Appetecchia and Baldelli Journal of Experimental & Clinical Cancer Research 2010, 29:19 http://www.jeccr.com/content/29/1/19 Page 7 of 12 presence of the SSTR 2 receptor or its clinical expres- sion. Consequently, most of them were likely not to be treated with the optimal drug required to achieve appro- priate receptor saturation. The effects of higher than usual dose of SST analogues It was suggested that higher than usual dose of somatos- tatin analogues treatments (>3,000 μg/day) may promote the anti-proliferative effect, especially in those patients responding to standard doses [2,15,16,78,88,89]. An high-dose treatment with lanreotide (up to 12 mg/day) produced tumour size reduction in 5% and stabilisation in 70% of the 19 patients. In responding patients was observed an induction of apoptosis in the tumours, a phenomenon not seen with regular doses of somatosta- tin analogs, but often produced by chemotherapeutic agents [62]. Subcutaneously injections of 5 mg lanreo- tide three times a day for a period of 1 year produced one complete and one partial remission in 30 patients with functional midgut NETs; stable disease in 11 patients (36%) and progression of the disease after 3-12 months of treatment in 11 patients [63]. The treatment with high-dose somatostatin analogues induced apopto- sis in neuroendocrine tumours, while this was not found during treatment with low-dose somatostatin, in a study where biopsy specimens were taken before and during somatostatin analogue treatment [61]. In a highly select group of patients with progressive disease, 47% of the patients demonstrated at least stable disease when treated with a high dose of lanreotide (3-5 g/day) [77]. High-dose formula of octreotide has been recently reported to stabilize hormone production and tumour growth in 75% of patients with advanced midgut carci- noid tumours and progressive disease with stabilisation for 6-24 months, [78]. These effects may be attributable to SSTR 2 which is the most frequently expressed subtype and/or SSTR 5, 1 and 3 which are also expressed [90,91]. Data from a study with ultra-high dose octreotide pamoate (Onco-LAR; Novartis) at 160 mg intramuscu- larly every 2 weeks for 2 months followed by the same dose once monthly, appear to show some promise. Tumour size stabilisation was obtained in 12 patients, a biochemical responses in 9 patients and/or stability in 11. No significant tumour reduction was noted. At 6 months, the median plasma concentrations of octreotide were 25-100 times higher than those obtained by using octreotide LAR at regular doses. A significant inhibition of angiogenesis was also showed through the down-reg- ulation of proliferative factors such as vascular endothe- lial growth factor (VEGF) and fibroblast growth factor [12]. The highest response rates were reported using octreotide in doses greater than 30 mg/day or lanreotide in doses greater than 5 mg/day (and up to 15 mg/day) [63]. Tomassetti et al. have reported that after one-year therapy, the tumour completely disappeared in three patients suffering from gastric carcinoid, two of whom were treated with lanreotide 30 mg i.m. every 10 days [92]. Cirillo in his retrospective study on 165 patients with digestive NETs confirmed that somatostatin analogs can have a role in the treatment of digestive neuroendocrine tumors with low grades of malignancy, a low cellular proliferation index and a high specific receptorial den- sity in vivo, showing a SD ranging from 60 to 66%. Moreover, an increase of the dosage of somatostatin analogs seems to have a better control both of the dis- ease progression and the chronic refractory diarrhea [24]. Somatostatin analogues and interferon The combination of SSAs and interferon (IFN) has been used in an effort to enhance the antiproliferative effect of interferon therapy, to add the positive effect of SSAs on hypersecretory syndromes, and to reduce the dose of IFN and thus the number of IFN-related side-effects. Whether somatostatin analogues and IFN show a synergistic effect on tumour growth and in carcinoid syndrome symptom management is matter of debate. The combination therapy with somatostatin analogues and IFN is in fact limited by the small number of trials, with variable results. This combination seems of benefit in patients where the usual octreotide treatment failed to achieve a bio- chemical and symptomatic control [93]. This combination therapy leaded to a significantly lower risk of progressive disease compared with soma- tostatin analogues alone, and had a higher median survi- val (51 vs 35 months) [94]. An anti-proliferative effect of the addition of a-interferon to octreotide was showed in a subgroup of patients with advanced metastatic disease unresponsive to octreotide monotherapy, and prolonged survival was reported in the responder group [95]. How- ever, most published data do not support a major effect of interferons over and above that of somatostatin ana- logues. In a prospective multicenter study on the effect of combination therapy, Faiss et al showed no advantage on either biochemical or antiproliferative results, while the number of side-effects increased [96]. Novel somatostatin analogues Recently the universal or “pan-receptor” somatostatin ligand pasireotide (SOM230) has been developed, which possess high affinity binding to SSTs 2, 3 and 5, moder- ate affinity for SSTR 1. Its receptor binding profile is