Octreotide is approved for the control of hormone-related symptoms in NETs in the U.S. and in Europe, and lanreotide is approved for the same indication in Europe only. Since their introduction in routine clinical practice in the 1980–1990s, SST analogs have clearly improved therapeutic management of patients with functional NETs [17]. The first clinical trial with octreotide, published in 1986, involved 25 patients with carcinoid syndrome [18]. Flushing and diarrhea were promptly relieved in 22 patients (88 %), and 18 (72 %) had a decrease of ≥50 % in their urinary 5-HIAA levels compared with pretreatment values, leading to approval of octreotide by the Food and Drug Administration (FDA). Subsequently, about 30 studies were conducted with SST analogs, involving more than 500 patients, most of whom had carcinoid syndrome (review in [3]). The mean symptom control rate was 73.2 %, and no difference was found between the various agents and formulations. SST analogs appeared more effective against flushing than diarrhea. In a study published in 2004 by Ruszniewski et al. [19], 71 patients with carcinoid syndrome were enrolled to receive lanreotide Autogel® at a dose of 90 mg every 4 weeks for two injections, after which the dose was adapted over 6 months according to the patient’s response. Flushing episodes and diarrhea were significantly decreased at 6 months compared with baseline (p <0.001 and p = 0.006, respectively), and biochemical response (decrease of ≥ 50 % in serum chromogranin A and/or urinary 5-HIAA levels) was observed in 30 % of patients. In a crossover study comparing octreotide with lanreotide in 33 patients with carcinoid syndrome, O’Toole et al. [20] demonstrated equivalent efficacy for the two compounds in terms of symptom control and reduction in tumor markers. Pooled data analysis from 15 studies confirmed that octreotide LAR® and lanreotide Autogel® yield similar symptom control rates of 74.2 % (95 % confidence interval [CI], 61.9–92.8 %) and 67.5 % (95 % CI, 40.0–100 %), respectively, as well as for biochemical response rates (51.4 % [95 % CI, 31.5–100 %] and 39.0 % [95 % CI, 17.9–58 %], respectively) (Fig. 4.2, part 1) [3]. These findings were also reported in acute situations, such as during carcinoid crisis, which may occur spontaneously or during tumor manipulation in surgical or radiologic procedures [21]. A phase III study of pasireotide LAR® versus octreotide LAR® in metastatic NET patients with functional symptoms inadequately controlled by SST analogs was presented at the ASCO 2013 meeting (abstract #4031, NCT00690430). A total of 110 patients have been randomized and were stratified by predominant symptom at baseline (diarrhea, flushing, or both). Symptom response rates at 6 months were not significantly different between pasireotide LAR® and octreotide LAR® (21 vs. 27 %; odds ratio [OR] = 0.73, p = 0.53).

SST analogs are also effective against other NET hormone-related symptoms (review in [22, 23]). While insulinomas and gastrinomas are the most frequent functional pancreatic NETs, use of SST analogs in these indications is limited [9, 17]. In gastrinomas, high doses of proton-pump inhibitors are essential to control Zollinger–Ellison syndrome caused by gastrin hypersecretion, and the use of SST analogs is limited to rare refractory cases. In insulinomas, the effect of SST analogs on glycemia is unpredictable and hypoglycemia may be either improved or worsened by SST analogs due to glucagon suppression, requiring careful management of this treatment with initiation during hospitalization. Moreover, other treatments are available and effective in controlling insulin hypersecretion: diazoxide, which inhibits insulin release by direct action on β cells, or more recently, everolimus [24]. In contrast, the beneficial role of SST analogs has been well documented in less common types of functional pancreatic NETs [9, 17]. In glucagonomas, SST analogs are effective in controlling necrolytic migratory erythema in 80–90 % of patients, although their effect on the associated diabetes and weight loss is less pronounced [9, 17]. In VIPomas, diarrhea and electrolyte imbalance, also known as Werner–Morrisson syndrome or WDHA (watery diarrhea, hypokalemia, achlorhydria) syndrome, are significantly improved by SST analogs in 80–90 % of patients, although their effect may be limited by tachyphylaxis [9, 17].

Recently, SST analogs were demonstrated to exert antitumor effects in selected NET patients and underlying molecular mechanisms have been elucidated.

Given their mechanisms of action, SST analogs can be considered targeted agents directed against SSTR. As for all targeted therapies, their use in the clinic is limited by the emergence of acquired resistance, also known as tachyphylaxis. Furthermore, in some NET patients, SST analogs lose effectiveness within months of treatment initiation, whereas in other patients, tumor symptoms and growth can be controlled for several years. The reasons for tachyphylaxis are unclear but may be due to reduced SSTR expression on NET cells, activation of alternative pathways, and/or changes in SST analog pharmacokinetics when chronically administered. Three major strategies have been developed to enhance SST analogs efficacy and/or overcome acquired resistance: dose optimization, combination with other agents, and new SSTR-binding molecules.

Peptide-receptor scintigraphy such as octreoscan is useful in NET imaging for diagnosis and staging (see Chap.​ 2). Moreover, it can be used to select patients for the therapeutic strategy using radiolabeled SST analogs, PRRT [44]. Different radiolabeled SST analogs have been used, all of which share a common structure, comprising three parts: the radionuclide itself (Indium-111 [¹¹¹In], Yttrium 90 [⁹⁰Y], or Lutetium 177 [¹⁷⁷Lu]), a chelator (diethylene triamine penta-acetic acid [DOTA] or 1,4,7,10-tetra-azacyclododecane-1,4,7,20-tetra-acetic acid [DTPA]), and an SST analog (octreotide or lanreotide). Modifications in the radionuclide and chelator can considerably affect compound characteristics, including pharmakocinetics and SSTR-binding affinity [45].

Early studies were performed with high doses of ¹¹¹In-DTPA⁰-octreotide, the same radiolabeled peptide as is used for octreoscan imaging. ¹¹¹In is a γ-emitter creating Auger electrons with short range and low tissue penetration (review in [46]), which may only be effective for the treatment of micrometastatic or low-burden disease, and is unsuitable for treating bulky tumors. This may explain the disappointing results of ¹¹¹In-coupled peptides in clinical studies in metastatic NET patients, with low rates of objective tumor response (0–17 %) compared with ⁹⁰Y- or ¹⁷⁷Lu-coupled peptides. ⁹⁰Y- or ¹⁷⁷Lu are β-emitter with higher energy and tissue penetration (reviewed in [47] and [48], respectively). ⁹⁰Y-DOTA-octreotide (DOTATOC) and ¹⁷⁷Lu-DOTA-octreotate (DOTATATE) are the two most widely used radiopeptides for PRRT in metastatic NETs, both yielding similar response rates (15–35 %) [45, 49]. More than 500 patients have been treated with ¹⁷⁷Lu-DOTATATE and more than 300 with ⁹⁰Y-DOTATOC in clinical studies, respectively. Results are summarized in Table 4.1. Differing antitumor effects between studies may be due to different administered doses and dosing schemes, total tumor burden including the extent of liver involvement, and patient characteristics.