tumours have demonstrated an increase in incidence over past decades, partly due to increased awareness and improved diagnosis.
*Based on embryological origin, NETs were traditionally classified in 1963 as foregut (thymus, oesophagus, lung, stomach, duodenum and pancreas), midgut (appendix, ileum, caecum and ascending colon) and hindgut (distal large bowel and rectum) tumours, but this system is now considered outdated as it does not distinguish biologically relevant differences.
The diagnosis of NETs is multimodal, based on clinical symptoms, hormone levels (for functioning NETs), radiological and nuclear imaging, and histological confirmation. However, a large proportion of NETs are non-functioning and diagnosed incidentally during imaging for other indications. Most patients with NETs have metastatic disease at diagnosis, with regional or distant metastasis observed in 50% of patients (in regional lymph nodes, then liver, then distant sites such as bone).
A number of biochemical tests are available, which can assist with the initial diagnosis and assessment of required treatment. The most common are:
Chromogranin A (CgA) is present in the chromaffin granules of neuroendocrine cells. CgA measurement via a blood test can be used to diagnose both functioning and nonfunctioning NETs1 and plays an important role in the assessment of treatment response and monitoring of recurrence. However CgA may be elevated in a number of non-malignant conditions therefore the use of CgA as a diagnostic or screening test for NET should be discouraged.1
Ki-67, a protein found in the nucleus during cell division, can be used in NET as a marker of tumour proliferation. Low Ki-67 levels indicate lower proliferation which correlates with longer survival.
As a general rule, aggressive malignancies are tumours with: 1
- a high grade (grade 3),
- a mitotic count > 20 per 10 high powered fields,
- or a Ki-67 proliferation index > 20%
5-hydroxyindoleacetic Acid (5-HIAA) is a serotonin metabolite can be used to predict the presence of a midgut NET.
While most pancreatic NETs are considered ‘non-functional’, with no symptoms of hypersecretion, the functional tumours on the other hand can present with various and sometimes puzzling symptoms (Kurke pNET) (see Table 2 for clinical presentation of pancreatic NETs). Specific hormones related to clinical syndromes are:
- gastrin (Zollinger–Ellison syndrome)
- insulin/proinsulin (hypoglycemia symptoms)
- glucagon for glucagonomas
- vasoactive intestinal peptide (VIP) (VIP-omas).
Imaging techniques can be used to determine the location of the primary tumour and assess tumour extent (localisation and metastases). Common imaging techniques include computed tomography (CT) or MRI scans. As pancreatic NETs and carcinoid tumours both frequently over-express somatostatin receptors, somatostatin-receptor scintigraphy (SRS, Octreoscan) has been commonly used to localise and stage NET. SRS is also the diagnostic test of choice for locating secondaries as whole-body imaging enables the identification of distant metastases. Also, over the past decade, PET tracers for somatostatin receptor imaging led to better results and should improve staging and follow-up.3
Surgery is the only curative approach, and as such represents the traditional first line therapy for localised NETs. However, it is not always possible as most patients with NETs are diagnosed after metastases have occurred.
Evidence increasingly shows that pancreatic NETs are more responsive to therapeutic agents, most agents being associated with higher response rates in pancreatic compared to carcinoid NETs.
Traditionally, therapeutic approaches for patients with advanced, unresectable NETs have included hepatic-directed therapies ( e.g. surgical resection and hepatic artery embolisation) and systemic treatment options including the use of somatostatin analogues or interferon for control of hormonal hypersecretion, as well as alkylating chemotherapy. In addition, biologically targeted therapies may play an increasing role in patients with progressive advanced pancreatic NETs.
In patients with advanced NETs symptoms of hormone hypersecretion can usually be treated effectively with somatostatin analogues (e.g., octreotide, lanreotide), which will continue to be main therapies for functioning neuroendocrine tumours over the next few years.
- In midgut carcinoid, treatment with somatostatin analogues is also associated with improved time to tumour progression (results from PROMID with octreotide LAR).1,3
- Pasireotide, a new panreceptor analogue, might control clinical symptoms and hormone release in patients resistant to standard somatostatin analogue therapy.1,3
Interferon alpha is generally recommended as a second-line approach in patients with functioning NETs and low proliferation. Though their effect on symptom control is similar to that of somatostatin analogues and they may have greater antiproliferative activity, they do not act as rapidly and have a less favourable safety profile (fever, fatigue, anorexia and weight loss commonly reported).3
- In contrast to carcinoid tumours, pancreatic NETs are clearly responsive to cytotoxic chemotherapy.1,2
- Streptozocin– or temozolomide-based chemotherapy is likely to continue to play a role, particularly in patients with pancreatic NETs and a high tumour burden for whom tumour response is a priority.1
In phase II studies in pancreatic NETs, temozolomide has been combined with thalidomide, bevacizumab, or everolimus, with response rates ranging from 24% to 45%. The most promising response rates (70%) have been reported in studies of temozolomide combined with capecitabine. Altogether, these studies suggest that temozolomide-based regimens are at least comparable with streptozocin-based regimens in pancreatic NETs, and have a more favourable toxicity profile.1
Although the response rate of NETs to external beam radiation is limited, the introduction of systemic receptor-targeted therapy (peptide receptor radiotherapy [PRRT]) has provided beneficial effects in patients with high tumour content of somatostatin type 2 receptors.3
Biologically targeted therapies
Both the vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathways have emerged as an attractive target in NETs.1,2,3 Biologically targeted therapies thus involve agents such as TOR and VEGF inhibitors (including anti-VEGF receptor antibodies and tyrosine kinase inhibitors).
- NETs are highly vascular and characterised by upregulated VEGF and VEGF receptor (VEGFR) expression, which correlates with angiogenesis, metastases, and decreased progression free survival (PFS) among patients with low-grade NETs.
- mTOR is a central regulator of protein synthesis, promoting cell growth and proliferation, as well as cell metabolism and angiogenesis (in part by mediating VEGF and insulin growth factor (IGF)-1 signalling)
- For advanced pancreatic NETs, treatment with either mTOR inhibitor everolimus or VEGFR tyrosine kinase inhibitor sunitinib has been shown to prolong progression-free survival in randomised studies (see Table 3 for randomised trials of biologically targeted therapies in pancreatic NETs).
1- Kulke MH, Chan JA, and Bergsland EK. New treatment options for advanced neuroendocrine tumours. American Society of Clinical Oncology (ASCO). 2011 137-43, available at http://www.asco.org
2- Kulke MH, Bendell J, Kvols L, Picus J, Pommier R, Yao J. Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumours. J Hematol Oncol. 2011; 4: 29.
3- Öberg KE. Management of neuroendocrine tumours: Current and future therapies. Expert Rev Endocrinol Metab. 2011;6(1):49-62.
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