These malignancies predominately arise in the gastrointestinal (GI) tract or pancreas but can develop in any organ derived from the primitive endoderm.¹ NETs have the unique ability to produce polypeptide hormones and biogenic amines, both of which can lead to significant symptomatology. 

In 1907, a German pathologist Siegfried Oberndorfer coined the term karzinoide or ‘carcinoma-like’ to describe NETs in their unique feature of behaving like a benign tumour while having a malignant appearance microscopically. Although this term is still used in the World Health Organization’s (WHO) classification of NETs and often as a synonym for NETs arising in the GI tract, it has been criticised as it does not convey the malignant potential of NETs.

Epidemiology

NETs are relatively rare with approximately 1,900 cases diagnosed between 1994 and 2010 in Ireland, roughly 100 per year² (see Table 1). The numbers in both men and women are almost equal although those located in the small bowel and thyroid are more frequently found in males. The incidence has steadily risen with an annual percentage increase of 8% and a current rate of 4.6 per 100,000. The highest incidence occurs in patients aged 50-70. 

Approximately two-thirds of NETs arise in the GI tract with sites of origin including the stomach, small bowel, appendix and rectum and this subgroup encompasses the gastrointestinal NETs.^3,4 Most appear to be sporadic with risk factors not very well understood, however NETs can arise in the context of genetic syndromes such as multiple endocrine neoplasia types 1 and 2, von Hippel-Lindau disease and neurofibromatosis.^5,6

Presentation

NETs may be subclassified based on their ability to secrete different hormones and vasoactive peptides, and are termed either non-functioning or functioning. Non-functional NETs usually have a more indolent course and tend to present with local symptoms relating to mass effect. In patients where the NET is functioning and producing hormones, patients may become symptomatic due to hormone hypersecretion rather than local tumour bulk.⁷

Carcinoid syndrome, characterised by flushing, wheezing and diarrhoea, occurs in less than 10% of cases and is more common in those tumours originating in the ileum and jejunum. 5-hydroxytryptamine (5-HT) and amines are rapidly cleared by the liver, therefore the presence of liver metastases, or rarely retroperitoneal disease, is essential in order to avoid the entero-hepatic circulation. 

Other presentations that are more uncommon include pellagra and carcinoid heart disease, which result in tricuspid regurgitation and pulmonary stenosis. Bronchial and thymic carcinoids are typically associated with ACTH production leading to Cushing syndrome, while pancreatic NETs (PNET) can secrete gastrin, insulin, glucagon or vasoactive intestinal peptide. A significant number of patients will present with metastatic disease at the time of diagnosis with the most common sites of metastases being regional lymph nodes, liver and bone.⁷

Classification

The classification of NETs is complex and continues to evolve with a number of different organisations having developed classification systems including the WHO, the European Neuroendocrine Tumor Society (ENETS) and the North American Neuroendocrine Tumor Society (NANETS). Most commonly, NETs are classified histologically based on the tumour differentiation (well or poorly differentiated).⁸ The WHO classification of NETs is based on the tumour cell proliferation, grade I (Ki67 < 3%), grade II (between 3% and 20%), and grade III (> 20%) with grade I and II encompassing the well differentiated group and grade III being poorly differentiated. The term neuroendocrine carcinoma (NEC) is used for poorly differentiated tumours with a Ki67 > 20% (see Table 2).⁹

A number of different studies have shown that a high Ki67 index is associated with a more aggressive clinical picture and poorer prognosis.⁸ NECs share features and behaviour patterns resembling more aggressive small-cell lung cancer.¹⁰

Diagnosis and staging

The appropriate diagnosis and management of NETs requires the collaboration of a number of different specialists along with the use of biochemical and radiological tests. NETs are staged according to the American Joint Committee on Cancer (AJCC) tumour (T), node (N) and metastasis (M) system.

Imaging

Molecular functional-based imaging techniques including 68Gallium-DOTATOC/TATE positron emission tomography (PET/CT), octreoscan, and 18F-fluorodeoxyglucose (18FDG)-PET/CT have increased the sensitivity in the detection of NETs. As most NETs express receptors for somatostatin, somatostatin receptor scintigraphy (octreoscan) has remained the standard of care for many years as not only does it provide useful information regarding overall tumour burden, it also confirms the presence of somatostatin receptors which has therapeutic implications. Poorly differentiated tumours have generally less avidity for 68Ga-PET/CT and FDG-PET/CT may have greater sensitivity.

Biochemistry

Biochemical evaluation is important in NETs, both in diagnosis and monitoring treatment response. Chromogranin-A (CgA) is the most important circulating biomarker especially in non-functioning tumours¹¹ and raised levels have been shown to be associated with a poorer prognosis.¹² Elevated levels are seen in approximately 80% of patients with small intestinal NETs and in gastrin and glucagon secreting PNETs. 

CgA can be elevated in the absence of NETs in cases such as renal insufficiency, cardiovascular disease, hyperthyroidism and inflammatory bowel disease. Proton pump inhibitors are also known to cause false elevations in CgA. Serotonin levels can be measured using a 24-hour urine collection for 5-hydroxyindoleacetic acid, which is recommended in metastatic lung and gastrointestinal NETs, particularly if symptoms are present. 

Treatment

All patients should be discussed at a multidisciplinary meeting to determine the best treatment for the individual. In Ireland, St Vincent’s University Hospital, Dublin, is the only ENETs accredited centre of excellence. With a wide variety of beneficial treatment options now available, the most challenging issue is determining the most appropriate and effective sequence of treatments. A watch-and-wait approach remains a reasonable option in patients that are minimally symptomatic with well differentiated NETs.

Loco-regional treatment

Surgery remains the mainstay of treatment for localised resectable NETs and for a select number of patients with limited hepatic metastases, resection of the primary tumour and of metastatic deposits can be performed with curative intent.¹³ A meta-analysis reported five-year overall survival rates ranging from 41% to 100% in those that underwent hepatic resection.¹⁴

Surgical debulking also plays a role in the management of NETs, with other local treatment options including hepatic regional therapy with embolisation both bland or with chemotherapy.

Systemic therapies

Somatostatin analogues

Currently first-line medical treatment for well differentiated NETs is somatostatin analogues. The PROMID trial was a phase IIIb placebo-controlled trial in patients with metastatic well differentiated midgut NETs.¹⁵ Patients were assigned to either octreotide LAR 30mg intramuscularly monthly or placebo. The median time to progression in the treatment arm was 14.3 months compared to six months in the placebo group. Stable disease at six months was seen in 66.7% of the treatment group compared to 37.2% in the placebo group. Recently reported long-term follow-up results failed to demonstrate a significant difference in median OS between the two groups, however, 38 of the 43 patients on the placebo arm were treated with octreotide.¹⁶

The CLARINET study looked at the antiproliferative effects of lanreotide (a long-acting somatostatin analogue) in over 200 patients with gastroenteropancreatic (GEP) NETs with Ki67 values < 10%.¹⁷ The primary end-point of the trial was progression-free survival (PFS), which was significantly prolonged in the lanreotide group at 24 months (65.1% vs 33%). Overall survival was not different between the two groups, however this is complicated due to crossover. 

Overall, it is well tolerated with the majority of adverse events being mild; the most common side-effects being diarrhoea and cholelithiasis. 

For those patients whose symptoms are not controlled with a somatostatin analogue, telotristat ethyl is a novel tryptophan hydroxylase inhibitor has been developed and recently approved by the European Medicines Agency (EMA).¹⁸

Biologics

Interferon-alpha

Interferon-alpha was first introduced in the 1980s, which demonstrated a response in around 10% of patients but offered symptom control in as many as 60%.¹⁹ However, due to challenging side-effects, treatment with interferon-alpha is reserved for patients who cannot tolerate or are resistant to somatostatin analogues.

mTOR inhibitors

Patients with metastatic NETs appear to benefit from mTOR inhibition with everolimus when used in combination with somatostatin analogues. The RADIANT-2 trial was a phase III randomised controlled trial with 429 patients with advanced NET and carcinoid syndrome.²⁰ Median PFS was 16.4 months for those receiving everolimus with octreotide compared to 11.3 months for patients receiving octreotide alone. Adverse events relating to everolimus were stomatitis, rash, fatigue and diarrhoea. 

A subsequent trial, RADIANT-3 looked at everolimus in advanced PNETs.²¹ The median PFS was 11.0 months with everolimus as compared with 4.6 months in the placebo group, with a hazard ratio for disease progression with everolimus of 0.35. RADIANT-4 looked at patients with progressive non-functioning lung or gastrointestinal NET.²² Different to the RADIANT-2 trial, patients were not receiving a somatostatin analogue at the time of participation. The median PFS in the everolimus group was 11 months compared to 3.9 months in the placebo group.

Anti-angiogenesis

The multi-tyrosine kinase inhibitor sunitinib has demonstrated significant activity in clinical studies of PNETs.²³ A phase III study of 171 patients with well differentiated PNETs who received either sunitinib or placebo, demonstrated a statistically significant prolongation of the PFS in the sunitinib group (11.4 vs 5.5 months). Bevacizumab combined with everolimus has been compared with everolimus alone in a phase II study of patients with advanced PNETs and combination therapy yielded a median PFS of 16.7 vs 14 months in those treated with everolimus alone.²⁴

Chemotherapy

The benefits of cytotoxic chemotherapy appear to be modest in patients with advanced well differentiated NETs. Temozolomide in combination with capecitabine (CAPTEM) has been shown to be effective in well differentiated PNETs with radiological response rates of 60-70% reported.²⁵ A phase II trial of CAPTEM presented at the 2014 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, demonstrated a partial response in 4 of 12 patients with metastatic NET.²⁶

More recently at ASCO 2018 a further phase II trial, E2211, compared temozolomide with capecitabine to temozolomide alone in PNETs. This showed a median PFS of 22.7 months for CAPTEM versus 14.4 months for temozolomide monotherapy.²⁷

Peptide receptor radioligand therapy (PRRT)

Evidence for the use of 177Lu-Dotatate PRRT has come from the randomised phase III international NETTER-1 study where 230 patients with somatostatin receptor-positive advanced midgut NETs, who had progressed on standard doses of octreotide LAR, were randomised to either four doses of 177Lu-Dotatate every eight weeks or octreotide LAR 60mg every four weeks.²⁸

The median PFS for octreotide LAR alone was 8.4 months and it had not been reached in the PRRT group with nearly 30 months of follow-up. Objective radiological response rates were 18% in the treatment group versus 3% in the octreotide group. The hazard ratio for disease progression or death also significantly demonstrated the benefits of 177Lu-Dotatate at 0.21. 

Overall, PRRT with 177Lu-Dotatate is well tolerated. The most common adverse event in the treatment group was nausea (all-grade 59%) which was felt to be related to the supportive medications to protect nephrotoxicity. The most serious long-term toxicity associated with PRRT however is irreversible myelotoxicity – three large studies with a prolonged duration of follow-up demonstrated that myelodysplastic syndrome occurs in approximately 2% and acute leukaemia in approximately 0.5% of those treated.²⁹

Immunotherapy

Immunotherapy, inhibition of PDL-1 and PD-1, continues to rapidly evolve proving beneficial in a variety of tumour types. As immune checkpoint inhibitors appear to have greater efficacy in patients with a higher mutational burden, it is conceivable that they are unlikely to play a major role in the well differentiated NETs. However, a recent retrospective review of PD-L1 expression status in metastatic GEP NET found that 7 of 32 samples were positive for PD-L130. 

There a number of trials ongoing looking at the potential benefits of immunotherapy in NETs.

Neuroendocrine carcinoma (NEC) treatment

Metastatic or unresectable NEC chemotherapy options are similar to those that are typically seen in small-cell lung cancer such as carboplatin/etoposide. However, more recent data suggest that well differentiated tumours with intermediate Ki67 level in the 20-50% range may not respond as well to platinum/etoposide as patients with small-cell histology or high Ki67 >55%. 

Recent data published in the New England Journal of Medicine showing a benefit of adding atezolizumab, a PDL-1 inhibitor, to standard chemotherapy in extensive-stage small-cell lung cancer may, in the future, have implications for the treatment of other poorly differentiated NEC.³¹

Conclusion

NETs represent a heterogenous group of malignancies with a wide range of subtypes, and their classification continues to evolve. Previously, treatment options were limited whereas over the past decade significant advances have been made with multiple biologic agents and PRRT now available. The overall prognosis for patients with NETs has considerably improved as a result of more aggressive surgery and improved therapeutic advances. 

Recent studies have reported that even in the setting of advanced metastatic disease, well differentiated NETs five-year survival rates are as high as 77-95% when treated aggressively.³ The difficulty we are faced with now in the setting of multiple effective treatment options is finding the optimal and most appropriate sequence of treatments. 

While advances in therapeutics have been made there is a need for ongoing research and, as this is a rare malignancy, trial design and appropriate patient selection is critical in order to continue to improve survival.

References 

1. Niederle MB, Hackl M, Kaserer K, et al. Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European Neuroendocrine Tumour Society classification: an analysis based on prospectively collected parameters. Endocr Relat Cancer 2010; 17(4): 909-18
2. https://www.ncri.ie/sites/ncri/files/pubs/CancerTrendsNo.18-NeuroendocrineCancers.pdf
3. Tsikitis VL, Wertheim BC, Guerrero MA. Trends of incidence and survival of gastrointestinal neuroendocrine tumors in the United States: a seer analysis. J Cancer 2012; 3: 292-302
4. Fraenkel M, Kim M, Faggiano A, et al. Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocr Relat Cancer 2014; 21: R153-163
5. Marx S, Spiegel AM, Skarulis MC, et al. Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med 1998; 129: 484-494
6. Anlauf M, Garbrecht N, Bauersfeld J, et al. Hereditary neuroendocrine tumors of the gastroenteropancreatic system. Virchows Arch 2007; 451 Suppl 1: S29-38
7. Uri I, Grozinsky-Glasberg S. Current treatment strategies for patients with advanced gastroenteropancreatic neuroendocrine tumors. Clin Diabetes Endocrinol 2018; 4: 16
8. Kim JY, Hong SM. Recent updates on neuroendocrine tumors from the gastrointestinal and pancreatobiliary tracts. Arch Pathol Lab Med 2016; 140(5): 437-48
9. Ohike N, Adsay NV, La Rosa S, et al. Mixed neuroendocrine-non-neuroendocrine neoplasms.c In: WHO classification of tumours of endocrine organs, 4th ed, Lloyd RV, Osamura RY, Kloppel G, Rosai J (Eds), IARC Press, Lyon 2017. p.238
10. Sorbye H, Welin S, Langer SW, et al. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol 2013; 24: 152-160
11. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97: 934-959
12. Chou WC, Chen JS, Hung YS, et al. Plasma chromogranin A levels predict survival and tumor response in patients with advanced gastroenteropancreatic neuroendocrine tumors. Anticancer Res 2014; 34(10): 5661-5669
13. Basuroy R, Srirajaskanthan R, Ramage JK. A multimodal approach to the management of neuroendocrine tumour liver metastases. Int J Hepatol 2012; 819193
14. Yuan CH, Wang J, Xiu DR, et al. Meta-analysis of liver resection versus nonsurgical treatments for pancreatic neuroendocrine tumors with liver metastases. Ann Surg Oncol 2016; 23(1): 244-9
15. Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol 2009; 27: 4656-4663
16. Arnold R, Wittenberg M, Rinke A, et al. Placebo controlled, double blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID): Results on long-term survival. ASCO Meeting Abstracts 2013; 31: 4030
17. Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 2014; 371: 224-233
18. Kulke MH, Hörsch D, Caplin ME, et al: Telotristat ethyl, a tryptophan hydroxylase inhibitor for the treatment of carcinoid syndrome. J Clin Oncol 2017; 35:14-23
19. Mirvis E, Mandair D, Garcia-Hernandez J, et al. Role of interferon-alpha in patients with neuroendocrine tumors: a retrospective study. Anticancer Res 2014; 34(11): 6601-7
20. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 2011; 378: 2005-2012
21. Yao JC, Shah MH, Ito T, et al; for the RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group Everolimus for Advanced Pancreatic Neuroendocrine Tumors. N Engl J Med 2011; 364: 514-523
22. Yao JC, Fazio N, Singh S, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 2016; 387: 968-977
23. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 501-513
24. Kulke MH, Niedzwiecki D, Foster NR, et al. Randomized phase II study of everolimus (E) versus everolimus plus bevacizumab (E+B) in patients (Pts) with locally advanced or metastatic pancreatic neuroendocrine tumors (pNET), CALGB 80701 (Alliance). Journal of Clinical Oncology 2015; 33 (15 suppl): 4005-4005
25. Fine RL, Gulati AP, Krantz BA, et al. Capecitabine and temozolomide (CAPTEM) for metastatic, well-differentiated neuroendocrine cancers: The Pancreas Center at Columbia University experience. Cancer Chemother Pharmacol 2013; 71(3): 663-70
26. Ramirez RA, Beyer DT, Chauhan A, et al. The role of capecitabine/temozolomide in metastatic neuroendocrine tumors. Oncologist 2016; 21(6):671-5
27. Kunz PL, Catalano PJ, Nimeiri H, et al. A randomized study of temozolomide or temozolomide and capecitabine in patients with advanced pancreatic neuroendocrine tumors: A trial of the ECOG-ACRIN Cancer Research Group (E2211). ASCO 2018 abstract
28. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med 2017; 376: 125
29. Gabriel M, Nilica B, Kaiser B, et al. Twelve-year follow-up after peptide receptor radionuclide therapy (PRRT). J Nucl Med 2018; pii: jnumed.118.215376
30. Tsuruoka K, Horinouchi H, Goto Y, et al. PD-L1 expression in neuroendocrine tumors of the lung. Lung Cancer 2017; 108: 115-20
31. Horn L, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. New Engl J Med 2018; DOI: 10.1056/NEJMoa1809064