The Role of Somatostatin Analogues in the Management of Gastroenteropancreatic Neuroendocrine Tumours

The term neuroendocrine tumours (NETs) is used to describe a heterogeneous group of rare, typically slow-growing neoplasms originating from specialised cells in the neuroendocrine system. These cells are capable of releasing hormone-like substances into the blood in response to signals from the nervous system. NETs can develop anywhere in the body, but they most commonly occur in the gastrointestinal tract (stomach, small and large intestine, appendix), followed by lungs, pancreas, and to a lesser extent in the gonads (ovaries and testes), liver, and the biliary tract. This extensive diversity means that NETs display different behavioural patterns depending on the cell of origin and site of the tumours.

Clinical manifestations of NETs do not only depend on the tumour’s type, size, and location, but also whether it is functional (produces excess hormones to cause symptoms), and has metastasised. NETs also frequently demonstrate elevation of one or more biochemical markers. Serum chromogranin A (CgA) is the most established one, and may be useful in making diagnosis, estimating prognosis, and measuring response to therapy. Pathological evaluation of the disease extent involves both anatomical imaging and functional nuclear imaging with radiolabelled somatostatin analogues (e.g. ¹¹¹Indium-labelled pentetreotide, OctreoScan®), which help determine the TNM (Tumour-Node-Metastasis) classification of the tumour. All of the aforementioned factors, along with mitotic count or Ki-67 index (as a marker of cell proliferation), will affect how NETs are classified and graded, and ultimately influence the management options.

Surgical resection of the primary tumour and as much of the metastatic disease as possible is the mainstay of curative therapy, and will increase the efficacy of subsequent medical therapy. However, in patients where surgery is not feasible, selective hepatic embolisation techniques such as trans-catheter arterial chemo-embolisation (TACE) or selective internal radiation therapy (SIRT) may be used to treat liver metastases regardless of the origin of the primary tumour. Depending on the tumour grade, effective management strategies may also include cytotoxic chemotherapy, which is more beneficial in refractory, high grade or poorly differentiated tumours. On the other hand, somatostatin analogues (SSAs) and targeted therapies such as tyrosine kinase inhibitors and anti-angiogenics are preferable as early treatment for well differentiated disease. Patients with tumours expressing somatostatin receptors, as indicated by the degree of radionuclide uptake in somatostatin receptor scintigraphy, will benefit the most from peptide receptor radionuclide therapy (PRRT) as well as SSAs.

The Somatostatin Analogues

Somatostatin is a neurotransmitter peptide that generally serves to inhibit cellular secretion. In the body, it controls the release of several other hormones such as insulin and glucagon. Synthetic somatostatin analogues arise from the pharmacological reconfiguration of endogenous somatostatin, which substantially prolongs the half-life of the peptide and hence improves its efficacy.

The characteristic of gastroenteropancreatic (GEP) NETs presents a major challenge to its management due to the varying neuroendocrine cell types involved and the subsequent diversity of the secretory spectrum of neuropeptides and amines produced (which may include serotonin, catecholamines, dopamine, histamine, gastrin, glucagon, and prostaglandins, among others). The clinical manifestation is a collection of non-specific symptoms commonly referred to as carcinoid syndrome, such as diarrhoea, cutaneous flushing, bronchoconstriction, and cardiac disease – more specifically right-sided heart failure; as well as sweating, intermittent abdominal pain, and gastrointestinal bleeding.

Somatostatin analogues that are currently available in the market, Sandostatin® LAR® (octreotide) and Somatuline® Autogel (lanreotide) display high affinity binding for somatostatin receptors. As NET cells often express high density of somatostatin receptors, this effectively induces biochemical responses that result in the inhibition of hormone secretion and provides symptom relief for patients with GEP NETs.

Some of the approved indications of SSA therapy are:

1. Treatment of patients with symptomatic carcinoid syndrome
2. Prevention or treatment of carcinoid crisis as part of the perioperative management of patients with GEP NETs, and for at risk patients prior to commencing PRRT or chemotherapy
3. Treatment of progressing well-differentiated metastatic GEP NETs regardless of the presence or absence of carcinoid syndrome
4. Treatment of symptomatic vasoactive intestinal peptide secreting tumours

The SSAs are generally well tolerated, although side effects such as mild gastrointestinal upset (bloating, abdominal pain and nausea), hyperglycaemia, hypothyroidism, and development of gallstones (cholelithiasis) with long-term treatment may occur. The recommended starting doses when used as anti-proliferative treatment are octreotide LAR 30 mg (IM injection) or lanreotide autogel 120 mg (deep SC injection) given every four weeks. The long-lasting depot formulation allows the drugs to be administered monthly, which largely eliminates the need for once daily injections. However, it may be useful to initially commence patients on a short-acting SSA to assess treatment tolerability before converting to a long-acting preparation.

The role of SSAs in the management of GEP NETs is well established. It not only ameliorates symptoms of the carcinoid syndrome from functional GEP NETs but also demonstrates considerable anti-proliferative activity, which prolongs patients’ progression-free survival.  Therefore the general consensus favours treating both functional and non-functional NETs with SSAs, regardless of whether or not the tumours produce a distinct clinical syndrome.