Carcinoid crisis is defined as an episode of severe hypotension caused by an acute release of serotonin and other vasoactive substances into the circulation. It occurs most commonly in the operative setting since triggers include general anesthesia, epinephrine, and physical manipulation of tumors. Patients with carcinoid syndrome or elevated urine 5-HIAA who undergo an invasive procedure should receive a supplementary dose of octreotide 250–500 mcg subcutaneously or intravenously 1 h prior to the procedure [27]. Hypotension occurring in the setting of carcinoid crisis can be managed with bolus intravenous doses of octreotide 500–1,000 mcg until control of symptoms is achieved. Alternatively, continuous intravenous infusion of 50–10 mcg/h may be given after a bolus dose [28].

In recent years, strong evidence has emerged that SSAs can inhibit the growth of neuroendocrine tumors. Antitumoral activity, also known as the “antiproliferative effect” of SSAs, can occur via direct and indirect mechanisms [6, 9, 29]. Direct mechanisms involve the binding of SSAs to somatostatin receptors on tumor cells leading to activation of intracellular signaling transduction pathways. Multiple in vitro studies using cell lines transfected with somatostatin receptors indicate that all receptor subtypes (sst1-5) can participate in inhibition of cellular proliferation and that specific receptor subtypes (sst2,3) mediate apoptosis [30, 31]. Indirect antiproliferative mechanisms include inhibition of circulating growth factors such as vascular-endothelial growth factor (VEGF) and insulin-like growth factor (IGF) [32], as well as inhibition of tumor angiogenesis through interaction with somatostatin receptors on endothelial cells [33].

Multiple phase II and retrospective studies have investigated the effects of SSAs on tumor progression in patients with GEP-NETs. In general, these studies have documented low rates of objective radiographic response (<5 %) but high rates of disease stabilization [11, 14, 47–50]. One of the first prospective studies to report on the antiproliferative effects of SSAs in GEP-NETs was conducted by the German Sandostatin Study Group [51]. In this study, 103 patients with GEP-NETs were treated with octreotide 200 μg t.i.d. until evidence of radiographic progression. Among patients who had disease progression documented at treatment outset, 37 % experienced disease stability lasting at least 3 months, whereas among patients with stable disease at baseline, disease stability lasting at least 12 months was documented in 54 % of patients. Another phase II clinical trial testing octreotide in 34 patients with progressive metastatic NETs reported disease stabilization rate in 50 % of patients lasting a median of 5 months [49].

The antiproliferative activity of lanreotide was tested in several phase II clinical trials. In a study of 55 patients with GEP-NETs, 7 % of 31 assessable patients achieved a partial response to lanreotide, and 81 % experienced disease stability [17]. In another study of 46 patients with GEP-NETs, 2 patients (4 %) achieved an objective radiographic response, while 19 patients (41 %) had stable disease for a mean duration of 9.5 months [11]. In one study of patients with progressive tumors, participants received either octreotide LAR 30 mg or lanreotide SR 60 mg. Among 31 assessable patients, 14 (45 %) achieved disease stability [52]. In multivariate analysis, tumor control appeared to be significantly higher in small bowel NETs compared to pancreatic NETs. Extrahepatic metastases were associated with a poorer prognosis.

Definitive evidence of the antiproliferative effect of SSAs emerged with the PROMID trial, the first randomized placebo-controlled study performed in the field of neuroendocrine tumors [26]. Eighty-five patients with metastatic well-differentiated NETs originating in midgut were randomized to receive either octreotide LAR 30 mg or placebo. Patients with severe uncontrolled carcinoid syndrome were excluded. The primary endpoint was time-to-tumor progression. Median time-to-tumor progression (TTP) was 14.3 months in the octreotide LAR 30 mg group versus 6.0 months in the placebo group (P = 0.000072). Serious adverse events were nearly evenly balanced (11 patients in the octreotide LAR 30 mg arm and 10 patients in the placebo arm). On multivariate analysis, patients with resected primary tumor and low hepatic tumor burden (<10 %) appeared to benefit most significantly from octreotide treatment versus placebo. The small number of deaths in each treatment arm and the high rate of post-trial crossover precluded any analysis of differences in overall survival. Based on the PROMID data, octreotide LAR therapy is now considered an appropriate first-line treatment for patients with metastatic midgut NETs that are not surgically resectable, regardless of presence or absence of the carcinoid syndrome.

Non-midgut NETs tend to progress more aggressively than midgut NETs and are less likely to express somatostatin receptors. It is still uncertain whether SSAs are appropriate for use as antiproliferative agents in non-midgut NETs. The CLARINET study (clinical trial on nonfunctioning enteropancreatic endocrine tumors) is intended to address this question by randomizing patients with hormonally nonfunctioning GEP-NETs to treatment with depot-lanreotide versus placebo. The target enrollment of 200 patients has been achieved, and results are pending [53].

While the highest dose of octreotide LAR tested prospectively in patients with metastatic NET has been 30 mg every 4 weeks, higher doses and/or frequencies are often prescribed for patients with suboptimal control of hormonal syndromes. Data supporting this practice derive primarily from retrospective studies. In a longitudinal database conducted by the National Comprehensive Cancer Network (NCCN) encompassing 7 cancer centers, 40 % of carcinoid tumor patients and 23 % of pancreatic NET patients who received SSAs underwent dose escalations beyond 30 mg every 4 weeks [54]. The most common dose/frequency combinations were 40 mg every 4 weeks and 40 mg every 3 weeks. In one retrospective institutional study, 100 patients out of a total of 338 with metastatic midgut NETs (30 %) received octreotide LAR at doses and/or frequency above the standard label dose of 30 mg every 4 weeks [55]. Indications for dose increase were worsening carcinoid syndrome (60 patients), radiographic progression of tumors (33 patients), and rising urine 5-HIAA (6 patients). Among patients whose doses were increased for refractory carcinoid syndrome, 34 patients (62 %) experienced improvement in diarrhea, and 28 patients (56 %) experienced improvements in flushing. A single prospective trial investigated octreotide LAR 30 mg every 3 weeks among 28 patients with disease progression on 30 mg every 4 weeks [56]. Complete and partial control of clinical symptoms were observed in 40 and 60 % of treated patients, respectively.

Pasireotide is a novel somatostatin analog which binds avidly to four of the five somatostatin receptors (sst_1,2,3 and sst₅) [57]. Compared with octreotide, pasireotide has a 40-, 30-, and 5-fold higher binding affinity for sst_5, sst_1, and sst₃, but a 2.5-fold lower affinity for sst₂. An open-label trial evaluated the activity of short-acting subcutaneous pasireotide in 45 patients with carcinoid syndrome whose symptoms (flushing and diarrhea) were suboptimally controlled with octreotide LAR [58]. In this trial, 27 % of patients experienced some degree of improvement in their symptoms. However, a randomized phase III trial of long-acting intramuscular pasireotide vs. octreotide LAR in patients with refractory carcinoid syndrome was halted at interim analysis for futility [59]. The main toxicity observed with pasireotide is hyperglycemia, caused by suppression of insulin secretion which is mediated through the binding of pasireotide to sst₅. In the phase III trial of pasireotide vs. octreotide, Grade 3 or 4 hyperglycemic events occurred in 11 % of patients in the pasireotide arm vs. 0 % in the octreotide arm. Clinical trials are currently testing the antiproliferative effects of pasireotide in advanced GEP-NETs.

Interferons are a complex array of cytokines with antiviral and antitumoral properties. They are divided into several classes. Type I interferons consist of IFNα (leukocyte interferon) and IFNβ (fibroblast interferon) which bind to a unique interferon receptor [63]. IFNs activate STAT (signal transducer and activator of transcription) complexes including the Janus-kinase-STAT (JAK-STAT) signaling pathway leading to signaling cascades involving the tumor cell and the host immune system [64]. Immune-related mechanisms of action include induction of major histocompatibility complex (MHC) type I expression in tumor cells which leads to enhanced immune surveillance. Other effects of IFNs include promotion of dendritic cell proliferation and differentiation and alterations of T-cell CD4:CD8 ratios [65]. Angiogenesis inhibition appears to be another indirect mechanism of action. In a study of neuroendocrine tumor xenografts in nude mice, IFNα treatment reduced microvessel density and suppressed vascular-endothelial growth factor (VEGF) gene expression [66].

IFNs may also exert a direct antiproliferative effect on tumor growth through induction of cell cycle arrest; however, the precise mechanism remains elusive. In one in vitro study of lymphoid cell lines, G0/G1 cell cycle arrest was mediated through induction of the cyclin-dependent kinase inhibitors (CKIs) p21 and p15 and the expression of p27 [67]. However, another in vitro study of neuroendocrine tumor cells demonstrated that IFNα delayed progression from S-phase to G2 due to reduction of cyclin B levels and inhibition of Cdc2 kinase activity [68]. A third study demonstrated that IFNα induced apoptosis through activation of caspases-1, -2, -3, -8, and -9 in a variety of malignant cell lines [69].

An early study of IFNα three to six million units/day reported objective tumor responses in 4 of 36 patients (11 %) with advanced carcinoid tumors and major reductions in urine 5-HIAA in 16 patients (53 %) [70]. Another study of 22 patients with pancreatic NETs reported high rates of symptomatic and biochemical responses [71]. A more recent phase II study of 49 patients with advanced NETs evaluated IFNα-2a at a daily dose of six million units daily for 8 weeks followed by the same dose 3 times weekly thereafter [72]. Among 34 patients with carcinoid tumors, partial radiographic responses were observed in 4 patients (12 %), and major improvements in carcinoid syndrome were reported in 64 % of cases. The most frequently observed side effects were fever, flu-like symptoms, and leukopenia. In the United States, Moertel et al. treated 27 patients with metastatic carcinoid tumors with IFNα at a high dose of 24 million units/m² [73]. Despite an objective radiographic response rate of 20 % and major urine 5-HIAA reductions in 39 % of patients, the authors concluded that any therapeutic gains seemed to be outweighed by severity of side effects which included fevers/chills, anorexia, weight loss, leukopenia, and liver function abnormalities.

Studies evaluating the combination of IFNα and SSAs emerged in the 1990s, based on in vitro data demonstrating that interferons can upregulate the expression of somatostatin receptors. One trial of patients with carcinoid syndrome who had become refractory to octreotide reported symptomatic improvement in 49 % of patients after addition of IFNα [74]. Another study reported disease stabilization in 14 of 21 patients in whom IFNα was added to preexisting octreotide therapy [75]. A more recent trial investigated pegylated IFN (PEGIFN), a long-acting formulation which enables weekly dosing. Of 17 patients who progressed on SSA therapy, inhibition of tumor growth was observed in 13 patients. The side effect profile of PEGIFN appeared to be superior to that of IFNα [76].