Neuroendocrine Tumors, Version

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1 78 NCCN Neuroendocrine Tums, Version Clinical Practice Guidelines in Oncology Matthew H. Kulke, MD; Manisha H. Shah, MD; Al B. Benson III, MD; Emily Bergsland, MD; Jdan D. Berlin, MD; Lawrence S. Blaszkowsky, MD; Lyska Emerson, MD; Paul F. Engstrom, MD; Paul Fanta, MD; Thomas Gidano, MD, PhD; Whitney S. Goldner, MD; Thvardur R. Halfdanarson, MD; Martin J. Heslin, MD; Fouad Kandeel, MD, PhD; Pamela L. Kunz, MD; Bis W. Kuvshinoff II, MD, MBA; Christopher Lieu, MD; Jeffrey F. Moley, MD; Gitonga Munene, MD; Venu G. Pillarisetty, MD; Leonard Saltz, MD; Julie Ann Sosa, MD; Jonathan R. Strosberg, MD; Jean-Nicolas Vauthey, MD; Christopher Wolfgang, MD, PhD; James C. Yao, MD; Jennifer Burns; and Debah Freedman-Cass, PhD Overview Neuroendocrine tums (NETs) are thought to arise from cells throughout the diffuse endocrine system. They comprise a broad family of tums, the most common of which are carcinoid tums (most commonly arising in the lungs and bronchi [so-called bronchopulmonary], small intestine, appendix, rectum, and thymus) and pancreatic NETs. Other less common NETs include those arising in the parathyroid, thyroid, adrenal, and pituitary glands. Abstract Neuroendocrine tums (NETs) comprise a broad family of tums that may may not be associated with symptoms attributable to hmonal hypersecretion. The NCCN Clinical Practice Guidelines in Oncology f Neuroendocrine Tums discuss the diagnosis and management of both spadic and hereditary NETs. This selection from the guidelines focuses on spadic NETs of the pancreas, gastrointestinal tract, lung, and thymus. (J Natl Compr Canc Netw 2015;13:80 110) NCCN Categies of Evidence and Consensus Categy 1: Based upon high-level evidence, there is unifm NCCN consensus that the intervention is appropriate. Categy 2A: Based upon lower-level evidence, there is unifm NCCN consensus that the intervention is appropriate. Categy 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Categy 3: Based upon any level of evidence, there is maj NCCN disagreement that the intervention is appropriate. All recommendations are categy 2A unless otherwise noted. Clinical trials: NCCN believes that the best management f any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Please Note The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) are a statement of consensus of the auths regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient s care treatment. The National Comprehensive Cancer Netwk (NCCN ) makes no representation warranties of any kind regarding their content, use, application and disclaims any responsibility f their applications use in any way. The full NCCN Guidelines f Neuroendocrine Tums are not printed in this issue of JNCCN but can be accessed online at NCCN.g. National Comprehensive Cancer Netwk, Inc. 2015, All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any fm without the express written permission of NCCN. Disclosures f the NCCN Neuroendocrine Tums Panel At the beginning of each NCCN Guidelines panel meeting, panel members review all potential conflicts of interest. NCCN, in keeping with its commitment to public transparency, publishes these disclosures f panel members, staff, and NCCN itself. Individual disclosures f the NCCN Neuroendocrine Tums Panel members can be found on page 108. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.g.) These guidelines are also available on the Internet. F the latest update, visit NCCN.g.

2 Journal of the National Comprehensive Cancer Netwk NCCN Guidelines Neuroendocrine Tums 79 NCCN Neuroendocrine Tums Panel Members *Matthew H. Kulke, MD/Chair Dana-Farber/Brigham and Women s Cancer Center Manisha H. Shah, MD/Vice Chair The Ohio State University Comprehensive Cancer Center James Cancer Hospital and Solove Research Institute Al B. Benson III, MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University *Emily Bergsland, MD UCSF Helen Diller Family Comprehensive Cancer Center Jdan D. Berlin, MD Vanderbilt-Ingram Cancer Center Lawrence S. Blaszkowsky, MD Massachusetts General Hospital Cancer Center *Lyska Emerson, MD Huntsman Cancer Institute at the University of Utah Paul F. Engstrom, MD Fox Chase Cancer Center *Paul Fanta, MD UC San Diego Moes Cancer Center Thomas Gidano, MD, PhD University of Michigan Comprehensive Cancer Center *Whitney S. Goldner, MDð Fred & Pamela Buffett Cancer Center at The Nebraska Medical Center Thvardur R. Halfdanarson, MDÞ Mayo Clinic Cancer Center Martin J. Heslin, MD University of Alabama at Birmingham Comprehensive Cancer Center Fouad Kandeel, MD, PhDð City of Hope Comprehensive Cancer Center An analysis of the SEER database estimated that the incidence of NETs in the United States was 5.25 cases per 100,000 people in This analysis suggested that the incidence of NETs is increasing and that the prevalence of individuals with NETs in the United States may exceed 100, A recent independent analysis of the SEER database also found that the incidence of gastrointestinal NETs increased from 1975 to The reasons f this increase are unclear, although it seems likely that improved diagnosis and classification is a fact. Most NETs seem to be spadic, and risk facts f spadic NETs are poly understood. NETs may also arise in the context of inherited genetic syndromes, including multiple endocrine neoplasia (MEN) types 1 and 2. MEN1, associated with mutations in the menin gene, is characterized by multiple tums of the parathyroid, pituitary, and pancreatic glands. 3 MEN2, associated with mutations in the RET proto-oncogene, is characterized by the development of medullary thyroid cancer, pheochromocytoma (often bilateral), and hyperparathyroidism. 4 NETs have also been associated with von Hippel-Lindau, tuberous sclerosis complex, and neurofibromatosis. 5,6 Patients with NETs may may not have symptoms attributable to hmonal hypersecretion. These symptoms include intermittent flushing and diarrhea in patients with carcinoid syndrome, 7 hypertension in patients with pheochromocytoma, 8 and symptoms attributable to secretion of insulin, glucagon, gastrin, and other peptides in patients with pancreatic NETs. 9 Text cont. on page 93. *Pamela L. Kunz, MD Stanfd Cancer Institute Bis W. Kuvshinoff II, MD, MBA Roswell Park Cancer Institute Christopher Lieu, MD University of Colado Cancer Center Jeffrey F. Moley, MD Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine Gitonga Munene, MD St. Jude Children s Research Hospital/ The University of Tennessee Health Science Center Venu G. Pillarisetty, MD University of Washington/Seattle Cancer Care Alliance *Leonard Saltz, MD Þ Memial Sloan Kettering Cancer Center Julie Ann Sosa, MD ð Duke Cancer Institute Jonathan R. Strosberg, MD Moffitt Cancer Center Jean-Nicolas Vauthey, MD The University of Texas MD Anderson Cancer Center Christopher Wolfgang, MD, PhD The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins James C. Yao, MD The University of Texas MD Anderson Cancer Center NCCN Staff: Jennifer Burns and Debah Freedman-Cass, PhD KEY: *Writing Committee Member Specialties: Medical Oncology; Pathology; Surgery/Surgical Oncology; ðendocrinology; ÞInternal Medicine

3 80 Neuroendocrine Tums of the Gastrointestinal Tract, Lung, and Thymus (Carcinoid Tums) CLINICAL LOCATION EVALUATION a,b PRIMARY TREATMENT OF NON-METASTATIC DISEASE c SURVEILLANCE b,g,h Jejunal/ileal/ colon Duodenal Recommended: Abdominal/pelvic multiphasic CT MRI As appropriate: Somatostatin scintigraphy Colonoscopy Small-bowel imaging Chest CT Biochemical evaluation as clinically indicated Recommended: Abdominal/pelvic multiphasic CT MRI As appropriate: Somatostatin scintigraphy EGD/endoscopic ultrasound (EUS) Chest CT Biochemical evaluation as clinically indicated Locegional Metastatic Locegional Metastatic Bowel resection with regional lymphadenectomy c,d Consider prophylactic cholecystectomy c,e when appropriate Metastatic Disease (CARC-6) Endoscopic resection c,f Local excision (transduodenal) c ± lymph node sampling Pancreatoduodenectomy c Metastatic Disease (CARC-6) 3 12 mo postresection: H&P Consider abdominal/pelvic multiphasic CT MRI Biochemical evaluation as clinically indicated >1 y postresection up to 10 y: Every 6 12 mo H&P Consider multiphasic CT MRI Biochemical evaluation as clinically indicated *Available online, in these guidelines, at NCCN.g. a See Principles of Pathology f Diagnosis and Repting of Neuroendocrine Tums (NE-A*). b See Principles of Biochemical Testing (NE-B*). c See Surgical Principles f Management of Neuroendocrine Tums (NE-C*). d Should include: Careful examination of the entire bowel, as multiple synchronous lesions may be present. Assessment of the proximity to involvement of the superi mesenteric artery and superi mesenteric vein. e If possible future need f octreotide. f If endoscopic resection perfmed, follow-up EGD as appropriate. g Earlier, if symptoms. h Somatostatin scintigraphy and FDG-PET scan are not recommended f routine surveillance. CARC-1 Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

4 81 NCCN Clinical Practice Guidelines in Oncology Neuroendocrine Tums of the Gastrointestinal Tract, Lung, and Thymus (Carcinoid Tums) CLINICAL LOCATION EVALUATION a,b PRIMARY TREATMENT OF NON-METASTATIC DISEASE c SURVEILLANCE g,h 2 cm and confined to the appendix Simple appendectomy c,j As clinically indicated Appendix i >2 cm incomplete resection (nodes, margins) Recommended: Abdominal/pelvic multiphasic CT MRI As appropriate: Chest CT Biochemical evaluation as clinically indicated Re-explation Right hemicolectomy c 3 12 mo postresection: H&P Consider abdominal multiphasic CT/MRI Biochemical evaluation as clinically indicated >1 y postresection up to 10 y: Every 6 12 mo H&P Consider multiphasic CT MRI Biochemical evaluation as clinically indicated Metastatic Metastatic Disease (CARC-6) *Available online, in these guidelines, at NCCN.g. a See Principles of Pathology f Diagnosis and Repting of Neuroendocrine Tums (NE-A*). b See Principles of Biochemical Testing (NE-B*). c See Surgical Principles f Management of Neuroendocrine Tums (NE-C*). g Earlier, if symptoms. h Somatostatin scintigraphy and FDG-PET scan are not recommended f routine surveillance. i Some appendiceal carcinoids will have mixed histology, including elements of adenocarcinoma. Such tums should be managed accding to colon cancer guidelines. See NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) f Colon Cancer; to view the most recent version of these guiedlines, visit NCCN.g. j Some institutions will consider me aggressive treatments f 1- to 2-cm tums with po prognostic features. See Discussion f details. CARC-2 Version , National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

5 82 Neuroendocrine Tums of the Gastrointestinal Tract, Lung, and Thymus (Carcinoid Tums) CLINICAL LOCATION EVALUATION a,b PRIMARY TREATMENT OF NON-METASTATIC DISEASE c SURVEILLANCE g,h 2 cm k Resection c (transanal endoscopic excision, if possible) <1 cm: No follow-up required 1 2 cm: Endoscopy with rectal MRI EUS at 6 and 12 mo, then as clinically indicated Rectal Recommended: Colonoscopy Abdominal/Pelvic multi-phasic CT MRI Endectal MRI EUS As appropriate: Somatostatin scintigraphy Chest CT Biochemical evaluation as clinically indicated >2 cm Low anteri resection c Abdominoperineal resection (APR) c 3 12 mo postresection: H&P Consider abdominal/pelvic multiphasic CT MRI Biochemical evaluation as clinically indicated >1 y postresection up to 10 y: Every 6 12 mo H&P Consider multiphasic CT MRI Biochemical evaluation as clinically indicated Metastatic Metastatic Disease (CARC-6) *Available online, in these guidelines, at NCCN.g. a See Principles of Pathology f Diagnosis and Repting of Neuroendocrine Tums (NE-A*). b See Principles of Biochemical Testing (NE-B*). c See Surgical Principles f Management of Neuroendocrine Tums (NE-C*). g Earlier, if symptoms. h Somatostatin scintigraphy and FDG-PET scan are not recommended f routine surveillance. k F 1- to 2-cm tums, consider examination under anesthesia (EUA) and/ EUS with radical resection if muscularis propria invasion node positive. CARC-3 Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

6 NCCN Clinical Practice Guidelines in Oncology 83 Neuroendocrine Tums of the Gastrointestinal Tract, Lung, and Thymus (Carcinoid Tums) CLINICAL LOCATION EVALUATION a,b PRIMARY TREATMENT OF NON-METASTATIC DISEASE c SURVEILLANCE g,h Gastric Recommended: EGD Gastrin level l Multiphasic CT MRI f patients with nmal gastrin As appropriate: EUS Chest CT Somatostatin scintigraphy f patients with nmal gastrin B 12 level if hypergastrinemia Biochemical evaluation as clinically indicated Locegional Hypergastrinemic patients m Metastatic Patients with nmal gastrin Tum 2 cm Solitary multiple Tum >2 cm Solitary multiple Observe Endoscopic resection c + biopsy of tum(s) and adjacent mucosa Octreotide n lanreotide n f patients with Zollinger-Ellison syndrome Endoscopic resection, c if possible Surgical resection c Radical gastric resection c + lymph node removal Consider endoscopic wedge resection c f tums 2 cm Metastatic Disease (CARC-6*) H&P Years 1 3: every 6 12 mo with EGD Years 4+: Annually with EGD Imaging studies as clinically indicated New lesion(s) increasing tums, consider antrectomy 3 12 mo postresection: H&P Biochemical evaluation as clinically indicated Multiphasic CT MRI >1 y postresection up to 10 y: Every 6 12 mo H&P Consider multiphasic CT MRI Biochemical evaluation as clinically indicated *Available online, in these guidelines, at NCCN.g. a See Principles of Pathology f Diagnosis and Repting of Neuroendocrine Tums (NE-A*). b See Principles of Biochemical Testing (NE-B*). c See Surgical Principles f Management of Neuroendocrine Tums (NE-C*). g Earlier, if symptoms. h Somatostatin scintigraphy and FDG-PET scan are not recommended f routine surveillance. l Gastrin levels need to be completed while fasting and off protein pump inhibits f 1 week. m If gastric ph is low there is clinical radiographic evidence, see gastrinoma on PanNET-2. n See Principles of Systemic Anti-Tum Therapy (NE-D*). CARC-4 Version , National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

7 84 Neuroendocrine Tums of the Gastrointestinal Tract, Lung, and Thymus (Carcinoid Tums) CLINICAL LOCATION EVALUATION a,b PRIMARY TREATMENT OF NON-METASTATIC DISEASE c SURVEILLANCE g,h Bronchopulmonary Recommended: Chest CT and abdominal multiphasic CT MRI As appropriate: Somatostatin scintigraphy Bronchoscopy Biochemical wkup f Cushing s syndrome if clinically indicated Other biochemical evaluation as clinically indicated Localized Locegional Metastatic See NCCN Guidelines f Small Cell Lung Cancer; Lung Neuroendocrine Tum algithm (to view the most recent version of these guidelines, visit NCCN.g) Metastatic Disease (CARC-6) Thymus o Recommended: Chest/mediastinal multiphasic CT and abdominal multiphasic CT MRI As appropriate: Somatostatin scintigraphy Bronchoscopy Biochemical wkup f Cushing s syndrome if clinically indicated Other biochemical evaluation as clinically indicated Localized Locegional Metastatic Resect c Resect c Complete Resection Incomplete Resection Metastatic Disease (CARC-6) RT and/ chemotherapy p (categy 3) 3 12 mo postresection: H&P Biochemical evaluation as clinically indicated Chest/mediastinal multiphasic CT MRI >1 y postresection up to 10 y: Every 6 12 mo H&P Consider CT MRI Biochemical evaluation as clinically indicated *Available online, in these guidelines, at NCCN.g. a See Principles of Pathology f Diagnosis and Repting of Neuroendocrine Tums (NE-A*). b See Principles of Biochemical Testing (NE-B*). c See Surgical Principles f Management of Neuroendocrine Tums (NE-C*). g Earlier, if symptoms. h Somatostatin scintigraphy and FDG-PET scan are not recommended f routine surveillance. o Thymic carcinoids are often associated with MEN1. See Multiple Endocrine Neoplasia, Type 1 (MEN1-1*). p Consider 5-FU capecitabine at radiosensitizing doses. Cisplatin carboplatin with etoposide may be appropriate f patients with atypical poly differentiated tums. CARC-5 Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

8 NCCN Clinical Practice Guidelines in Oncology 85 Neuroendocrine Tums of the Gastrointestinal Tract, Lung, and Thymus (Carcinoid Tums) MANAGEMENT OF LOCOREGIONAL UNRESECTABLE DISEASE AND/OR DISTANT METASTASES c If complete resection possible c,q Resect primary c + metastases Locegional unresectable and/ distant metastases Imaging: Multiphasic CT MRI Consider Somatostatin scintigraphy Consider 24-hour urine 5-HIAA b, if not already done Consider chromogranin A b (categy 3) Asymptomatic, r low tum burden Locally symptomatic from primary tum Clinically signifi cant tum burden Carcinoid syndrome Observe with markers and scans every 3 12 mo Octreotide n lanreotide n Consider resection of primary tum c Octreotide n lanreotide n Octreotide n lanreotide n Echocardiogram s Clinically signifi cant progressive Octreotide n lanreotide n, if not already receiving and Consider hepatic regional therapy (arterial embolization, chemoembolization, radioembolization [categy 2B]) Consider cyteductive surgery/ ablative therapy t,u (categy 2B) Consider everolimus n (10 mg/d) (categy 3) Consider interferon alfa-2b n (categy 3) Consider cytotoxic chemotherapy n (categy 3), if no other options feasible *Available online, in these guidelines, at NCCN.g. b See Principles of Biochemical Testing (NE-B*). c See Surgical Principles f Management of Neuroendocrine Tums (NE-C*). n See Principles of Systemic Anti-Tum Therapy (NE-D*). q Noncurative debulking surgery might be considered in select cases. r Resection of a small asymptomatic (relatively stable) primary in the presence of unresectable metastatic is not indicated. s If signs and symptoms of heart planning maj surgery. t Includes ablative techniques such as radiofrequency, microwave, and cryotherapy. There are no randomized clinical trials and prospective data f these interventions are limited. However, data on the use of these interventions are emerging. u Only if near complete resection can be achieved. CARC-6 Version , National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

9 86 CLINICAL LOCATION EVALUATION b,c,d Neuroendocrine Tums of the Pancreas MANAGEMENT OF PRIMARY NON-METASTATIC DISEASE e,f Nonfunctioning pancreatic tums a Recommended: Multiphasic CT MRI As appropriate: Somatostatin scintigraphy EUS Biochemical evaluation as clinically indicated Locegional h Metastatic Small ( 2 cm) Larger (>2 cm), invasive tums Head Distal Enucleation ± regional nodes e,g Distal pancreatectomy ± regional nodes/splenectomy e Pancreatoduodenectomy ± regional nodes e Consider observation in selected cases h Pancreatoduodenectomy + regional nodes e Distal pancreatectomy e + splenectomy + regional nodes See Metastases (PanNET-7) See Surveillance (PanNET-6) *Available online, in these guidelines, at NCCN.g. a F tums secreting hmones such as somatostatin, ACTH, PTHrP, and PP, follow the nonfunctioning pancreatic tum pathway. b See Principles of Pathology f Diagnosis and Repting of Neuroendocrine Tums (NE-A*). c See Principles of Biochemical Testing (NE-B*). d F all patients with PanNET, evaluate personal and family histy f possibility of MEN1 and see Multiple Endocrine Neoplasia, Type 1 (MEN1-1*). e See Surgical Principles f Management of Neuroendocrine Tums (NE-C*). f Preoperative trivalent vaccine (ie, pneumococcus, haemophilus infl uenzae b, meningococcal group C), if considering surgery with possible splenectomy. g Neuroendocrine tums of the pancreas that are 1 2 cm have a small, but real risk of lymph node metastases. Therefe, lymph node resection should be considered. h Observation can be considered in select cases: tums <1 cm, incidently discovered. Decision based on estimated surgical risk, site of tum, and patient combidities. PanNET-1 Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

10 NCCN Clinical Practice Guidelines in Oncology 87 Neuroendocrine Tums of the Pancreas CLINICAL LOCATION EVALUATION b,c,d MANAGEMENT OF PRIMARY NON-METASTATIC DISEASE e,f Occult No primary tum metastases on imaging Observe Explaty surgery including duodenotomy and intraoperative ultrasound; local resection/enucleation of tum(s) + periduodenal node dissection e Gastrinoma (usually duodenal head of pancreas) Recommended: Gastrin levels c,i (basal, stimulated as clinically indicated) Multiphasic CT MRI As appropriate: Somatostatin scintigraphy EUS Other biochemical evaluation as clinically indicated Locegional Metastatic Manage gastric hypersecretion with proton pump inhibits Consider octreotide j lanreotide j See Metastases (PanNET-7) Duodenum Head Distal Exophytic peripheral tums by imaging k F deeper invasive tums and those in proximity to the main pancreatic duct Duodenotomy and intraoperative ultrasound; local resection/enucleation of tum(s) + periduodenal node dissection e Enucleation of tum + periduodenal node dissection e Pancreatoduodenectomy e Distal pancreatectomy ± splenectomy e,f,l See Surveillance (PanNET-6) *Available online, in these guidelines, at NCCN.g. b See Principles of Pathology f Diagnosis and Repting of Neuroendocrine Tums (NE-A*). c See Principles of Biochemical Testing (NE-B*). d F all patients with PanNET, evaluate personal and family histy f possibility of MEN1 and see Multiple Endocrine Neoplasia, Type 1 (MEN1-1*). e See Surgical Principles f Management of Neuroendocrine Tums (NE-C*). f Preoperative trivalent vaccine (ie, pneumococcus, haemophilus infl uenzae b, meningococcal group C), if considering surgery with possible splenectomy. i Gastrin levels need to be completed while fasting and off proton pump inhibits f 1 week. j See Principles of Systemic Anti-Tum Therapy (NE-D*). k Not adjacent to the main pancreatic duct. l There is some disagreement among panel members regarding the role of splenectomy in all cases. PanNET-2 Version , National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

11 88 Neuroendocrine Tums of the Pancreas CLINICAL LOCATION EVALUATION b,c,d MANAGEMENT OF PRIMARY NON-METASTATIC DISEASE e,f Exophytic peripheral tums by imaging k Head Distal Tum enucleation, consider laparoscopic resection e Insulinoma Recommended: Multiphasic CT MRI As appropriate: EUS Biochemical evaluation as clinically indicated Locegional Stabilize glucose levels with diet and/ diazoxide Deeper invasive tums and those in proximity to the main pancreatic duct Head Distal Pancreatoduodenectomy e Distal pancreatectomy (spleenpreserving n ), consider laparoscopic resction e See Surveillance (PanNET-6) Metastatic As appropriate: Somatostatin scintigraphy m See Metastases (PanNET-7) *Available online, in these guidelines, at NCCN.g. b See Principles of Pathology f Diagnosis and Repting of Neuroendocrine Tums (NE-A*). c See Principles of Biochemical Testing (NE-B*). d F all patients with PanNET, evaluate personal and family histy f possibility of MEN1 and see Multiple Endocrine Neoplasia, Type 1 (MEN1-1*). e See Surgical Principles f Management of Neuroendocrine Tums (NE-C*). f Preoperative trivalent vaccine (ie, pneumococcus, haemophilus influenzae b, meningococcal group C), if considering surgery with possible splenectomy. k Not adjacent to the main pancreatic duct. m Somatostatin scintigraphy only if treatment with a somatostatin analog is planned. Somatostatin analogs should only be given if tum demonstrates somatostatin recepts. In the absence of somatostatin recepts, somatostatin analogs can profoundly wsen hypoglycemia. (See Discussion f details). n Splenectomy should be perfmed f larger tums involving splenic vessels. PanNET-3 Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

12 89 NCCN Clinical Practice Guidelines in Oncology Neuroendocrine Tums of the Pancreas CLINICAL LOCATION EVALUATION b,c,d MANAGEMENT OF PRIMARY NON-METASTATIC DISEASE e,f Glucagonoma (usually tail) Recommended: Glucagon/blood glucose Multiphasic contrastenhanced CT MRI As appropriate: Somatostatin scintigraphy EUS Biochemical evaluation as clinically indicated Locegional Metastatic Stabilize glucose levels with IV fl uids and octreotide j lanreotide j Treat hyperglycemia and diabetes, as appropriate Head (rare) o Distal o See Metastases (PanNET-7) Pancreatoduodenectomy + peripancreatic lymph nodes e,p Distal pancreatectomy + peripancreatic lymph node dissection + splenectomy e,f,p See Surveillance (PanNET-6) *Available online, in these guidelines, at NCCN.g. b See Principles of Pathology f Diagnosis and Repting of Neuroendocrine Tums (NE-A*). c See Principles of Biochemical Testing (NE-B*). d F all patients with PanNET, evaluate personal and family histy f possibility of MEN1 and see Multiple Endocrine Neoplasia, Type 1 (MEN1-1*). e See Surgical Principles f Management of Neuroendocrine Tums (NE-C*). f Preoperative trivalent vaccine (ie, pneumococcus, haemophilus infl uenzae b, meningococcal group C), if considering surgery with possible splenectomy. j See Principles of Systemic Anti-Tum Therapy (NE-D*). o Small (<2 cm), peripheral glucagonomas are rare; enucleation/local excision + peripancreatic lymph dissection may be considered. p Hypercoaguable state has been described. Perioperative anticoagulation can be considered. PanNET-4 Version , National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

13 90 Neuroendocrine Tums of the Pancreas CLINICAL LOCATION EVALUATION b,c,d MANAGEMENT OF PRIMARY NON-METASTATIC DISEASE e,f VIPoma Recommended: Electrolytes VIP levels Multiphasic CT MRI As appropriate: Somatostatin scintigraphy EUS Biochemical evaluation as clinically indicated Locegional Metastatic Stabilize with IV fluids and octreotide j lanreotide j Crect electrolyte imbalance (K +, Mg 2+, HCO 3- ) Head q Distal q See Metastases (PanNET-7) Pancreatoduodenectomy + peripancreatic lymph nodes e Distal pancreatectomy + peripancreatic lymph node dissection + splenectomy e,f See Surveillance (PanNET-6) *Available online, in these guidelines, at NCCN.g. b See Principles of Pathology f Diagnosis and Repting of Neuroendocrine Tums (NE-A*). c See Principles of Biochemical Testing (NE-B*). d F all patients with PanNET, evaluate personal and family histy f possibility of MEN1 and see Multiple Endocrine Neoplasia, Type 1 (MEN1-1*). e See Surgical Principles f Management of Neuroendocrine Tums (NE-C*). f Preoperative trivalent vaccine (ie, pneumococcus, haemophilus infl uenzae b, meningococcal group C), if considering surgery with possible splenectomy. j See Principles of Systemic Anti-Tum Therapy (NE-D*). q Small (<2 cm), peripheral VIPomas are rare; enucleation/local excision + peripancreatic lymph dissection may be considered. PanNET-5 Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

14 91 NCCN Clinical Practice Guidelines in Oncology Neuroendocrine Tums of the Pancreas SURVEILLANCE r,s RECURRENT DISEASE MANAGEMENT OF RECURRENT DISEASE e Resectable Resection e 3 12 mo postresection: H&P and consider biochemical markers from preoperative evaluation as clinically indicated c Multiphasic CT MRI Locegional Unresectable See Management of Locegional Unresectable Disease and/ Distant Metastases (PanNET-7) >1 y postresection to a maximum of 10 y: Every 6 12 mo H&P Consider biochemical markers as clinically indicated c Consider multiphasic CT MRI Distant metastases See Management of Locegional Unresectable Disease and/ Distant Metastases (PanNET-7) *Available online, in these guidelines, at NCCN.g. c See Principles of Biochemical Testing (NE-B*). e See Surgical Principles f Management of Neuroendocrine Tums (NE-C*). r Earlier, if symptoms. s Somatostatin scintigraphy and FDG-PET scan are not recommended f routine surveillance. PanNET-6 Version , National Comprehensive Cancer Netwk, Inc. All rights reserved. The NCCN Guidelines and this illustration may not be reproduced in any fm without the express written permission of NCCN.

15 92 Neuroendocrine Tums of the Pancreas MANAGEMENT OF LOCOREGIONAL UNRESECTABLE DISEASE AND/OR DISTANT METASTASES e If complete resection possible e,t Resect metastases + primary u Clinically signifi cant progressive, see below Locegional unresectable and/ Distant metastases Asymptomatic, low tum burden, and stable Observe with markers and scans every 3 12 mo Consider treatment with octreotide j,v lanreotide j,v Clinically signifi cant progressive, see below Symptomatic Clinically signifi cant tum burden Clinically signifi cant progressive Manage clinically signifi cant symptoms as appropriate (PanNET-1, PanNET-2, PanNET-3, PanNET-4, and PanNET-5) Consider octreotide j,v lanreotide j,v if not already receiving and/ Everolimus j (10 mg/d) Sunitinib j (37.5 mg/d) Cytotoxic chemotherapy j Hepatic regional therapy (ie, arterial embolization, chemoembolization, radioembolization [categy 2B]) Cyteductive surgery/ablative therapy w (categy 2B) *Available online, in these guidelines, at NCCN.g. e See Surgical Principles f Management of Neuroendocrine Tums (NE-C*). j See Principles of Systemic Anti-Tum Therapy (NE-D*). t Noncurative debulking surgery might be considered in select cases. u Staged synchronous resection when possible. When perfming staged pancreatoduodenectomy and liver resection, consider hepatectomy pri to pancreatic resection in der to reduce risk of perihepatic sepsis. De Jong MC, Farnell MB, Sclabas G, et al. Liver-directed therapy f hepatic metastases in patients undergoing pancreaticoduodenectomy: A dual-center analysis. Ann Surg 2010;252: v Somatostatin analogs should be used with caution in patients with insulinoma as they may transiently wsen hypoglycemia. (See Discussion f details). w Includes ablative techniques such as radiofrequency, microwave, and cryotherapy. There are no randomized clinical trials and prospective data f these interventions are limited, but data on their use are emerging. PanNET-7 Clinical trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are categy 2A unless otherwise indicated.

16 NCCN Clinical Practice Guidelines in Oncology 93 Text cont. from page 79. Patients with hmonal symptoms are considered to have functional tums, and those without symptoms are considered to have nonfunctional tums. Appropriate diagnosis and treatment of NETs often involves collabation between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. The full version of these guidelines discuss the diagnosis and management of both spadic and hereditary NETs and are intended to assist with clinical decision-making. Most of the guideline sections pertain to well-differentiated, low- to intermediategrade tums, although poly differentiated/highgrade/large small cell carcinomas are also addressed (see Poly Differentiated Neuroendocrine Tums/ Large Small Cell Tums in the complete version of these guidelines, at NCCN.g). Medical practitioners should note that unusual patient scenarios (presenting in <5% of patients) are not specifically discussed in these guidelines. This selection from the guidelines focuses on spadic NETs of the pancreas, gastrointestinal tract, lung, and thymus. NETs of the Gastrointestinal Tract, Lung, and Thymus (Carcinoid Tums) Approximately one-third of carcinoid tums arise in the lungs thymus, and two-thirds arise in the gastrointestinal tract. Sites of igin within the gastrointestinal tract include the stomach, small intestine, appendix, and rectum. 1 The prognosis f patients with carcinoid tums varies accding to stage at diagnosis, histologic classification, and primary tum site (see Histologic Classification and Staging of Neuroendocrine Tums in the complete version of these guidelines, at NCCN.g). NETs of the gastrointestinal tract and lungs may secrete various hmones and vasoactive peptides. Bronchial and thymic NETs have been associated with adrenocticotropic hmone (ACTH) production and are a cause of Cushing s syndrome. 10,11 NETs arising in the small intestine appendix are me commonly associated with carcinoid syndrome, related to the secretion of serotonin, histamine, tachykinins into the systemic circulation causing episodic flushing and diarrhea. 12 Approximately 50% to 66% of patients with carcinoid syndrome develop valvular cardiac complications consisting of tricuspid regurgitation and/ pulmonary stenosis. 13 The metabolic products released by intestinal NETs are rapidly destroyed by liver enzymes in the ptal circulation. Thus, the classic syndrome, occurring in approximately 8% to 28% of patients with NETs, 14,15 is not usually observed unless liver metastases, rarely, retroperitoneal have occurred, in which case hepatic metastases release metabolic products directly into the systemic circulation via the hepatic veins. These guidelines address 7 maj subtypes of carcinoid tums: (1) jejunal/ileal/colon, (2) duodenal, (3) appendix, (4) rectal, (5) gastric, (6) bronchopulmonary, and (7) thymus. Evaluation of NETs of the Gastrointestinal Tract, Lung, and Thymus Patients who present with suspected carcinoid tums should be evaluated with imaging studies to assess burden and possible primary location. Commonly used techniques include CT and MRI. NETs of the gastrointestinal tract and lungs are highly vascular and can appear isodense with liver on conventional CT scan, depending on contrast phase. Multiphase CT MRI scans should therefe be used f evaluation of liver metastasis. Chest CT is also recommended as appropriate to assess f lung metastases. Because most NETs express high-affinity recepts f somatostatin, 12,16 radiolabeled somatostatin recept scintigraphy, perfmed using the radiolabeled somatostatin analogue [ 111 In-DTPA]- octreotide may also be used in the initial evaluation of patients with NETs. Additional recommendations vary by site and include colonoscopy and small bowel imaging as appropriate f jejunal, ileal, and colonic NETs; endoscopic ultrasound (EUS) and/ esophagogastroduodenoscopy (EGD) as appropriate f duodenal and gastric NETs; proctoscopic examination f rectal NETs; and bronchoscopy as appropriate f bronchopulmonary and thymic NETs. Biochemical evaluation can also be helpful in the initial diagnostic evaluation, particularly in patients with symptoms that are suggestive of hmone hypersecretion. Evaluation of serotonin secretion, using a 24-hour urine collection f 5-HIAA, is generally recommended in patients with metastatic lung gastrointestinal carcinoid tums, particularly if carcinoid

17 94 NCCN Clinical Practice Guidelines in Oncology syndrome, manifested by symptoms of flushing and diarrhea, is suspected. A wkup f Cushing s syndrome (discussed in Evaluation and Treatment of Cushing s Syndrome in the complete version of these guidelines, at NCCN.g) may also be indicated in cases of bronchopulmonary thymic NETs if signs and symptoms of hyperctisolemia are suspected. Details of the evaluation and diagnosis of Cushing s syndrome from a bronchial NET were recently published. 17 Management of Locegional Disease The management of locegional NETs of the gastrointestinal tract and lungs depends on tum size and primary site and the general condition of the patient. Resection is the primary treatment approach f most localized carcinoid tums. Although symptoms of hmone hypersecretion are me common in patients with metastatic, f patients with locegional and symptoms of hmone hypersecretion, symptom control with a somatostatin analogue is paramount (see Management of Locegional Unresectable and/ Metastatic NETs of the Gastrointestinal Tract, Lung, and Thymus, page 96). Specific recommendations f the management of NET subtypes are described herein. Gastric NETs: Three types of gastric NETs are generally recognized: type 1 (associated with antrum sparing type A chronic atrophic gastritis), type 2 (associated with Zollinger-Ellison syndrome), and type 3 (spadic). 18 Types 1 and 2 gastric NETs are both associated with hypergastrinemia; the maj difference between them is that patients with type 1 gastric NETs generally have antrum-sparing atrophic gastritis with a loss of the usual negative feedback loop on the gastrin-producing cells of the antrum by acid, resulting in hypergastrinemia and excess stimulation of the endocrine cells of the fundus, and patients with type 2 gastric NETs have evidence of acid hypersecretion secondary to gastrinoma (Zollinger- Ellison syndrome). 18 F hypergastrinemic patients whose tums are 2 cm smaller and either solitary multiple, options include (1) endoscopic resection, if feasible, with biopsy of the tum and adjacent mucosa; (2) observation; (3) octreotide lanreotide f symptom control in patients with gastrinoma and Zollinger-Ellison syndrome. F patients with hypergastrinemia with solitary multiple tums larger than 2 cm, endoscopic resection (if possible) surgical resection is indicated. Patients with nonmetastatic gastric NETs and nmal gastrin levels (type 3) have me aggressive tums and are usually treated with radical resection of the tum with regional lymphadenectomy. Alternatively, endoscopic wedge resection can be considered f tums 2 cm less. 19 Thymic NETs: Localized and locegional NETs in the thymus are treated with surgical resection, generally without adjuvant therapy. After incomplete resection of locegional, however, radiation therapy (RT) and/ chemotherapy are recommended (categy 3). If chemotherapy is offered, capecitabine 5-FU at radiosensitizing doses may be considered. Cisplatin carboplatin with etoposide may be appropriate f patients with atypical poly differentiated tums. Bronchopulmonary NETs: F localized locegional bronchopulmonary tums, please refer to the Lung Neuroendocrine Tums algithm in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) f Small Cell Lung Cancer (to view the most recent version of these guidelines, visit NCCN.g). NETs of the Duodenum, Small Intestine, and Colon: F localized lesions arising in the duodenum, endoscopic resection is recommended if feasible. Transduodenal local excision with without lymph node sampling and pancreatoduodenectomy are other options f primary treatment of nonmetastatic duodenal NETs. If endoscopic resection was perfmed, follow-up upper endoscopy (EGD) should be perfmed as appropriate. F patients presenting with tums in the jejunum, ileum, colon, surgical resection of the bowel with regional lymphadenectomy is recommended. The surgical procedure should include careful examination of the entire bowel, because multiple synchronous lesions may be present. In addition, the proximity to involvement of the superi mesenteric artery and superi mesenteric vein should be assessed during surgery. If future treatment with octreotide lanreotide is anticipated, a prophylactic cholecystectomy should be considered given the association between long-term treatment with somatostatin analogues and the development of biliary symptoms and gallstones. 20 Appendiceal NETs: Most appendiceal NETs are identified incidentally during appendectomy per-

18 NCCN Clinical Practice Guidelines in Oncology 95 fmed f appendicitis. Most appendiceal NETs have well-differentiated histology, and f most appendiceal tums 2 cm smaller and confined to the appendix, simple appendectomy is sufficient because metastases are uncommon. 21,22 However, some controversy exists regarding the management of appendiceal NETs measuring less than 2 cm with me aggressive histologic features. A recent population-based study analyzing the SEER database found evidence that lymph node metastases can develop in some patients with appendiceal NETs 2 cm smaller. 23 Some NCCN Member Institutions thus consider me aggressive treatment f 1- to 2-cm tums with po prognostic features, such as lymphovascular mesoappendiceal invasion atypical histologic features. Patients with an incomplete resection tums larger than 2 cm are at risk f locegional distant metastases. These patients should be staged using abdominal/pelvic CT MRI scans. If no distant is identified, they should undergo reexplation with a right hemicolectomy. Additionally, a small proption of appendiceal NETs may also contain evidence of adenocarcinoma (ie, adenocarcinoid goblet cell carcinoid). These tums should be managed accding to the NCCN Guidelines f Colon Cancer (to view the most recent version of these guidelines, visit NCCN.g). NETs of the Rectum: The treatment of rectal lesions is based on the size of the primary tum. If the lesion is 2 cm less, endoscopic transanal excision is recommended. Given the higher risk of invasion with larger tums, examination under anesthesia and/ EUS befe the procedure should be considered f tums 1 to 2 cm. A recent retrospective review found that metastases were present in 66% of 87 patients with well-differentiated rectal NETs 11 to 19 mm. 24 Tums larger than 2 cm, those with invasion of the muscularis propria, those associated with lymph node metastases should be treated with low anteri resection, in rare cases, an abdominoperineal resection. 25 Surveillance of Resected NETs of the Gastrointestinal Tract, Lung, and Thymus Surveillance of bronchopulmonary and gastrointestinal NETs should include complete patient histy and physical examination (H&P) and consideration of multiphasic CT MRI (usually abdominal and/ pelvic). Most patients with NETs of the jejunum/ ileum/colon, duodenum, rectum, and thymus, and type 3 gastric NETs with nmal gastrin levels should be reevaluated 3 to 12 months after resection (earlier if the patient is symptomatic) and then every 6 to 12 months f up to 10 years. Relevant biochemical evaluations can also be perfmed based on preresection findings. Chromogranin A may be used as a tum marker (categy 3); although not diagnostic, elevated levels have been associated with recurrence. 26 In addition, an analysis of a large prospective database showed that chromogranin A levels elevated twice the nmal limit higher were associated with shter survival times f patients with metastatic NETs (hazard ratio [HR], 2.8; 95% CI, ; P<.001). 27 Chromogranin A levels can be elevated in several concurrent medical conditions, including renal hepatic insufficiency, and are also commonly elevated in the setting of concurrent proton pump inhibits. Several panelists therefe caution that increasing chromogranin A levels in an asymptomatic patient with a tum that looks stable on imaging does not necessarily indicate that a patient should be initiated on a new therapy. 5-Hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin, in a 24-hour urine sample may also be considered as a biochemical marker in some cases, particularly in patients with metastatic smallintestinal NETs. During moniting of patients after treatment of a carcinoid tum, decreasing levels of 5-HIAA indicate a response to treatment, whereas increasing excessive concentration indicates that the treatment has not been successful. However, a patient with symptoms may still have a NET even if the concentration of 5-HIAA is nmal. Diet and a variety of drugs can affect the 5-HIAA test. Therefe, patients should be advised not to eat avocados, bananas, cantaloupe, eggplant, pineapples, plums, tomatoes, hicky nuts/pecans, plantains, kiwi, dates, grapefruit, honeydew, walnuts f 48 hours befe the start of urine collection. Additionally, patients should avoid coffee, alcohol, and smoking f this period. Medications that can increase 5-HIAA include acetaminophen, ephedrine, diazepam, nicotine, glyceryl guaiacolate (an ingredient found in some cough medicines), and phenobarbital. Somatostatin recept scintigraphy is not routinely recommended f surveillance after definitive resection, but may be indicated to assess lo-

19 96 NCCN Clinical Practice Guidelines in Oncology cation and burden f comparison in cases of subsequent possible recurrence. In specific cases, follow-up recommendations f patients with resected gastrointestinal NETs differ from the above general recommendations. F rectal tums smaller than 1 cm, prognosis is excellent and no follow-up is usually required. F rectal tums that are between 1 and 2 cm, follow-up endoscopies with rectal MRI EUS are recommended 6 and 12 months after primary therapy, and then as clinically indicated. F appendiceal tums 2 cm smaller without aggressive features, follow-up examinations are perfmed as clinically indicated. Patients with small, well-differentiated appendiceal NETs are at very low risk f recurrence, and some institutions recommend no follow-up in these patients. Other institutions recommend a follow-up examination 1 year after simple appendectomy and then with decreasing frequency. However, because recurrences have rarely been repted even after resection of small appendiceal tums, any patients with symptoms of hmone hypersecretion should be me fully evaluated. Follow-up recommendations also differ to some extent f patients with hypergastrinemia and type 1 2 gastric NETs. F these patients, follow-up endoscopies are recommended every 6 to 12 months f the first 3 years and annually thereafter if no evidence of progression is seen. Because gastrin levels remain persistently high in patients with atrophic gastritis, gastrin levels are generally uninfmative in patients with type 1 gastric NETs. If clinically indicated, imaging studies should also be perfmed. Antrectomy to remove the source of gastrin production can be considered in patients with type 1 gastric NETs if new lesions increasing tum burden is observed. Management of Locegional Unresectable and/ Metastatic NETs of the Gastrointestinal Tract, Lung, and Thymus Baseline imaging recommendations f patients suspected to have distant metastatic include multiphase technique CT MRI. 31,32 Baseline levels of chromogranin A (categy 3) 24-hour urine 5-HIAA may also be considered f moniting subsequent progression (as discussed previously). Somatostatin scintography can also be considered both to assess sites of metastases and to assess somatostatin recept status if treatment with octreotide lanreotide is being considered. The most common sites of metastases from intestinal NETs include regional/ mesenteric lymph nodes, liver, and bones. Resection of Metastatic Disease: In some cases, patients with limited hepatic metastases other sites of can undergo complete resection of the primary tum and metastases with curative intent. One study of 172 patients who underwent hepatic resection of metastatic NETs showed that long-term survival can be achieved in selected cases: the repted 10-year overall survival rate was 50.4%. 33 A recent meta-analysis repted 5-year overall survival rates ranging from 41% to 100% in patients undergoing hepatic resection. 34 Most patients with resected metastatic, however, will eventually experience recurrence. 35,36 Noncurative debulking surgery can also be considered in select cases, especially if the patient is symptomatic from either tum bulk hmone production. Resection of the primary site in the setting of unresectable metastases is generally not indicated if the primary site remains asymptomatic and is relatively stable. 34 However, it is not uncommon f patients with small bowel primary tums to experience symptoms of intermittent abdominal pain from episodic bowel obstruction bowel ischemia related to the primary tum and surrounding fibrosis. Palliative small bowel resection is recommended in these patients. Somatostatin Analogues f Control of Symptoms and Tum Growth: Patients who have metastatic NETs and carcinoid syndrome should be treated using a somatostatin analogue (octreotide lanreotide). 20 The long-acting release (LAR) fmulation of octreotide is commonly used f the chronic management of symptoms in patients with carcinoid syndrome. Standard doses of octreotide LAR are 20 to 30 mg intramuscularly every 4 weeks. Dose and frequency may be further increased f symptom control as needed. Therapeutic levels are not achieved f 10 to 14 days after LAR injection. Sht-acting octreotide (usually mcg subcutaneously 3 times daily) can be added to octreotide LAR f rapid relief of symptoms f breakthrough symptoms Lanreotide has a similar mechanism of action as octreotide, but is administered as a deep subcutaneous injection. Studies have shown it to be effective at controlling symptoms in patients with carcinoid tums, gastrinomas, vasoactive intestinal peptide tums (VIPomas) The multinational phase III ELECT trial randomized 115 patients with carcinoid syndrome who were either naïve to responsive to