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Biotherapy for metastatic endocrine tumours

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Somatostatin analogues have been the mainstay of symptomatic management of patients with neuroendocrine tumours (NETs) for two decades with the main mechanism of action being inhibition of peptide release. Evidence base for interferon use is perhaps less clear. It may contribute to symptom control by abrogating peptide release, and there is some evidence that it has an anti-proliferative action. Combination of somatostatin analogues and interferon provides symptom control, mainly by effecting a reduction in the amount of circulating, physiologically active, peptide hormones. Treatment can also provide disease stabilisation in a proportion of patients. In a minority of patients treatment may lead to partial response.

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Somatostatin analogues

Somatostatin (SS) is a natural polypeptide which circulates as physiologically active somatostatin-14 and somatostatin-28. It is a powerful inhibitor of endocrine and exocrine function affecting, amongst others, the release of insulin, gastrin, glucagon, gastric secretions, and pancreatic secretions. These inhibitory effects are the core basis for the role of somatostatin and its analogues in providing symptom control in NET patients. SS has also been shown to have apoptotic and cytostatic

Octreotide

This was the first clinically useful SS analogue which did not require a continuous intravenous infusion and therefore could be used by patients at home. Its current main uses are: (1) to treat hormonal symptoms/syndrome as a short acting preparation usually requiring three times daily, subcutaneous (TDS-SC) injections; (2) to provide short-term cover, at start of treatment, whilst the longer acting formulation reaches an effective steady state; (3) to provide prophylaxis against carcinoid

Prolonged release lanreotide

Lanreotide, an octapeptide somatostatin analogue, has been developed in two prolonged release formulations, lanreotide (Somatuline®) LA and Lanreotide (Somatuline®) Autogel.

Carcinoids

SS analogue treatment has been very effective in the management of symptoms related with malignant carcinoid syndrome (see above). Response rates of >60% are reported by most studies and may approach 100% depending on the selectivity of the patients recruited. Biochemical response (>50% reduction in urinary 5-HIAA) is also achieved in approximately two-third of patients. Partial tumour response may occur in up to 8% of patients but this is difficult to interpret owing to the concomitant use of

Somatostatin analogues during invasive procedures and carcinoid crisis

SS analogue use prior to invasive procedures is important in preventing ‘carcinoid crisis’. In patients with well controlled symptoms with long-acting octreotide or lanreotide, a supplementary bolus dose of 200–500 μg octreotide SC should be given 1–2 hours prior to the procedure. For emergency surgery in therapy naïve patients with functional NETs, a 200–500 μg intravenous bolus of octreotide or 500 μg SC should be given 1–2 hours before the procedure.49

The recommended intra-operative use of

INTERFERON alpha treatment in NETs

Interferons (IFNs) are biological response agents which have been shown to have an effect in a number of tumour types including melanoma and lymphoma. They exert their anti-tumour effects through various mechanisms including cellular proliferation, differentiation, apoptosis, and angiogenesis. There are a number of types of interferon, three of which (alpha, beta, and gamma) have been extensively clinically investigated. IFNs were initially obtained from human leukocytes which limited their

Combination therapy with SS analogues and IFNα

The development of tachyphylaxis in most patients treated with long-acting somatostatin analogues as well as case reports of tumour response to combination therapy, with SS analogues and IFN, acted as an impetus to trials assessing the effectiveness of this combination therapy approach.86, 87 Theoretically, the different modes of action of interferon (effects on cell cycle through prolongation of S-phase, impairment of hormone synthesis, induction of 2′,5′-A-sythase, reduction of viable tumour

Conclusion

Long-acting SS analogues are effective in controlling the symptoms of carcinoid syndrome in the majority of patients and display a tolerable side-effect profile. They are useful in controlling the severe diarrhoea associated with vasoactive intestinal peptide secreting tumours and can control hormone secretion associated with gastrinoma, glucagonoma, insulinoma, as well as somatostatinoma. Furthermore, they may improve symptoms, such as abdominal pain and asthenia, in patients with

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