Neuroendocrine tumors (NETs) are a heterogeneous group of tumors originating in various locations, including gastrointestinal tract, lung, and pancreas. The disease management poses a significant challenge because of the heterogeneous clinical presentations and varying degree of aggressiveness. The recent completion of several phase 3 trials, including those evaluating octreotide, sunitinib, and everolimus, demonstrate that rigorous evaluation of novel agents in this disease is possible and can lead to practice-changing outcomes. Nevertheless, there are many aspects to the treatment of NETs that remain unclear and controversial.
The North American Neuroendocrine Tumor Society (NANETS) was founded in 2006; and at that time, its board members convened a consensus guidelines committee in an effort to develop an expert consensus opinion on the treatment of these uncommon diseases. Although other comprehensive guidelines exist (ie, National Comprehensive Cancer Network Neuroendocrine Tumor guidelines, European Neuroendocrine Tumor Society (ENETs) guidelines), it was felt that the NANETS guidelines could enhance and complement these existing guidelines through the use of expert opinion added to evidenced-based recommendations. The first set of consensus guidelines1–7 was published in 2010 and were intentionally comprehensive in scope. Here, we present a set of consensus tables intended to complement these guidelines and serve as a quick, accessible reference for the practicing physician. Consensus tables were developed and revised during a series of meetings between October 2011 and October 2012. Eight tables were created to define treatment and workup recommendations. These tables include the following: (1) Pathology; (2) NETs of the thorax; (3) Gastric NETs; (4) Pancreatic NETs; (5) NETs of the small bowel and cecum (“midgut”); (6) NETs of the colon and rectum (“hindgut”); (7) Pheochromocytoma, paraganglioma, and medullary thyroid cancer; and (8) High-grade neuroendocrine carcinoma. The tables include 2 categories of recommendations as either Consider or Recommend. Emphasis was placed on the development of sound guidelines based on the data when available and consensus expert opinion; controversial topics were also addressed. Each table includes guidelines for workup, treatment, and follow-up. When the disease-specific full consensus guidelines documents are next updated these consensus tables will be incorporated.
It should be noted that there was unanimous decision that all patients should be considered for clinical trials when possible. In addition, all members believe that the approach to patient management should include a team of experts that include, but are not limited to, medical and surgical oncologists, radiologists, gastroenterologists, interventional radiologists, and pathologists. Additionally, some of the controversial topics included in the tables were brought back to NANETS members and further refined during subsequent meetings and teleconferences. This introduction has been structured to further address some of these key issues.
KEY UPDATES SINCE PUBLICATION OF 2010 NANETS CONSENSUS GUIDELINES
Since the 2010 publication of the NANETS Consensus Guidelines in Pancreas, a number of practice-changing studies have been published.
The RAD001 in Advanced Neuroendocrine Tumors-3 (RADIANT-3) study,8 published in 2011, is a randomized phase 3 study evaluating the efficacy of everolimus in advanced pancreatic NETs. In this international multisite study, 410 patients with low- or intermediate-grade, progressive, advanced pancreatic NETs were randomized to receive everolimus, 10 mg oral daily, or placebo. The median progression-free survival (PFS) was 11.0 months with everolimus compared with 4.6 months with placebo (hazard ratio, 0.35; 95% confidence interval, 0.27–0.45; P < 0.001). The response rate was 5% in the everolimus arm compared with 2% in the placebo arm. The median overall survival has not been reached.
In another phase 3 study published in 2011, 171 patients with advanced, well-differentiated, progressive pancreatic NETs were randomized to receive sunitinib, 37.5 mg orally daily, or placebo.9 The study was discontinued prematurely after an independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo arm and a difference in PFS that favored the sunitinib arm during an unplanned interim analysis. The median PFS was 11.4 months in the sunitinib arm compared with 5.5 months in the placebo arm (hazard ratio, 0.42; 95% confidence interval, 0.26–0.66; P < 0.001). Response rates in the sunitinib and placebo arms were 9.3% and 0%, respectively. The median overall survival could not be estimated given the high number of censored events in both groups.
In addition to the aforementioned treatment advances, there were 2 key publications on NET pathology reporting.4,10 A formal assessment of grade and differentiation using the minimum pathology data set described below in the pathology consensus table should be required for all patients before initiating therapy given the implications on treatment. There are different treatment algorithms for well-differentiated versus poorly differentiated NETs.
KEY CONTROVERSIAL TOPICS
Several controversial topics were identified during the course of guidelines development (Table 1). A few of these topics are highlighted here.
Indications for Targeted Therapies
Based on the aforementioned phase 3 clinical trials, sunitinib and everolimus are Food and Drug Administration approved and recommended for patients with progressive metastatic pancreatic NETs. Everolimus was also studied in metastatic functional (ie, hormone secreting) carcinoid tumors in a large phase 3 clinical trial. Although this study did not meet its primary endpoint of PFS, there was a trend toward longer PFS in the treatment arm.11 At the current time, we do not have sufficient evidence to recommend routine use of everolimus in carcinoid tumors; the level of recommendation for everolimus in the treatment of advanced carcinoid is listed as “consider”.
Indications for Cytotoxic Therapies
Cytotoxic therapies such as streptozocin, 5-fluorouracil, or temozolomide should be considered in the palliation of patients with advanced pancreatic NET and symptoms related to tumor bulk. There are no prospective randomized data for a temozolomide-based regimen; however, a single-institution series showed promising activity,12 and randomized clinical trials using temozolomide are planned. Cytotoxic therapies are currently listed as “consider” for pancreatic NET. There is currently no known role for cytotoxic therapies in advanced carcinoid.
Indication and Dosing of Somatostatin Analogs
Refractory carcinoid syndrome is an unmet medical need. Carcinoid syndrome is caused by the secretion of serotonin and other bioactive amines into the systemic circulation and is manifested by flushing and diarrhea, fibrosis of the right-sided heart valves, and intestinal mesentery. Currently available somatostatin analogs include octreotide and lanreotide and can ameliorate the symptoms of carcinoid syndrome. Over time, however, patients with the carcinoid syndrome may become refractory to somatostatin analogs. For this reason, NET physicians often increase the dose and/or frequency of somatostatin analogs in an attempt to control refractory carcinoid syndrome. Such an approach has anecdotally improved symptoms although has never been tested in a rigorous and/or randomized fashion. The committee “recommends” that somatostatin analog doses could be escalated or interval shortened in an attempt to control these symptoms, but note that no prospective data exist.
The 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 PROMID trial also demonstrated antitumor efficacy of octreotide in advanced midgut carcinoid tumors.13 Despite this evidence in midgut tumors, there are no prospective data for the use of somatostatin analogs as antiproliferative agents in pancreatic NETs, although ongoing clinical trials are poised to answer this question.
Serum Biomarkers in Diagnosis and Surveillance
Plasma chromogranin A (CgA) and 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA) levels can be elevated as surrogate markers of possible progression or response. 5-Hydroxyindoleacetic acid is not as useful in patients with foregut (bronchial or gastric) or hindgut (rectal) NETs or in most patients with pancreatic NETs that do not secrete serotonin. Chromogranin A is a 49-kd protein that is contained in the neurosecretory vesicles of the NET cells and is commonly detected in the plasma of patients with endocrine neoplasms. Elevated plasma CgA levels have been associated with poor overall prognosis in patients with NETs.14 Additionally, early decreases may be associated with favorable treatment outcomes in some studies. The committee “recommends” following CgA levels in patients with advanced disease in patients who have elevated CgA levels at diagnosis and “considers” following CgA in resected disease.
Role of Surgical Debulking
Progression of liver metastases is the predominant cause of mortality in many NET patients. The median survivals of 24 to 128 months are reported with treatment.15–17 For this reason, hepatic resection, radiofrequency ablation, and hepatic arterial embolization have been used to control tumor burden. In patients in whom all hepatic metastases seem to be resectable, and in whom no (or mild nonclinically significant) extrahepatic disease is observed, resection should be “considered”.18–21 The lack of randomized data and selection bias may confound quantitative interpretation of reported results. Nevertheless, resection should be considered in carefully selected patients, particularly with functional tumors, where the tumors can be removed safely. Asymptomatic patients, in the setting of resectable disease, should also be “considered” as candidates for surgical debulking.
In recent years, we have witnessed many advances in NET trial design, conduct, and accrual—culminating in the FDA approval of 2 new biologic agents in this disease. There is ongoing research in biomarkers, imaging, and novel agents. Below we present 8 consensus tables summarizing available data and expert consensus in the field of NETs (Tables 2–9).
The following NANETS members participated in several of NANETS meetings and were instrumental in the development of these tables. The authors thank them for their invaluable contributions and insights. J Phillip Boudreaux, MD; Thomas M O’Dorisio, MD; George A Fisher, MD, PhD; Vay Liang W Go, MD; Larry K Kvols, MD; William J Maples, MD; Susan O’Dorisio, MD, PhD; Rodney F Pommier, MD; and Karel Pacak, MD, PhD, DSc.
1. Anthony LB, Strosberg JR, Klimstra DS, et al. The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors (nets): well-differentiated nets of the distal colon and rectum. Pancreas
. 2010; 39 (6): 767–774.
2. Boudreaux JP, Klimstra DS, Hassan MM, et al. The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas
. 2010; 39 (6): 753–766.
3. Chen H, Sippel RS, O’Dorisio MS, et al. The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma
, paraganglioma, and medullary thyroid cancer. Pancreas
. 2010; 39 (6): 775–783.
4. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas
. 2010; 39 (6): 707–712.
5. Kulke MH, Anthony LB, Bushnell DL, et al. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas
. 2010; 39 (6): 735–752.
6. Phan AT, Oberg K, Choi J, et al. NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the thorax (includes lung and thymus). Pancreas
. 2010; 39 (6): 784–798.
7. Strosberg JR, Coppola D, Klimstra DS, et al. The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas
. 2010; 39 (6): 799–800.
8. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med
. 2011; 364 (6): 514–523.
9. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med
. 2011; 364 (6): 501–513.
10. Klimstra DS, Modlin IR, Adsay NV, et al. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set. Am J Surg Pathol
. 2010; 34 (3): 300–313.
11. Pavel ME, Hainsworth JD, Baudin E, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet
. 2011; 378 (9808): 2005–2012.
12. Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine and temozolomide in patients with metastatic pancreatic endocrine carcinomas. Cancer
. 2011; 117 (2): 268–275.
13. Rinke A, Muller HH, Schade-Brittinger C, et al. 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: a report from the PROMID Study Group. J Clin Oncol
. 2009; 27 (28): 4656–4663.
14. Yao JC, Pavel M, Phan AT, et al. Chromogranin A and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus. J Clin Endocrinol Metab
. 2011; 96 (12): 3741–3749.
15. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177 Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol
. 2008; 26 (13): 2124–2130.
16. Madoff DC, Gupta S, Ahrar K, et al. Update on the management of neuroendocrine hepatic metastases. J Vasc Interv Radiol
. 2006; 17 (8): 1235–1249; quiz 1250.
17. Reidy DL, Tang LH, Saltz LB. Treatment of advanced disease in patients with well-differentiated neuroendocrine tumors. Nat Clin Pract Oncol
. 2009; 6 (3): 143–152.
18. Schurr P, Strate T, Rese K, et al. Aggressive surgery improves long-term survival in neuroendocrine pancreatic tumors: an institutional experience. Ann Surg
. 2007; 245 (2): 273–281.
19. Touzios J, Kiely J, Pitt S, et al. Neuroendocrine hepatic metastases: does aggressive management improve survival? Ann Surg
. 2005; 241 (5): 776–783.
20. Sarmiento J, Heywood G, Rubin J. Surgical treatment of neuroendocrine metastases to the liver: a plea for resection to increase survival. J Am Coll Surg
. 2003; 197: 29–37.
21. Chamberlain R, Canes D, Brown K, et al. Hepatic neuroendocrine metastases: does intervention affect outcome? J Am Coll Surg
. 2000; 190: 432–445.