Neuroendocrine tumours of the small intestine

Best Practice & Research Clinical Gastroenterology 26 (2012) 755–773

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Neuroendocrine tumours of the small intestine Jonathan Strosberg, MD, Assistant Professor * H. Lee Moffitt Cancer Center and Research Institute, Dept. of GI Oncology, 12902 Magnolia Dr., Tampa, FL 33612, USA

a b s t r a c t Keywords: Neuroendocrine tumour Midgut Jejunum Ileum Duodenum Carcinoid Carcinoid syndrome

The prevalence of intestinal neuroendocrine tumours, also known as carcinoid tumours, has increased significantly over the past three decades. Tumours of the distal small intestine (midgut) are often indolent, but are characterized by a high potential to metastasize to the small-bowel mesentery and liver. Patients with distant metastases are prone to development of the carcinoid syndrome, a constellation of symptoms which includes flushing, diarrhoea, and valvular heart disease. The carcinoid syndrome is caused by secretion of serotonin and other vasoactive substances into the systemic circulation. Treatment options for metastatic intestinal NETs have expanded in recent years. Of particular importance has been the development of somatostatin-analogue therapies. Somatostatin analogues were originally introduced for palliation of the carcinoid syndrome; however recent clinical trials have demonstrated that they can exert an inhibitory effect on tumour growth. Other novel agents targeting the VEGF and mTOR pathways have recently been evaluated in phase III trials, however their role in the management of small-intestinal NETs remains controversial. This article examines the biological characteristics of small intestinal NETs, summarizes current guidelines on classification, staging and grading, and reviews developments in locoregional and systemic therapy. Ó 2013 Elsevier Ltd. All rights reserved.

Introduction Neuroendocrine tumours (NETs) originate in secretory cells of the diffuse neuroendocrine system [1,2]. They are characterized by a propensity to produce peptides, neuroamines and other vasoactive substances which give rise to a variety of clinical syndromes. The term ‘carcinoid’ was coined in 1907 by * Tel.: þ1 813 745 7257; fax: þ1 813 745 7229. E-mail address: jonathan.strosberg@moffitt.org. 1521-6918/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpg.2012.12.002

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Siegfried Oberndorfer, a pathologist who used the appellation to describe a small bowel NET which appeared less histologically aggressive than adenocarcinoma [3]. Although it is now clear that ‘carcinoid’ is a misnomer given the malignant potential of most small bowel NETs, the term has persisted in the medical literature. Carcinoid tumours are typically defined as well-differentiated NETs originating in the enterochromaffin (EC) cells of the aerodigestive tract. Functional NETs are characterized by the presence of a clinical syndrome caused by excess hormone secretion, whereas non-functional NETs are hormonally silent. Intestinal NETs have distinct features depending on their site of origin. In 1963, Williams and Sandler classified carcinoid tumours based on embryonic derivation, distinguishing between foregut (bronchial, gastric, duodenal), midgut (jejunal, ileal, cecal) and hindgut (distal colic and rectal) tumours [4]. Although intestinal NETs originating in any site can produce hormone(s), metastatic NETs of the midgut are most strongly linked to the classical carcinoid syndrome, characterized by flushing, diarrhoea, and right-sided valvular heart disease. Midgut NETs are also notable for their tendency to metastasize to locoregional lymph nodes, root of the mesentery, and liver; however once metastatic, they often progress at an indolent pace and are associated with a relatively long life expectancy compared to metastatic NETs originating in foregut or hindgut organs [5,6]. NETs originating in the duodenum are not well characterized. Many are discovered incidentally during upper endoscopy [7]. Unlike midgut NETs, they are not commonly associated with the typical carcinoid syndrome. Epidemiology The incidence of NETs diagnosed in the United States has increased significantly over the past four decades. In a series of 35,618 carcinoid tumours reported to the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, the reported annual age-adjusted incidence of NETs increased from 1.09/100,000 in 1973 to 5.25/100,000 in 2004 [6]. The precise reasons for this steep rise in incidence are unclear; however increases in endoscopic procedures and cross-sectional imaging, as well as improved recognition of neuroendocrine histology are thought to play a role. Tumours of the jejunum/ileum were the third most common primary site (after lung and rectum) with an annual incidence of 0.67 per 100,000. The incidence of duodenal NETs was 0.19 per 100,000. The median age of diagnosis for jejunal/ileal NETs was 66, and the male to female ratio was 1.4/1.0. 29% of patients with jejunal/ileal tumours had localized disease, 41% had locoregional disease, and 30% had distant metastases at time of diagnosis. Similar increases in incidence rates were found in a Swedish national database that included 5184 NETs registered between 1958 and 1998 [8]. Although no clear risk factors were identified, a regression analysis of this database suggested that risk was increased in the setting of a family history of carcinoid in a first-degree relative (relative risk 3.6). The male to female ratio in this registry was 1.0/1.2. In another analysis of 13,715 cases registered in several national databases in the United States between 1950 and 1999, the majority of NETs were located in the gastrointestinal tract (67.5%) and lungs (25%). Within the gastrointestinal tract, a plurality of NETs arose in the small intestine (42%), followed by rectum (27%), stomach (20%), colon (20%) and appendix (18%) [9]. Clinical characteristics Patients with small intestinal NETs may develop symptoms due to effects of the primary tumour, due to enlarging metastases, or secondary to hormonal secretion. Small intestinal NETs originate most commonly in the distal ileum, within 60 cm of ileocaecal valve [10]. More than 25% of tumours are multifocal, with intraluminal lesions often clustered in close proximity to each other [10,11]. The most common presenting symptom of small intestinal NETs is abdominal pain, which is often crampy and paroxysmal [12,13]. Intermittent bowel obstruction is another common manifestation of small intestinal NETs. Bowel obstruction and/or abdominal pain may be due to the mechanical effect of the intraluminal tumour, or due to mesenteric lymph node involvement which can produce a secondary desmoplastic response. Desmoplasia can lead to bowel tethering and kinking (Fig. 1) as well as mesenteric ischaemia [14]. Duodenal carcinoids may produce duodenal or biliary obstruction; however many are detected incidentally.

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Fig. 1. Neuroendocrine tumor in the small bowel mesentery with surrounding desmoplasia (arrow).

Although small intestinal NETs usually progress in an indolent fashion, even subcentimeter tumours can metastasize [10,11]. The risk of metastatic spread appears to correlate with primary tumour size; however the absolute sized-based risk of malignant dissemination is uncertain since data derives from retrospective institutional series which are confounded by referral biases (Fig. 2) [10,15]. The most common sites of distant metastatic spread are liver, mesentery, and peritoneum [16]. Liver metastases can be quite extensive before causing significant abnormalities in liver function tests. Skeletal metastases are often a late occurrence in the natural history of small intestinal NETs and are associated with a relatively poor prognosis [16]. Ovarian metastases occur in approximately 18% of female patients, are almost invariably bilateral, and are often associated with peritoneal disease [16,17]. Carcinoid syndrome The clinical carcinoid syndrome was first described in 1954 by Thorson et al who drew an association between a metastatic carcinoid tumour of the small intestine and a constellation of unusual signs and symptoms [18]. These included diarrhoea, cutaneous vasomotor symptoms, bronchospasm, and right heart valvular disease. A subsequent case report elaborated on the flushing phenomenon, describing an ephemeral erythematous rash resembling in clinical miniature the ‘fickle phantasmagoria of the Aurora Borealis’ [19]. One year earlier, serotonin (5-hydroxytryptamine) was extracted from a carcinoid tumour and identified as the primary hormonal factor responsible for the carcinoid syndrome [20,21]. Serotonin is derived from the amino acid tryptophan, and is enzymatically

Fig. 2. Incidence of metastases stratified by primary tumor size in two analyses: single-center database of 165 cases (Moertel [10]; left) and literature review (Rorstad [15]; right).

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inactivated in the liver into 5-hydroxyindoleacetic acid (5-HIAA), a urinary metabolite. Consequently, the carcinoid syndrome occurs primarily in patients with liver metastases that secrete serotonin directly into the systemic (rather than portal) circulation. Other vasoactive substances elaborated by small bowel NETs include biogenic amines (such as histamine, dopamine, and hydroxytryptophan), tachykinins (kallikrein, substance P) and prostaglandins [22]. The carcinoid syndrome is associated, in nearly all cases, with metastatic NETs of the distal small intestine. In an analysis of 91 patients with the carcinoid syndrome, diarrhoea and flushing were the most commonly observed phenomena, occurring in 73% and 65% of patients respectively [23]. Carcinoid heart disease was detected in 10% of cases and bronchospasm in 8%. A variety of hormones contribute to development of diarrhoea and abdominal pain, including serotonin, prostaglandins, histamines, and tachykinins. Serotonin is thought to stimulate peristalsis, resulting in significantly accelerated colonic transit times [24]. It may also affect intestinal fluid and electrolyte secretion via 5-HT2A receptors [25]. The flushing phenomenon is attributable to multiple vasoactive substances including prostaglandins, tachykinins and serotonin [26–28]. Flushing typically involves the face, neck and upper torso, and may be precipitated by exercise, stress, alcohol, and certain foods [29]. Patients with chronic flushing can develop facial telangiectasias resembling rosacea. Massive releases of vasoactive substances may occur during surgery leading to a ‘carcinoid crisis’ characterized by severe hypotension [30,31]. Presurgical prophylaxis with somatostatin analogues can ameliorate this problem [31]. Carcinoid heart disease (CHD) typically occurs in patients with severe and long-standing elevations of circulating serotonin [32,33]. Deposition of fibrotic tissue on right-sided heart valves can produce tricuspid regurgitation and pulmonary valve stenosis. The right heart is invariably affected due to its direct exposure to serotonin secreted by liver metastases [34]. Left heart valves are clinically involved in fewer than 10% of cases due to inactivation of hormones in the pulmonary circulation [35]. The underlying mechanism of fibroblast proliferation in the cardiac valves is uncertain. There is some controversy regarding the indications for CHD screening. While some experts recommend that echocardiograms be performed on all patients with carcinoid syndrome [36], other guidelines suggest that only patients who develop symptoms of cardiac dysfunction or who are being evaluated for surgery require echocardiography [37]. The definitive management of CHD involves surgical replacement of the tricuspid and pulmonic valves. Pathology, staging and prognosis Histological grade and differentiation correlate closely with clinical behaviour. Grade refers to the proliferative activity of tumours, commonly measured by the mitotic rate (number of mitotic figures per 10 high-powered fields) and Ki-67 index. Differentiation refers to the extent to which neoplastic cells resemble normal endocrine tissue. Poorly differentiated NETs are nearly always high-grade and behave in a biologically aggressive fashion [38]. The most recent nomenclature proposed by the World Health Organization (WHO) distinguishes between well-differentiated tumours (low-grade or intermediate-grade) and poorly differentiated tumours (Table 1) [39]. Nearly all small intestinal NETs fall into the well-differentiated category. In one large series, only 1% of jejunal and ileocaecal (midgut) tumours were poorly differentiated [40]. The 5-year survival rates for low and intermediate grade tumours were 79% and 74% respectively, whereas high-grade (poorly differentiated) NETs had a 5-year survival rate of only 40%. Until recent years, neuroendocrine tumours lacked a formal TNM staging classification. The SEER database in the United States stratified patients into localized, locally advanced, and metastatic categories. In one analysis of the SEER registry, the respective 5-year survival rates for these stages were Table 1 Pathological classification of neuroendocrine tumors. Differentiation

Grade

Criteria

Well differentiated

Low (Typical) Intermediate (Atypical) High

<2 mitoses/10 HPF and 2% Ki67 index 2–20 mitoses/10 HPF or 3%–20% Ki67 index >20 mitoses/10 HPF or >20% Ki67 index

Poorly differentiated

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95%, 84% and 51% among patients with primary small intestinal NETs [5]. The survival rates for patients with metastatic small bowel primaries compared favourably with metastatic tumours originating in other sites including the colon, rectum, stomach and appendix [5]. In 2007, The European Neuroendocrine Tumour Society (ENETS) proposed a formal TNM staging system for tumours of the lower jejunum and ileum (Table 2), a system that was subsequently adopted by American Joint Committee on Cancer [41,42]. A single-institution analysis of overall survival stratified by TNM stage revealed that 5-year survival rates were 100% for stage I and II tumours vs. 91% for stage III (locoregionally advanced) and 72% for stage IV tumours. The median overall survival for stage IV tumours was 103 months. Among stage III patients, survival differed significantly between patients with resectable mesenteric tumours (95% 5-year survival) vs. unresectable (78% 5-year survival) [40]. Another analysis of 270 NETs (which included a combination of midgut and hindgut tumours) reported a 5-year disease-specific survival rate of 100% for patients with stage I and II tumours vs. 97% for stage III and 83% for stage IV tumours [43]. Tumour markers NETs often produce functional hormones as well as hormonally inactive proteins, such as chromogranins, that are associated with secretory vesicles. Metastatic small bowel NETs are characterized by a strong propensity to secrete serotonin as well as other vasoactive substances which give rise to the carcinoid syndrome. Serotonin is derived from the amino acid tryptophan and is enzymatically inactivated in the liver into 5-HIAA, a urinary metabolite. Urine 5-HIAA Measurement of 24-hour urinary excretion of 5-HIAA is a useful test for evaluating patients with suspected carcinoid syndrome as well as for monitoring patients with known small-intestinal NETs [44]. Foregut NETs rarely produce serotonin and hindgut tumours virtually never produce the hormone [45]; consequently, an elevated 5-HIAA in a patient with a metastatic NET of unknown primary points towards a probable small bowel origin. Urine 5-HIAA is typically normal among patients with localized tumours, and is usually elevated in patients with liver metastases. Normal ranges vary by laboratory; however upper normal limits range from six mg/day to 15 mg/day in most assays. False positive results may be induced by the ingestion of certain drugs and tryptophan or serotonin-rich foods. As a result, patients should be provided with detailed lists of foods and drugs to avoid beginning several days prior to the urine collection. Although many patients with the carcinoid syndrome have modest 5-HIAA elevations, some have values for urinary 5-HIAA excretion above 100 mg/day. Patients with carcinoid heart disease typically have levels exceeding 5–10 times upper limits of normal [33,34].

Table 2 ENETS/AJCC TNM staging classification of small bowel NETs. T1 T2 T3 T4 N0 N1 M0 M1

Tumor invades lamina propria or submucosa and size one cm or less Tumor invades muscularis propria or size >one cm Tumor invades through the muscularis propria into the subserosa or into the nonperitonealized tissue Tumor invades the visceral peritoneum (serosa) or any other organs or structures No regional LN metastasis Regional LN metastasis No distant metastasis Distant metastasis

Stage

T

N

M

I IIA IIB IIIA IIIB IV

T1 T2 T3 T4 Any T Any T

N0 N0 N0 N0 N1 Any N

M0 M0 M0 M0 M0 M1

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Blood serotonin and 5-HIAA Various serotonin assays have been described in the literature including platelet-rich plasma serotonin, platelet-poor plasma serotonin, and whole blood serotonin. However, the sensitivities and specificities of these assays have not been well established. False positive serotonin tests may occur due to release of platelet serotonin [46]. As a result, the specificity of blood serotonin measurement appears to be inferior to urine 5-HIAA collection. More recently, plasma 5-HIAA assays have been described which appear to be more accurate than blood serotonin measurements. In one study of 57 patients, plasma 5-HIAA showed a sensitivity of 89% and specificity of 97% [47]. Chromogranin Chromogranins (designated as A, B, and C) are glycoproteins that are stored within secretory vesicles and released with peptides and amines in a variety of neuroendocrine tissues. Well-differentiated NETs are associated with elevated blood levels of chromogranin which often correlates with tumour burden. Chromogranins B and C are less sensitive indicators of neuroendocrine tumours as compared to chromogranin A (CgA). The sensitivity and specificity of CgA depends on the cutoff value. This was demonstrated in a series that compared plasma CgA levels in 238 patients with well-differentiated neuroendocrine tumours, 42 with chronic atrophic gastritis, and 48 healthy individuals [48]. Using a DAKO ELISA kit, the optimal cutoff range between participants without neoplasia and those with neuroendocrine tumours was 31 U/L, with a sensitivity and specificity of 75 and 84 percent, respectively. When specificity was set at 95 percent and the cutoff was 84 U/L, sensitivity was only 55 percent. There is a lack of international standardization that makes it difficult to extrapolate these values to other CgA assays. False positive elevations of CgA can be present in a number of conditions, including atrophic gastritis, renal insufficiency and inflammatory bowel disease [49]. Patients taking proton pump inhibitors will almost invariably have elevated CgA [50]. Due to its relatively low specificity, the use of CgA is not recommended as a screening test for NETs. It is more appropriately used as a tumour marker in patients with an established diagnosis in order to assess disease progression, response to therapy or recurrence after surgical resection. For example, in one series of patients with carcinoid syndrome undergoing surgical hepatic cytoreduction, decreases of 80% in levels of serum CgA correlated with symptom relief and disease control [51]. Elevations of CgA have also correlated inversely with progression-free survival in prospective clinical trials [52]. Other tumour markers There are multiple secretory proteins which can function as tumour markers in patients with NETs. These include neuron specific enolase (NSE) substance P, neurokinin A, and pancreastatin. In one study of 127 patients with a variety of NETs, CgA proved to be a more sensitive marker than NSE as well as a more accurate prognostic test for progression [53]. Pancreastatin is a posttranslational processing product of CgA circulating in picomolar concentrations. An advantage of pancreastatin versus CgA is that proton pump inhibitors do not seem to cause false-positive elevations of pancreastatin [54]. While numerous studies suggest that any of the aforementioned tumour markers can be prognostic in patients with small-bowel NETs and that changes in these tumour markers correlate with treatment response or progression, their value in the practical management of patients is uncertain. The National Comprehensive Cancer Network (NCCN) guidelines for neuroendocrine tumours do not endorse routine measurement of any particular tumour marker, including CgA [37]. Radiographic scans NETs of the small intestine commonly metastasize to mesentery, peritoneum and liver. Radiographic studies should therefore image the abdomen and pelvis. CT scans, MRIs and somatostatin-

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receptor scintigraphy (SRS; OctreoScanÒ) are the primary imaging modalities used to identify and follow metastatic NETs of the small intestine. Novel imaging techniques include 18F-DOPA, 11C-5-HTP, and 68Ga-DOTATOC scans. Computed tomography (CT) 3-phase CT scans are recommended for optimal evaluation of liver metastases. NETs are typically vascular and may enhance with iodinated contrast during early arterial phases of imaging, or with washout during the portal venous imaging phase [55]. Therefore, arterial phase (approximately 20 seconds after contrast injection) and portal venous phase (approximately 70 seconds after contrast injection) sequences can be used to maximize the conspicuity of lesions compared to the liver parenchyma (Fig. 3). NETs originating in the small intestine often produce mesenteric masses with dense desmoplastic fibrosis, either due to direct extension of primary tumours into the mesentery, or due to mesenteric lymph node metastases. CT scans are ideal for identification of these tumours, which are often located in the root of the mesentery, and are characterized by a circumferential pattern of fibrosis which tethers surrounding small bowel (Fig. 1). CT enterography can be performed for identification of primary intestinal tumours which may not be readily seen on conventional CT scans [56]. Magnetic resonance imaging (MRI) MRI scans represent a sensitive method for detection of liver metastases. In one study of 64 patients with metastatic gastrointestinal NETs, MRI scans detected significantly more hepatic lesions than SRS or CT scans [57]. In some cases, vascular metastases are best detected by early arterial-phase imaging

Fig. 3. Arterial and venous phase CT scans in two patients illustrating that multi-phase imaging maximizes sensitivity for detection of liver metastases.

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sequences. In a study of 37 patients with liver metastases, the most sensitive sequences were hepatic arterial phase and fast spin-echo T2-weighed images [58]. Eovist contrast may be used to optimize detection of sub-centimetre liver metastases [59]. This is particularly useful when evaluating potential candidates for hepatic cytoreductive surgery. Somatostatin-receptor scintigraphy (SRS; OctreoScan) Many NETs express somatostatin receptors and can therefore be imaged with a radiolabeled form of the somatostatin analogue octreotide (111indium pentetreotide; OctreoScan) [60]. This technique images the entire body enabling detection of metastases outside of the abdominopelvic region. The accuracy of SRS has improved with the addition of single photon emission computed tomography (SPECT) to planar imaging, since SPECT permits more accurate differentiation between areas of pathologic and physiologic uptake in the abdomen. In one report describing 72 patients with NETs who were examined with SPECT/CT hybrid imaging, the combination improved localization in 23 of 44 cases, affecting clinical management in 10 patients [61]. In addition to anatomical information, SRS offers functional information regarding intensity of somatostatin-receptor expression. In centres that perform peptide-receptor radiotherapy, SRS is essential because levels of radiotracer uptake predict response to treatment. However, it is not clear whether levels of radiotracer uptake predict response to non-radiolabeled somatostatin-analogues such as octreotide. In older studies, the sensitivity of SRS compared favourably with other imaging modalities. However, recent advancements in CT and MRI technology have raised questions regarding the role of SRS in the staging workup of NETs. In one series of 121 NET patients, multiphase contrast-enhanced CT or MRI scans detected more pathologic lesions than did SPECT-OctreoScans [62]. OctreoScans are particularly inadequate for detection of metastases <1.5 cm, with a sensitivity of <35% [57]. Functional PET imaging techniques Although not widely available, several positron emission tomography (PET) radiotracers for functional imaging have emerged, including 18F-dihydroxy-phenyl-alanine [18F-DOPA], 11C-5-hydroxytryptophan [11C-5-HTP]), and 68Ga-DOTATOC. These novel PET modalities offer higher spatial resolution than conventional SRS and improved sensitivity for detection of small lesions. One study of 68Ga-DOTATOC PET compared to SRS imaging in 27 NET patients demonstrated superior sensitivity of PET imaging for detection of skeletal and pulmonary tumours [63]. In another study of 47 NET patients (including 24 carcinoid), 11C-5-HTP was compared to 18F-DOPA, SRS, and CT scans. On per-patient analysis, the sensitivity for 11C-5-HTP in carcinoid patients was 100% versus 96% for 18F-DOPA, 86% for SRS, and 96% for CT scan [64]. Recommendations for imaging and biomarker testing Small intestinal NETs are typically slow-growing tumours. Consequently, imaging studies and tumour marker measurements can often be performed at relatively infrequent intervals (e.g. every 4– 12 months). In patients with well-differentiated tumours, we typically obtain baseline CT (or MRI) and SRS along with 24 hour urine 5-HIAA and CgA. For post-operative surveillance of localized resected tumours, we normally evaluate patients twice yearly for the first 1–2 years, then annually with CT or MRI scans and tumour markers. Long-term follow-up (>5 years) is important since recurrences can occur many years after initial diagnosis. For patients with unresectable metastatic tumours, visits with imaging studies (typically CT or MRI) and tumour markers can be scheduled at a frequency that is based on rate of prior disease progression. Some patients with a prolonged history of stable disease can be seen and imaged as infrequently as once a year. Since tumour markers can sometimes fluctuate in absence of changes in clinical status or radiographic scans, treatment decisions are rarely made based on tumour marker changes alone.

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Treatment of local and locally advanced tumours NETs of the small intestine are most commonly found in the distal ileum. Because of their malignant potential, surgical resection of midgut NETs is recommended even for small, asymptomatic tumours detected incidentally. The most common surgery performed for a tumour in or near the ileocaecal valve is right hemicolectomy. Partial small bowel resection can be performed for more proximal tumours. Resection of the involved small bowel mesentery is recommended for lymph node sampling. Because tumours are multifocal in one quarter of cases, the remainder of the small bowel should be examined at the time of surgery [37]. Resection of lymph-node metastases in the root of the mesentery can be complicated by involvement of superior mesenteric vessels. Borderline resectable cases should be evaluated at centres of surgical expertise. There is some controversy regarding the necessity of resecting primary small bowel NETs in patients with distant metastases. While some studies suggest that resection of the primary tumour is associated with improved survival, the data supporting this practice derives from non-randomized institutional series [65]. Most experts advocate resection of the primary tumour in patients who are experiencing symptoms (such as pain, bleeding or intermittent bowel obstruction) or who are likely to survive long enough to experience such symptoms in the future [37]. There is very little data guiding the treatment of small duodenal NETs. Many are discovered incidentally during upper endoscopies. If possible, endoscopic resection, using techniques such as endomucosal resection (EMR) can be considered for patients with superficial, asymptomatic tumours [37]. Duodenotomy can be performed with relatively low morbidity for patients with tumours that are more invasive. In some cases, pancreaticoduodenectomy (Whipple surgery) is necessary for patients with tumours that are in close proximity to the ampula of Vater [66].

Systemic treatment of metastatic tumours Somatostatin analogues The development of somatostatin analogues (SSAs) has had a profound impact on management of metastatic small bowel NETs. Native human somatostatin is a peptide hormone that has an inhibitory effect on gastrointestinal motility, secretion and absorption. It also inhibits the release of other neuroendocrine hormones, including serotonin [67]. Its actions are mediated through five somatostatin receptor subtypes (SSTRs 1–5) belonging to a family of G-protein coupled receptors [68]. The clinical use of native somatostatin is impeded by its short half-life of approximately 2 minutes. Consequently, SSAs were developed by shortening the somatostatin polypeptide chain, eliminating enzymatic cleavage sites but conserving binding sites, thus prolonging half-life significantly. The two commercially available SSAs, octreotide and lanreotide, bind avidly to SSTR2 and moderately to SSTR5 [69]. The first clinical trial of subcutaneous octreotide evaluated 25 patients with carcinoid syndrome and reported prompt palliation of flushing and diarrhoea in 22 patients (88%), as well as major reductions of urine 5-HIAA in 18 patients (72%) [70]. Subsequent studies have confirmed the palliative effect of octreotide and lanreotide for patients with the carcinoid syndrome [71,72]. Side effects of SSAs, which are generally mild, include nausea, bloating and steatorrhoea. An increased rate of biliary stone and sludge formation is observed due to inhibitory effects of SSAs on gallbladder contractility. Therefore, prophylactic cholecystectomy should be considered in patients undergoing abdominal surgery. Long-acting, depot formulations of octreotide and lanreotide have been available for the past decade, enabling monthly dosing [73,74]. Standard dosing schedules include monthly intramuscular administration of octreotide long acting repeatable (LAR) 20–30 mg and deep subcutaneous injections of depot-lanreotide 60–120 mg. Above-label doses can be considered in patients whose symptoms are inadequately controlled on standard doses. Patients who experience exacerbation of symptoms towards the end of each treatment cycle may benefit from increased frequency of administration (i.e. every 3 weeks) [75,76]. Supplemental dosing with subcutaneous octreotide is occasionally of benefit to patients with breakthrough symptoms.

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Treatment and prophylaxis of the carcinoid crisis The term “carcinoid crisis” refers to an episode of circulatory collapse caused by an acute release of serotonin and other vasoactive substances into the circulation. Triggers include general anaesthesia and epinephrine. Carcinoid syndrome patients who undergo an invasive procedure should receive a supplementary dose of octreotide 250–500 mcg subcutaneously or intravenously one to two hours prior to the procedure [31]. Patients who develop intra-operative hypotension should receive bolus intravenous doses of 500–1000 mcg until control of symptoms is achieved. Alternatively, continuous intravenous infusion of 50–200 mcg/h may be given after a bolus dose. The antiproliferative effect of SSAs Shortly after SSAs were developed for palliation of the carcinoid syndrome, clinical evidence emerged that they were also capable of inhibiting tumour growth. Although rarely associated with objective tumour regression, SSAs were found to stabilize tumours in nearly 50% of patients with prior evidence of tumour progression [77]. In-vitro data suggests that tumour growth inhibition is mediated by direct interaction with somatostatin receptors (causing downstream stimulation of phosphotyrosine phosphatases) and indirectly through inhibition of growth factors such as insulin-like growth factor (IFG) and vascular endothelial growth factor (VEGF) [78–80]. High-level evidence for the antiproliferative effect of SSAs emerged with publication of the PROMID trial, a phase III study which randomized 85 patients with metastatic midgut (jejunal and ileocaecal) NETs to treatment with octreotide LAR 30 mg vs. placebo [81]. The study reported a statistically and clinically significant improvement in median time to progression from 6 months on the placebo arm to 14.3 months on the experimental arm (hazard ratio 0.34; P¼0.000072). On multivariate analysis, patients with relatively low hepatic tumour burden (<10%) and resected primary tumour appeared to benefit most significantly from octreotide treatment vs. placebo. The small number of deaths in each treatment arm and the high rate of crossover precluded any analysis of differences in overall survival. Based on the PROMID data, octreotide LAR therapy is now considered an appropriate first-line treatment for patients with metastatic midgut NETs that are not surgically resectable, regardless of presence or absence of the carcinoid syndrome. Interferon-a Interferons (IFN) exert their effects through a variety of mechanisms, including stimulation of Tcells, inhibition of angiogenesis, and induction of cell cycle arrest in the G1 and G0 phases [82]. In neuroendocrine tumours, interferons can also induce expression of somatostatin receptors. Early trials of IFN-a in hormonally functional NETs took place prior to introduction of somatostatin analogues and reported significant palliation of flushing and diarrhoea along with reductions of tumour markers in over 50% of patients with carcinoid syndrome [83]. Objective tumour responses have generally been observed in fewer than 10% of patients. With the development of somatostatin analogues, in-vitro studies suggested synergism between IFN-a and SSAs, leading several investigators to evaluate the combination of the two therapies. In one trial of patients with suboptimally controlled carcinoid syndrome 49% of patients reported symptomatic improvement from addition of IFN-a to octreotide [84]. Three randomized clinical trials have investigated SSAs alone versus in combination with IFN-a. In one multicenter study of 68 patients with metastatic midgut NETs, patients were randomized to octreotide plus IFN-a versus octreotide monotherapy. There was a strong trend towards improvement in the five-year survival rate (57% versus 37%) that was not statistically significant (P¼0.13) [85]. Another three-arm trial compared subcutaneous lanreotide to IFN-a alone or in combination among patients with metastatic NETs of the digestive tract and pancreas [86]. Objective response rates were rare (7%) in all three arms and tumour progression rates were nearly identical. A third randomized study of 105 patients compared octreotide alone or in combination with IFN-a. Median overall survival was longer in the combination (54 months vs. 32 months) but the difference was not statistically significant (P¼0.38). Response rates in both arms were low (<6%) [87]. The underpowered design of these randomized studies precludes any definitive conclusions regarding the impact of IFN-a on overall survival. Moreover, an optimal dosing regimen has never been

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established. IFN-a therapy is associated with chronic toxicities such as flu-like symptoms, depression, myalgias, and myelosuppression. However, the relatively low doses of IFN-a studied in most NET trials are fairly tolerable. mTOR inhibitors The mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that regulates cell growth, metabolism and proliferation [88]. The mTOR enzyme lies downstream of the PI3K/AKT pathway and is activated in response to stimulation by growth factors and cytokines. Whole exome analysis of pancreatic NETs reveals that mutations in mTOR associated genes (such as PTEN and PI3K) occur in approximately 15% of cases [89]. It is still unknown whether small bowel NETs are associated with mTOR pathway mutations. Everolimus is an oral mTOR inhibitor which has been studied extensively in NETs. The phase III RADIANT 2 trial randomized 429 patients with metastatic NETs and evidence of carcinoid syndrome to treatment with everolimus plus octreotide LAR vs. placebo plus octreotide LAR [90]. The majority of patients in both arms had primary small intestinal NETs. On central radiographic review, median progression-free survival improved from 11.3 months on the placebo arm to 16.4 months on the everolimus arm (HR 0.77; P¼0.026). While clinically significant, the result fell just short of the prespecified statistical significance of 0.024. One major reason for the failure to achieve statistical significance was loss of progression events in central versus local radiographic review. Overall survival was not improved in the experimental arm, a fact that is attributable to the crossover design of the study. Side effects of everolimus include oral aphthous ulcers, rash, hyperglycemia, cytopenias, and pneumonitis. The results of the RADIANT 2 study have generated some controversy as to the role of everolimus in NETs of the intestinal tract. At this time, everolimus is not approved by the U.S. Food and Drug Administration (FDA) for treatment of NETs originating outside of the pancreas, and major guideline organizations, such as the NCCN, do not recommend everolimus for management of small bowel NETs. An ongoing phase III study of everolimus in non-functional NETs (RADIANT 4) may expand the role of this drug if results are positive. Angiogenesis inhibitors NETs are highly vascular tumours which frequently over-express the VEGF receptor and its ligand [91]. Consequently, inhibition of the VEGF pathway has been a promising treatment target. Bevacizumab is a monoclonal antibody to circulating VEGF. In a randomized phase II trial, 44 patients with metastatic carcinoid tumours were randomly assigned to treatment with bevacizumab or pegylated IFN-a for 18 weeks, after which they received both agents in combination [92]. After 18 weeks of treatment, the rate of PFS was 95% on the bevacizumab arm versus 68% on the IFN-a arm. Moreover, the objective radiographic response rate in the bevacizumab arm was 18%, indicating a high degree of clinical activity. A larger phase III study led by the South West Oncology Group (SWOG) comparing bevacizumab to IFN-a has recently completed accrual. Several tyrosine kinase inhibitors of VEGFR have been evaluated for metastatic NETs. Sunitinib inhibits VEGFRs-1, -2, and -3, as well as PDGF, cKIT and Flt3. In a two-cohort (carcinoid and pancreatic NET) phase II study of sunitinib, only one of 41 (2%) of patients with carcinoid tumours experienced an objective radiographic response. However the median time to tumour progression (TTP) of 10.2 months was relatively encouraging [93]. Pazopanib, an inhibitor of VEGFRs-1, -2, and -3, as well as PDGF and cKIT, was also evaluated in a two-cohort study [94]. No responses were seen in the first 20 carcinoid patients treated leading to discontinuation of this treatment arm. It is unclear whether objective radiographic response rates are an appropriate endpoint for evaluation of angiogenesis inhibitors which are more likely to stabilize tumour growth rather than shrink tumour size significantly. Randomized trials, or early-phase trials focussing on alternative endpoints (such as changes in vascularity on functional CT scans) may be preferable to conventional single-arm phase II studies for evaluating drug activity.

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Cytotoxic chemotherapy Small intestinal NETs appear to be particularly resistant to cytotoxic chemotherapy. This is particularly apparent in modern clinical trials using strict radiographic response criteria. For example the combination of temozolomide and thalidomide has been associated with a response rate of only 7% in carcinoid tumours (versus 45% in pancreatic NETs) [95]. Likewise a study of temozolomide plus bevacizumab revealed no responses in 18 patients with carcinoid tumours (versus 33% response rate in pancreatic NETs) [96]. One potential explanation for the low-response rates in carcinoid tumours compared to pancreatic NETs is that carcinoid tumours express high levels of methylguanine-DNAmethyltransferase (MGMT), a DNA repair enzyme [97]. Another explanation is that the low proliferative rate of small bowel NETs renders tumours relatively insensitive to agents targeting DNA replication. Cytotoxic drugs are therefore not recommended for treatment of advanced small bowel NETs with the rare exceptions of poorly-differentiated tumours, or tumours which are progressing at an unusually rapid rate. Radiolabeled somatostatin analogues Nearly 80% of well-differentiated NETs express high levels of somatostatin receptors. This is the basis for development of radiolabeled somatostatin-analogue treatment, otherwise known as peptide receptor radiotherapy (PRRT). Selection criteria for PRRT include evidence of strong radiotracer uptake on SRS (at least as high as normal liver tissue). Early clinical trials of PRRT used high doses of 111Inpentetreotide, the isotope used in SRS [98,99]. While clinical benefit was observed in some cases, objective radiographic responses were rare, possibly due to the short tissue penetration of Auger electrons emitted by the 111In isotope. The next generation of radiolabeled somatostatin analogues used 90Y, a high-energy b-particle emitter [100]. Objective response rates associated with 90Y-DOTATyr [3]-octreotide (also known as 90Y-DOTATOC) were initially reported to be approximately 25%. However, a large multicenter trial of 90 patients with metastatic carcinoid tumours recently reported an objective response rate of only 4% (with a stable disease rate of 70% and high rate of symptom control) [101]. Adverse events consisted primarily of nausea and vomiting attributed to amino-acid solutions which were administered to prevent radiation nephrotoxicity. The latest generation of radiolabeled somatostatin-analogues utilizes 177Lu-octreotate (177Lu-DOTATyr [3]-octreotate), a b and g-particle emitting compound with enhanced affinity for SSTR2. An objective radiographic response rate of 23% among 188 patients with carcinoid tumours was reported in a large non-randomized trial [102]. Adverse effects were mild. An international phase III registration trial of 177Lu-octreotate versus high-dose octreotide is being planned for patients with functional midgut NETs. Management of liver metastases The liver is the predominant site of metastases in patients with small bowel NETs. Patients with liver metastases may experience symptoms such as anorexia, weight-loss and pain related to enlarging tumours, as well as flushing and diarrhoea caused by secretion of hormones directly into the systemic circulation. Liver-directed therapies include liver resection or ablation, hepatic transarterial embolization (TAE) or chemoembolization (TACE), and liver transplantation. These therapies are generally reserved for patients whose tumours are predominantly confined to the liver. Liver resection has been advocated for patients with limited hepatic disease if greater than 90% of tumours can be successfully resected or ablated [103,104]. Various ablation techniques can be used, including cryoablation, alcohol ablation and radiofrequency ablation (RFA) [105]. RFA involves conversion of radiofrequency waves to heat using an alternating current which generates ionic vibration. Ablation methods are usually reserved for unresectable oligometastases smaller than five to seven cm in diameter. Proponents of cytoreductive resection and ablation cite numerous institutional series reporting palliation of symptoms and prolonged survival durations among patients undergoing surgery with curative or near-curative intent [106,107]. However, there are no randomized studies

First author/ Reference

Year

Number of patients

Tumor type

Therapy

Cytotoxic/Embolic agent

Carrasco Ruszniewski Therasse Perry Diamandidou Desai

1986 1993 1993 1994 1998 2000

25 23 23 30 20 34

Carcinoid Carcinoid and pNET Carcinoid Carcinoid and pNET Carcinoid and pNET Carcinoid

TAE TACE TACE TACE TACE TACE

Dominguez Gupta

2000 2003

15 81

Carcinoid and pNET Carcionid

Eriksson Kim

1998 1999

41 30

Carcinoid and pNET Carcionid and pNET

TACE TAE and TACE TAE TACE

Loewe Fiorentin Strosberg

2003 2004 2006

23 10 84

Carcinoid Carcionid Carcinoid and pNET

TAE TACE TAE

PVA Dox Dox Dox Cisplatin Dox and Mitomycin STZ PVA or Gelfoam  multiagent chemorx Gelfoam Cisplatin and Dox Or 5-FU and STZ Cyanoacrylate and lipiodol Gelfoam þ multiagent chemorx PVA or Embospheres

Major biomarker responsea

Symptom response

Radiographic response (PRþCR)

Median overall survivalb

87% 73% 100% 90% 67% 78%

33% (6 of18) 45% (18 of 34)

63%

53% (8 of 15) 67% (46 of 69)

31 months

39%

52% (15 of 29) 37% (11 of 30)

54 months 15 months

61% 100% 80%

73% (16 of 22) 70% (7 of 10) 48% (11 of 23)

22 months 36 months

57% 91% 79% 73% 60%

80%

33% (6 of 18) 35% (6 of 17)

24 months 24 months

Abbreviations: pNET, pancreatic neuroendocrine tumors; PR, partial response; CR, complete response; TAE, transarterial (bland) embolization; TACE, transarterial chemoembolization; PVA, polyvinyl alcohol particles; Dox, doxorubicin. a >50% decrease or normalization of tumor marker. b Survival from onset of embolization therapy.

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Table 3 Clinical and radiographic outcomes of hepatic transarterial (chemo) embolizations: institutional series.

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comparing surgical to non-surgical approaches; thus the degree of survival benefit conferred by surgical therapy remains speculative. Hepatic transarterial embolization (TAE) or chemoembolization (TACE) is typically performed in patients with diffuse or widely scattered liver metastases. The theoretical basis for embolization is that liver metastases are supplied predominantly by the hepatic arterial circulation, whereas the normal liver parenchyma derives its blood supply primarily from the portal vein. In patients with bilobar hepatic metastases, staged lobar embolizations are typically performed at 4–6 week intervals. Various particulate and occlusive materials have been used including polyvinyl alcohol (PVA) and trisacryl gelatin microspheres. Chemoembolization (TACE) can also be performed by combining an emulsion of cytotoxic drugs, such as doxorubicin or cisplatin, with iodized oil and injecting into hepatic arterial branches until near-complete stasis of flow. There are no randomized studies comparing bland embolization to chemoembolization and no consensus favouring a particular approach. Reported response rates, derived primarily from institutional series, are relatively similar, (Table 3) [108–113]. There is also no indication that response rates differ significantly between different types of NETs. Side effects of TAE/TACE include nausea, abdominal pain, fevers and fatigue, all caused by induction of ischaemic hepatitis. Serum transaminases typically increase significantly, peaking 2–3 days after each embolization. Prospective data on the impact TAE on small bowel NETs can be extrapolated from a phase II study of TAE followed by sunitinib [114]. Among 39 patients enrolled, 26 had primary small intestinal NETs. Twenty eight patients (72%) experienced a partial radiographic response and median progression-free survival was 15 months. Among 19 patients with baseline elevations of urine 5-HIAA, 16 (84%) experienced a major biochemical response (defined as 50% decrease or normalization of 5-HIAA). Other retrospective series confirm that palliation of the carcinoid syndrome occurs in the majority of patients who undergo transarterial embolization. A novel approach to hepatic metastases involves embolization of 90Yttrium embedded either in a resin microsphere (Sir-Sphere) or a glass microsphere (TheraSphere). This technique (also known as selective intrahepatic radiotherapy; SIRT) enables direct delivery of a radionuclide to hepatic metastases. Acute toxicities associated with 90Yttrium microsphere embolization appear to be lower than other embolization techniques, primarily due to the fact that the procedure does not induce ischaemic hepatitis. Thus, the procedure can be performed on an outpatient basis. A rare, but potentially serious complication is radiation enteritis, which can occur if particles are accidentally infused into arteries supplying the GI tract. Chronic radiation hepatitis is another potential toxicity. Response rates associated with radioembolization in metastatic neuroendocrine tumours have been encouraging. In one retrospective multi-center study of 148 patients treated with SirSpheres, the objective radiographic response rate was 63% with a median survival of 70 months [115]. Another study of 42 patients treated with either TheraSpheres or SirSpheres reported a response rate of 51%; however only 29 of the 42 enrolled patients were evaluable for response [116]. The role of liver transplantation for patients with metastatic NETs remains undefined. Data is all retrospective and confounded by selection biases. In the largest reported meta-analysis of 103 patients, the 5-year survival rate was 47% with only 24% of patients free of disease recurrence [117]. Another multicenter analysis of 85 cases reported a 5-year survival of 47% and recurrence-free survival of 20% at 5 years [118]. Since recurrence-free survival curves have not plateaued, it is unclear whether transplantation can be considered potentially curative. Negative prognostic factors for recurrence have included high burden of hepatic tumour, pancreatic primary site (as opposed to small intestinal), and elevated Ki-67 index. Conclusions Small intestinal NETs, also known as carcinoid tumours, are strongly associated with the carcinoid syndrome. Although they are highly prone to metastasize, they tend to be fairly slow growing and are associated with relatively favourable survival durations compared to other metastatic cancers. SSAs have had a profound impact on management of small intestinal NETs. While initially developed for palliation of the carcinoid syndrome, they have also been found to exert a potent inhibitory effect on tumour growth. Other systemic agents with potential benefit include interferon-a and everolimus. However the role of everolimus remains undefined given the failure of the RADIANT 2 trial to meet its

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primary endpoint of improved PFS on central radiographic review. Liver-directed therapies such as cytoreductive surgery and transarterial embolization remain important for patients with liverpredominant disease. In the absence of any clearly-defined second-line treatments beyond SSAs, clinical trials are critically important. The recently-completed SWOG study comparing bevacizumab to IFN-a may expand the therapeutic armamentarium to include anti-angiogenic agents. Another phase III trial comparing 177 Lutetium-octreotate to high-dose octreotide in midgut NETs represents the first randomized study of radiolabeled SSA therapy, and will hopefully expand the availability of this novel treatment. Future research into underlying genetic abnormalities associated with small bowel NETs may lead to identification of new therapeutic targets. Conflict of interest statement Author has consulted for Novartis, Pfizer, and Genentech. Practice points  Metastatic neuroendocrine tumours of the midgut (distal small intestine) are strongly associated with the malignant carcinoid syndrome consisting of flushing, diarrhoea and right-sided valvular heart disease.  Neuroendocrine tumours of the small intestine are prone to metastasize to mesentery and liver, but tend to progress indolently in the metastatic setting.  Clinicopathological evaluation should include assessment of tumour stage, differentiation and grade (proliferative activity).  Octreotide LAR significantly prolongs time to tumour progression among patients with metastatic midgut neuroendocrine tumours.  Liver directed therapies include cytoreductive surgery and/or radiofrequency ablation for patients with oligometastases; and hepatic transarterial embolization (TAE) or chemoembolization (TACE) for patients with widespread metastases.

Research agenda  The role of resection of an asymptomatic primary tumour in the setting of unresectable metastases needs to be defined.  Further randomized studies are needed to clarify the role of everolimus for treatment of progressive metastases.  Randomized studies are needed to establish the benefit of radiolabled somatostatin analogues.  Randomized studies comparing various transarterial hepatic embolization techniques are warranted. References [1] Feyrter F. Über diffuse endocrine epitheliale Organe. Leipzig: Barth; 1938. [2] Modlin IM, Champaneria MC, Bornschein J, Kidd M. Evolution of the diffuse neuroendocrine system–clear cells and cloudy origins. Neuroendocrinology 2006;84(2):69–82. [3] Oberndorfer S. Karzinoide Tumoren des Dünndarms. Frankf Z Pathol 1907;1:425–9. [4] Williams ED, Sandler M. The classification of carcinoid tum ours. Lancet Feb 2 1963;1:238–9. [5] Maggard MA, O’Connell JB, Ko CY. Updated population-based review of carcinoid tumors. Ann Surg Jul 2004;240(1):117–22. [6] Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol Jun 20 2008; 26(18):3063–72.

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