Appetecchia and Baldelli Journal of Experimental & Clinical Cancer Research 2010, 29:19 http://www.jeccr.com/content/29/1/19 Page 3 of 12 comfortable for patients to use [13]. A new slow-release depot preparation of lanreotide, Lanreotide Autogel (Ipsen), is administered subcutaneously up to 120 mg once a month [14]. Native SST and its synthetic analogues show different affinity for the five specific receptor subtypes [9,10,15]. Native SST binds all the five receptor subtypes (SSTRs 1-5). The effects of the SST analogues are mediated by the interaction with SSTR 2 and 5 receptors while the new somatostatin analogue, pasireotide (SOM 230), shows higher binding capacity towards SSTRs 1, 2, 3 and 5 with no agonist activity at the type 4 receptor [15] (Table 3). The different receptor subtypes binding affinities seem to result in different biological and clini- cal activities. Octreotide is, for instance, 45 times more potent in inhibiting growth hormone (GH) secretion and 11 times more potent in inhibiting glucagon secre- tion than native SST [10]. The symptomatic and biochemical effects of SST analogues The initial treatment of GEP NETs is, where possible, always an aggressive surgical approach, aimed at obtain- ing a curative tumour ablation, even in the presence of metastatic disease. However, in patients with functioning or metastatic tumours, the treatment goal is to improve their quality of life, while monitoring or alleviating the tumour-associated symptoms and increasing survival. Recently, the diagnostic and therapeutic approach of GEP NETs has considerably improved, mainly due to better imaging techniques (CT, MRI, PET) and somatos- tatin analogue-based imaging methods, as well as recep- tor subtype characterisation and the introduction of long-acting somatostatin analogues. Somatostatin receptor scintigraphy (SRS, OctreoScan®), (e.g. 111In-pentetreotide) can visualise in vivo tumours and metastases that express the somatostatin receptor subtypes 2, 3 or 5 [16] except for metastatic insulino- mas, of which only 50% express SSTR 2. Imaging by SRS is not dependent on endocrine function of a NET but is determined by the tumour’s endowment of Table 3 Somatostatin receptor subtype-binding affinity of somatostatin analogues Receptor subtype affinity [IC50, nM] Compound SSTR1 SSTR2 SSTR3 SSTRs. This somatostatin analogue-based imaging method may help to decide which patients are suitable for treatment with somatostatin analogues (octreotide or lanreotide), or for tumour-targeted radioactive therapy with radiolabelled somatostatin analogues [13,17-22]. Its overall is high, ranging from 86% to 95% for gut carci- noid tumours to 75-100% for pancreatic endocrine tumours [21,22]. The uptake of radiolabeled octreotide is also predictive of clinical response to therapy with somatostatin analogues. Since 1980, SST analogues have been used to sympto- matically control GEP NETs, especially carcinoids and VIPomas [11,13]. Usually, the treatment with long acting preparations of SST analogues consists in an intramus- cular injection (i.m.) every 2 or 4 weeks (octreotide long-lasting, 10-30 mg, LAR; lanreotide long-lasting 60- 120 mg LA). In the course of the first two months, addi- tional subcutaneous (s.c.) administrations of short half- life octreotide may be required before achieving such properly stable blood levels of the long half-life synthetic analogue, as to allow adequate symptom control. Their efficacy in the control of symptoms is well-documented [2,12,13], even if patients with islet cell tumour often show a transient (median time 2.5 months) and non-sig- nificant response. These are safe and well-tolerated drugs, in both long- and short-term treatments [23-27]. However, after 9-12 months, drug resistance often spreads and patients may show symptom recrudescence. In such cases, the approach proposed was to continue the treatment, by increasing the analogue dosage (for octreotide with gradual increments of 10 mg every 28 days up to 60 mg every 28 days) or, by shortening the administration range by a week [28], if the symptomato- logic escape occurs in the week before the next drug injection.A randomised double-blind trial compared long- acting octreotide LAR at 10, 20, and 30 mg every 4 weeks with open-label short-acting octreotide every 8 h for the treatment of carcinoid syndrome. It showed that the efficacy of short-acting octreotide and of the long-acting octreotide-LAR was the same once circulat- ing octreotide steady-state concentrations were achieved [29]. O’Toole et al in a multicentre study on 33 patients with the carcinoid syndrome comparing the treatment with lanreotide (30 mg i.m. every 10 days) versus octreotide (200 μg s.c. twice or thrice daily) founded no significant differences in controlling symptoms; 53.8% and 45.4%, respectively, of the patients treated with lan- reotide referred disappearance or improvement in flushes and diarrhoea, while these symptoms were observed in 68% and 50%, respectively, of patients on octreotide. Lanreotide and octreotide may also signifi- cantly lower the levels of urinary 5-hydroxyindoleacetic acid (5-HIAA), the catabolite of serotonin [30]. SMS-14 SMS-28 Octreotide Lanreotide Pasireotide 2.26 1.85 1140 2330 9.3 0.23 0.31 0.56 0.75 1 1.43 1.3 34 107 1.5 SMS, Somatostatin; ND, not determined. [Data from Grozinsky-Glasberg S., Endocrine-Related Cancer 2008 Sep;15 [3]:701-20]. SSTR4 1.77 ND 7030 2100 >100 SSTR5 0.88 0.4 7 5.2 0.16