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Neuroendocrine tumors (NETs) are neoplasms arising most often in the GI tract, pancreas, or lung. Diagnosis of NETs is often delayed until the disease is advanced, because of the variable and nonspecific nature of the initial symptoms. Surgical resection for cure is therefore not an option for most patients.
Somatostatin analogues represent the cornerstone of therapy for patients with NETs. This article reviews the important role that somatostatin analogues continue to play in the treatment of patients with NETs.
Octreotide was the first somatostatin analogue to be developed; more than 30 years of data have accumulated demonstrating its efficacy and safety. Lanreotide is another somatostatin analogue in clinical use, and pasireotide is a promising somatostatin analogue in development. Newer long-acting depot formulations are now available offering once-monthly administration. Although octreotide was initially developed for symptom control, recent results indicate that it also has an antiproliferative effect, significantly increasing time to progression in patients with midgut NETs. Combinations of octreotide with other targeted therapies may further improve patient outcomes. Findings in recent studies of the combination of octreotide and the mTOR inhibitor everolimus are encouraging. The combinations of octreotide with other agents (eg, interferon-α, bevacizumab, cetuximab, AMG-706, and sunitinib) are being investigated.
Somatostatin analogues have been used to treat the symptoms of NETs for decades and also have an antineoplastic effect, markedly prolonging progression-free survival. Somatostatin analogues are likely to remain the cornerstone of treatment for most patients with advanced NETs. Promising new combination therapies are undergoing clinical investigation.
Neuroendocrine tumors (NETs) are epithelial neoplasms that undergo predominantly neuroendocrine differentiation and arise in many organs of the body.1 Although NETs are uncommon, the reported incidence has been steadily increasing. An analysis of 35,825 NET cases in the Surveillance, Epidemiology, and End Results database demonstrated a 5-fold increase in the annual age-adjusted incidence of NETs from 1.09/100,000 population in 1973 to 5.25/100,000 population in 2004.2
NETs are often classified by their organ of origin (eg, lung, pancreas, or gastrointestinal tract) and by their secretion of various peptides and neuroamines.3 Functional NETs are defined by the presence of a clinical syndrome caused by excessive hormone secretion. An example is carcinoid syndrome from the secretion of serotonin and other vasoactive substances, resulting in diarrhea and flushing.4 In contrast, nonfunctional NETs have no specific clinical syndrome but may still secrete peptides or neuroamines, measurable in plasma or urine. NETs are classified as either well differentiated (low and intermediate grade) or poorly differentiated (high grade). NET survival rates vary by primary site and grade and are lower in patients with poorly differentiated tumors than in those with well-differentiated tumors and in distant vs. locoregional disease.2 This review is focused on the treatment of patients with well-differentiated NETs.
If NETs are diagnosed early, surgical resection is often curative.5–7 However, the variable and nonspecific symptoms of NETs often delay diagnosis until the disease has progressed to an advanced state, when complete surgical resection may no longer be possible. More than 50% of NETs are unresectable at diagnosis.8 Metastatic NETs can be treated with localized therapy for liver metastases (eg, resection, radiofrequency ablation, hepatic artery radioembolization, chemoembolization, and bland embolization) and systemic management with chemotherapy and biologic therapies (eg, interferon [IFN]-α, antiangiogenic drugs, mammalian target of rapamycin [mTOR] inhibitors, multikinase inhibitors, and peptide receptor radiotherapy).4,9–11 Somatostatin analogues (SSAs) play a central role in managing the symptoms of excessive hormone secretion and appear to control tumor growth.12–15
Somatostatin is a peptide hormone that mediates its inhibitory effects through binding to specific cell surface, G-protein–coupled receptors, of which five distinct subtypes (sst1–sst5) have been characterized.16–18 Cells and tissues targeted by somatostatin frequently express multiple receptor subtypes, and tumors arising from these tissues generally express a high density of receptors.19 In NETs, sst2 expression predominates, although multiple other subtypes have also been found.19 Well-differentiated tumors express somatostatin receptors more often, and at higher density, than do poorly differentiated tumors.20 The activated somatostatin receptors mediate their inhibitory effects through at least 4 intracellular pathways. These include inhibition of adenyl cyclase, activation of K+/Ca2+ channels, activation of protein phosphatases, and activation of intracellular tyrosine phosphatase.20
Somatostatin was initially viewed as a candidate for cancer treatment because of its ability to impede hormone release and cell growth after binding to its receptors.21 Unfortunately, the short half-life of native somatostatin and the impact of rebound hypersecretion on discontinuation limit its use as a therapeutic agent. This prompted the development of clinically useful analogues with longer biological half-lives.18,20,22
In the 1980s, production of the 8-residue SSA octreotide (Sandostatin®; Novartis) was reported.23 Several cyclic octapeptides soon followed, all of which demonstrated increased resistance to peptidase inactivation, substantially longer half-lives, and improved pharmacologic efficacy.20 Unlike natural somatostatin, octreotide binds with high affinity only to the sst2 receptor subtype and with lower affinity to the sst5 receptor (Table 1). Octreotide does not cause rebound hormone hypersecretion.19,24 The U.S. Food and Drug Administration (FDA) has approved octreotide for treating patients with several types of NETs. It is indicated for the severe diarrhea/flushing episodes associated with metastatic carcinoid tumors and the profuse watery diarrhea associated with vasoactive intestinal polypeptide (VIP)-secreting tumors.25 Another SSA in clinical use, lanreotide (Somatuline®; Ipsen), has a similar activity and affinity profile, although it has not yet been approved by the FDA for the treatment of patients with NETs. Pasireotide (SOM230; Novartis) is a cyclohexapeptide in clinical development.19 Pasireotide has a more universal binding profile and mimics the action of natural somatostatin,26 with high binding affinity for sst1–3 and particularly high affinity for sst5. Long-acting depot SSA formulations have also been developed. Octreotide long-acting repeatable (LAR) is administered intramuscularly once every 4 weeks.27,28 Lanreotide prolonged-release (PR) is injected once every 10 to 14 days.29,30 Lanreotide autogel (AG), administered by deep subcutaneous injection once every 4 weeks, is also available.31 Pasireotide long-acting release, administered by intramuscular injection every 4 weeks, is being evaluated in clinical trials.
The most common adverse events related to octreotide treatment in patients with carcinoid or VIP-secreting tumors are nausea, abdominal pain, headache, dizziness, fatigue, and back pain25,28 (Table 2). Local pain and erythema at the injection site are also common, as is the case with other depot injections.13 In a phase III study of patients randomly assigned to octreotide LAR (10–30 mg/month) or daily subcutaneous octreotide, 84% to 95.4% of patients reported adverse events, most of mild or moderate severity and thought to be unrelated to therapy.28 A similar safety and tolerability profile was seen with octreotide, lanreotide, and pasireotide, all of which were generally well tolerated.32,33
Other studies have reported gastrointestinal toxicity, such as loose stool, mild steatorrhea, and flatulence. These adverse events may begin shortly after the first administration of drug and subside over subsequent weeks as treatment continues.13 SSAs can cause steatorrhea by inhibiting the production of pancreatic digestive enzymes. Pancreatic enzyme supplementation is helpful in this context. Impaired glucose tolerance has also been observed during SSA therapy. The risk for gallstones or bile duct stones is increased with prolonged SSA treatment13,25,28 (Table 2).
There are several known drug interactions with octreotide (and other SSAs), including interaction with cyclosporine, insulin, and bromocriptine (Table 3).25,34 In most cases, drug monitoring and possible dose adjustment are all that is required.
In a recent retrospective study of 146 patients with metastatic midgut NETs, of whom 91% had received long-term octreotide treatment, the overall 5-year survival rate was 75%, in contrast to a rate of just 19% in historical controls.35 In phase II studies in patients with NETs receiving lanreotide PR 30 mg intramuscularly every 10 to 14 days, the rate of objective response was low (5%–8%), but a large percentage of patients (40%–49%) achieved stable disease; the median duration of disease stabilization was 8.5 to 9.5 months.29,30 In a small-scale study of NET patients with hormone-related symptoms, treatment with lanreotide PR (30 mg every 14 days) was shown to reduce or normalize the levels of tumor markers in 47% of the those assessed, whereas 87% had reduced or stabilized tumor size over the 6-month duration of the trial.36 In a 9-year retrospective study involving 76 patients with metastatic midgut NETs and carcinoid syndrome, symptoms were well controlled with lanreotide AG alone in 74% of patients, with only 30% demonstrating radiologic progression.37,38
In a crossover study involving octreotide and lanreotide in patients with carcinoid syndrome, half the patients received octreotide 200 μg 2 or 3 times daily for 1 month, followed by lanreotide 30 mg intramuscularly every 10 days for 1 month, and the other half received the 2 drugs in the opposite order. Octreotide and lanreotide were equally effective in reducing symptoms of carcinoid syndrome and tumor biomarkers.39 Direct comparison between most octreotide and lanreotide clinical studies cannot be made because of differences in study design (eg, inclusion criteria, tumor grade, extent of disease, and end points). However, in a review of almost 500 patients in 15 studies, it was noted that octreotide LAR achieved symptomatic relief in 74.2% of NET patients (range, 61.9%–92.8%), biochemical response in 51.4% (range, 31.5%–100%), and tumor response in 69.8% (range, 47.0%–87.5%).20 Long-acting lanreotide resulted in similar levels of symptomatic relief (67.5%; range, 40.0%–100%), biochemical response (39.0%; range, 17.9%–58%), and tumor response (64.4%; range, 48.0%–87.0%).
Although SSA therapy effectively reduces symptoms of excessive hormone secretion in most patients, a considerable number experience escape from clinical response and return of symptoms.37 In a phase II study, pasireotide 600 to 900 μg administered subcutaneously twice a day was evaluated in 45 patients with advanced NETs with symptoms of carcinoid syndrome inadequately controlled by octreotide LAR. Most (63.6%) had stage IV cancer at baseline. Pasireotide was effective at controlling diarrhea and flushing in 12 (27%) of the 44 patients included in the efficacy population.37,40 Three of these patients achieved complete symptom control, and 9 experienced partial symptom control. In 23 patients evaluated for tumor response at study end, 13 had stable disease and 10 had progressive disease. It has been postulated that pasireotide, which has higher affinity for sst1, sst3, and sst5 than octreotide and lanreotide, may offer symptom control in patients in whom disease is inadequately controlled with octreotide or lanreotide. Although this study did not meet the primary end point of achieving at least partial symptom control in 30% of the patients, the potential activity of pasireotide in patients with advanced NETs refractory to octreotide LAR warrants further investigation.
As mentioned earlier, octreotide has been approved by the FDA for the treatment of symptoms associated with carcinoid tumors. A distinct group of NETs is of pancreatic origin; many of these tumors are functional and produce hormone-related side effects. In a retrospective analysis of 191 duodenopancreatic NETs, there were 80 (42%) cases of insulinoma, 66 (35%) cases of gastrinoma, 12 (6%) cases of glucagonoma, and 6 (3%) cases of VIPoma.41 In this patient context, octreotide is the only FDA-approved SSA, but is used solely for treating profuse, watery diarrhea in patients with VIPoma. However, the authors describe the routine clinical use of octreotide for the control of hormone-related symptoms in patients with these types of NETs. Octreotide is effective both before and after surgery and in patients with metastatic disease if surgery is not an option. A study evaluating lanreotide PR in patients with NETs and hormone-related symptoms included 6 patients with gastrinoma and 1 with VIPoma. Lanreotide PR 30 mg was administered by intramuscular injection every 14 days for 6 months. Four (67%) of the patients with gastrinoma and the patient with VIPoma showed symptomatic improvement (>50% reduction) and biochemical responses.36 The use of SSAs in patients with functional pancreatic NETs deserves further clinical investigation.
In addition to reducing hormone production by NETs, SSAs have been reported to reduce upper abdominal pain, improve quality of life and performance status,13 promote healing of pancreatic fistulae,42 and improve orthostatic hypotension.43
In addition to alleviating the symptoms of functional NETs, SSAs can inhibit the growth of NETs. Clinical trials have shown that SSAs can halt tumor progression, but patients rarely have objective tumor regression.44 SSAs work both directly and indirectly to control tumor growth. The direct antimitotic effect is mediated by somatostatin receptors on tumor cells. Indirect effects of SSAs, such as inhibition of growth factor secretion, inhibition of angiogenesis, and immunomodulatory effects on peripheral target organs, also contribute to tumor control.14,44 By suppressing the synthesis and secretion of growth factors, such as insulin-like growth factor (IGF)-1, an important modulator of many neoplasms, octreotide is able to exert antiproliferative effects and reduce tumor growth.14 Angiogenesis can also be inhibited by SSAs. Compared with native somatostatin, octreotide and pasireotide are able to inhibit neovascularization to a greater extent, possibly through interactions with peritumoral vascular sst2 receptors.45,46 SSAs may also exert antiangiogenic effects through the inhibition of growth factors (eg, platelet-derived growth factor, IGF-1, and epidermal growth factor), which are known to stimulate important processes in angiogenesis, such as endothelial and smooth muscle cell proliferation.47,48 Finally, because somatostatin receptors are expressed on various cells of the immune system (eg, lymphocytes, monocytes), octreotide may regulate inflammatory and immune mechanisms, possibly enhancing its antiproliferative activity.14
PROMID was a prospective, randomized, placebo-controlled, double-blind, phase IIIb study in treatment-naive patients with locally inoperable or metastatic well-differentiated midgut NETs.15 Eighty-five patients were randomly assigned to receive either octreotide LAR 30 mg/month intramuscularly or placebo for 18 months or until tumor progression or death.15 The primary end point was median time to tumor progression. Octreotide LAR significantly increased the median time to tumor progression compared with placebo (14.3 months vs. 6.0 months, respectively; hazard ratio, 0.34; 95% confidence interval [CI], 0.20–0.59; P = .000072; Figure 1).15 Prolongation of progression-free survival (PFS) by octreotide LAR was seen in patients with either functional or nonfunctional NETs. However, the effect of octreotide LAR on overall survival (OS) could not be established. The hazard ratio for OS was 0.81 (95% CI, 0.30–2.18; P = .77). Results from PROMID indicate that octreotide LAR significantly inhibits tumor growth in patients with metastatic midgut NETs.15 In the United States, no somatostatin analogues or any other medications have been approved by the FDA for the management of asymptomatic carcinoid tumor. However, based on the results of the PROMID study, octreotide is frequently used as an antineoplastic to halt the growth of metastatic carcinoid and is, in fact, in the National Comprehensive Cancer Network (NCCN) treatment guidelines for this purpose.6
The ongoing CLARINET study is a phase III, randomized, double-blind, placebo-controlled, multicenter study to assess the effect of lanreotide autogel 120 mg administered by deep subcutaneous injection every 28 days on PFS in patients with nonfunctioning enteropancreatic endocrine tumors (ClinicalTrials.gov identifier, NCT00353496). The results of this study should determine whether lanreotide has an inhibitory effect on tumor growth in patients with advanced nonfunctioning neuroendocrine tumors of intestinal or pancreatic origin. Final data collection for the primary outcome measure is estimated to occur in June 2013.
Octreotide use is critical in treating and preventing perioperative carcinoid crisis, a life-threatening condition in patients with metastatic functional NETs, usually triggered by anesthesia or surgical/radiologic procedures.49 Carcinoid crisis is characterized by a sudden and profound decrease in or elevation of blood pressure, sometimes accompanied by tachycardia, elevated blood glucose, and severe bronchospasm. It can be fatal without pharmacologic intervention.50 In a retrospective analysis of 119 patients who underwent abdominal surgery for metastatic functional NETs, none of the 45 who received intraoperative octreotide experienced carcinoid crisis, compared with 8 (11%) of the 73 who did not receive octreotide (P = .023).49 The 2012 NCCN guidelines on NETs specifically state that octreotide therapy should be initiated in all patients before resection of primary or metastatic functional (carcinoid) endocrine tumors.6
In a pooled evaluation of data from 700 patients in 25 centers, octreotide LAR and lanreotide AG both controlled symptoms after surgical cytoreduction of metastases in up to 80% of patients, stabilized disease progression in approximately 50% to 80%, and reduced biomarkers in approximately 40%.51 A second overview of NET management options in large, specialized referral centers also concluded that when residual tumor remained after surgery, long-acting SSAs were effective in managing symptoms.52 Results of the PROMID study, in which octreotide LAR demonstrated antiproliferative activity in addition to symptom reduction, provide a further rationale for the use of long-acting SSA therapy in patients who have undergone cytoreduction.15
The suggested daily dose of octreotide acetate for patients with carcinoid tumors during the first 2 weeks ranges from 100 to 600 μg/day in 2 to 4 divided doses, usually starting at the lower end of the range; the dose can be slowly escalated as tolerated. Dosage can be adjusted on an individual basis to control symptoms; some patients may require significantly higher doses (up to 1.5 mg/day).25 After 2 weeks of daily injections, if not limited by toxicity, the first dose of octreotide LAR (20 mg by deep intramuscular injection) should be given. Doses of octreotide LAR (20 or 30 mg administered intramuscularly) are then repeated every 4 weeks.25 To maintain steady state blood levels and to reduce the risk for symptom exacerbation caused by a decrease in therapeutic blood level, it is recommended that subcutaneous octreotide be continued for 2 weeks after the first octreotide LAR injection. In patients who experience exacerbation of symptoms while receiving maintenance octreotide LAR, subcutaneous octreotide 300 μg administered 3 times/day as a “rescue” dose can be added. This commonly occurs in the days preceding a scheduled octreotide injection, when octreotide blood levels are at nadir. Monitoring of plasma octreotide levels may be helpful in treating patients with symptom exacerbation or cancer progression who are receiving conventional doses of octreotide, but its role in routine clinical practice is yet to be determined.53
In some patients with NETs, SSAs may lose effectiveness within months of treatment initiation, whereas in other patients, the NETs can be controlled for several years.20 The reasons for tachyphylaxis are unclear but may be due to reduced somatostatin receptor concentration on NET cells. In some patients, increasing the dose may restore the original response.53
The highest approved dose of octreotide LAR is 30 mg administered intramuscularly every 4 weeks, though higher (eg, ≤60 mg every 4 weeks) or more frequent (30 mg every 14–21 days) doses have been used on occasion to control symptoms in patients refractory to conventional doses of octreotide.54 Escalated doses of octreotide LAR (60 mg every 28 days) have proved both safe and effective in a subset of patients with active acromegaly inadequately controlled with long-term SSAs.54 The results of one trial (ClinicalTrials.gov identifier, NCT00990535) evaluating more frequent doses (30 mg octreotide LAR every 21 days) in patients with NETs will be examined with interest (www.clinicaltrials.gov).
In a 6-month dose-titration study of 71 patients with carcinoid syndrome, the participants were administered 6 treatments of 28-day lanreotide PR by deep subcutaneous injection.55 The first 2 were 90-mg doses, and subsequent doses were titrated (60, 90, 120 mg) based on symptom response. At 6 months, 11 (73%) of 15, 4 (33%) of 12, and 12 (27%) of 44 patients responded to lanreotide PR 60, 90, and 120 mg, respectively. A consequence of the dose-titration design of the study was that patients with severe symptoms were given higher doses. Therefore, nonresponders disproportionately received higher doses. Presumably, patients who responded to lower doses would also respond to higher doses. A more lucid statistic is that 27 (38%) of 71 patients responded to doses of lanreotide PR of 120 mg or less, 15 (21%) of 71 to 90 mg or less, and 11 (15%) of 71 to 60 mg. Dose optimization caused a reduction in episodes of flushing and diarrhea by a mean of 1.3 and 1.1 episodes/day, respectively (both P ≤ .001).
Octreotide LAR and other SSAs are likely to remain a cornerstone of therapy for NETs. However, several other therapeutic targets have emerged (Figure 2).56 Recently, the mTOR inhibitor everolimus and the multitargeted receptor tyrosine kinase inhibitor sunitinib were approved for the treatment of patients with advanced pancreatic NETs. However, the safety and efficacy of these agents have not been established for the treatment of nonpancreatic NETs. In recent years, the use of octreotide in combination with agents directed at other NET therapeutic targets, including mTOR, IGF-1 and its receptor, and various growth factors and cytotoxic agents (eg, vascular endothelial growth factor [VEGF] and IFN) have been investigated.20,56
mTOR, a critical regulator of cell growth, proliferation, metabolism, and angiogenesis, often has increased activity in NETs, stimulating research in mTOR inhibitors, such as everolimus, as therapeutic options.56 Given that somatostatin receptors are known to modulate mTOR, a somatostatin analogue plus an mTOR inhibitor have been combined for potential synergy.57,58 In a phase II study evaluating the impact of everolimus (5–10 mg/day) plus octreotide LAR (30 mg every 28 days) in patients with advanced low- to intermediate-grade NETs, 22% of patients had a partial response and 70% had stable disease.59 The overall median PFS time was 60 weeks, and the 3-year survival rate was 78%.59 The large, double-blind, placebo-controlled, phase III RADIANT-2 study demonstrated that octreotide LAR could be safely administered in combination with everolimus to patients with advanced NETs and a history of diarrhea, flushing, or both.60
The addition of an SSA to chemotherapy or biologic therapy may increase efficacy.53 In a study of octreotide plus IFN-α vs. octreotide plus the antiangiogenic monoclonal antibody bevacizumab, the combination with bevacizumab appeared to improve objective response and PFS after 18 weeks of treatment (95% vs. 68% with IFN).61 This combination is now being evaluated by a much larger clinical trial, SWOG 051, comparing octreotide plus IFN-α with octreotide plus bevacizumab. In a prospective, randomized, multicenter trial on the antiproliferative effects of lanreotide IFN-α, or the combination of the 2, in 80 patients with metastatic NETs, researchers found that lanreotide and IFN-α had comparable antiproliferative effects. However, the antiproliferative effects of the combination of lanreotide and IFN-α were not significantly better than those of either monotherapy. The combination of lanreotide and IFN-α did result in better symptom control, but side effects were more common.62
A phase I study of octreotide, everolimus, and the anti–IGF-1 receptor monoclonal antibody cetuximab in patients with low- to intermediate-grade NETs is recruiting participants (ClinicalTrials.gov identifier, NCT01204476). An ongoing phase II study (ClinicalTrials.gov identifier, NCT00427349) in patients with low-grade NETs is also evaluating the efficacy and safety of octreotide plus daily oral AMG-706, a multikinase inhibitor that selectively targets VEGF (www.clinicaltrials.gov). Tyrosine kinase inhibitors, such as sunitinib, may also have synergistic actions with SSAs in the management of NETs.53
SSAs represent the cornerstone of therapy for patients with advanced NETs. Octreotide, the first SSA to be developed, has more than 30 years of available clinical data, providing convincing demonstration of its efficacy and tolerability in thousands of patients. The SSA lanreotide has a similar activity and affinity profile in numerous clinical trials, although it has not yet been approved in the United States for the treatment of patients with NETs. The introduction of long-acting SSA formulations has further improved efficacy by providing a sustained plasma level of active agent and increasing the period of symptom control from hours to as much as 4 weeks. Although SSAs were developed primarily to benefit patients with hormone secretion symptoms, recent data from the PROMID study indicate that octreotide also has an antiproliferative effect. The new multireceptor-targeted SSA pasireotide may be useful for patients in whom symptoms are no longer controlled by octreotide or lanreotide. The activity of an SSA may also be improved by combination with other antineoplastic therapies. Recent trials of octreotide LAR with the mTOR inhibitor everolimus are encouraging. Further studies are needed to assess other combinations with octreotide LAR and new SSAs to improve cancer control and symptom relief in patients with NETs.
This study was supported by Novartis Pharmaceuticals Corporation. Writing assistance, provided by Duke Duguay, PhD, of ApotheCom, was paid for by Novartis. The study sponsor had no role in the writing or revision of the manuscript or in the decision to submit the manuscript for publication. The author had full access to all the data and takes complete responsibility for the integrity of the data and the accuracy of the data analysis. He conducted the literature review, wrote and revised the manuscript, and submitted the manuscript for publication, independent of the study sponsor.
Disclosures of Potential Conflicts of Interest
The author has received consulting fees from Novartis, Ipsen, and Pfizer.