Management of Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEPNETs): A Review

Clinical Therapeutics/Volume 39, Number 11, 2017

Management of Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEPNETs): A Review Gurleen Pasricha, MD; Parikshit Padhi, MD; Nour Daboul, MD; and Dulabh K. Monga, MD Allegheny Health Network Cancer Institute, Allegheny General Hospital, Pittsburgh, Pennsylvania ABSTRACT Purpose: Neuroendocrine tumors (NETs) are heterogeneous tumors that arise from the neuroendocrine cells of the digestive tract and other organs, such as the lung, ovary, and thyroid glands. They can be well differentiated or poorly differentiated, and management of these tumors differs for each histologic subtype. We have performed a review of NETs and focused on management of well-differentiated gastroenteropancreatic neuroendocrine tumors (GEPNETs) and carcinoid syndrome. Methods: A PubMed search was performed to obtain articles on the management of well-differentiated NETs. Using the key words neuroendocrine tumors, carcinoid, pNET, octreotide, somatostatin analogues, and radiolabeled therapy, we reviewed Phase II and III trials that were published over the past 30 years. We also reviewed guidelines from the European Neuroendocrine Tumor Society, North America Neuroendocrine Tumor Society, and National Comprehensive Cancer Network in our search. Findings: NETs are usually slow-growing tumors that remain asymptomatic for a long duration and can be either nonfunctioning or functioning. Surgical resection is recommended for locoregional disease, impending obstruction, symptom control, and advanced disease. Nonsurgical treatment options include somatostatin analogues (SSAs), multikinase inhibitors, targeted therapy, chemotherapy, and radiolabeled SSAs. Carcinoid syndrome is mainly treated with SSAs. Implications: Although GEPNETs are slow-growing tumors, most patients are diagnosed with metastatic disease, and therefore it is important that the management of each patient be discussed in a multidisciplinary setting to optimize the treatment strategy. Patients should be considered for clinical trials and refractory cases referred to a specialty center.

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(Clin Ther. 2017;39:2146–2157) & 2017 Elsevier HS Journals, Inc. All rights reserved. Key words: cancer, carcinoid, gastroenteropancreatic neuroendocrine tumors, neuroendocrine tumor, octreotide, pNET, radiolabeled therapy, somatostatin analogues.

INTRODUCTION Neuroendocrine tumors (NETs) are epithelial neoplasms with predominant neuroendocrine differentiation that can arise in various organs. The location of the primary tumor can determine clinical and pathologic features of the disease. The most common type are well differentiated (low or intermediate grade), also known as carcinoid tumors, that arise from the lung (bronchopulmonary), small intestine, appendix, rectum, and thymus. Other less common sites are the parathyroid, thyroid, adrenal, and pituitary glands. Those arising in the pancreas are referred to as pancreatic NETs (pNETs). The prevalence of NETs in the United States in 2004 was 5.25 cases per 100,000 people.1 The Surveillance, Epidemiology, and End Results database analysis published in 2012, which included data from 19,669 individuals with newly diagnosed gastrointestinal NETs, suggested that the prevalence is increasing due to improvements in imaging and endoscopic detection.2 Diagnosis is based on clinical symptoms, hormone levels, radiologic and nuclear imaging, and histologic confirmation.3 Accepted for publication October 5, 2017. http://dx.doi.org/10.1016/j.clinthera.2017.10.010 0149-2918/$ - see front matter & 2017 Elsevier HS Journals, Inc. All rights reserved.

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G. Pasricha et al. NETs can be functioning or nonfunctioning. Nonfunctioning tumors can be asymptomatic or may present with nausea, abdominal pain, weight loss or symptoms secondary to mass effect, including but not limited to intestinal obstruction and bleeding. Functioning tumors, on the other hand, secrete peptides and neurotransmitters that cause the typical carcinoid syndrome.4 The most common symptoms are diarrhea, abdominal pain, and flushing. Bronchospasm is rare in the carcinoid syndrome due to intestinal NETs. It is more characteristic of foregut NETs. Carcinoid is derived from the German word karzinoide, which means “cancerlike,” and was coined by Oberndorfer5 in 1907. Functioning tumors can also secrete other hormones, such as insulin, glucagon, parathyroid hormone related peptide (PtHrp), vasoactive intestinal peptide, or growth hormone. Excessive production of these hormones can cause symptoms such as hypoglycemia, hyperglycemia, hypercalcemia, diarrhea, or acromegaly. The World Health Organization's classification of NETs is based on the histopathology, mitotic count, and Ki-67 proliferation index, as follows: well differentiated, low grade (G1); well differentiated, intermediate grade (G2); and well differentiated, high grade (G3).6 It is important to distinguish the World Health Organization G3 of the pancreas, which includes both well-differentiated NETs and poorly differentiated neuroendocrine carcinoma, due to the differences in treatment and prognosis (Table I).

The biochemical evaluation of serum and urine peptides is required as clinically indicated. Most patients are diagnosed with advanced disease, which makes curative surgery challenging. Medical management includes somatostatin analogues (SSAs), everolimus, sunitinib, chemotherapy, and peptide receptor radiotherapy.8 This review of NETs focuses on the management of well-differentiated gastroenteropancreatic neuroendocrine tumors (GEPNETs) and carcinoid syndrome.

MATERIALS AND METHODS A PubMed search was performed to obtain articles on the management of well-differentiated NETs. Using the key words neuroendocrine tumors, carcinoid, pNET, octreotide, somatostatin analogues, and radiolabeled therapy, we reviewed Phase II and III trials that were published over the past 30 years. We also reviewed guidelines from the European Neuroendocrine Tumor Society, North America Neuroendocrine Tumor Society, and National Comprehensive Cancer Network in our search.

RESULTS Diagnosis of GEPNETs and Carcinoid Syndrome Most patients with NETs have metastatic disease at diagnosis, with regional or distant metastasis observed in 50% of patients.1 Usually metastases are noted in regional lymph nodes, liver, and distant sites.

Table I. Pathological classification of GEPNETs.6,7 GEPNET Differentiation/Grade Well differentiated Low grade Intermediate grade High grade Poorly differentiated (high grade)

Description o2 Mitoses per 10 hpf, AND o3% Ki-67 index 2–20 Mitoses per 10 hpf OR 3%–20% Ki-67 index 420 Mitoses per 10 hpf, OR 420% Ki-67 index 420 Mitoses per 10 hpf, OR 420% Ki-67 index

GEPNET Type Neuroendocrine neoplasm, grade Neuroendocrine neoplasm, grade Neuroendocrine neoplasm, grade Neuroendocrine, neoplasm, grade

IHC Findings – 1 – 2 3 3

Loss of DAXX or ATRX expression Loss of Rb or abnormal p53 expression

ATRX = alpha-thalassemia/mental retardation syndrome X-linked protein; DAXX = death-domain associated protein; GEPNET = gastroenteropancreatic neuroendocrine tumor; hpf = high-power field; IHC = immunohistochemistry; Rb = retinoblastoma protein.

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Clinical Therapeutics Carcinoid syndrome is usually diagnosed after a workup for symptoms such as flushing or diarrhea. Biochemical markers, imaging, and histologic confirmation may be required to make an accurate diagnosis. A workup can be initiated with measurement of 24hour urinary excretion of 5-hydroxyindoleacteic acid (HIAA) in patients with intestinal NETs and/or carcinoid syndrome. This test has 90% sensitivity and specificity for the diagnosis of carcinoid syndrome.9 Serotonin released by functioning NETs is metabolized to 5-HIAA by monoamine oxidases in the liver, lungs, and brain. 5-HIAA can be elevated with the ingestion of food such as bananas, avocados, and pineapple, and medications such as warfarin and acetaminophen. Various serotonin assays are described in the literature; however, the sensitivity and specificity of these assays are not well established. Chromogranin (Cg) A is present in the chromaffin granules of neuroendocrine cells. Serum CgA levels can be used to diagnose both functioning and nonfunctioning NETs.8 However, due to low specificity, it is useful as a marker for disease progression rather than as a diagnostic test. Overall, CgA is the most important circulating tumor marker for the diagnosis and follow-up of NETs.10 pNETs may produce gastrin, glucagon, insulin/proinsulin, and vasoactive intestinal peptide, which can result in specific clinical symptoms.8 The measurement of blood levels of these hormones may be required for diagnosis. Imaging modalities, including computed tomography, magnetic resonance imaging, and positron emission tomography, are often used for diagnosis and staging. Endoscopic ultrasound has an important role in the preoperative assessment of the pancreas in which a small functioning tumor or multiple tumors are suspected. It has an overall sensitivity of 82% and a specificity of 95% in localizing pNET lesions.11 Sensitivity increases to 87% when endoscopic ultrasound is combined with fine-needle aspiration for the diagnosis of pNETs.12 GEPNETs have a high expression of somatostatin receptors, especially receptors 2 and 5. This expression can be detected on scanning with either the octreotide (indium-111 pentetreotide) or gallium-68DOTA-octreotate (68Ga-DOTATATE), with the latter being more sensitive.13

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Treatment of GEPNETs Localized (Nonfunctioning) Disease Surgical resection is recommended for the treatment of locoregional disease, advanced disease, and impending obstruction14. The extent of surgery depends on the size and location within the gastrointestinal tract, as will be discussed subsequently.

Gastric Neuroendocrine Tumors Gastric NETs are managed according to biological type. Type 1 is associated with atrophic gastritis. Type 2 is associated with Zollinger-Ellison syndrome, which in turn is associated with multiple endocrine neoplasia type 1. Both types 1 and 2 are mostly low grade, with a low potential for metastasis.15 Types 1 and 2 tumors that are o1 cm in diameter can be endoscopically removed or observed due to their low risk for metastasis.16 In cases of evidence of submucosal invasion and diameter between 1 and 2 cm, endoscopic mucosal resection is recommended. If endoscopic mucosal resection is not performed, close annual surveillance with endoscopic ultrasound to assess depth is recommended. For tumors larger than 2 cm, endoscopic or surgical resection is recommended.14 Type 3 tumors have a higher potential for malignancy.15 Type 3 tumors have a unique feature of atypical carcinoid syndrome, which is histamine mediated rather than serotonin mediated.17 These tumors are best managed with radical resection, either partial or total gastrectomy, and lymph node dissection.14

Pancreatic Neuroendocrine Tumors In nonfunctioning sporadic pNETs, enucleation with lymph node dissection is recommended, except in patients with significant comorbidities or advanced age. When associated with multiple endocrine neoplasia type 1, if the tumor size is o2 cm, observation may be utilized; if 42 cm, surgical resection is recommended. In tumors 43 cm associated with von Hippel–Lindau syndrome, resection is recommended.14

Small-intestinal Neuroendocrine Tumors Small-intestinal tumors are managed by localized bowel resection with adjacent mesentery and lymphadenectomy.18 A careful examination of the remainder of the bowel is recommended to avoid missing any

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G. Pasricha et al. smaller lesions. Unlike other gastrointestinal NETs, subcentimeter small-intestinal tumors and ampulla of Vater tumors have a higher propensity for nodal or distant metastasis.19 In patients with NETs in the ampulla of Vater, pancreaticoduodenectomy is recommended.20 Surgical management of appendiceal NETs depends on the size of the tumor. A simple appendectomy is performed for tumors o1 cm. A right hemicolectomy is performed for tumor size 1 to 2 cm with high-risk features and in tumors 42 cm.14

Colorectal Neuroendocrine Tumors Patients with colonic NETs unfortunately have a worse prognosis than do those with rectal NETs because of later detection. Colonic NETs are more commonly right sided.21 Endoscopic resection is recommended for tumors o1 cm in patients with mucosal or submucosal disease. A transanal excision is recommended for tumors between 1 and 2 cm or after endoscopic resection with positive margins.14 A partial colectomy and regional lymphadenectomy is recommended for tumors 42 cm and invasive tumors.22 For rectal NETs, it is important to assess the tumor size and depth of invasion prior to surgical resection. Patients with tumors 42 cm, lymphovascular invasion, a high mitotic rate, and deep invasion (muscularis mucosa or deeper) are at higher risk for metastatic spread, ranging from 60% to 80%.23,24 It is recommended that high-risk tumors be treated with either a low anterior resection or abdominoperineal resection. Tumors o1 cm are mostly indolent and can be treated with endoscopic resection. For tumors that are 1 to 2 cm and lack high-risk features, advanced endoscopic surgeries should suffice.25,26

Metastatic Disease The management of metastatic GEPNETs depends on the site of metastatic disease, symptoms, and surgical resectability. Surgery The most common site of metastatic disease with GEPNETs is the liver. Patients who do not have bi-lobar liver involvement, poor liver function, or extrahepatic metastatic disease are candidates for debulking surgery. It is recommended that, prior to debulking surgery, each case is discussed in a

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multidisciplinary conference. The role of debulking surgery was evaluated in a multi-institutional analysis in 339 patients. The median overall survival (OS) was 125 months and 5-year survival was 74%.27 Symptomatic patients derived the most benefit, while patients with nonfunctional disease and extrahepatic disease fared poorly. Other retrospective studies have shown similar survival outcomes. In a review of data from multiple series, complete resection was associated with a 5-year survival close to 80%.28 In asymptomatic patients, the role of debulking is unclear due to a lack of comparative trials. Despite complete resection, the prevalence of recurrence remains high.29 The role of resection of the primary tumor in metastatic NETs is controversial. If a patient is symptomatic from the primary tumor, resection is recommended.18 It is recommended that midgut tumors be resected because of the higher risk for small bowel obstruction.30 Liver-directed Treatment Multiple nonsurgical options are now available to reduce tumor burden and achieve symptom control. Radiofrequency ablation can be used in patients with low-burden, asymptomatic liver metastases as an adjunct to surgical resection or for local recurrence after hepatectomy.31,32 Radiofrequency ablation has been shown to improve symptom control and reduce 5-HIAA and chromogranin levels.33,34 In different studies, 70% to 90% of patients had partial or complete relief of symptoms, with minimal complications. The mean duration of response ranged from 10 to 11 months.33,34 Hepatic artery embolization is recommended in patients who are deemed nonsurgical candidates for palliation of symptoms and can be performed via gelfoam powder (bland), chemotherapeutic drugs, or radioactive isotopes such as yttrium-90 (90Y). In a retrospective study, both the bland and chemoembolization approaches were compared, and morbidity was 2.4% versus 6.6%, respectively; 30-day mortality, 0.8% versus 1.8%; and symptom improvement, 88% versus 83%. No difference in median OS was seen.35 In patients who did not have prior chemoembolization, median survival with 90Y was 56 months in the carcinoid group versus 31 months in the pNET group and 28 months in the unclassified NET group.36 Major adverse events included biliary injury, liver injury, and abscess. 90Y has a response rate

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Clinical Therapeutics ranging from 30% to 89% and has been associated with reduced chromogranin and serotonin levels.37 Symptom control has been achieved in ~90% of the patients using 90 37 Y. There are no Phase III trials comparing surgery with radiofrequency ablation, transcatheter arterial chemoembolization, or bland embolization. Somatostatin Analogues Somatostatin is a peptide that binds to somatostatin receptors 1 to 5 and inhibits the release of various hormones, such as gastrin, prolactin, adrenocorticotropic hormone, and other gastrointestinal hormones.38 However, it has a short half-life and cannot be used clinically. SSAs such as Octreotide acetate injectable suspension (Sandostatin LAR Depot, Novartis pharmaceuticals) or Lanreotide autogel (Somatuline Depot, Ipsen pharmaceuticals) are used, given their longer half-lives. SSAs are recommended for hormonal symptom control in symptomatic patients and in asymptomatic, unresectable, highburden patients. Asymptomatic patients with lowburden disease can be observed.14 The optimal timing of the initiation of treatment with SSAs in these patients remains uncertain (Figure 1). The role of SSAs as antiproliferative agents in welldifferentiated NETs has been reported in the 2 studies discussed subsequently. The Phase III CLARINET (Lanreotide in Metastatic Enteropathic Neuroendocrine Tumors) trial39 compared lanreotide versus placebo in all GEPNETs grade 1 or 2. Over 2 years, median progression-free survival (PFS) was not reached with lanreotide and was 18 months in the placebo arm. The 2-year PFS rate was 65.1% versus 33.0%, favoring lanreotide. There was no OS benefit; however, crossover was permitted in this trial. PROMID (Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR [Long-Acting Release] in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors)40 compared octreotide LAR versus placebo in metastatic midgut grade 1 NETs and found a statistically significant improvement in PFS, 14.3 versus 6 months, respectively, with patients having o10% liver disease showing the most benefit. There are no trials comparing octreotide LAR versus lanreotide. Octreotide LAR should be initiated at 20 to 30 mg IM monthly and can be titrated up to 60 mg monthly for symptom control.41 Dose escalation may provide longer disease control and was associated with an

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increased median time to any other intervention from 2.9 to 17.7 months.42 Chemotherapy/Molecular Targeted Therapy The role of the mechanistic target of rapamycin (mTOR) pathway was established based on inherited NETs associated with tuberous sclerosis.3 These tumors demonstrate loss of tuberous sclerosis proteins 1 and 2. Inactivation of these genes results in a deregulation of TOR signaling.43 Blockade of mTOR has been associated with inhibition of downstream signaling and hence cell growth and proliferation.44 Everolimus, an mTOR inhibitor, has shown modest activity in Phase II studies, especially in nonfunctioning NETs.45 The RADIANT (Everolimus Plus Octreotide Long-Acting Repeating for the Treatment of Advanced Neuroendocrine Tumours Associated with Carcinoid Syndrome)-2 trial46 was a Phase III study in progressive NETs and history of carcinoid syndrome. RADIANT-2 compared 10 mg/d of oral everolimus with placebo, both in conjunction with 30 mg of octreotide LAR IM every 28 days. The group that received everolimus and octreotide LAR had a PFS of 16.4 months versus 11.3 months in the comparator arm; that difference was not statistically significant. The Phase III RADIANT-3 trial compared everolimus and placebo in patients with low- or intermediate-grade advanced pNETs whose disease had progressed within 12 months, and showed statistically significant improvements in PFS (11.0 vs 4.6 months) and tumor response (5% vs 2%).47 The RADIANT-4 randomized trial compared everolimus with placebo in progressive, nonfunctional gastrointestinal NETs and lung carcinoids, and demonstrated a significant PFS improvement (11 vs 3.9 months) in patients who had progressed on a prior SSA.48 Sunitinib, a small-multikinase inhibitor, has been associated with improvement in relapsed or progressive pNETs. In a study of sunitinib versus placebo, median PFS was 11.4 versus 5.5 months, and the response rate was improved (9.3% vs 0%).49 The role of sunitinib in gastrointestinal NETs is less well established compared with that in pNETs, although Phase II data revealed a median PFS of 10.2 months50 (Table II). Pazopanib, another multikinase inhibitor, was shown to have a response rate of 21.9% in advanced metastatic pNETs in a Phase II trial.53 The Alliance Phase II trial A021202

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G. Pasricha et al. (ClinicalTrials.gov identifier: NCT01841736) is assessing the efficacy of pazopanib versus placebo in progressive carcinoid tumors. There is no established role for bevacizumab despite NETs having high levels of vascular endothelial growth factor receptors. The SWOG S0518 (Phase III Prospective Randomized Comparison of Depot Octreotide Plus Interferon Alpha-2b Versus Depot Octreotide Plus Bevacizumab in Advanced, Poor Prognosis Carcinoid Patients) trial54 comparing SSA þ bevacizumab or interferon reported a median PFS of 16.6 months in the bevacizumab arm and 15.4 months in the interferon arm (difference not statistically significant). In retrospective trials and case series, interferon has been associated with improvements in symptoms in patients with carcinoid syndrome.55 Cytotoxic chemotherapy can be used in patients who are refractory to SSA or mTOR inhibitors or are intolerant to these medications. Streptozocin combinations with 5-fluorouracil (FU) or doxorubicin have activity in NETs. In pNETs the response rate is ~30%.56,57 The Eastern Cooperative Oncology Group E1281 trial comparing streptozocin/5-FU versus 5-FU/ doxorubicin showed improvement in OS with the streptozocin combination (24.3 vs 15.7 months), with similar response rates and PFS.58 The combination of capecitabine and temozolomide is effective in metastatic NETs, showing an overall response rate of 43% (complete response ¼ 11%) and a median PFS of 420 months in a recent Phase II trial.59 Ramirez et al60,61 reported a median PFS of 12 months, while another retrospective review of data from 10 patients showed a median OS of 48 months with this combination. Oxaliplatin-based regimens with 5-FU, gemcitabine, and capecitabine have shown activity in metastatic NETs, with a disease control rate of 80%.62 In one study, folinic acid, fluorouracil, and oxaliplatin (FOLFOX) with bevacizumab had some activity in NETs; however, the study was underpowered.63 There are no Phase III trials comparing chemotherapy to mTOR/multikinase inhibitors. Radiolabeled Somatostatin Analogues Peptide receptor radiotherapy (PRRT) uses radiolabeled analogues like [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTA-TOC) and 177Lu-DOTATATE. In NETTER-1 (Phase 3 Trial of 177Lu-DOTATATE for Midgut Neuroendocrine Tumors),52 177Lu-DOTATATE

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(7.4 GBq q8w for 4 doses) was compared to high-dose octreotide (60 mg q4w) in patients with somatostatin receptor–positive midgut NETs who had progressed on a standard-dose SSA. 177Lu-DOTATATE was associated with improved 20-month PFS (65.2% vs 18%) and objective response rate (18.8% vs 3%). Long-term toxicity data have yet to be published. The administration of the radiolabeled product is logistically challenging. Patients require an antiemetic prior to the amino acid infusion, which is given to prevent nephrotoxicity.51,64 The availability of experienced staff members who can administer the agent, manage nausea and vomiting, and monitor patients during the 4-hour infusion is recommended. Response to 90Y-DOTA-TOC was shown in a Phase II trial, and responders had an improved OS.65 A subgroup with high tumor uptake on radiopeptide scanning was also shown to have an improved median OS.

Carcinoid Syndrome Pathophysiology Carcinoid syndrome is caused by the release of serotonin that is no longer metabolized in the liver, and other substances, such as tachykinins, prostaglandins, and bradykinins.8 Some bronchial and gastric carcinoids may produce 5-hydroxytryptophan and histamine. The release of bioactive substances such as serotonin and CgA is a marker of the carcinoid syndrome. The classic carcinoid syndrome occurs after NETs that originated in the midgut have metastasized to the liver.10 Rare exceptions are bronchial and ovarian carcinoids, which can release hormones directly into the systemic circulation, thereby producing symptoms without metastases. Carcinoid symptoms include flushing, diarrhea, abdominal pain, lacrimation, profuse sweating, telangiectasias, cardiac fibrosis, and pellagralike cutaneous manifestations due to a deficiency of niacin.10 Bronchospasm is a symptom of atypical carcinoid syndrome seen in patients with foregut NETs. Carcinoid crisis is a life-threatening condition that could occur spontaneously, or due to stress, anesthesia, tumor manipulation by biopsy, or surgery.8 It manifests as an exacerbation of the usual carcinoid symptoms, such as flushing and diarrhea with or without bronchospasm. It can also lead to tachycardia and hypotension due to cardiac exposure to high levels of vasoactive substances released from the hepatic metastases.8 Higher doses of IV SSAs are required to manage such crises. In

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Drug

Target

Trial*

Number of patients

Octreotide

SSTR-2

PROMID40

Lanreotide

SSTR-2

CLARINET39

204

Pasireotide

SSTR 1,2,3,5 SSTR-2

Wolin EM et al51 NETTER-152

88

177

Lu-DOTA Octreotate

Sunitinib (PNET Multi only) Kinase Inhibitor

90

Tumor type

Response Rate

Progression free survival (PFS) 14.3mo

Overall survival Not estimated

Significant Adverse Events

Midgut

2%

PNET Midgut Hindgut Digestive tract

Not reported 2y 65.1%

Not estimated

Diarrhea Cholelithiasis Diarrhea

2%

11.8mo

Not estimated

Hyperglycemia

229

Midgut

18.8%

20mo 65.2%

Awaiting final data

Nausea Vomiting

Raymond E et al49

171

PNET

9.3%

11.4mo

Not statistically significant

Hypertension Neutropenia

Stomatitis Anemia Hyperglycemia

Everolimus

mTOR

RADIANT 346

410

PNET

5%

11mo

Not Statistically significant

Everolimus

mTOR

RADIANT 448

302

Midgut, hindgut and unknown

2%

11 mo

Not statistically significant

Diarrhea Stomatitis Anemia Hyperglycemia

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CLARINET= Lanreotide in Metastatic Enteropathic Neuroendocrine Tumors; GEPNET = gastroentero pancreatic neuroendocrine tumor; mTOR = mechanistic target of rapamycin; NETTER = Phase3 Trial of 177Lu-DOTATATE for Midgut Neuroendocrine Tumors; OS = overall survival; PFS = progression-free survival; mo = month; y = year; pNET = pancreatic neuroendocrine tumors; PROMID = Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors; RADIANT = Everolimus Plus Octreotide Long-Acting Repeating for the Treatment of Advanced Neuroendocrine Tumours Associated with Carcinoid Syndrome; SSTR = somatostatin receptors. * All trials were Phase III.

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Table II. Summary of key clinical trials in GEPNET.

G. Pasricha et al. patients with carcinoid syndrome, a preoperative dose of octreotide 250 to 500 μg IV is recommended prior to major operative procedures, with additional doses as needed. Antihistamines such as chlorpheniramine can be administered to prevent bronchospasm. Occasionally, a prophylactic SSA may be warranted in patients with known liver metastases.66

Management Medical management of the symptoms of carcinoid syndrome includes SSAs, which allow control of hormonal-related symptoms and should be used in both preoperative settings and inoperable tumors. The beneficial effect of octreotide was demonstrated in the PROMID study40 (details in the section on SSAs), which showed improved symptom control of diarrhea and flushing, and biochemical response. Lanreotide compared with placebo in the CLARINET study39 showed PFS benefit, with no difference in symptom control. Escape from response phenomenon or tachyphylaxis may occur almost 6 to 18 months after the initiation of treatment with the selective SSAs, such as octreotide and lanreotide.8 In a Phase III study of pasireotide LAR in patients with metastatic NETs and carcinoid symptoms refractory to available SSAs, pasireotide LAR and high-dose octreotide LAR had similar efficacy in symptom control in patients with

functional NETs.51 However, pasireotide LAR was associated with a longer PFS compared with octreotide LAR, and a numerically higher tumor control rate was observed with pasireotide LAR, although the difference was not statistically significant. Surgical resection to debulk the tumor and liverdirected therapies are recommended for refractory carcinoid syndrome with stable tumor volume.14 α-Interferon, alone or in combination with SSAs, can be used to inhibit hormone hypersecretion and to stabilize the disease. Biochemical response has been reported in 40% to 60% of patients; symptom improvement in 40% to 70% of patients; and significant tumor shrinkage in a median of 10% to 15% of patients.67 Unfortunately, the use of α-interferon in carcinoid tumors is limited due to severe immune and psychiatric adverse events.68 Therefore, this treatment is considered only if no other option is available for a patient. Telotristat is an oral tryptophan hydroxylase inhibitor. It was used in combination with SSAs to control diarrhea in the TELESTAR (Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome) study.69 The arithmetic mean reductions in bowel movements at week 12 were –1.7 and –2.1 with telotristat 250 and 500 mg, respectively, and –0.9 with placebo. A total of 80%

Lanreotide or Octreotide every 4 weeks or Short-acting Octreotide

Diarrhea > 4 BM’s/day

Symptoms Controlled

Add Telotristat

and/or

Tachyphylaxis

Progression of Multiple Symptoms

Increase SSA dose and/ Shorten interval

Refractory symptoms

Rescue SQ Octreotide Loperamide Diphenoxylate atropine

Evaluate for alternate causes of diarrhea

Refractory symptoms Pellagra Short Gut Syndrome

Malabsorption due to high doses of SSA

Niacin Cholestyramine

Pancreas enzymes

No cause found

Switch SSA

Tumor Debulking Surgery Hepatic artery embolization RFA PRRT Interferon alpha

Tumor Debulking Peptide receptor radionuclide therapy IFN Pasireotide

Figure 1. Algorithm for the management of carcinoid syndrome.

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Clinical Therapeutics WELL DIFFERENTIATED METASTATIC GEP-NET

SURGICAL DEBULKING

LOW OR INTERMEDIATE TUMOR VOLUME OR STABLE DISEASE

LIVER DOMINANT DISEASE BLAND EMBOLIZATION RADIOEMBOLIZATION CHEMOEMBOLIZATION

HORMONAL SYMPTOMS

NO

HIGH VOLUME DISEASE

PROGRESSIVE DISEASE

LIVER DOMINANT DISEASE BLAND EMBOLIZATION RADIOEMBOLIZATION CHEMOEMBOLIZATION

EVEROLIMUS

YES EVEROLIMUS

OBSERVE

LANREOTIDE OCTREOTIDE LAR

SUNITINIB (PANCREAS NET) SUNITINIB (PANCREAS NET) PRRT CYTOTOXIC THERAPY

Adapted from NANETS guidelines, Pancreas Volume 42, Number 4, May 2013

INTERFERON ALPHA

Figure 2. Management and treatment of well-differentiated metastatic gastroenteropancreatic neuroendocrine tumors. LAR ¼ long-acting release; PRRT ¼ peptide receptor radiotherapy. Adapted with permission.14

of the patients on telotristat had a reduction in 5HIAA levels of 430%. Diarrhea secondary to pellagra responds to supplementation with niacin or niacinamide (Figure 1).70

Carcinoid Heart Disease Pathognomonic plaquelike deposits of fibrous tissue characterize carcinoid heart disease. It occurs in over 50% of patients with carcinoid syndrome and may be the initial presentation in up to 20% of patients.71 Chronic exposure to excessive circulating serotonin is considered one of the most important contributing factors. Clinical symptoms include elevated jugular venous pressure, palpable right ventricular impulse, and murmurs of the right side of the heart (tricuspid and pulmonary valve regurgitation). Echocardiography is required in patients with symptoms or signs of cardiac involvement, elevated pro b-type natriuretic peptide, or prior to major surgery.71 Cardiac magnetic resonance imaging and computed tomography are helpful in evaluating valve pathology and right ventricle size and function. Treatment is surgical valve replacement. Treatment of the tumor does not result in regression of the valvular disease.72

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CONCLUSIONS Over the past 5 years, new advances have been made in the diagnosis and management of GEPNETs and carcinoid syndrome. 68Ga-DOTATATE scanning has improved the detection of these tumors. Surgery remains the mainstay of treatment of localized disease, and SSAs are indicated as first-line treatment in the metastatic setting to control tumor growth as well as symptoms. For symptom management, telotristat has been effective in controlling diarrhea. Everolimus and sunitinib are approved and recommended for progressive metastatic pNETs. Recently the PFS benefit of everolimus in nonfunctional gastrointestinal NETs and lung carcinoids was demonstrated. Pazopanib appears to have promising data, and there are ongoing trials of pazopanib and sorafenib. Peptide receptor radiotherapy is a promising treatment option for metastatic midgut NETs (Figure 2). Hopefully in the near future the results of ongoing trials will provide patients with more treatment options that will improve overall outcomes and quality of life.

ACKNOWLEDGMENTS None.

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CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest with regard to the content of this article.

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Address correspondence to: Dulabh K. Monga, MD, Temple University, SOM, Allegheny Health Network, Pittsburgh PA 15212. E-mail: dulabh. [email protected]

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