Neuroendocrine tumor disease: an evolving landscape

in Endocrine-Related Cancer

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) represent a heterogenous group of tumors arising from a variety of neuroendocrine cell types. The incidence and prevalence of GEP-NENs have markedly increased over the last three decades. Symptoms are often absent in early disease, or vague and nonspecific even in advanced disease. Delayed diagnosis is thus common. Chromogranin A is the most commonly used biomarker but has limitations as does the proliferative marker Ki-67%, which is often used for tumor grading and determination of therapy. The development of a multidimensional prognostic nomogram may be valuable in predicting tumor behavior and guiding therapy but requires validation. Identification of NENs that express somatostatin receptors (SSTR) allows for SSTR scintigraphy and positron emission tomography imaging using novel radiolabeled compounds. Complete surgical resection of limited disease or endoscopic ablation of small lesions localized in stomach or rectum can provide cure; however, the majority of GEP-NENs are metastatic (most frequently the liver and/or mesenteric lymph nodes) at diagnosis. Selected patients with metastatic disease may benefit from advanced surgical techniques including hepatic resection or liver transplantation. Somatostatin analogs are effective for symptomatic treatment and exhibit some degree of antiproliferative activity in small intestinal NENs. There is a place for streptozotocin, temozolomide, and capecitabine in the management of pancreatic NENs, while new agents targeting either mTOR (everolimus) or angiogenic (sunitinib) pathways have shown efficacy in these lesions.

Abstract

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) represent a heterogenous group of tumors arising from a variety of neuroendocrine cell types. The incidence and prevalence of GEP-NENs have markedly increased over the last three decades. Symptoms are often absent in early disease, or vague and nonspecific even in advanced disease. Delayed diagnosis is thus common. Chromogranin A is the most commonly used biomarker but has limitations as does the proliferative marker Ki-67%, which is often used for tumor grading and determination of therapy. The development of a multidimensional prognostic nomogram may be valuable in predicting tumor behavior and guiding therapy but requires validation. Identification of NENs that express somatostatin receptors (SSTR) allows for SSTR scintigraphy and positron emission tomography imaging using novel radiolabeled compounds. Complete surgical resection of limited disease or endoscopic ablation of small lesions localized in stomach or rectum can provide cure; however, the majority of GEP-NENs are metastatic (most frequently the liver and/or mesenteric lymph nodes) at diagnosis. Selected patients with metastatic disease may benefit from advanced surgical techniques including hepatic resection or liver transplantation. Somatostatin analogs are effective for symptomatic treatment and exhibit some degree of antiproliferative activity in small intestinal NENs. There is a place for streptozotocin, temozolomide, and capecitabine in the management of pancreatic NENs, while new agents targeting either mTOR (everolimus) or angiogenic (sunitinib) pathways have shown efficacy in these lesions.

Introduction

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are also referred to as neuroendocrine tumors (NETs) or ‘carcinoids’, although this term is archaic and should be discarded in favor of a nomenclature reflective of specific cellular types and secretory products. These tumors are relatively rare, though increasing rapidly in prevalence (Lawrence et al. 2011a), tend to be slow-growing (although very aggressive variants exist), and often present a considerable diagnostic and therapeutic challenge. GEP-NENs are mainly found in the small and large intestines (∼80%) with the remainder in the stomach and pancreas. The latter generally exhibit a more aggressive phenotype in comparison with tumors from other sites and, depending on the cell type of origin (α, β, etc.), produce specific symptom complexes such as glucagonoma or insulinoma. The clinical presentation and biological characteristics such as local invasion, fibrosis, and metastatic potential of gut tumors vary considerably depending on anatomical site, neuroendocrine cell(s) of origin (ECL, EC, D, G), and secretory products.

Overall, the primary tumor is usually small and overt clinical symptoms are often absent until metastasis has occurred. Despite considerable improvement in the understanding of GEP-NENs, the diagnosis of these lesions is commonly overlooked and, on average, is delayed for up to 5–7 years following the onset of clinical symptoms. This delay in diagnosis has resulted in a failure to optimize patient outcome because of the development of metastasis or significant local invasion. Some tumor lesions are only apparent when mechanical issues supervene. Tumors release a variety of bioactive products (amines/peptides) that may result in a systemic (carcinoid) syndrome. However, at least 50% of GEP-NENs (∼50% of pancreatic and 15–20% of small intestinal (SI)), may be asymptomatic and are characterized as ‘nonfunctional’ (Schimmack et al. 2011). Local (peritoneal ∼50%) or distant (cardiac ∼25%) fibrosis may be an issue in EC cell small bowel-derived lesions. In general, the most effective, ‘commonly’ available imaging modality is somatostatin receptor (SSTR) scintigraphy (SRS; Modlin et al. 2005). Nevertheless, diagnosis is usually so late in the disease course that the only curative treatment, radical surgical intervention, is rarely an option.

Most surgery in advanced tumor stages reflects an attempt to ameliorate local tumor effects or an endeavor (Sisyphean) to diminish hepatic tumor burden. Somatostatin analogs (SSAs) are effective in ameliorating symptoms in ∼80% and may prevent tumor progression with stabilization in ∼50% of SI NENs (Rinke et al. 2009). Although ‘predictably effective’ specific tumor-targeted curative treatments are lacking, initial studies on novel agents such as tyrosine kinase inhibitors (TKIs) alone or in combination with the SSA class of agents have been reported to be ‘variably’ efficacious. This manuscript addresses a series of key areas relevant to the diagnosis and management of GEP-NEN disease.

Epidemiology and incidence

In the USA, the incidence of the disease based on the 2007 National Cancer Institute's (NCI) Surveillance, Epidemiology and End Results (SEER) database encompassing the period 2003–2007 was 5.76/100 000, and the prevalence was estimated to be ∼35/100 000 in 2004. The incidence is increasing at a rate of 3–10% per year depending on the subtype. Furthermore, the overall NEN incidence (1973–2005) has increased from 1.1/100 000 in 1973 to 6.2/100 000 in 2005 (Lawrence et al. 2011a). Much of this increase probably reflects the introduction of more sensitive diagnostic tools as well as an increased awareness among physicians. Nevertheless, over the last 32 years (1973–2005), the incidence has increased to 520% representing an annual percentage increase of 5.8% (Modlin et al. 2008, Yao et al. 2008). Using regression analysis, it may conservatively be predicted that by 2015, the incidence and prevalence will be 10.9/100 000, and 65/100 000 respectively. The incidence is equivalent to esophageal cancer (4.5/100 000), testicular cancer (5.4/100 000), and myeloma (5.4/100 000). NENs occur most frequently in the gastrointestinal (GI) tract (60.9%) with the second most common location in the bronchopulmonary system (27.4%), followed by considerably less frequent locations such as the ovaries, testes, hepato-biliary system, and pancreas (Modlin et al. 2003). GEP-NENs are most common in the small intestine (30.8%), followed by the rectum (26.3%), colon (17.6%), pancreas (12.1%), stomach (8.9%), and appendix (5.7%) (Fig. 1). Given the overall indolence of the disease, the prevalence renders GEP-NENs the second most common GI cancer after colon cancer (Schimmack et al. 2011), and more prevalent than pancreatic, gastric, esophageal, or hepatic cancer or any two of these combined.

Figure 1
Figure 1

Distribution of 49 012 NENs from the SEER 1973–2007 tumor registry database. Pie charts reflect the distribution of NENs by anatomical site and tumor type. Total NEN distribution (top), GEP-NEN distribution (bottom left), and pancreatic NEN distribution (right). Non-GEP-NENs are predominantly located in the respiratory system (bronchopulmonary NENs ∼70%, top right). Pancreatic ‘carcinoids’ does not reflect serotonin-secreting tumors, but instead reflects SEER-based reporting annotations for the lesions.

Citation: Endocrine-Related Cancer 19, 5; 10.1530/ERC-12-0024

Protean symptomatology: late diagnosis: causes and sequelae

An early and accurate diagnosis is often delayed as most GEP-NENs are small, initially asymptomatic, and often misdiagnosed (Modlin et al. 2005). When symptoms and signs occur, they may be vague and nonspecific (e.g. intermittent acute abdominal pain in some instances due to intussusceptions; Wilson et al. 1974) and misinterpreted as irritable bowel syndrome, asthma, perimenopausal neurotic or part of an anxiety, or food allergy response (Mooney 1985, Jacobs 2009). In bioactive tumors, variable symptoms may develop depending on the tumor cell of origin and the effects of the individual secretory agents (e.g. serotonin (Robiolio et al. 1995) among others). The classical carcinoid syndrome is relatively uncommon (10–15%), typically consisting of diarrhea and cutaneous flushing and sweating (Mills 1956, Ringertz 1967). Emergency clinical presentations (∼1–5%) such as acute abdomen (obstruction, perforation, bleeding, appendicitis; Brophy & Cahow 1989, Sieren et al. 2010) and abdominal angina (major vessel compromise) arise due to either local tumor mass effects or tumor-induced fibrosis (Pellikka et al. 1993).

Strategies for identification and biological assessment

The development of sensitive and specific plasma and/or serum assays for peptides and amines produced by GEP-NENs as well as the development of immunohistochemistry panels has facilitated both blood and tissue diagnosis. In particular, the measurement of chromogranin A (CgA) has provided a platform to support the diagnosis of the disease (Modlin et al. 2010a), while the use of a variety of imaging techniques has significantly enhanced the anatomical identification and diagnosis of lesions (Kayani et al. 2008).

Circulating and tissue expression of CgA

CgA is a water-soluble acidic glycoprotein stored in the secretory granules of neuroendocrine cells, and its detection in plasma can be used as a general tumor marker for GEP-NENs including ‘nonfunctioning’ tumors (Lawrence et al. 2011b). Other markers that are generally less sensitive and specific overall but may be useful in unambiguously identifying lesions include 5-hydroxy tryptophan (HT) (EC cell-derived tumors), histamine (ECL cell-derived tumors), gastrin (gastrinomas), or pancreatic products e.g. insulin (insulinomas). Although plasma CgA levels are sensitive (70–85%) markers of GEP-NENs, they are nonspecific and elevated in other types of NENs as well as pancreatic, small-cell lung, and even some prostate carcinomas (Lawrence et al. 2011b). In addition to its diagnostic value, plasma CgA levels have some correlation with tumor burden and may, in some circumstances, be used to monitor treatment of NENs (Arnold et al. 2008b). CgA reduction of >80% following surgery of neuroendocrine hepatic metastases is predictive of subsequent symptom relief and disease control and associated with improved outcome. False-positive elevations of CgA occur in renal impairment and during proton-pump inhibitor therapy.

Urinary 5-hydroxyindole-5-acetic acid

Urinary 5-hydroxyindole-5-acetic acid (5-HIAA; 24 h measurement), the degradation product of 5-HT, is a useful but cumbersome laboratory marker. The specificity of 5-HT-producing NENs is ∼85% although tryptophan/serotonin-rich foods (bananas, avocados, plums, eggplant, tomatoes, plantain, pineapples, and walnuts) can provide false elevations. Overnight 5-HIAA collection may be as sensitive as the more burdensome 24-h collection in identifying patients with 5-HT producing tumors (O'Toole et al. 2009).

Tissue Ki-67 assessment

The rate of proliferation of a NEN can be quantified by counting the number of mitoses per high powered field on a hematoxylin- and eosin-stained slide, or by counting the percentage of cells that stain positive with the Ki-67 antibody. The defining quality of Ki-67 as a ‘proliferative’ marker is an exclusive expression by dividing cells in the S, G2, and M phases of the cell cycle. The percentage of cells that show positive immunohistochemical staining (the Ki-67%) is ‘presumed’ to denote the proportion of cells that are actively dividing as viewed on a pathological slide. The Ki-67% has been widely accepted as the cardinal feature of tumor grading. Indeed, in the most recent WHO NEN classification, it is used as a key determinant in tumor grading (Bosman et al. 2010).

In NENs, the prognostic value of the Ki-67% separates NENs into NET grade 1 (NET G1), NET grade 2 (NET G2), and neuroendocrine carcinoma (NEC) by Ki-67% of ≤2, 3–20, and >20% respectively. Validation of the prognostic ability of Ki-67 has shown differences in 5-year survival using a binary schema of <2 or >2%: pancreatic NENs (PNENs) showed 100 vs 54% survival at 5 years (La Rosa et al. 1996); a mixed group of GEP-NENs showed 56 vs 14% and 90 vs 54%, and a mixed group of pancreatic, SI, and colorectal NENs showed 76 vs 29% (Arnold et al. 2008a). More recently, the use of Ki-67 was defined for PNENs in a study on 1072 patients with at least 2 years of follow-up (Rindi et al. 2012). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second best independent predictor of survival in the absence of staging information. A direct comparison of the UICC/AJCC/WHO 2010 TNM and the ENETs TNM staging system identified the latter to be superior (Rindi et al. 2012).

Topographic and functional localization

Upper GI endoscopy

Upper GI endoscopy can identify lesions to the level of the ligament of Treitz, and colonoscopy can detect colon and rectal NENs as well as some terminal ileal tumors. Enteroscopy, both fiberoptic and capsule, is effective but have limitations. The double balloon or push technique is time consuming and uncomfortable. Endoscopic ultrasonography (EUS) is a highly sensitive method for diagnostic and preoperative evaluation of NENs of the stomach, duodenum, pancreas, and rectum, as it identifies submucosal lesions and facilitates staging. EUS with fine needle aspiration is useful for histological assessment and grading.

Contrast techniques

Contrast techniques such as enteroclysis and barium contrast studies have been widely supplanted by computed tomography (CT) and magnetic resonance imaging (MRI). A small primary tumor is difficult to visualize if a secondary tumor effect due to fibrosis has not developed. Characteristic findings include mass lesions, radiating strands of fibrosis, and spiculation (calcification) with traction or fixation of bowel. Specificity may be as low as 22% for CT, and both MRI and CT can be negative in up to 50% of SRS positive lesions. The advent of multidetector CT and CT enteroclysis techniques may enhance the detection of small primary tumors.

Nuclear imaging techniques

Approximately 70–90% of GEP-NENs express multiple SSTR subtypes with a predominance of sstr2 and sstr5 receptors. Labeling of SSAs with diagnostic radioisotopes enables visualization of SSTR expressing tissues via receptor mediated internalization and consecutive intracellular trapping of the degraded peptide. SRS, based on the use of [indium-111](111In)-diethylenetriamine-pentaacetic acid DTPA)-d-Phe1-octreotide (111In pentetreotide, OctreoScan, Mallinckrodt Medical BV, Petten, The Netherlands), has proven to be superior to standard imaging modalities in detection of primary tumors and their metastases. A review of over 1200 patients revealed a median detection rate of 89% and median sensitivity of 84% (Modlin et al. 2010c). This reflects an identification of lesions predominantly expressing high density of sstr2. The role of SRS as a monitor of treatment efficacy and disease progression remains to be verified (Stokkel et al. 2011).

Although SRS is very effective, the method is hampered by various factors, such as the necessity of a background ratio of at least 2:1, relatively low spatial resolution particularly for small tumors, and the lack of precise quantification of receptor density and radionuclide biodistribution. These drawbacks have, to some extent, been overcome by the introduction of newer SSAs such as DOTA-d-Phe1-Try3-octreotide (DOTATOC), DOTA-d-Phe1-Try3-octreotate (DOTATAE), and DOTA-1-NaI Try3-octreotide (DOTANOC), which exhibit not only a higher sstr2 affinity but also affinity to sstr3 and sstr5 (DOTANOC). Optimization of the profile is achieved when labeled with a generator-derived positron emitter such as 68Ga, which is suitable for positron emission tomography (PET) imaging (Kwekkeboom et al. 2010). Precise fusion of functional PET images with a morphological image tools such as CT (PET/CT) has provided additional anatomical information with regard to localization of lesions and definition of lesion boundaries with the added benefit of CT-based attenuation correction of the emission results (Fig. 2). Treatment with SSAs does not markedly reduce binding of tracers to SSTR and does not need to be interrupted before imaging (Haug et al. 2011).

Figure 2
Figure 2

Abdominal CT of a 62-year-old patient with a 20 cm pancreatic neuroendocrine tumor (A). 68Ga-DOTATOC PET/CT confirmed the location and dimensions of the primary lesion (B) and in addition disclosed a solitary bone metastasis (C). The skeletal deposit was identifiable only on the PET sequence.

Citation: Endocrine-Related Cancer 19, 5; 10.1530/ERC-12-0024

Comparison of OctreoScan with PET using 68Ga-DOTA reveals the potential of this novel technique. Thus, additional evidence of metastatic lesions was evident in >30%, particularly when localized within the skeletal system (Buchmann et al. 2007), and localization of unknown primary NENs was established in 39% of cases (Prasad et al. 2010). The superiority of 68Ga-DOTA-based PET/CT over anatomic imaging using CT or MRI and its impact on treatment were demonstrated in a recent study on 52 NEN patients who underwent both standard morphological imaging and 68Ga-DOTATOC PET/CT (Frilling et al. 2010). The primary treatment decision, based solely on CT and/or MRI results, was altered in 59.6% of patients when 68Ga-DOTATOC PET/CT results were considered.

Given the low metabolic rate of most well-differentiated NENs, standard PET imaging using 18F-fluorodeoxyglucose is relatively ineffective, but positivity denotes highly aggressive lesions (poorly differentiated NENs). 11C-5-HT and 18F-DOPA may have a role in patients with pancreatic and intestinal NENs that have negative or inconclusive results on SSTR-based imaging (Koopmans et al. 2008).

Predictive indices of tumor behavior

Gastric NENs

For gastric NENs, the important predictors of tumor behavior are type, size, and histology. When a gastric NEN is detected, it is crucial to determine serum gastrin levels, obtain a tumor biopsy, as well as multiple biopsies from the gastric body and fundic mucosa, to reveal signs of atrophic gastritis vs hypertrophy, and also to determine pH of the gastric aspirate. This will reveal the type of gastric NEN and guide the treatment approach, and provide information in regard to prognosis.

Type 1

Type 1 gastric NENs occur in patients with chronic atrophic gastritis (CAG), with hypergastrinemia due to the absence of gastric acid, as multiple, small gastric body and fundus polyps, together with mucosal atrophy and ECL-cell hyperplasia (Borch et al. 2005, Ruszniewski et al. 2006, Akerstrom & Hellman 2009, Åkerström et al. 2009). Polyps <1 cm are generally indolent and can be followed with yearly endoscopic surveillance. Tumors >1 cm, or multiple lesions without invasion can be treated with endoscopic mucosal resection or multiple band mucosectomy (Hopper et al. 2009), a few larger invasive tumors require local surgical excision, and only rare larger, multifocal lesions need gastric resection (Burkitt & Pritchard 2006). The CAG–NENs have low incidence of lymph node metastases, exceptionally liver metastases (LM), and disease-related deaths are rare. As an alternative, SSA therapy has been used. This was associated with regression of these lesions and occasionally reductions in circulating gastrin (Fykse et al. 2004, Campana et al. 2008), but the effects are short term (∼1 year) and disease progression has been noted at 5 years following the termination of therapy (Jianu et al. 2011).

Type 2

Type 2 gastric NENs occur in multiple endocrine neoplasia type 1 (MEN1) Zollinger–Ellison syndrome (ZES) patients, as multiple polyps in the gastric body and fundus, with hypertrophic surrounding mucosa, and low pH in the gastric aspirate (pH<2; Borch et al. 2005, Ruszniewski et al. 2006, Akerstrom & Hellman 2009, Åkerström et al. 2009). The malignant potential is intermediate, with lymph node metastases in ∼30% and LM in 10–20%. Polyps >1 cm are treated with local excision, whereas gastric resection is required for larger lesions. Removal of the source of hypergastrinemia is the critical aim of surgery; regression of type 2 lesions may be encountered following successful gastrinoma excision (Richards et al. 2004). SSAs may have efficacy in treatment of these lesions (Tomassetti et al. 2000) and have been used to control hypergastrinemia and ulceration (Campana et al. 2005), although proton-pump inhibitors are the treatment of choice (Lew et al. 2000).

Type 3

Type 3 sporadic gastric NENs occur in patients with normal serum gastrin, as often large (>2 cm), clearly invasive gastric body and fundus tumors (Fig. 3; Borch et al. 2005, Ruszniewski et al. 2006, Akerstrom & Hellman 2009, Åkerström et al. 2009). The tumors are aggressive and often infiltrated the entire gastric wall, with regional lymph node metastases in 20–50% and LM ultimately in two-thirds of patients. Large tumors with a high mitotic rate and high Ki-67% are even more aggressive. In general, the type 3 gastric NEN requires partial gastric resection with regional lymph node clearance or gastrectomy for metastasized tumors comparable to procedures for gastric adenocarcinoma. Only occasionally endoscopic resection may be performed for small nonmetastasized tumors (Kaehler et al. 2006). The 5-year survival rate is ∼50% in locoregional disease and ∼10% with distant metastases.

Figure 3
Figure 3

Sporadic, solitary type 3 gastric NEN with lymph node metastasis treated with a partial gastric resection. Reproduced, with permission, from Åkerström G, Hellman P & Hessman O 2009 Gastrointestinal carcinoids. In Endocrine Surgery, 4th edn, pp 147–176. Ed T Lennard. Copyright 2009 Elsevier.

Citation: Endocrine-Related Cancer 19, 5; 10.1530/ERC-12-0024

Midgut NENs

While in gastric, appendiceal, and colorectal NENs the risk for metastases relates to tumor size, midgut NENs have regional and ultimately distant metastases irrespective of primary tumor size. Most midgut NENs have a low proliferation rate with Ki-67% of <2% and can present with LM, although Ki-67%-based staging appears to have prognostic significance (Jann et al. 2011). Some tumors have higher proliferation rate and tend to progress more rapidly. Midgut NENs often originate in the distal small intestine as either a small, submucosal tumor or as multicentric lesions. The incidence of mesenteric lymph node metastases is as high as 70–90% irrespective of tumor size (Makridis et al. 1996, 1997, Ohrvall et al. 2000, Hellman et al. 2002, Akerstrom & Hellman 2009, Åkerström et al. 2009). Large mesenteric tumors mass together with marked surrounding fibrosis may encase the mesenteric root and cause intestinal obstruction or vascular impairment (Fig. 4). Venous ischemia may occur in part of the intestine, causing diarrhea, or functional obstruction, and ultimately, intestinal angina and malnutrition. Mesenteric metastases may often be removed by dissection of the mesenteric root, with preservation of main mesenteric vessels, and collateral circulation along the intestine, allowing limited intestinal resection (Ohrvall et al. 2000, Akerstrom & Hellman 2009). Studies on survival have revealed favorable outcome in patients subjected to radical resection of mesenteric metastases, with survival benefit also in presence of LM (Makridis et al. 1997, Hellman et al. 2002). Several authors have reported marked palliation of abdominal symptoms after removal of the mesenteric tumor burden (Makridis et al. 1996, 1997, Wangberg et al. 1996, Ohrvall et al. 2000, Hellman et al. 2002, Boudreaux et al. 2005). Early surgical intervention may avoid abdominal complications and should be done before mesenteric tumor growth exacerbates and renders local inoperability (Makridis et al. 1996). The midgut NEN, however, is tenacious and, in almost all patients, is often associated with synchronous or metachronous LM with delayed manifestation of up to 10 years or even more (Makridis et al. 1997, Åkerström et al. 2009).

Figure 4
Figure 4

CT image of mesenteric metastasis of midgut NEN, the distal intestine is edematous due to venous stasis (indicated by *).

Citation: Endocrine-Related Cancer 19, 5; 10.1530/ERC-12-0024

Pancreatic NENs

PNENs consist of functioning lesions related to syndromes of hormone excess and of nonfunctioning tumors. All these entities may be sporadic or associated with inherited neoplasia syndromes such as MEN1 (Akerstrom & Hellman 2009) or VHL (Oberg 2010). Apart from sporadic insulinomas, which are in general benign, PNENs are frequently malignant with tumor size as an important predictor of progression in both, sporadic and MEN1-related tumors.

Insulinomas

Insulinomas are sporadic, benign small tumors in 90% of cases, whereas the malignant forms should be suspected when tumor size exceeds 4 cm. In contrast to the sporadic type, the MEN1-associated insulinomas may be malignant also when small in size (Akerstrom & Hellman 2009). According to the benign nature of the disease, the vast majority of insulinomsa are amendable to parenchyma-sparing types of resection.

Gastrinomas

Gastrinomas occur in most instances within the head of the pancreas and/or duodenum either as sporadic or MEN1-associated lesions (∼30%) with comparable rates of malignancy in both sites (Metz & Jensen 2008, Akerstrom & Hellman 2009). They have a low tendency to grow; however, 60–70% are malignant at initial manifestation (Jensen et al. 2008, Goudet et al. 2010). Resection of the primary tumor should be anticipated in all patients suitable for surgery, as it was shown to improve prognosis in both, sporadic and hereditary cases due to lower rate of LM when compared with conservatively managed patients (Norton et al. 2006). During the last decades, duodenal gastrinomas have been increasingly recognized and are now known to account for ∼60% of sporadic and ∼90% of MEN1-associated ZES case. In this location, the tumors are often small with diameters of 5–10 mm or even less but are associated with lymph node metastases, which often have grown larger than the primary tumor themselves and are easily be mistaken as such.

Most pancreatic gastrinomas are suitable for limited, locally focused resections in combination with peripancreatic lymphadenectomy. In the absence of locoregional lymph node metastasis, preoperative location can be extremely difficult and precise localization depends on the adept fingers of the surgeon during duodenectomy. Depending on the localization, pylorus-preserving pancreatoduodenectomy or distal pancreatic resection and lymph node dissection may be the procedure of choice for larger or invasively growing lesions. A duodenal gastrinoma tumor can be managed with local excision via longitudinal duodenotomy and regional lymph node resection. Survival is excellent for small duodenal gastrinomas (∼90% at 3 years) (Mortellaro et al. 2009) but worse for pancreatic and large duodenal tumors, particularly when LM are present (Norton 2005).

The extent of surgery is a controversial debate in MEN1-ZES. More conservative approaches encompass duodenotomy with excision of duodenal wall tumors, enucleation of any lesion localized within the pancreatic head, peripancreatic lymph node dissection, and concomitant distal pancreatic resection (Thompson procedure) (Thompson 1998, Gauger et al. 2009). For tumors regionalized mainly in the pancreatic head and with the presumption that virtually all MEN1-ZES patients also have duodenal lesions, several groups now favor pylorus-preserving pancreaticoduodenectomy, a radical approach that can achieve biochemical cure but is associated with a higher morbidity risk and may complicate consecutive surgery for recurrent tumors in the pancreatic remnant (Norton & Jensen 2004, Tonelli et al. 2006, Fendrich et al. 2007). Pancreas-preserving total duodenectomy as reported by Imamura et al. (2005) is an effective technique to entirely remove multiple duodenal gastrinomas in selected patients.

Glucagonomas and VIPomas

Glucagonomas and VIPomas are rare tumors, often presenting with metastases at initial diagnosis (∼70%) and requiring aggressive treatment to alleviate the severe hormonal symptoms (Doherty 2005, Akerstrom & Hellman 2009). In both tumor types formal, oncological pancreatic resection with peripancreatic lymph node dissection is mandatory to attempt favorable survival (Akerstrom et al. 2004). Slow tumor progression may necessitate repeated surgical interventions for lymph node and/or LM during the course of the disease (Madeira et al. 1998). Prophylactic cholecystectomy to facilitate later SSA therapy significantly ameliorated symptoms in a series of patients with VIPoma and glucagonoma and may be considered (Nikou et al. 2005, Kindmark et al. 2007). Overall survival is ∼4 years and may extend to 15 years in single cases (Smith et al. 1998). In a series of six patients with glucagonoma treated during a period of 25 years, Eldor et al. (2011) achieved a median survival time of 6.25 years (range 2–11) from diagnosis and 8 years (range 8–16) from initial symptoms by following a multimodal treatment concept including SSAs, surgery (in three/six patients), peptide receptor radiotherapy (two responses in three/six patients), and chemotherapy (two responses in three/six patients. Ghaferi et al. reported on four patients with VIPomas. Of them, two patients were tumor-free 17–22 months after surgery and one patient, 68 months postoperatively after adjuvant SSA treatment and radiofrequency ablation of LM (Ghaferi et al. 2008).

Nonfunctioning PNENs

Nonfunctioning PNENs are often large when detected, although smaller lesions are being increasingly recognized due to the widespread use of cross-sectional imaging techniques (Vagefi et al. 2007). Sporadic nonfunctioning PNENs >2 cm are more likely malignant and are often associated with lymph node or LM (Ekeblad et al. 2008, Bettini et al. 2011) as tumors originating from MEN1 deletions (Falconi et al. 2006). In these larger tumors, a standard oncological pancreatic resection with peripancreatic lymphadenectomy is recommended, whereas parenchyma-preserving resections (i.e. enucleation or central pancreatectomy) could be advocated for PNENs <2 cm (Aranha & Shoup 2005, Falconi et al. 2010). In a series of 177 patients, Bettini et al. (2011) showed a clear correlation between tumor size and malignancy and recommended nonsurgical management of incidentally detected lesions <2 cm in size. Patients with well-differentiated PNENs have favorable prognosis after radical surgical removal, whereas those with poorly differentiated tumors have a poor survival despite surgery. These patients appear to benefit from chemotherapy as an up front treatment (Ekeblad et al. 2008). Survival is clearly related to the Ki-67%, nodal status, and evidence of LM (Bettini et al. 2008). Patients with Ki-67 <2% have a 5-year survival rate of 80% compared with 40% for those with Ki-67 >2% (Ekeblad et al. 2008). Results of surgery in PNENs with vascular involvement, of mainly the portal vein, are encouraging and surgery should also be considered for the treatment of LM (Bartsch et al. 2000, Hellman et al. 2000, Kouvaraki et al. 2005, Akerstrom & Hellman 2009, Capurso et al. 2011). In general, surgical approach is recommended in well-differentiated NENs (WHO groups I and II), whereas patients with poorly differentiated NEC (WHO group III) should primarily be treated with chemotherapy.

Pancreaticoduodenal tumors account for the major cause of death in patients with MEN1 syndrome. Elevated serum hormone biomarkers indicate development of functioning lesions even before a clinical hormonal syndrome has occurred (Bartsch et al. 2005, Kouvaraki et al. 2006, You et al. 2007, Ekeblad et al. 2008, Akerstrom & Hellman 2009). When such a syndrome has developed, 30–50% of patients already have metastases. Up to 80% of patients affected by MEN1 develop synchronous or metachronous pancreatic islet cell or duodenal tumors, of them gastrinomas in 54%, insulinomas in 18%, and nonfunctional tumors in 80–100% (Triponez & Cadiot 2007). As occurrence of metastases in nonfunctioning PNENs rises markedly with tumor size (>10 mm), several groups consequently recommend surgical removal of lesions exceeding this size (Bartsch et al. 2005, Kouvaraki et al. 2006, Triponez et al. 2006, You et al. 2007, Ekeblad et al. 2008, Akerstrom & Hellman 2009). Others claim a tumor size >2 cm as indication for surgery, but it is clear that a large proportion of these patients already have metastases (Bartsch et al. 2005, Kouvaraki et al. 2006, Triponez et al. 2006, Triponez & Cadiot 2007, You et al. 2007, Ekeblad et al. 2008, Akerstrom & Hellman 2009). Clearly this remains an open question as outlined in current guidelines and deserves a prospective analysis (Falconi et al. 2012, Ramage et al. 2012). Due to the high rate of multicentric lesions, intraoperative ultrasound is mandatory. In most instances, distal pancreas resection for the removal of tumors localized within the tail combined with enucleation of pancreatic head lesions is performed. Total pancreatectomy may be needed for recurrent, rapidly growing, or unusually large multicentric tumors but is avoided as long as possible due to diabetes that will follow.

Options for surgical management of LM

The propensity of GEP-NENs to commonly metastasize to the liver represents an important adverse prognostic factor in the advance of the disease. At the time of diagnosis, ∼75% of GEP-NENs (excluding appendix and stomach) exhibit synchronous LM (Saxena et al. 2010). Under such circumstances, 5-year survival has been reported to be 13–54% in historical series (McDermott et al. 1994). This outcome is worse than that for localized or locally advanced disease but is better in respect of ductal adenocarcinoma. Moreover, individuals with synchronous LM also often present with debilitating symptoms related both to the extent of the hepatic tumor mass and the sequel of excessive production of bioactive products by the tumor.

There are a number of invasive options available for the treatment of GEP-NEN LM, with either curative or palliative intent for decreasing the tumor burden. These include resective strategies as well as locally ablative techniques (e.g. radio frequency ablation, cryoablation, and microwave ablation), percutaneous liver-directed interventions (transcatheter arterial bland embolization or chemoembolization and selective internal radiation therapy), and liver transplantation (LT). Surgery is of specific benefit in that it is effective in relieving symptoms and is the only potentially curative treatment if complete resection (R0/R1 resection) of the primary tumor and liver lesions is achieved. Unfortunately, given the late stage presentation and the high incidence of multifocal and bilobar deposits, radical liver resection is possible in <20% of patients (Steinmuller et al. 2008). In order to facilitate better patient selection for treatment, a classification system for neuroendocrine LM based on morphological extent of hepatic involvement has been proposed: type I, a single metastasis of any size; type II, an isolated metastatic bulk accompanied by smaller deposits, with both liver lobes always involved, and type III, disseminated metastatic spread, with both liver lobes always involved, with single lesions of varying size and virtually no normal liver parenchyma (Frilling et al. 2009). Significant differences in Ki-67% and in outcome among the three types suggest that not only the tumor grade but also the growth type reflects the biological aggressiveness of the disease (Hentic et al. 2010). Of note is that intratumoral heterogeneity causing discrepant proliferative rates, as reported in nearly 50% of cases, has to be considered (Yang et al. 2011).

Under ideal circumstances, resection is associated with a low mortality rate (0–5%) while an acceptable morbidity is ∼30% (Steinmuller et al. 2008). Irrespective of the primary tumor site and in absence of nonresectable extrahepatic disease, surgery should therefore be proposed in all well-differentiated GEP-NEN patients with LM in whom complete resection is feasible. It should be noted that individuals with high-grade NENs probably represent a separate disease entity and are unsuitable for surgical treatment as they exhibit a median overall survival of only 6 months after partial hepatectomy (Cho et al. 2008). It is therefore critical that a core needle biopsy or laparoscopically guided biopsy is undertaken before the decision for surgery to establish tumor grading. This preemptive strategy will optimize patient management by excluding those with poorly differentiated tumors who will not benefit from surgical treatment.

The extent of hepatic resection is defined by variables including the number and size of LM, intrahepatic location of disease, and the hepatic reserve itself. It ranges from a limited, nonanatomical resection to hepatectomy, in some instances in combination with locally ablative measures (Elias et al. 2003, Sarmiento et al. 2003). Ideally, these patients should be treated in units with extensive experience in advanced hepatic surgery in order to achieve complete disease elimination particularly when the metastatic spread is primarily assessed as nonresectable (Kianmanesh et al. 2008). Postresectional overall 5-year survival rates range from 46% in earlier series (Dousset et al. 1996) to 85–94% in more recent reports (Mazzaferro et al. 2007, Kianmanesh et al. 2008, Frilling et al. 2009, Scigliano et al. 2009). Early recurrence however is to be expected with 5-year disease-free survival of <50% in most series (Sarmiento et al. 2003, Mazzaferro et al. 2007, Kianmanesh et al. 2008, Scigliano et al. 2009). The limited number of patients suitable for hepatic resection and the high postresectional recurrence rate highlight the need for neoadjuvant and adjuvant strategies, such as in approaches for colorectal LM. While TACE (Touzios et al. 2005) has been shown to have the potential to increase the number of patients eligible for hepatic surgery, adjuvant therapy with streptozotocin and 5-fluorouracil (FU) has failed to demonstrate the benefit in terms of longer recurrence-free survival (Maire et al. 2009).

In contrast to liver secondaries of adenocarcinomas, nonresectable neuroendocrine LM are an indication for LT under consideration of strict evaluation process (Lerut et al. 2007, Bonaccorsi-Riani et al. 2010, Gedaly et al. 2011). While nonresectable extrahepatic tumor manifestation, Ki-67% >15%, and severe carcinoid heart disease are generally accepted as exclusion criteria for LT, patient age (<50 vs >50 years), the dynamics of the hepatic tumor growth (stable disease vs rapid tumor progress), the extent of hepatic involvement, and timing of transplantation (first-line treatment vs an ultima ratio approach after unsuccessful previous treatment) remain controversial (Olausson et al. 2002, Rosenau et al. 2002, Le Treut et al. 2008). Although encouraging overall 5-year survival rates of 50–90% have been reported in newer series, disease recurrence within 2–3 years after LT is to be expected (Frilling et al. 2006, van Vilsteren et al. 2006, Olausson et al. 2007). The availability of novel effective targeted therapies for pretransplant tumor downstaging or for post-transplant tumor recurrence and immunosuppressive regiments with antineoplastic components, e.g. rapamycin, justify LT for neuroendocrine LM even when realistically considered as a palliative rather than a curative treatment modality.

The clinical and biological rationale for SSA treatment

Somatostatin (SS), a cyclic tetradecapeptide first identified in 1972 in the hypothalamus and subsequently detected in several other central and peripheral tissues including the GI tract and endocrine system, plays a key role in regulating physiological functions of NENs. Two bioactive forms of this ubiquitous inhibitor are known, a 14-amino acid form (SST-14) and a carboxyl terminally extended and more active 28-amino acid form (SST-28; Yamada et al. 1992). The various endocrine and paracrine functions of SST are triggered through G-protein-coupled receptors with seven transmembrane domains. In humans, five SSTR subtypes (sstr1–5) have been cloned and characterized (Lamberts et al. 1990). The presence of SSTRs has been demonstrated to a different degree of distribution and a regionally heterogenous subtype-specific expression is evident in over 80% of well-differentiated GEP-NENs. Overall, there is a clear predominance of sstr2 (Taylor et al. 1994). Tumor dedifferentiation is usually associated with diminution of receptor density and changes in receptor subtype profile; thus, the presence of SSTRs serves as a tumor-specific predictor of prognosis. It remains unclear if only numeric reduction of SSTRs or also their downregulation occurs with tumor dedifferentiation (Modlin et al. 2010c).

The clinical use of native SST is limited in the therapeutic setting because of its short half-life (∼90 s) and a postadministration hypersecretion rebound phenomenon. In contrast, bioactive synthetic SSAs, which are less sensitive to serum peptidases, evade these drawbacks and have therefore opened the conduit to various diagnostic and therapeutic purposes. The analog, octreotide, and a long-acting formulation of octreotide, lanreotide, exhibit high affinity to sstr2 and lower affinity to sstr3 and sstr5. Multi-SSTR-targeted analog SOM230 (pasireotide) activates sstr1–5, while Try0-(cyclo-d-Dab-Arg-Phe-Phe-d-Trp-Lys-Thr-Phe (KE108) binds avidly to all five known receptor subtypes (Reubi et al. 2002).

Symptomatic and antiproliferative effects of SSAs

Numerous studies on tolerability and efficacy of octreotide and lanreotide have demonstrated a mean symptomatic response rate of 73.2% (range 50–100%). Mean biochemical response rates (partial and complete response) for octreotide, octreotide long-acting release (LAR), and for long-acting lanreotide were 50.9% (range 28–77%), 51.4% (31.5–100%), and 39.0% (17.9–58%) respectively (Toumpanakis et al. 2009, Modlin et al. 2010c; Table 1).

Table 1

Clinical studies on the efficacy (biochemical response) of different somatostatin analogs adapted, with permission, from Modlin IM, Pavel M, Kidd M & Gustafsson BI 2010c Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Alimentary Pharmacology & Therapeutics 31 169–188

Author (year)nSSASD (%)PR (%)CR (%)BR (%)
Kvols et al. (1986)25OCT72
Arnold et al. (1996)103OCT38.528.25.133.3
Ricci et al. (2000)15OCT LAR3383341
Eriksson et al. (1997)19LAN58
Wymenga et al. (1999)55LAN SR522747
Bajetta et al. (2006)30LAN AG18.529.611.140.7

OCT, octreotide; LAR, long-acting repeatable; LAN, lanreotide; SR, slow release; AG, autogel; SSA, somatostatin analog; SD, stable disease; PR, partial response; CR, complete response; BR, overall biochemical response (PR+CR).

Clinical objective evidence of the antiproliferative effect of octreotide was first described with a high level of evidence in the PROMID phase III trial of midgut NENs (Rinke et al. 2009). Treatment with octreotide LAR 30 mg/day achieved a median time to tumor progression of 14.3 months compared with 6.0 months in the placebo group. After 6 months of treatment, the disease remained stable in 66.7% of patients in the treatment arm and in 37.2% in the placebo group. Patients with NENs poorly responsive to treatment with octreotide or lanreotide may benefit from combining SSAs with interferon (IFN)-α although there is no clear evidence for a beneficial effect of the combination. While an additive effect has been reported in nonrandomized trials, in three randomized trials no significant survival benefit was evident (Fazio et al. 2007). In a presently recruiting phase III trial, patients with advanced low- or intermediate-grade non-islet cell NENs are randomized to treatment with depot octreotide and IFN-α or depot octreotide and bevacizumab (www.clinicaltrials.gov, NCT00569127). This trial has the potential to further elucidate the effect of combination therapy.

Peptide receptor radionuclide therapy

Adequate density of SSTRs quantifiable on SRI is a prerequisite for the evaluation of patient eligibility for PRRT. In the initial phase, [111In-DTPA-d-Phe1]octreotide was the isotope of choice. Due to its short-range radiotoxicity and limited antiproliferative effect, this analog has been supplanted in favor of more suitable beta-emitting 90Yttrium (90Y)- or 177Lutetium (177Lu)-coupled analog. These have proven to be efficacious both for symptom relief and tumor remission (Kwekkeboom et al. 2008). Adverse events associated with PRRT using the new generation radiopharmaceuticals are, for the most part, uncommon and mild. They include hematological and renal deleterious effects that can, however in a minority of patients, be severe. Maximum tolerated dose per cycle and administration of nephroprotective agents are implemented in treatment protocols.

In a study on 504 patients who underwent 1772 treatment sessions, Kwekkeboom et al. (2008) documented the efficacy of PRRT with (177Lu-octreotate). The treatment protocol comprised four treatment cycles with intervals of 6–10 weeks and a cumulative activity of up to 750–800 mCi (27.8–29.6 GBq). While complete and partial tumor remissions were documented in 2 and 28% of patients, respectively, minor tumor response was seen in 16%. Uptake of OctreoScan and Karnofsky performance status >70 proved to be significant predictors of tumor remission. Twenty-five percent developed nausea within 24 h of the treatment initiation, and hematological toxicity was evident in 9.5%. In nine patients, serious delayed side effects occurred. Temporary hair loss was evident in 62%. An overall survival benefit from the time of initial diagnosis of 40–72 months was evident when the outcome was compared with the historical experience of the group. Imhof et al. (2010) obtained encouraging results in a phase II study on 1109 patients treated with (90Y-octreotide). Morphological, biochemical, and clinical responses were seen in 34.1, 15.5, and 29.7% respectively. Results of initial functional imaging were predictive for overall survival and for severe renal toxicity. Efficacy of PRRT in a neoadjuvant setting for downstaging either of unresectable primary tumor or hepatic metastases has also recently been reported (Stoeltzing et al. 2010). There exist some general reservations in respect of the outcome data of PRRT as, to date, there are no prospective randomized studies, and the long-term toxicities remain unknown. Nevertheless, there is compelling clinical logic for the use of this therapeutic modality given the limited treatment options available when other treatments fail.

Novel targeted therapeutic strategies

The choice of the appropriate treatment for GEP-NENs represents a challenge due to the variety of different NET types, the absence of comparative data for many of the therapeutic approaches, and the numerous disciplines involved in the development of a personalized management strategy. Ideally, therefore, it is commonly and most effectively undertaken in a tumor board comprised experts in the field. Treatment is highly individualized and based on data gathered over decades from smaller clinical studies. In recent times, data have become available from placebo-controlled studies, which support the value of specific drugs with its use in individual tumor types based on the identification of specific molecular targets (Table 2).

Table 2

Molecular targeted medical therapies and agents in neuroendocrine tumors adapted, with permission, from Gupta S, Engstrom PF & Cohen SJ 2011 Emerging therapies for advanced gastroenteropancreatic neuroendocrine tumors. Clinical Colorectal Cancer 10 298–309. Copyright 2011 Elsevier.

Inhibition of somatostatin receptors
 Octreotide, lanreotide, pasireotide
Inhibition of angiogenesis
 Anti-VEGF monoclonal antibody
  Bevacizumab
 Receptor tyrosine kinase inhibitors
  Sunitinib, Soarafenib, Pazopanib, Imatinib, Vatalinib
 Other
  Thalidomide
Signal transduction inhibitors
 Inhibition of PIK-3/Akt/mTOR pathway
  Everolmus, temsirolimus
 Inhibition of insulin-like growth factor receptor
  Cixitumumab
  Dalotuzumab
 Inhibition of epidermal growth factor receptor
  Gefitinib
Immune-modulators
  Interferon-α

The current status of medical therapy in GEP-NENs

Until recently, the only approved drugs for the treatment of NENs were the SSAs (octreotide and lanreotide). The main indication for therapy was the presence of the carcinoid syndrome. These two classes of agents act as secretory inhibitors by targeting tumor cell receptors and may also inhibit tumor cell proliferation. Their antiproliferative efficacy, however, is limited and rarely associated with objective tumor remissions (8–11%). Nevertheless, these drugs have a value in tumor growth stabilization and prolongation of time to tumor progression (Dahan et al. 2009, Rinke et al. 2009, Modlin et al. 2010c). Although there is no regulatory approval for antiproliferative indications in all GEP-NENs (except for midgut NENs), SSAs especially are frequently used as first-line therapy in G1/G2 NENs. This usage is based on the evidence derived from a placebo-controlled trial with octreotide in therapy-naïve patients with midgut NENs (Rinke et al. 2009). The antiproliferative value of lanreotide in nonfunctioning GEP-NENs is currently under evaluation in a placebo-controlled trial (CLARINET study). Although systemic chemotherapy can be of value in some PNENs, the vast majority of midgut NENs are slow proliferating and are nonresponsive to cytotoxic drugs (Sun et al. 2005, Dahan et al. 2009). Data supporting the use of streptozotocin-based chemotherapy either with 5-FU and/or doxorubicin mainly come from older studies using a variety of nonstandard endpoints (Moertel et al. 1992). Despite the limitations of the latter study, recent retrospective and small prospective studies have demonstrated the efficacy of this regimen with reports of tumor remissions of ∼40% (Kouvaraki et al. 2005, Turner et al. 2010). Smaller, phase II trials support the efficacy of temozolomide-based chemotherapy in PNENs (Kulke et al. 2009). In a retrospective study on patients with metastatic PNENs treated with first-line chemotherapy with a combination of capecitabine and temozolamide, a response rate of 70% and a median progression-free survival of 18 months were achieved compared with a response rate of 39% and a median progression-free survival of 9.3 months achieved with a triple combination of streptozotocin, doxorubicin, and 5-FU (Strosberg et al. 2011). These data warrant further confirmation in prospective trials. Nevertheless, it remains unclear in which group of patients this regimen might be used and if determination of the (O-6-methylguanine-DNA methyltransferase) expression or methylation status is helpful in preselecting patients for this therapy. For poorly differentiated tumors, platinum-based chemotherapy is still the sole available treatment.

Molecular targets in GEP-NENs

The recent availability of novel drugs (e.g. small molecule TKIs) has provided new treatment opportunities and holds promise given the expression in GEP-NENs of a variety of targets including angiogenic factors and their receptors (e.g. VEGF(R), PDGF(R)), peptide receptors (e.g. sstr15, EGFR, IGF1(R)), or intracellular molecules (e.g. mTOR; Hofland & Lamberts 1996, Welin et al. 2006, Srirajaskanthan et al. 2010; Tables 3 and 4). The mTOR pathway is especially activated in PNENs (Missiaglia et al. 2010, Kasajima et al. 2011) and somatic mutations have been identified in ∼14% (Jiao et al. 2011). To date there has been limited efficacy of current therapy in the long-term management of GEP-NENs in respect of syndrome and tumor control as well as limited survival (Surveillance Epidemiology 2009). Thus, a key unmet need has been the development of novel drugs and drug combinations to improve overall response rates and progression-free survival. A variety of targeted agents have been explored in GEP-NENs including angiogenesis inhibitors (e.g. PTK787/ZK, bevacizumab, thalidomide, and endostatin), single and multiple TKIs (imatinib, gefitinib, sorafenib, and sunitinib), mTOR inhibitors (temsirolimus and everolimus), novel SSAs (universal ligand pasireotide, chimeric molecule dopastatin targeting dopamine, and SSTR), and others (e.g. tryptophan hydroxylase inhibitors (LX1606) for carcinoid syndrome control, histone deacetylase inhibitors, and IGF receptor antibodies for tumor growth control). Overall, the objective response rates achieved with targeted drug monotherapy is <10% and may reach ∼25% with drug combinations in phase II trials. Among the angiogenesis inhibitors, bevacizumab is the only agent that is currently under evaluation in other clinical trials, while sorafenib and everolimus are being investigated with various drug combinations (www.clinicaltrials.gov).

Table 3

Current clinical trials using agents that target growth factor receptors and signaling pathways for the treatment of GEP-NENs

DrugTargetCotreatmentPhaseReference/trial no.
BevacizumabVEGFPeg IFN-α depotPhase IICarcinoid SWOG:S50518
OctreotidePhase III
2-Methoxy-estradiolPhase I/IICarcinoid NCT00328497
FOLFOXPhase I/IIAdvanced GEP-NEN NCT00227617
Oxaliplatin, capecitabinePhase IIAdvanced GEP-NEN NCT00398320
TemozolomidePhase IIPNEN, SI NEN (‘carcinoid’)
PazopanibPan-VEGFR, PDGF-R, c-KITPhase IILow-grade GEP-NEN NCT00454363
MotesanibVEGFR, PDGF-R, c-KITOctreotidePhase IIGEP-NEN NCT00427349
BortezomidProteasome inhibitorPhase II, completedGEP-NEN NCT00017199
Table 4

Current clinical trials for the treatment of GEP-NENs (from www.clinicaltrials.gov)

Drug combinationTarget(s)PhaseGEP-NEN targeted
Sorafenib+bevacizumabVEGF, PDGF, Raf, c-KITPhase IISI NEN (‘carcinoid’) PNEN
Sorafenib+metronomic cyclophosphamideVEGFR, PDGF, Raf, c-KIT, mTORPhase IIGEP-NEN
Sorafenib+RAD001VEGFR, PDGF, Raf, c-KIT, mTORPhase ISI NEN (‘carcinoid’) PNEN
RAD001 (RAMSETE)mTORPhase IINF NEN other than PNEN
RAD001+pasireotidemTOR, SSTRPhase ISI NEN (‘carcinoid’) PNEN
RAD001+bevacizumabmTOR, VEGFPhase IILow-grade NEC
RAD001+temozolomidemTOR, cytotox.Phase I/IIPNEN
IMC-12+octreotide LARIGF1-RPhase IISI NEN (‘carcinoid’) Islet cell
AMG-479IGF1-RPhase IISI NEN (‘carcinoid’) Islet cell

Sunitinib and everolimus (RADIANT-3) have been evaluated in phase III placebo-controlled trials in progressive NENs of pancreatic origin, while everolimus in combination with octreotide LAR has also been assessed in NENs associated with the carcinoid syndrome (RADIANT-2). These studies were large, international prospective trials and used progression-free survival (PFS) as the primary endpoint given the low remission rates noted in the phase II clinical trials.

Sunitinib (37.5 mg/day) was evaluated in patients (n=171) with well-differentiated nonresectable progressive PNENs. The majority received prior antitumor drug treatment (66% in the sunitinib arm and 72% in the placebo arm). Significant prolongation of PFS by 5.9 months compared with placebo was achieved with tumor remissions of <10% (Raymond et al. 2011a). Based on the trial results, sunitinib was approved (2011) for the treatment of progressive PNENs by the US FDA and European health authorities. The study exhibited some weaknesses including low recruitment (50% of preplanned patients), low number of patients at risk beyond 10 months, high death rate indicating inclusion of highly advanced patients, and lack of central radiology. The initially reported survival benefit was not evident with further follow-up (Raymond et al. 2011b). Most frequent side effects included diarrhea (59%), nausea (45%), asthenia (34%), and vomiting (34%).

In a similar study design, everolimus (10 mg/day) was compared with placebo in a large number of patients (n=410) with progressive well to moderately differentiated PNENs. Everolimus significantly prolonged PFS by 6.4 months compared with placebo, and this effect was long lasting (35% stable at 18 months). Tumor remissions were rare (5%; Yao et al. 2011). Everolimus was approved (2011) by the US FDA for the treatment of progressive PNENs, and European approval is pending. The most frequent adverse events included stomatitis (64%), rash (49%), diarrhea (34%), and fatigue (31%), while infections (23%) or pulmonary infiltrates (17%) require careful monitoring.

Everolimus has also been evaluated in a large placebo-controlled phase III trial (n=429) in different types of NENs (SI and lung) associated with the carcinoid syndrome. Although PFS was prolonged by 5.1 months, the primary endpoint was not determined by central reading. This has been suggested to reflect different judgments of tumor progression by local radiologists, leading to a loss of events in the central analysis and imbalances between study arms (e.g. WHO performance status, lung as primary tumor site) favoring the placebo arm (Pavel et al. 2010). Results of local and central analysis were, nevertheless, consistent. Further studies are required to clarify which subgroup might benefit from everolimus.

Although targeted agents such as everolimus and sunitinib have broadened the spectrum of available agents in GEP-NEN therapy, there future treatment issues that require consideration remain. Thus, in the case of a multiple TKIs such as sunitinib, activation of mechanisms of resistance, development of angiogenic rescue, potential acceleration of tumor growth, and incompatibility with surgery and other drugs in sequential therapy have to be evaluated. Potential side effects with broader and long-term use are reported in other types of cancers (including bleeding, cardiac events, among others).

Similar concerns occur with the mTOR inhibitors including the development of mechanisms of resistance, such as reactivation of PI3K Akt and MAP kinase pathways (Carracedo et al. 2008, Carew et al. 2011, Svejda et al. 2011). In addition, the question of compatibility with other drug treatments needs further clarification. A further consideration is the risk posed by surgery for which withdrawal of the mTOR agent may be required to lower the subsequent risk associated with a drug-induced chronic immunosuppressive state. The most important potential side effects, however, appear to be infections and pneumonitis, which may occur more frequently with broader and long-term use.

The specific role of targeted drugs in the management of GEP-NENs remains to be defined (Fig. 5). Most data are available for low- or intermediate-grade PNENs. Everolimus and sunitinib were evaluated in patients with PNENs mostly after failure of SSAs and/or systemic chemotherapies. Thus, there is a place for these agents after failure of chemotherapy, which is considered as a standard palliative therapy for PNENs in many centers, before tumor progression is required. Both drugs may be considered earlier in the treatment algorithm under special circumstances (e.g. intolerability or contraindication for chemotherapy). As in the placebo-controlled trial with everolimus (RADIANT-3), 40% of the patients were therapy-naïve, the potential long-term risks have to be considered if these drugs are used as a first-line treatment. There are currently insufficient data to support the use of sunitinib in patients with other GEP-NENs (Kulke et al. 2008). Everolimus may, however, be considered in patients with progressive NENs of the lung or midgut, if available or approved. Given the current lack of evidence of superiority of single drugs and combinations, the treatment approach remains a very individualized one. Combination therapies with targeted drugs are probably required in the future to improve response rates and overcome mechanisms of resistance. Clearly, further comparative clinical trials are required to clarify the precise therapeutic strategy.

Figure 5
Figure 5

Molecular targets in GEP-NENs. Proliferation is regulated by a number of different growth factors (e.g. TGFβ) through activation of AKT/ERK/SMAD and mTOR pathways. Negative regulators include somatostatin (SS), which target cell cycle activators through the P38/cGMP pathways. Targeting mTOR kinase or SS receptors are currently considered the most effective approach for inhibiting cell growth.

Citation: Endocrine-Related Cancer 19, 5; 10.1530/ERC-12-0024

Future directions

Two areas that have begun to be explored are identification of known or novel markers that can be identified in tissue peripheral blood as well as the development of a nomogram as an adjunct in the clinical setting.

Identification and use of tissue or circulating markers

A panel of gene markers have been identified from microarray studies and used to develop a classification system for midgut NENs. This has been used with success to differentiate the subtypes and can accurately predict metastasis (Drozdov et al. 2009). Detection of CgA using real-time PCR is more sensitive than conventional histochemical and immunohistochemical techniques to identify micrometastases (Kidd et al. 2006). PCR-based approached for different target genes may be of use in more accurately defining management strategy.

As an alternative to tissue analyses, the detection of circulating tumor-derived mRNA transcripts by PCR, either alone or in combination with detection of circulating peptides and amines by standard immunoassay, represents a novel approach to the diagnosis of GEP-NENs (Modlin et al. 2009). The identification of a gene panel of NEN transcripts encoding secreted markers, indicators of cell proliferation, and markers of metastasis has enabled the development of a mathematical predictive algorithm by which transcripts expressed in GEP-NEN tissue can be identified in blood with an accuracy that allows prediction of metastasis and determination of the pathological character of the NEN. For example, using real-time PCR to measure plasma or tissue levels of mRNA for a variety of neuroendocrine markers (e.g. 5-HT, CgA, ghrelin, and connective tissue growth factor) and using a predictive mathematical model for GEP-NEN diagnosis, various types of NENs can be distinguished from normal cells solely based on their molecular signature. This are still under development and are not currently in clinical use. Circulating tumor cells have also been detected (Khan et al. 2011), but their relevance is not known.

Prognostic nomogram

Approximately 18 000 cases and 8200 deaths attributable to this disease are predicted for 2011 in the USA based on the NCI SEER data. Given the wide range of the 5-year survival rates of 41–95% depending on disease extent, grade, and tumor site, patients with a NEN require a precise prognosis. With accurate prediction, patients at low risk of disease-specific death can be safely reassured, whereas patients at high risk can be considered for appropriate surgery and systemic therapy.

The recent description of an objective multivariate analysis of indices that defines SI NEN prognosis provides a rigorous mathematical-based tool – a nomogram – for the assessment of parameters that define progress, determine prognosis, and can guide therapy (Modlin et al. 2010b). The NEN nomogram is designed for prognosis prediction, patient group comparisons, and a guide for stratification of treatment and surveillance. It uses hazard ratio (HR), Cox and Kaplan–Meier analyses of published data, and the current SEER database to provide a nomogram from 15 variables that are demonstrated to provide significant multivariate HRs. These include age, gender, ethnicity, symptoms, urinary 5-HIAA, plasma CgA, liver function tests, tumor size, invasion, metastasis, histology, the Ki-67%, carcinoid heart disease, and therapy (surgery or long-acting SSAs). Internal validation enabled development of a GEP-NEN nomoscore using HR weighting and stratification into low (<75), medium (75–95), and high risk (>95). This enabled identification of significant differences in survival (15.5±4.3, 9.7±2.5, and 6.4±1.1 years respectively). The nomoscore was significantly elevated (P<0.01) in deceased compared with alive patients. The introduction of a nomogram represents an optimized construct based on the currently analyzable data and its application will facilitate accurate stratification for comparison in clinical trials (Fig. 6). In addition, the development of a mathematically validated nomogram provides a platform for objective assessment of SI NEN disease, a finite basis for precise prognostication and a tool to guide management strategy.

Figure 6
Figure 6

Five- and 10-year probability survival nomogram for SI NENs based on the overall literature review (n=12 412) and additional analysis of 7445 patients in the NCI-SEER database. F, female; M, male; W, white; B, black; O, other.

Citation: Endocrine-Related Cancer 19, 5; 10.1530/ERC-12-0024

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Acknowledgements

The authors would like to thank Dr Panagiotis Drymousis for his excellent assistance in preparation of this manuscript. The work was presented at the 9th Congress of the European–African Hepato-Pancreato-Biliary Association, 12–16 April 2011, Cape Town, South Africa.

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(A Frilling, G Åkerström, M Falconi, M Pavel, J Ramos, M Kidd and I M Modlin contributed equally to this work.)

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Figures

  • View in gallery

    Distribution of 49 012 NENs from the SEER 1973–2007 tumor registry database. Pie charts reflect the distribution of NENs by anatomical site and tumor type. Total NEN distribution (top), GEP-NEN distribution (bottom left), and pancreatic NEN distribution (right). Non-GEP-NENs are predominantly located in the respiratory system (bronchopulmonary NENs ∼70%, top right). Pancreatic ‘carcinoids’ does not reflect serotonin-secreting tumors, but instead reflects SEER-based reporting annotations for the lesions.

  • View in gallery

    Abdominal CT of a 62-year-old patient with a 20 cm pancreatic neuroendocrine tumor (A). 68Ga-DOTATOC PET/CT confirmed the location and dimensions of the primary lesion (B) and in addition disclosed a solitary bone metastasis (C). The skeletal deposit was identifiable only on the PET sequence.

  • View in gallery

    Sporadic, solitary type 3 gastric NEN with lymph node metastasis treated with a partial gastric resection. Reproduced, with permission, from Åkerström G, Hellman P & Hessman O 2009 Gastrointestinal carcinoids. In Endocrine Surgery, 4th edn, pp 147–176. Ed T Lennard. Copyright 2009 Elsevier.

  • View in gallery

    CT image of mesenteric metastasis of midgut NEN, the distal intestine is edematous due to venous stasis (indicated by *).

  • View in gallery

    Molecular targets in GEP-NENs. Proliferation is regulated by a number of different growth factors (e.g. TGFβ) through activation of AKT/ERK/SMAD and mTOR pathways. Negative regulators include somatostatin (SS), which target cell cycle activators through the P38/cGMP pathways. Targeting mTOR kinase or SS receptors are currently considered the most effective approach for inhibiting cell growth.

  • View in gallery

    Five- and 10-year probability survival nomogram for SI NENs based on the overall literature review (n=12 412) and additional analysis of 7445 patients in the NCI-SEER database. F, female; M, male; W, white; B, black; O, other.

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