Chapter 26: Neuroendocrine Tumors

Neuroendocrine tumors (NETs) originate from enterochromaffin cells distributed throughout the body. This chapter focuses on low- to intermediate-grade gastroenteropancreatic NETs (GEP-NETs), although the term neuroendocrine tumor also denotes diseases such as small cell carcinoma, medullary thyroid carcinoma, neuroblastoma, and Merkel cell tumor. Pancreatic NETs (PNETs), previously known as islet cell carcinomas, arise from pancreatic ductal progenitors. Extrapancreatic low- to intermediate-grade NETs are generally called carcinoids and most often originate along the aerodigestive tract. These tumors share the capacity for hormone production and usually have an indolent clinical course. Presenting symptoms are caused by secreted hormones, local tumor growth, and/or metastasis. Surgical resection is the curative approach for localized disease. In unresectable or metastatic disease, long-acting somatostatin analogues improve quality of life and progression-free survival. In PNETs, recent randomized studies support the use of targeted therapies such as everolimus and sunitinib, with older prospective and retrospective data supporting the use of alkylating chemotherapy such as streptozocin and temozolomide. This chapter presents a comprehensive overview of the diagnosis and management of pancreatic and extrapancreatic NETs.

The overall incidence of NETs in the United States is rising and presently estimated at 5.25 cases per 100,000 (¹). Most NETs progress slowly and may remain undiagnosed for years or even a person’s entire natural life. Small bowel NETs are found in 0.65% to 1.2% of patients during unselected necropsy (^2,3). These tumors are usually diagnosed in the sixth and seventh decades of life (^1,4). The gastrointestinal tract is the most common primary site of NETs, accounting for 58% of NETs (¹). The distribution of NETs is illustrated in Table 26-1.

The prognosis for patients with NETs varies by histologic grade, stage, and primary site. High-grade NETs demonstrate similar biology and prognosis to small cell lung carcinoma. Low- to intermediate-grade NETs have a more favorable prognosis. The median overall survival of patients with localized low- to intermediate-grade NET is 223 months, according to a recent analysis of the Surveillance, Epidemiology, and End Results (SEER) database of patients registered from 1973 to 2004. For patients with regional disease, defined as involvement of regional lymph nodes, extension to adjacent tissue, or both, the median overall survival is 111 months. For metastatic disease, the median overall survival is 33 months (¹). The prognoses of NETs by anatomic site are discussed subsequently.

Sporadic and hereditary tumors have yielded insights into NET biology. The MEN1 gene, mutated in multiple endocrine neoplasia, type 1, was mutated in 44% of patients with resected sporadic PNETs in a recent exome sequencing study, with 43% having mutations in the DAXX/ATRX complex and 14% harboring mutations in the mammalian target of rapamycin (mTOR) pathway (⁵). Menin, the protein product of the MEN1 gene, suppresses tumorigenesis by multiple mechanisms, including transcription regulation via interaction with histone methyltransferases, direct cell cycle regulation via interaction with the genetic loci of cyclin dependent kinase inhibitors, and facilitation of apoptosis by increased caspase 8 production (⁶). Genomic analyses of small intestinal NETs revealed rare mutation events, with alterations in CDKN2B observed in nearly 10% of cases (⁷). Multiple older techniques, such as comparative genomic hybridization (⁸) and single-nucleotide polymorphism–based array technology (⁹), have confirmed chromosome 18 loss in up to 43% of midgut NETs. Therefore, the somatic genomic alterations in pancreatic and extrapancreatic NETs are qualitatively and quantitatively different, aligning their genetic and clinical heterogeneity. By immunohistochemistry, vascular endothelial growth factor (VEGF) has been associated with poorer clinical outcomes in GEP-NETs (¹⁰), generating significant interest in antiangiogenic therapies, as discussed later.

A significant minority of NETs (5%-10%) occur in the context of multiple endocrine neoplasia, type 1 (MEN1), an autosomal dominant disorder characterized by pituitary tumors, hyperparathyroidism, and PNETs. Neuroendocrine tumors related to MEN1 demonstrate a unique pattern of symptomatic and asymptomatic lesions. Duodenal gastrinomas, causing the Zollinger-Ellison syndrome of peptic ulcers, gastroesophageal reflux, and diarrhea, afflict nearly 60% of MEN1 patients. Characteristic asymptomatic lesions include small duodenal foci of somatostatin expression and pancreatic adenomas secreting glucagon or pancreatic polypeptide. Roughly 20% of MEN1-associated pancreatic macroadenomas are “insulinomas,” causing hyperinsulinemic hypoglycemic syndrome. Notably, approximately 10% of PNETs are associated with MEN1 syndrome (¹¹). Neurofibromatosis type 1, von Hippel-Lindau syndrome, and tuberous sclerosis complex 2 also predispose to NETs, but with very low penetrance, and these diseases account for far fewer NETs than MEN1 (¹¹).

NETs are characterized by monotonous sheets of small round cells with uniform nuclei and cytoplasm (Fig. 26-1). Neuroendocrine cells store secreted substances in membrane-bound vesicles. Malignant neuroendocrine cells have minimal mitotic activity, cytologic atypia, or nuclear polymorphism. Immunohistochemical markers used to confirm a NET diagnosis include neuron-specific enolase, CD56, chromogranin A (CgA), and synaptophysin (Table 26-2).

Assessing tumor grade is critical in all NETs. Modern grading schemes distinguish principally between high-grade (grade 3) tumors, with mitotic count >20/10 high-powered fields or Ki-67 proliferation index >20%, and low- or intermediate-grade (grade 1-2) tumors. Clinical behavior and therapy are largely determined by this distinction (¹²). However, a large retrospective analysis revealed a Ki-67 index of 55% or greater to better predict responsiveness to the platinum-based chemotherapy recommended for high-grade NETs (¹³). Therefore, it is likely that grading systems will evolve with our biological understanding and therapeutic options.

Although NETs are well known for their hormonal syndromes, many malignant PNETs are nonfunctional, and carcinoid syndrome is typically present only in the setting of metastases. Symptoms can be insidious and present for years before diagnosis. Symptoms of local and regional extrapancreatic and nonfunctional pancreatic NETs are often vague, relating to obstruction, mesenteric fibrosis, or vascular compromise.

Neuroendocrine Tumor Laboratory Tests and Markers

Although general serum and urine biomarkers are useful for tumor monitoring, they are insufficient for NET diagnosis, which requires pathologic evaluation. Frequently measured tumor markers in carcinoid disease include serum CgA and 5-hydroxyindoleacetic acid (5-HIAA) levels in a 24-hour urine sample. False-positive results occur with consumption of tryptophan- or serotonin-rich foods (bananas, butternuts, kiwis, mockernuts, pecans, pineapples, plantains, plums, shagbark, sweet pignuts, tomatoes, and walnuts). Common medications affecting urinary 5-HIAA levels include guaifenesin, acetaminophen, and salicylates. Serum CgA level is a sensitive, but nonspecific, marker for NETs, and is elevated among patients receiving proton pump inhibitors or with impaired renal, hepatic, or cardiac function.

In addition to CgA and 5-HIAA, NETs can synthesize other bioactive amines and peptides including 5-hydroxytryptamine (5-HTP), 5-hydroxytryptophan (5-HT), serotonin, insulin, gastrin, glucagon, somatostatin, vasoactive intestinal polypeptide (VIP), adrenocorticotropic hormone, melanocyte-stimulating hormone, pancreatic polypeptide, and pancreastatin (¹⁴).

Imaging

Endoscopy

Endoscopic techniques localize tumors and facilitate biopsy. Esophagogastroduodenoscopy (EGD) can often locate gastric and duodenal NETs. Colonoscopy can identify colorectal NETs. Double-balloon enteroscopy and capsule endoscopy may assist in localizing small bowel NETs. Disadvantages of endoscopy include the requirement for patient sedation and the difficulty in visualizing small submucosal lesions. Endoscopic ultrasound is useful in the assessment, visualization, and biopsy of pancreatic and some small duodenal NETs.

Computed Tomography and Magnetic Resonance Imaging

Computed tomography (CT) and magnetic resonance imaging (MRI) are the preferred initial imaging studies for localizing NETs. However, the utility of cross-sectional imaging for diagnosing typical small bowel NETs is limited; usually their presence must be inferred from luminal narrowing, adenopathy, and mesenteric fibrosis. Computed tomography and MRI technologies are far more useful in detection of hepatic metastases, which frequently present convenient sites for diagnostic biopsy. Computed tomography and MRI are helpful in the detection of PNETs, for which the sensitivities of CT and MRI are up to 82% and 100%, respectively (¹⁵).

Somatostatin Receptor Scintigraphy

Somatostatin receptor scintigraphy (SRS) has improved the visualization of NETs. Somatostatin receptor scintigraphy uses a somatostatin analogue, ¹¹¹In-labeled diethylenetriamine penta-acetic acid octreotide (DTPA-D-Phe¹-octreotide), to visualize tumors expressing somatostatin receptors 2 and 5. Compared with CT or MRI, SRS detects additional metastases in about one-third of patients. Moreover, SRS may help to identify small tumors when conventional scans are unrevealing. The overall sensitivity of SRS is 80% to 90% (¹⁶).

Positron Emission Tomography

Because ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) identifies tumors with significant proliferative activity, it is unreliable in NETs. Gallium-68 (⁶⁸Ga)-DOTA-NOC PET, which uses labeled octreotide to detect somatostatin-avid tumors, had a sensitivity of 78.3% and a specificity of 92.5% in an initial study (¹⁷). Ongoing studies are evaluating alternative ⁶⁸Ga-labelled somatostatin analogues, and this technology may emerge as more convenient than SRS, with potentially improved test characteristics.

Other Nuclear Scintigraphy Techniques

Metaiodobenzylguanidine (MIBG) is absorbed by carcinoid tumor cells. Iodine-131-labeled MIBG (¹³¹I-MIBG) has an overall sensitivity of 55% to 70% in detecting NETs (¹⁸). Although ¹³¹I-MIBG is less sensitive than SRS, it may be used in patients receiving long-acting octreotide, which competitively inhibits uptake of radiolabeled somatostatin analogues.

Clinical Staging

The American Joint Committee on Cancer (AJCC) has proposed site-specific staging systems for grade 1 to 2 NETs using the TNM system (¹⁹). The details vary, particularly with respect to the T stage, which can depend on depth of invasion or involvement of critical structures. This staging is prognostic, but not predictive of the benefit with any therapy. The relevant distinction is therefore between resectable and unresectable/metastatic disease. High-grade NETs are described with a TNM stage according to guidelines for carcinomas of the primary site but are summarized as limited stage or extensive stage disease, defined by the ability of the cancer to be treated in a single radiation port, based on the staging of the biologically analogous small cell lung cancer (²⁰).

Gastric Carcinoid

Gastric carcinoid tumors are divided into three types. Type 1 (75%) is associated with chronic atrophic gastritis, type 2 (5%-10%) is associated with with Zollinger-Ellison syndrome, and type 3 (15%-25%) is sporadic (²¹). Conceptually, type 1 and 2 gastric carcinoids arise as a physiologic response to excessive gastrin secretion, with the gastrin being physiologic in type 1 gastric carcinoids and pathologic in type 2 gastric carcinoids. Because they are independent of known stimuli, type 3 gastric carcinoids have the worst prognosis, frequently presenting with metastatic disease. A SEER analysis revealed a median overall survival of 13 months for patients with metastatic gastric carcinoid (¹). Clinical features of the three groups of gastric carcinoid are summarized in Table 26-3.

Small Intestine Carcinoid

Small intestine NETs, most frequently associated with carcinoid syndrome, are often found in the distal ileum within 60 cm of the ileocecal valve. At diagnosis, multiple putative “primary” lesions may be present. Analysis of SEER data from 1973 to 2004 demonstrates that jejunum and ileum NETs (30%) were far more likely than duodenal (9%), rectal (5%), or appendiceal (9%) lesions to be metastatic at diagnosis. The median overall survival times of patients with duodenal and jejunum/ileum carcinoids were 107 and 111 months, respectively, for localized disease and 57 and 56 months, respectively, for metastatic disease (¹).

Appendiceal Carcinoid

Neuroendocrine tumors are found incidentally in 1 of 200 to 300 appendectomies in young adults. For appendiceal NETs under 1 cm in diameter, surgical resection is sufficient. For tumors over 2 cm, the risk of metastasis is significantly higher, and a right hemicolectomy is recommended (²²). Histologic subtype also influences surgical management; right hemicolectomy is recommended for goblet cell (including signet ring) NETs, regardless of size, because of their aggressiveness (²²). The median overall survival of patients with NET restricted to the appendix is over 360 months. In contrast, individuals with metastatic disease at diagnosis have a median overall survival of 27 months (¹).

Rectal Carcinoid

Rectal NETs occur most frequently in middle-aged adults. They are found incidentally in approximately 1 in 2,500 proctoscopies as a small yellow-gray submucosal nodule in the rectal wall. Most rectal NETs are under 1 cm in diameter and rarely metastasize, whereas 60% to 80% of lesions over 2 cm metastasize. Local excision is adequate for rectal NETs smaller than 1 cm. Lesions measuring 1 to 1.9 cm without evidence of high-risk features such as muscularis, lymphovascular, or perineural invasion can be excised locally (²³). A tumor displaying any of these high-risk features should prompt consideration of a more aggressive segmental rectal resection, preferably sphincter sparing. In patients with metastatic disease at diagnosis, palliative excision may still be required. The median overall survival of patients with metastatic rectal NET is 22 months (¹).

Insulinoma

Insulinoma is the most common type of PNET. The incidence of insulinoma peaks in patients between 30 and 60 years of age and is more frequent in women. Insulinoma is usually benign (90%), intrapancreatic (nearly 100%), solitary, and small (<2 cm). About 5% of insulinomas are associated with the MEN1 syndrome; screening of family members of an MEN1 index case should be considered (²⁴). Hyperinsulinemia causes a classic “Whipple triad” of hypoglycemia, neuroglycopenic symptoms, and resolution with eating.

The insulinoma diagnosis is made by detection of inappropriately high serum concentrations of insulin and C-peptide at a symptomatic blood glucose level <50 mg/dL. Although single imaging modalities fail to localize an insulinoma in about 40% of cases, over 90% sensitivity can be achieved with combinations of MRI, pancreatic protocol CT scan, and endoscopic ultrasound. Somatostatin receptor scintigraphy is another noninvasive modality available to assist in localization. Portal venous sampling and arterial calcium stimulation are technically demanding, invasive procedures that are not widely available. When preoperative studies cannot definitively localize the insulinoma, surgical exploration with intraoperative ultrasonography can be considered (²⁵). At some institutions, radiologic innovations have eliminated blind surgical exploration.

Gastrinoma

Gastrinoma causes Zollinger-Ellison syndrome, marked by multiple recurrent peptic ulcers. Most gastrinomas are located in the “gastrinoma triangle,” encompassing the duodenum, pancreatic head, and hepatoduodenal ligament. Duodenal gastrinoma is often submucosal and difficult to visualize during routine EGD; gastrinoma of the pancreas can exceed 1 cm in size (²⁶).

The diagnostic workup for gastrinoma often involves two steps. Elevated fasting serum gastrin and increased basal gastric acid output (>15 mEq/h) suggest hypergastrinemia, with a secretin stimulation test differentiating gastrinoma from other causes. Somatostatin receptor scintigraphy has 77% sensitivity for gastrinoma. Sixty percent of gastrinomas are malignant, and 50% of those have metastases at diagnosis. The median survival of patients with gastrinoma is 3 to 6 years. Roughly one-fifth of gastrinomas occur in the context of MEN1 syndrome (²⁶).

Glucagonoma

Glucagonoma is a rare α-cell tumor that typically occurs in people age 50 to 70 years. These tumors are located primarily within the pancreas; most are malignant. Symptoms may not appear until the tumor is over 5 cm in diameter. At diagnosis, up to 80% of these tumors have metastasized. Serum glucagon levels are usually elevated (>1,000 pg/mL; normal range, 150-200 pg/mL), assisting in diagnosis.

Mild glucose intolerance is the most common clinical feature of glucagonoma. A characteristic red-brown maculopapular skin rash of the face, abdomen, perineum, or extremities called necrolytic migratory erythema may precede the diagnosis by up to 5 years. The erythematous areas form bullae that eventually break and encrust. Thromboembolic disease and psychiatric disturbances are also seen. Anticoagulation therapy is recommended (²⁷).

Somatostatinoma

Somatostatinoma is very rare. Most occur in the pancreas or duodenum. Patients often present with diabetes mellitus, cholelithiasis, steatorrhea, hypochlorhydria, anemia, and/or weight loss. These tumors are typically metastatic at diagnosis (²⁷).

VIPoma

VIPoma is characterized by watery diarrhea (>3 L/d), mediated by vasoactive intestinal peptide (VIP) and other tumor-secreted peptides. VIPomas are located in the pancreas in adults. They are often metastatic at diagnosis. Their syndrome, known as “pancreatic cholera,” manifests as secretory diarrhea with potassium and bicarbonate wasting, causing hypokalemia and metabolic acidosis. Diagnosis is made from the typical clinical presentation, the presence of a large pancreatic mass on imaging, and the elevated plasma VIP levels. Somatostatin analogues can effectively control the hormonal syndrome (²⁷).

Pancreatic Polypeptidoma

Pancreatic polypeptide is synthesized and released from pancreatic polypeptide cells in the normal pancreas. Pancreatic polypeptidoma is often found unexpectedly in patients with symptoms produced by metastases (²⁸).

Carcinoid Syndrome

Carcinoid syndrome often occurs with metastatic disease or when the primary tumor site allows secreted amines to escape the enterohepatic circulation (Table 26-4). Common symptoms include flushing, diarrhea, abdominal cramping, and, less frequently, wheezing, heart valve dysfunction, and pellagra, resulting from 5-HTP metabolites, kinins, and prostaglandins. The incidence of carcinoid syndrome ranges from 10% in localized carcinoid to 50% in advanced tumors. Somatostatin analogues are the mainstay of medical therapy.

Carcinoid Heart Disease

Carcinoid heart disease is due to right heart endocardial fibrosis, occasionally causing tricuspid regurgitation and right heart failure. However, the relationship between carcinoid heart disease and frank heart failure in the somatostatin analogue era is unclear. A study of 150 patients with carcinoid syndrome described a 20% prevalence of carcinoid valvulopathy on echocardiography. Of those with valvulopathy, 53% had minimally symptomatic heart failure. Over 70% of the patients received a somatostatin analogue, but no relationship was demonstrated between somatostatin analogue use and carcinoid heart disease or heart failure. Patients with carcinoid heart disease exhibited increased urine 5-HIAA and serum CgA levels (²⁹). Currently, echocardiography is recommended for patients with carcinoid syndrome and clinical evidence of heart failure or in whom major surgery is planned (³⁰).

Carcinoid Crisis

Carcinoid crisis is caused by a massive release of bioactive products to the systemic circulation and is characterized by hypotension, diarrhea, and abdominal cramps. Carcinoid crisis is often precipitated by a procedure; treatment consists of prompt initiation of octreotide infusion, typically beginning at 50 to 100 μg/h. Premedication of carcinoid patients with octreotide in subcutaneous or intravenous form is often used as prophylaxis against periprocedural carcinoid crisis (³¹).

Treatment is largely dependent on the tumor grade and the primary site. Grade 3 NETs are treated similarly to small cell lung cancer, with platinum-based chemotherapy or chemoradiotherapy, depending on the disease stage. For grade 1 or 2 NETs, surgical removal of all gross disease is advocated whenever feasible. For advanced grade 1 or 2 NETs, regional therapeutic options are largely similar, whereas systemic therapies diverge for pancreatic and extrapancreatic NETs.

Somatostatin analogues are the primary medical treatment for advanced NETs. When carcinoid syndrome persists despite somatostatin analogue or mass effect symptoms worsen, debulking surgery can provide effective palliation. Liver-directed therapy, such as hepatic artery embolization and radiofrequency ablation, should be considered for bulky disease, progression, or symptom palliation. Targeted therapies, such as everolimus and sunitinib, as well as alkylating chemotherapy, such as streptozocin and temozolomide, are also options for systemic therapy in PNETs, with our preference being to use chemotherapy when cytoreduction of larger-volume disease is desired. A general approach to the therapy of advanced disease is depicted in Fig. 26-2.

Surgery offers the only potential cure for NETs. Principal considerations include the site and histology of the primary tumor, the extent of detectable disease, and the clinical presentation. Types I and II gastric carcinoids under 2 cm can be removed endoscopically, whereas partial gastrectomy should be considered for larger tumors. Type III gastric carcinoids are more aggressive, requiring excision even when small. Small bowel NET should be managed with resection of the intestinal segment and its associated mesentery because of the risk of nodal involvement. The rest of the intestinal tract should be examined carefully because 20% of tumors are accompanied by a second primary malignancy (³²). Low-risk appendiceal NETs under 2 cm can be treated with appendectomy; larger and high-risk lesions are treated with right hemicolectomy. Colorectal NETs are successfully treated with formal hemicolectomy, adhering to the usual techniques of mesenteric lymphadenectomy as with colon adenocarcinoma. Grade 3 NETs are rare and aggressive, seldom benefit from resection, and are usually treated with chemotherapy.

The current goal of treatment of advanced unresectable NET is improvement of symptoms and survival. Tumor burden reduction is desirable insofar as it is subsumed in these goals. The current standard of care for hormone-related symptom control remains a somatostatin analogue. Other therapies, including surgical resection of hepatic metastases, hepatic artery embolization/chemoembolization, and peptide receptor radionuclide therapy, are useful adjuncts. For PNETs, additional systemic treatment options are also available.

Somatostatin Analogues

Somatostatin analogues such as octreotide and lanreotide are the primary medications for control of symptoms from hormonally active NETs. Octreotide is an intermediate-acting somatostatin analogue that can be administered subcutaneously every 6 to 12 hours. It provides complete or partial relief of flushing or diarrhea in about 85% of patients with carcinoid syndrome and produces a biochemical response rate of up to 72% (³³). The dose of octreotide varies from 50 to 500 μg.

Long-acting somatostatin analogues have obviated the need for multiple daily injections in most patients. Depot octreotide (10, 20, or 30 mg) is given intramuscularly once a month (³⁴). An intermediate-acting somatostatin analogue should be used to supplement long-acting agents until steady state is reached. Rarely, somatostatin analogue can cause sinus bradycardia or cardiac conduction abnormalities. Caution is advised in patients with preexisting cardiac disease. Cholelithiasis may develop with long-term use of somatostatin analogues. Hypoglycemia or, more commonly, hyperglycemia may occur, especially among patients with brittle diabetes. Steatorrhea may occur but can be managed with pancreatic enzymes. Lanreotide is an alternative somatostatin analogue and, in extended release form, is administered subcutaneously monthly in doses of 60, 90, or 120 mg.

Somatostatin analogues also have anticancer activity. Interim analysis of the phase III randomized trial of depot octreotide 30 mg monthly in untreated metastatic midgut NET (PROMID) demonstrated a significantly longer time to progression with octreotide compared with placebo (14.3 vs 6 months, P < .001) (³⁵). An international, double-blind, placebo-controlled, phase III trial of lanreotide (120 mg every 28 days) in patients with a nonfunctioning NET (CLARINET) also demonstrated significantly improved progression-free survival with lanreotide compared with placebo (median, not reached vs 18 months, P < .001) (³⁶).

Surgical Resection of Hepatic Metastases

Liver metastases are generally resectable if: (1) all tumors in the liver can be completely resected and (2) an adequate volume of liver (20% of the standardized total liver volume) with adequate biliary drainage, arterial inflow, and venous outflow can be preserved. If the locoregional and hepatic tumor burden is completely resectable, then this is the preferred management of metastatic NETs, whether functional or nonfunctional. Hepatic resection is most effective for low-grade NETs (³⁷). Debulking at least 90% of the hepatic tumor burden in patients with functional metastases improves endocrine symptoms and may prolong survival (³⁸).

Radiofrequency Ablation

Local ablative therapies such as radiofrequency ablation (RFA) are being used increasingly for treatment of liver tumors. Radiofrequency ablation involves placing a probe in the liver tumor percutaneously or intraoperatively using image-guidance techniques. The radiofrequency waves increase the intratumoral temperature, resulting in tumor destruction.

Radiofrequency ablation has been used for the treatment of hormone-related symptoms in selected patients with NET liver metastases, alleviating symptoms in up to 80% of cases (³⁹). Furthermore, RFA may achieve local control of liver metastases in up to 74% of patients. The use of RFA is generally limited to patients with five or fewer lesions in the liver, with each tumor measuring less than 3 cm in size. The largest reported series using RFA in NET patients with liver metastases included 34 patients with 234 tumors treated in 42 sessions with laparoscopic RFA. “Complete” or “significant” symptom relief was achieved in 80% of the symptomatic patients and lasted an average of 10 months (range, 6-24 months) (³⁹).

Hepatic Arterial Embolization and Chemoembolization

Liver metastases from NETs are hypervascular, receiving over 80% of their blood supply via the hepatic artery, whereas liver parenchyma receives 60% to 70% of its perfusion from the portal vein. Thus, embolizing the hepatic artery targets tumor metastases while leaving parenchyma relatively unharmed. The addition of a chemotherapeutic agent to the embolic material, also known as transcatheter arterial chemoembolization (TACE), allows delivery of relatively larger doses of chemotherapy to the tumor, combining local cytotoxicity and ischemia. The most frequently used chemotherapeutic agents for NET TACE include doxorubicin, cisplatin, mitomycin C, and streptozocin (^40,41).

Potential benefits include symptom relief, slowing progression, and reducing tumor burden before resection or ablation. Many retrospective reports in markedly heterogeneous populations have shown that either technique can reduce tumor burden, hormone levels, and symptoms in NET patients. No study has clearly demonstrated one technique to be superior. The primary risk is postembolization syndrome, which is typically self-limited and characterized by gastrointestinal distress, fever, leukocytosis, and transaminitis. Major complications such as liver and/or renal failure, gallbladder perforation, cholangitis, peptic ulcer hemorrhage, and abscess formation are rare (⁴²). Embolization can occasionally precipitate carcinoid crisis as well.

In patients with extensive liver tumor burden, multiple embolization sessions may be required, starting with the hepatic lobe with greatest tumor burden. Embolization of the whole liver in one session runs the risk of prolonged postembolization syndrome or liver failure. The timing of subsequent embolizations is determined primarily by symptoms, tumor behavior, and patient tolerance.

The timing of embolizations in the disease course remains controversial. Although some investigators advocate early embolization to reduce tumor burden before initiating systemic therapy, late embolization can also be effective. In a randomized study, NET patients treated with initial liver embolization followed by interferon therapy had a higher objective response rate after 1 year (86%) than patients who received interferon only (42%), without altering survival (⁴³). In contrast, when embolization or chemoembolization was performed at a median of 37 months after diagnosis, the median survival after embolization was 80 months, indicating that later embolization is still effective (⁴⁴).

Selective Internal Radiation Therapy

Intra-arterial radioembolization with yttrium-90 (⁹⁰Y) microspheres is an emerging technique being used increasingly in patients with unresectable liver lesions. Yttrium-90 is a pure β emitter with a mean soft tissue penetration of 2.5 mm and a maximal depth of 1.1 cm. Radioembolization with ⁹⁰Y has a significantly lower incidence of postembolization syndrome than embolization or chemoembolization, allowing it to be performed as an outpatient procedure. However, great care must be taken with ⁹⁰Y radioembolization to avoid nontarget delivery of radioactive microspheres to organs, making an angiogram with selective embolization of all extrahepatic arteries essential before treatment.

There is limited literature on the use of radioembolization for treatment of neuroendocrine liver metastases. In a retrospective review of 148 patients with NET liver metastases treated with 185 separate ⁹⁰Y radioembolization procedures, complete response was observed in 3% of patients, and a partial response was observed in 66.7%. The median survival duration was 70 months (⁴⁵). Further investigation, long-term follow-up, and prospective clinical trials are warranted to determine the exact role of this treatment method in the management of NET.

Peptide Receptor Radionuclide Therapy

Radiolabeled somatostatin analogues have also been developed. A prospective study of ⁹⁰Y-DOTA-Tyr³-octreotide in 90 patients with metastatic, symptomatic carcinoid tumors refractory to octreotide treated showed subjective improvement in over 50% of patients and objective radiologic responses in 4% of patients (⁴⁶). In another report of 310 patients treated with ¹⁷⁷Lu-DOTA-Tyr³-octreotate, the reported radiologic response rate was 30%, but without intent-to-treat analysis incorporating the additional 194 patients accrued to the protocol, meaningful interpretation is challenging (⁴⁷). The ongoing phase III NETTER-1 study, comparing ¹⁷⁷Lu-DOTA-Tyr³-octreotate to high-dose octreotide long-acting release (60 mg intramuscularly every 28 days) in patients with advanced small bowel NETs should allow clearer conclusions to be drawn.

Chemotherapy

High-grade NETs are responsive to platinum-based chemotherapy (¹³). Well-differentiated extrapancreatic NETs respond poorly to cytotoxic chemotherapy. Pancreatic NETs respond better. The authors’ group noted radiographic response rates of 39% in a series of 84 PNET patients using a regimen of 5-fluorouracil, doxorubicin, and streptozocin (FAS) (⁴¹). This regimen is derived from prior streptozocin-based chemotherapy regimens observed in randomized studies to achieve biochemical responses (^48,49).

Targeted Therapy

The NET field has made significant progress over the past 5 years, principally in the area of targeted therapy. Building on the observation that increased VEGF portends poor survival in NET patients, the VEGF receptor (VEGFR) inhibitor sunitinib was tested in a phase III study (⁵⁰). An interim analysis demonstrated a hazard ratio for progression or death of 0.42 favoring sunitinib over placebo (P < .001) in 154 PNET patients with advanced and progressive disease. This resulted in the regulatory approval of sunitinib for the indication. Simultaneously, the mTOR inhibitor everolimus was studied in RADIANT-3. This randomized phase III trial investigated everolimus versus placebo in 410 patients with advanced, progressive PNET. The hazard ratio for progression or death was 0.35 (P < .001) favoring everolimus over placebo (⁵¹).

The phase II study of sunitinib showed limited evidence of benefit in extrapancreatic NET patients (⁵²). The RADIANT-2 study of everolimus in extrapancreatic NET patients, although limited by randomization imbalance and informative censoring in central radiology review, also failed to demonstrate statistically significant benefit (⁵³). It is hoped that RADIANT-4, a randomized study of everolimus in nonfunctional extrapancreatic NET patients buttressed against informative censoring, will convincingly answer the question of whether mTOR inhibition has a role in a broader range of NETs.

Additional Symptom Control Methods

Carcinoid symptoms can be exacerbated by epinephrine, exercise, emotions, eating tryptophan-rich foods, and ethanol and may be controlled through modulating these factors or supplementing dietary nicotinamide. Medical management of carcinoid symptoms can include a bronchodilator for bronchospasm, loperamide or diphenoxylate for diarrhea, and diuretics for fluid overload secondary to valvular dysfunction. A proton pump inhibitor can manage gastric hypersecretion in gastrinoma patients. Since our initial report, multiple groups have confirmed the efficacy of everolimus for the management of malignant hypoglycemia due to insulinoma (⁵⁴).

Multidisciplinary diagnosis and management of NETs is mandatory. For localized disease, clear communication between the surgeon and the pathologist is required for appropriate prognostication and treatment. Advanced NETs present different challenges, and surgeons, interventional radiologists, medical oncologists, and endocrinologists may all play roles in improving the quality and quantity of life for the patient. Despite recent advances in targeted therapy for PNET, extrapancreatic NETs remain challenging to treat, and NETs remain life-limiting diseases for many patients. Ongoing studies of targeted agents, peptide receptor radionuclide therapy, and immunotherapy will hopefully continue to advance our understanding of the biology of these diverse diseases while bringing needed therapies to this growing patient population.