Neuroendocrine tumors (NETs) are neoplasms (tumors) that arise from cells in the body that secrete peptide molecules that can function as neurotransmitters when secreted at synapses between neurons (nerve cells) or as hormones when secreted directly into the blood to exert their chemical effect at sites remote from the site of the secreting cells.
Within the gastrointestinal system and pancreas there are many different types of neuroendocrine cells secreting many different hormones. The functions of some of these hormones (e.g. insulin) are well known, but the precise functions of some of the other hormones are not well understood yet.
Some neuroendocrine tumors secrete excessive volumes of hormones that cause symptoms that can severely affect quality of life and can actually be life-threatening e.g. extremely low blood glucose levels caused by excessive insulin secretion by Insulinomas. Those tumors that secrete excessive hormones that produce symptoms are referred to as “functioning” NETs.
However, most GEPNETs do not secrete excessive hormones that create clinical syndromes and are, therefore, referred to as “non-functioning” NETs.
Neuroendocrine tumors are all inherently malignant in that they have the ability to metastasize (spread in the blood or lymph) to lymph nodes and distant organs in the body and they often do.
However, despite being inherently malignant, the majority of GEPNETs behave in a much more indolent manner than the more common cancers (carcinomas and sarcomas), so people can often live for many years, despite having metastases, even widespread metastases. These are grade 1 and 2 neuroendocrine tumors. There are, however, some GEPNETs (grade 3 neuroendocrine tumors and neuroendocrine carcinomas, NECs) that behave in an aggressively malignant fashion.
Endocrine systems are characterized by control mechanisms to regulate normal secretion of hormones in accordance with the current needs of the organism. Somatostatin is one of the hormones produced by neuroendocrine cells and it functions as one of the important inhibitory regulators of other endocrine cells. Somatostatin is a peptide, comprising 14 amino acids, which binds to five different receptors on various cell types, which control different functions in those cells. Most GEPNET cells (grade 1 and 2 and some grade 3) have receptors for somatostatin on their cell membranes.
In the 1980’s synthetic analogues of somatostatin were produced by pharmaceutical companies. Octreotide (Sandostatin®Novartis) and Lanreotide (Somatuline®Ipsen) were the first of these. They comprise eight amino acids and bind to two of the five somatostatin receptors. Initially they were used to inhibit secretion of hormones by the tumour cells that caused severe symptoms like diarrhoea and flushing. It was later noted that people given somatostatin analogues appeared to survive longer than those who were not given these agents. Subsequent large, prospective, randomized, placebo-controlled trials (PROMID & CLARINET) confirmed that both octreotide and lanreotide, compared with placebo, significantly prolonged survival of patients with GEPNETs, whether their tumors were “functioning” (secreting excessive volumes of hormones) or “non-functioning”.
Principles of Treatment of GEPNETs
As with all malignant solid tumors confined to their organ of origin, surgical resection is the treatment most likely to cure the disease.
Surgical resection is also the optimal treatment for GEPNETs with limited metastatic disease in regional lymph nodes or the liver.
Somatostatin analogues (SSAs) can inhibit proliferation and growth of well-differentiated (grades 1 & 2) GEPNETs, but SSAs are not chemotherapy drugs, so they do not “kill” tumour cells. Logically, this effect would be more effective if the number of SSA molecules in a given dose is sufficient to bind to all the tumour cells. Where there is a large bulk of tumour, larger doses of SSA would be required to bind to and inhibit all the malignant cells. Increasing the dose of SSA can be expected to increase the likelihood of side effects and make the cost of treatment prohibitive – they are very expensive agents!
To actually kill tumors with SSA, radioactive isotopes can be attached to the SSA and the complex is then injected intravenously. This is called peptide receptor radiation therapy (PRRT). The SSA takes the radioactive isotope to the surface of the malignant cells and the isotope then irradiates the cells. The isotopes that have been used effectively are 177Lu and 90Yt.
The grade 1 and 2 GEPNETs, the majority of GEPNETs, are not responsive to chemotherapy, but grade 3 neuroendocrine tumors may respond, while chemotherapy is the first-line treatment for neuroendocrine carcinomas.
Newer pharmaceuticals, Sunitinib, a tyrosine kinase inhibitor and Everolimus, a mTOR inhibitor have been shown to significantly prolong survival of patients with disseminated metastases from GEPNETs.
For lower grade metastases from GEPNETs that are localized to or dominant in the liver there are a variety of locoregional treatment options. Cytoreductive (debulking) surgical resection, with or without additional radiofrequency or microwave ablation is an accepted option for GEPNETs, which would not be appropriate for most other types of malignant tumors. Radiofrequency or microwave ablation may also be administered by percutaneous approaches. Bland embolization, chemoembolization and radioembolization involve selectively occluding the arterial blood supply of tumors in the liver, alone or with chemotherapy drugs or radioactive isotopes, delivered by catheters introduced into the hepatic arteries.
There are therefore many factors to consider in managing patients afflicted by these tumors, so it is highly desirable that the treatment of all patients with neuroendocrine tumors is discussed by teams comprising specialists from several different medical specialities – our team in Cape Town, which meets once a month, includes pathologists, diagnostic radiologists, nuclear medicine physicians, a surgical oncologist / hepato-pancreato-biliary surgeon, medical / radiation oncologists, endocrinologists and interventional radiologists. Some of these specialists are in full-time private practice, some in state practice and some work across both sectors. There are also Multi-Disciplinary Teams (MDTs) in place at Tygerberg Hospital and Groote Schuur Hospital.