Chromogranin A is present in chromaffin granules of neuroendocrine cells and is usually raised in NET . Concentration correlates with tumour burden [26]. 5-Hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin is the breakdown product of serotonin and may be detected in urine. Measurement of HIAA may achieve a sensitivity and specificity of 73 % and 100 % respectively [27]. Furthermore, depending on the specific origin of the NET, correlating biochemical markers may be detected (Table 32.2).

For localization of the primary tumour and staging purposes multimodality imaging including the use of CT, MRI, endoscopic ultrasound, somatostatin receptor scintigraphy (SSRS) and positron emission tomography (PET) may be employed [15]. SSRS involves the intravenous injection of radiolabelled somatostatin analogue. Gallium-68 labelled octreotide PET may assist the detection tumours not apparent on conventional CT [28]. Iodine-131-labelled metaiodobenzylguanidine (¹³¹I-MIBG) scintigraphy is useful for identifying tumour uptake and may also be used for therapeutic purposes.

Radical resection in localized NET is the only curative approach in patients with NET. Patients may undergo elective resection but occasionally those with bowel NET may present with acute bowel obstruction requiring emergency resection.

Traditionally, interferon alpha (IFNa) therapy has been used. It activates T-lymphocytes and causes apoptosis . In patients with functional NET , improvement of symptoms due to hormonal hypersecretion and tumour reponse of around 10 % have been reported [29–31]. However, a range of associated toxicities such as fatigue, headache, myalgia and depression mean that long term use may not be tolerated and its use has become less common place in current management.

Known subtypes of somatostatin receptors are SST1, SST2a, SST2b, SST3, SST4 and SST5. Somatostatin analogues include octreotide and lanreotide are commonly used, but newer generation analogues like pasireotide block a wider range of these G protein-coupled transmembrane receptors. Treatment leads to the down regulation of peptide secretion in functional tumours thus providing symptomatic improvement. Beyond its functional ability, evidence from the PROMID trial suggested an anti-proliferative effect. Eighty five patients with locally inoperable or metastatic well differentiated midgut tumors were randomized to octreotide or placebo [32]. The median time to tumour progression was found to be significantly longer with octreotide compared to placebo (14.3 vs 6 months). Benefit was seen in both functional as well as non-functional tumours. CLARINET (Lanreotide Antiproliferative Response in patients with GEP-NET ) was a large phase III randomised controlled trial assessing the effect of lanreotide on progression free survival (PFS) in non-functioning well to moderately differentiated NET. In the treated group, a significant extension of PFS was reported (HR 0.47; p = 0.0002) [33]. Side effects included pain at the injection site, anorexia, nausea, diarrhoea, lethargy and hypoglycaemia.

Systemic radionuclide therapy with ¹³¹I-MIBG is useful as a therapeutic adjunct in managing diffuse metastases demonstrating tracer uptake. Biochemical and radiological response rates reaching 40–60 % and 10–15 % respectively have been reported [34, 35]. However, repeated use may increase the risk of radiation nephritis, pancytopenia and myelodysplasia.

In patients with liver-only metastases, hepatic arterial embolization may be used alone or with infusional chemotherapy. Radioactive microspheres like yttrium-90 injected into tumour sites deliver a high concentration of therapeutic radiation with a sharp fall off which minimizes damage to normal tissue. Percutaneous radiofrequency ablation (RFA) under radiological guidance employs rapidly alternating electric current which generate heat leading to tumour necrosis at the target site.

One of the earliest trials using chemotherapy was in the 1980s showing modest tumour activity. A randomised controlled study compared 5-fluorouracil (5FU) combined with streptozocin versus doxorubicin showing similar response rates of 22 % and 21 %. However, this did not translate to any survival benefit [36]. In 1992, a randomised trial using streptozocin combined with doxorubicin reported a combined biochemical and radiological response rate of 69 % and a median survival of 26 months [37]. Follow-up investigation in 2004 compared this two drug combination with the addition of 5-fluorouracil vs triple combination with streptozocin/5-fluorouracil/cisplatin. Radiological response rate was reported at 36 %, 39 % and 38 % respectively rate with a median overall survival of 24, 37 and 32 months respectively [38].

Studies investigating capecitabine monotherapy, taxanes, topotecan, and gemcitabine have yielded response rates of between 0 % and 10 % [39–43].

Temozolamide has been used in together with other drugs with varying success. Combination of temozolomide with anti-angiogenic drugs like thalidomide and bevacizumab have reported overall response rates of 24–45 % [44, 45]. Addition of capecitabine, an oral anti-metabolite, however achieved a response rate of 70 % in a very small study [46]. Variation of tumour sensitivity to this alkylating agent could be due to the mediating effect of methylguanine DNA methyltransferase (MGMT). It is postulated that the varied expression of this regulatory protein could account for the effectiveness of the drug, and the absence of MGMT may explain the sensitivity of some tumours [47].

Combination of platinum with a topoisomerase inhibitor has shown some activity. Firstline treatment with carboplatin plus etoposide versus cisplatin plus etoposide demonstrated equivalent response rates of 30 % vs 31 %, and overall survival of 11 vs 12 months respectively [48]. However, it is postulated that tumours with Ki-67 of <55 % were less likely to respond to platinum based chemotherapy regimens [49].