Appetecchia and Baldelli Journal of Experimental & Clinical Cancer Research 2010, 29:19 http://www.jeccr.com/content/29/1/19 Page 5 of 12 models, octreotide shows a strong antiangiogenic effect, which is probably mediated by the inhibition of the Vas- cular Endothelial Growth Factor (VEGF) [64-66]. The response to the treatment with octreotide would result in a significant reduction in VEGF levels compared to the baseline, since it is related to patients’ survival [66]. It was observed that standard endothelial cells do not express the SSTR 2 that is present on the contrary, when they proliferate in order to form blood vessels. This could represent further opportunity to treat patients with octreotide that is able to recognise and inhi- bit new vessel formation both alone and with other drugs, thanks to its high affinity with such receptor (Table 3). Immunomodulation is another indirect mechanism of action of SST analogues. Preliminary evi- dence suggests that they stimulate the production of immune system components with antitumour effect, such as natural-killer cells [67,68], even if up to now it is not clear whether this can be clinically significant thus helping the antitumour efficacy of SST analogues. Few data exists on the functions mediated by the SSTR 4. However, no unanimity exists about the SST analogue ability to control (i.e. to slow) the tumour progression. In vitro studies reported that the response of different cell lines to the octreotide exposition produces a bipha- sic dose-response curve [69,70]. Consequently, overdose or underdose of SST analogues may result in a subopti- mal antineoplastic activity. Nevertheless, the negative results of some clinical studies in terms of tumour response could be due to the administration of too low doses to achieve receptor optimal saturation. After all, in other studies that used octreotide doses higher than 8 mg/day and lanreotide doses higher than 10 mg/day [71], no improvement of the SST analogue antitumour effect was observed. No study on the tumour response monitored plasma levels of an SST analogue up to now, in order to assess that optimal drug therapeutic levels SSA Lanreotide Lanreotide Octreotide Octreotide Lanreotide Octreotide Octreotide Octreotide LAR 30/ Lanreotide SR Total Percentage Dosage 3000 mg/day 30 mg/2 weeks 600 and 1500 mg/day 1500 and 3000 mg/day 15000 mg/day 600 mg/day median dose of 250 μg three times daily 60 mg/28 days (%) are reached but not exceeded [72]. Clonflicting results have given with regard to tumour regression. Tumour shrinkage was demonstrated in less than 10% of the patients. However, a stabilisation of tumour growth occurs in up to 50% of the patients with neuroendocrine tumours of various locations. Stable disease was observed in 37-45% of the patients with documented tumour progression before SSA therapy (Table 4). The median duration of stabilisation was 26.5 months [26,73-76]. In a study on a select group of patients with progressive disease, in the 47% of cases was demon- strated a stable disease when treated with a high dose of lanreotide (3-5 g/day) [77]. This result has been con- firmed in patients with advanced midgut carcinoids, who had a stabilisation of the disease for 6-24 months in the 75% of cases [78]. One patient with a pancreatic primary tumour, and distant extrahepatic metastases, showed a poor response to treatment in multivariate analysis. Age, size of the primary tumour, and Ki67 did not influence the response rate to SSA therapy [76]. A stabilisation of the disease was maintain throughout long-term follow-up in patients who achieve it after 6 months of treatment; these patients live longer than those unresponsive to therapy [76,79]. Very recently Rinke et al performed for the first time a placebo-controlled, double-blind, phase IIIB study in 85 patients with well-differentiated metastatic midgut NETs using octreotide LAR 30 mg intramuscularly in monthly intervals. Median time to tumour progression in the octreotide LAR and placebo groups was 14.3 and 6 months, respectively. After 6 months of treatment, stable disease was observed in 66.7% of patients in the octreotide LAR group and 37.2% of patients in the pla- cebo group. Functionally active and inactive tumours responded similarly. The most favorable effect was observed in patients with low hepatic tumour load and resected primary tumour. Octreotide LAR significantly N 22 35 52 58 24 10 34 31 256 CR 0 0 0 0 1 0 0 0 1 0.3 PR 1 1 0 2 1 0 1 0 6 2 SD 7 20 19 27 11 5 17 14 115 45 PD 14 14 33 29 11 5 0 4 105 41 References [97] [90] [74] [26] [97] [73] [75] [76] Table 4 Antiproliferative effect of somatostatin analogues in patients with progressive disease SSA, somatostatina analogues; CR, complete remission; PR, partial remission; SD, stable disease; PD, progressive disease.