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Octreotide – A Review of its Use in Treating Neuroendocrine Tumours

European Oncology & Haematology, 2013;9(2):105–9 DOI: http://doi.org/10.17925/EOH.2013.09.2.105

Abstract:

Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms whose incidence has dramatically increased in recent years. Octreotide is a somatostatin analogue used in the treatment of NETs, and its use in clinical trials has been associated with substantially increased survival. Although traditionally used for the relief of symptoms that result from release of peptides and neuroamines, there has been a growing body of evidence that suggest octreotide has antiproliferative effects. A phase III clinical study has demonstrated that the long-acting formulation (LAR), octreotide LAR, lengthens time to tumour progression in patients with well-differentiated metastatic midgut NETs, and that octreotide LAR is a treatment option for patients with metastatic midgut NETs, regardless of functional status. Furthermore, octreotide LAR has demonstrated clinical efficacy in different types of NETs. These data, along with emerging data on somatostatin analogs, may change the way doctors approach this patient population and reinforce the use of these drugs as a treatment option for patients with non-functioning tumours.
Keywords: Neuroendocrine tumours, octreotide, somatostatin analogues
Disclosure: The authors have no conflicts of interest to declare.
Acknowledgments: Editorial assistance was provided by Katrina Mountfort at Touch Medical Media.
Received: October 16, 2013 Accepted: October 26, 2013
Correspondence: Frederico Costa, Oncology Center, Hospital Sírio-Libanês, Adma Jafet Street, 91, São Paulo, SP, 0138-050, Brazil. E: Frederico.costa@hsl.org.br
Support: The publication of this article was supported by Novartis. The views and opinions expressed are those of the authors and not necessarily those of Novartis.

An erratum to this article can be found below.

Neuroendocrine tumours (NETs) is a collective term for a diverse range of neoplasms that arise from cells that originate in the endocrine and nervous systems and share common morphological and immunohistochemical features, including the presence of secretory granules. These tumours can secrete a variety of neuropeptides, which may or may not cause characteristic hormonal symptoms (functioning or non-functioning NETs).

NETs have generally been considered rare; their incidence has been estimated at 2.5 to 5 per 100,000 people per year and prevalence of 35 per 100,0001 and may be higher if undiagnosed NETs are included. Autopsy studies have indicated that pancreatic NETs (pNETs) occur in 0.8 % to 10 % of patients undergoing a post-mortem examination.2 However, data from the largest US epidemiological database (SEER) indicate that the incidence of gastroenteropancreatic NETs (GEP-NETs ) is increasing dramatically in the US: a fivefold increase has been reported between 1973 and 2004 (see Figure 1). The incidence of GEP-NETs has risen steeply since 1992, and more than doubled since 1985.3 This is in contrast to the overall incidence of malignant neoplasms, which has remained relatively consistent since 1992. NETs of the lung, rectum and small intestine are currently the most frequently diagnosed NETs in the US and are also the three subgroups of NETs that have increased in incidence by the greatest margin from 1973 to 2004.3 The age-adjusted incidence of NETs of the small intestine and digestive system has increased by 460 % and 720 %, respectively, over the past 30 years.4

NETs that secrete peptides and neuroamines can cause recognisable clinical syndromes, including carcinoid syndrome.4 However, due to the indolent nature of NETs, many patients are asymptomatic in the early stages, or present with only vague symptoms such as abdominal pain.4 As a result, NETs are frequently metastatic at the time of diagnosis: liver metastases are observed in 40 % of patients who present with small intestinal and 60–70 % of patients with pNETS.3,5 Other factors influencing the presence of liver metastases include the primary tumour site, tumour stage, histological differentiation and proliferative activity (grading; G1–G3). Carcinoid syndrome is frequently associated with distant metastases, especially in the liver. The prognosis for NETs varies according to proliferative activity: median survival in distant metastatic disease was 33 months in patients with G1–G2 graded NETs, but only 5 months in patients with poorly differentiated carcinomas.3 The 5-year survival rate was 35 % in well to moderately differentiated (grade 1/2) NETs, but less than 5 % in poorly differentiated grade 3 NETs.3

The first-line treatment strategy for NETs is surgery, but this is rarely curative, as most patients present at advanced stages of disease.3,5 Other treatment options include cytoreduction, radiological intervention (by embolisation and radiofrequency ablation) and chemotherapy.4 Surgical debulking can reduce the extent of hormone production and relieve symptoms, but owing to the long disease course, palliative care is important. Somatostatin analogues (SSAS), including octreotide and lanreotide, were introduced to control symptoms that result from release of peptides and neuroamines. Octreotide is the most studied SSA. This article aims to review the 25 years of clinical experience with octreotide in treatment of NETs.

Development and Clinical Uses of Octreotide
Octreotide is a synthetic octapeptide SSA with more prolonged pharmacological actions than the endogenous hormone. Native somatostatin has a half-life of 2–3 minutes; octreotide has a halflife of 90–120 minutes when administered subcutaneously, and a pharmacodynamic action lasting up to 8–12 hours.6 Since octreotide resembles somatostatin in its physiological activities, it affects numerous pathways that may confer antiproliferative effects in NETs through inhibition of tumour angiogenesis and inhibition of secretion of growth factors.7,8 Direct mechanisms by which octreotide achieves tumour regression include binding to somatostatin receptors sst2 and sst5 , which are found in high density on tumour cells,9 and thereby inhibiting hormone secretion from the tumour, inducing apoptosis and cell cycle arrest, mainly through the regulation of phosphotyrosine phosphatase (PTP) and mitogen-activated protein (MAP) kinase. Binding to sst2 and sst5 receptors, octreotide blocks the effects of growth factor receptor stimulation and results in increased production of the cell cycle inhibitor p27.7 Binding to sst2 receptors, SSAs affect the PI3K/Akt/mammalian target of rapamycin (mTOR) pathway and SHP1 signalling and may overlap with pathways used by the mTOR inhibitor, everolimus.10 Indirect effects include inhibition of angiogenesis and the release of secretory factors required for tumour growth, as well as modulation of the immune system (see Figure 2), and inhibition of insulin-like growth factor 1 (IGF-1) secretion.7,8,11

Octreotide is approved in the US and Europe for treatment of severe diarrhoea/flushing episodes associated with metastatic carcinoid tumours and profuse watery diarrhoea associated with vasoactive intestinal polypeptide (VIP)-secreting tumours.12,13 Octreotide is also approved in 42 countries for tumour control for advanced midgut NETs based on the Placebo-Controlled Prospective Randomized Study on the Antiproliferative Efficacy of Octreotide acetate LAR in Patients with Metastatic Neuroendocrine Midgut Tumours (PROMID) study.14 Additionally, treatment guidelines now recommend the use of octreotide as an antiproliferative agent in patients with functional and non-functional midgut NET,15,16 based on results from the randomised phase III PROMID trial.17 Pooled data from more than 14 trials including almost 400 patients revealed that 71 % of patients with GEP-NETs and carcinoid syndrome experience resolution or improvement of diarrhoea (range: 40–88 %) and flushing (range: 48–100 %) during treatment with octreotide.18–20 Octreotide can be used peri-operatively and may prevent carcinoid crisis, i.e. the immediate onset of debilitating and lifethreatening symptoms that are associated with carcinoid syndrome.21

Octreotide may also be used in asymptomatic patients at the time of diagnosis of metastatic disease.19 There is evidence that the impact of octreotide extends beyond symptom relief. A single-institution retrospective study of 90 consecutive patients with advanced GEP-NETs who received octreotide for carcinoid syndrome, found that a much greater percentage of patients treated with octreotide achieved 5-year survival from diagnosis compared with historical controls (67 % versus 18 %, respectively).22 Subsequent analysis of the SEER database found that survival in patients with metastatic NETs increased from 19 months (1973 to 1987) to 39 months (1988 to 2004) following the introduction of octreotide (see Figure 3).3 This increased survival was observed in patients with GEP-NETs and distant metastases; patients with localised and regional disease did not exhibit significantly extended survival time. A possible explanation for this improvement may be that not only does octreotide achieve control of the symptoms of carcinoid syndrome but also has a potential antiproliferative effect, which could alter the natural history of NETs. Potential lethal consequences associated with carcinoid crisis, such as severe flushing, diarrhoea, valvular heart disease and haemodynamic instability, are now rare occurrences. Complications due to tumour progression tend to occur later in the disease course.3

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Keywords: Neuroendocrine tumours, octreotide, somatostatin analogues
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