new issn 1007-9327 (print) issn 2219-2840 (online) world journal of · 2017. 9. 14. · world...

World Journal of GastroenterologyWorld J Gastroenterol 2017 September 7; 23(33): 6009-6196

ISSN 1007-9327 (print)ISSN 2219-2840 (online)

Published by Baishideng Publishing Group Inc

S

EDITORIAL

6009 Helminthsasanalternativetherapyforintestinaldiseases

Sipahi AM, Baptista DM

REVIEW

6016 Dextransodiumsulfatecolitismurinemodel:Anindispensabletoolforadvancingourunderstandingof

inflammatory bowel diseases pathogenesis

Eichele DD, Kharbanda KK

6030 Autoimmune hepatitis: Standard treatment and systematic review of alternative treatments

Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D

MINIREVIEWS

6049 Colorectal cancer, screening and primary care: A mini literature review

Hadjipetrou A, Anyfantakis D, Galanakis CG, Kastanakis M, Kastanakis S

6059 Behavioral gastroenterology: An emerging system and new frontier of action

Jia L, Jiang SM, Liu J

ORIGINAL ARTICLE

Basic Study

6065 PharmacologicalevaluationofNSAID-inducedgastropathyasa"Translatable"modelofreferredvisceral

hypersensitivity

Hummel M, Knappenberger T, Reilly M, Whiteside GT

6077 HighyieldreproducibleratmodelrecapitulatinghumanBarrett’scarcinogenesis

Matsui D, Omstead AN, Kosovec JE, Komatsu Y, Lloyd EJ, Raphael H, Kelly RJ, Zaidi AH, Jobe BA

6088 Changes in expression of inhibitory substances in the intramural neurons of the stomach following

streptozotocin-induceddiabetesinthepig

Bulc M, Palus K, Zielonka L, Gajęcka M, Całka J

6100 HOXtranscriptantisenseintergenicRNArepressesE-cadherinexpressionbybindingtoEZH2ingastric

cancer

Chen WM, Chen WD, Jiang XM, Jia XF, Wang HM, Zhang QJ, Shu YQ, Zhao HB

Contents Weekly Volume 23 Number 33 September 7, 2017

� September 7, 2017|Volume 23|�ssue 33|WJG|www.wjgnet.com

ContentsWorld Journal of Gastroenterology

Volume 23 Number 33 September 7, 2017

6111 Ca2+/calmodulin-dependentproteinkinaseⅡregulatescoloncancerproliferationandmigrationvia

ERK1/2 and p38 pathways

Chen W, An P, Quan XJ, Zhang J, Zhou ZY, Zou LP, Luo HS

6119 AberrantDNA-PKcsandERGIC1expressionmaybeinvolvedininitiationofgastriccancer

Wang FR, Wei YC, Han ZJ, He WT, Guan XY, Chen H, Li YM

Retrospective Cohort Study

6128 Real world treatment patterns of gastrointestinal neuroendocrine tumors: A claims database analysis

Benson III AB, Broder MS, Cai B, Chang E, Neary MP, Papoyan E

Retrospective Study

6137 Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases

Halling ML, Kjeldsen J, Knudsen T, Nielsen J, Koch-Hansen L

6147 Suspiciousbrushcytologyisanindicationforlivertransplantationevaluationinprimarysclerosing

cholangitis

Boyd S, Vannas M, Jokelainen K, Isoniemi H, Mäkisalo H, Färkkilä MA, Arola J

6155 Management of gastric mucosa-associated lymphoid tissue lymphoma in patients with extra copies of the

MALT1gene

Iwamuro M, Takenaka R, Nakagawa M, Moritou Y, Saito S, Hori S, Inaba T, Kawai Y, Toyokawa T, Tanaka T, Yoshino T,

Okada H

6164 Ketogenic diet poses a significant effect on imbalanced gut microbiota in infants with refractory epilepsy

Xie G, Zhou Q, Qiu CZ, Dai WK, Wang HP, Li YH, Liao JX, Lu XG, Lin SF, Ye JH, Ma ZY, Wang WJ

Observational Study

6172 Definition of colorectal anastomotic leakage: A consensus survey among Dutch and Chinese colorectal

surgeons

van Rooijen SJ, Jongen ACHM, Wu ZQ, Ji JF, Slooter GD, Roumen RMH, Bouvy ND

CASE REPORT

6181 How to treat intestinal obstruction due to malignant recurrence after Whipple’s resection for pancreatic head

cancer: Description of 2 new endoscopic techniques

Mouradides C, Taha A, Borbath I, Deprez PH, Moreels TG

6187 Arterioportal shunt incidental to treatment with oxaliplatin that mimics recurrent gastric cancer

Kim HB, Park SG

�� September 7, 2017|Volume 23|�ssue 33|WJG|www.wjgnet.com

ContentsWorld Journal of Gastroenterology

Volume 23 Number 33 September 7, 2017

LETTERS TO THE EDITOR

6194 Comment on “Effect of biofilm formation by clinical isolates of Helicobacterpylori on the efflux-mediated

resistancetocommonlyusedantibiotics”

Kazakos EI, Dorrell N, Polyzos SA, Deretzi G, Kountouras J

�� September 7, 2017|Volume 23|�ssue 33|WJG|www.wjgnet.com

�V September 7, 2017|Volume 23|�ssue 33|WJG|www.wjgnet.com

NAMEOFJOURNALWorld Journal of Gastroenterology

ISSNISSN 1007-9327 (print)ISSN 2219-2840 (online)

LAUNCHDATEOctober 1, 1995

FREQUENCYWeekly

EDITORS-IN-CHIEFDamian Garcia-Olmo, MD, PhD, Doctor, Profes-sor, Surgeon, Department of Surgery, Universidad Autonoma de Madrid; Department of General Sur-gery, Fundacion Jimenez Diaz University Hospital, Madrid 28040, Spain

Stephen C Strom, PhD, Professor, Department of Laboratory Medicine, Division of Pathology, Karo-linska Institutet, Stockholm 141-86, Sweden

Andrzej S Tarnawski, MD, PhD, DSc (Med), Professor of Medicine, Chief Gastroenterology, VA Long Beach Health Care System, University of Cali-fornia, Irvine, CA, 5901 E. Seventh Str., Long Beach,

CA 90822, United States

EDITORIALBOARDMEMBERSAll editorial board members resources online at http://www.wjgnet.com/1007-9327/editorialboard.htm

EDITORIALOFFICEJin-Lei Wang, DirectorYuan Qi, Vice DirectorZe-Mao Gong, Vice DirectorWorld Journal of GastroenterologyBaishideng Publishing Group Inc7901 Stoneridge Drive, Suite 501, Pleasanton, CA 94588, USATelephone: +1-925-2238242Fax: +1-925-2238243E-mail: [email protected] Desk: http://www.f6publishing.com/helpdeskhttp://www.wjgnet.com

PUBLISHERBaishideng Publishing Group Inc7901 Stoneridge Drive, Suite 501, Pleasanton, CA 94588, USATelephone: +1-925-2238242Fax: +1-925-2238243E-mail: [email protected] Desk: http://www.f6publishing.com/helpdesk

Contents

EDITORS FOR THIS ISSUE

Responsible Assistant Editor: Xiang Li Responsible Science Editor: Li-Juan WeiResponsible Electronic Editor: Yan Huang Proofing Editorial Office Director: Jin-Lei WangProofing Editor-in-Chief: Lian-Sheng Ma

http://www.wjgnet.com

PUBLICATIONDATESeptember 7, 2017

COPYRIGHT© 2017 Baishideng Publishing Group Inc. Articles pub-lished by this Open-Access journal are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license.

SPECIALSTATEMENTAll articles published in journals owned by the Baishideng Publishing Group (BPG) represent the views and opin-ions of their authors, and not the views, opinions or policies of the BPG, except where otherwise explicitly indicated.

INSTRUCTIONSTOAUTHORSFull instructions are available online at http://www.wjgnet.com/bpg/gerinfo/204

ONLINESUBMISSIONhttp://www.f6publishing.com

World Journal of GastroenterologyVolume 23 Number 33 September 7, 2017

Editorial Board Member of World Journal of Gastroenterology, Mostafa Sira, MD,AssociateProfessorofPediatricHepatology,GastroenterologyandNutri-tion, National Liver Institute, Menofiya University, Menofiya 32511, Egypt

World Journal of Gastroenterology (World J Gastroenterol, WJG, print ISSN 1007-9327, online ISSN 2219-2840, DOI: 10.3748) is a peer-reviewed open access journal. WJG was estab-lished on October 1, 1995. It is published weekly on the 7th, 14th, 21st, and 28th each month. The WJG Editorial Board consists of 1375 experts in gastroenterology and hepatology from 68 countries. The primary task of WJG is to rapidly publish high-quality original articles, reviews, and commentaries in the fields of gastroenterology, hepatology, gastrointestinal endos-copy, gastrointestinal surgery, hepatobiliary surgery, gastrointestinal oncology, gastroin-testinal radiation oncology, gastrointestinal imaging, gastrointestinal interventional ther-apy, gastrointestinal infectious diseases, gastrointestinal pharmacology, gastrointestinal pathophysiology, gastrointestinal pathology, evidence-based medicine in gastroenterol-ogy, pancreatology, gastrointestinal laboratory medicine, gastrointestinal molecular biol-ogy, gastrointestinal immunology, gastrointestinal microbiology, gastrointestinal genetics, gastrointestinal translational medicine, gastrointestinal diagnostics, and gastrointestinal therapeutics. WJG is dedicated to become an influential and prestigious journal in gas-troenterology and hepatology, to promote the development of above disciplines, and to improve the diagnostic and therapeutic skill and expertise of clinicians.

World Journal of Gastroenterology (WJG) is now indexed in Current Contents®/Clinical Medicine, Science Citation Index Expanded (also known as SciSearch®), Journal Citation Reports®, Index Medicus, MEDLINE, PubMed, PubMed Central and Directory of Open Access Journals. The 2017 edition of Journal Citation Reports® cites the 2016 impact factor for WJG as 3.365 (5-year impact factor: 3.176), ranking WJG as 29th among 79 journals in gastroenterology and hepatol-ogy (quartile in category Q2).

I-IX EditorialBoard

ABOUT COVER

INDEXING/ABSTRACTING

AIMS AND SCOPE

FLYLEAF

Al B Benson III, Northwestern University, Chicago, IL 60208, United States

Michael S Broder, Eunice Chang, Elya Papoyan, Partnership for Health Analytic Research, LLC, Beverly Hills, CA 90212, United States

Beilei Cai, Maureen P Neary, Novartis Pharmaceuticals, East Hanover, NJ 07936, United States

Author contributions: All authors were equally involved in the design of the study; Chang E conducted the statistical analyses and all authors contributed equally in the interpretation of results and writing of the manuscript.

Supported by Novartis Pharmaceuticals, One Health Plaza, East Hanover, No. NJ 07936-1080, United State.

Institutional review board statement: We conducted a retrospective cohort study using the Truven Health Analytics MarketScan Database and the IMS Health Pharmetrics Database, both commercial health insurance claims database for employer-insured beneficiaries in the United States. The databases are fully compliant with the Health Insurance Portability and Accountability Act and meets the criteria for a limited-use dataset. Since the patient and provider data included in this analysis were fully de-identified, this study was exempt from the Institutional Review Board review.

Conflict-of-interest statement: Cai B and Neary MP are employees of Novartis Pharmaceuticals Corporation; Benson III AB was paid as a research consultant for the study as a subject matter expert by Novartis and is an employee of Northwestern University; Broder MS, Chang E and Papoyan E are employees of Partnership for Health Analytic Research, LLC (PHAR, LLC), a health services research company paid by Novartis to conduct this research.

Data sharing statement: The study statistician, Eunice Chang, conducted all statistical analysis for this study using Health Insurance Portability and Accountability Act-compliant commercial-insurance secondary databases MarketScan and PharMetrics.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Manuscript source: Unsolicited manuscript

Correspondence to: Michael S Broder, MD, MSHS, Partnership for Health Analytic Research, LLC, 280 S. Beverly Drive, Suite 404, Beverly Hills, CA 90212,United States. [email protected] Telephone: +1-310-8589555Fax: +1-310-8589552

Received: February 9, 2017Peer-review started: February 9, 2017First decision: April 21, 2017Revised: May 9, 2017 Accepted: June 18, 2017 Article in press: June 19, 2017Published online: September 7, 2017

AbstractAIMTo describe real-world treatment patterns of gastro-intestinal neuroendocrine tumors (GI NET).

METHODSIn this retrospective cohort study, we used 2009-2014 data from 2 United States commercial claims databases to examine newly pharmacologically treated patients using tabular and graphical techniques. Treatments included somatostatin analogues (SSA), cytotoxic chemotherapy (CC), targeted therapy (TT), interferon

6128 September 7, 2017|Volume 23|Issue 33|WJG|www.wjgnet.com

ORIGINAL ARTICLE

Real-world treatment patterns of gastrointestinal neuroendocrine tumors: A claims database analysis

Retrospective Cohort Study

Al B Benson III, Michael S Broder, Beilei Cai, Eunice Chang, Maureen P Neary, Elya Papoyan

Submit a Manuscript: http://www.f6publishing.com

DOI: 10.3748/wjg.v23.i33.6128

World J Gastroenterol 2017 September 7; 23(33): 6128-6136

ISSN 1007-9327 (print) ISSN 2219-2840 (online)

(IF) and combinations. We identified patients at least 18 years of age, with ≥ 1 inpatient or ≥ 2 outpatient claims for GI NET who initiated pharmacologic treatment from 7/1/09-6/30/14. A 6 mo clean period prior to first treatment ensured patients were newly treated. Patients were followed until end of enrollment or the study end date, whichever was first.

RESULTSWe identified 2258 newly treated GI NET patients: mean (SD) age was 55.6 years (SD = 9.7), 47.2% of the patients were between 55 and 64 years, and 48.8% were female. All regions of the United States were represented. 59.6% started first-line therapy with SSA monotherapy (964 with octreotide LAR, 380 with octreotide SA, and 1 with lanreotide), 33.3% CC, 3.6% TT, and 0.5% IF. The remainder received combinations. Mean follow up was 576 d. Overall mean first-line the-rapy duration was 361 d (449 d for SSA, 215 for CC, 267 for TT). 58.9% of patients had no pharmacological treatment beyond first line. The most common second-line was combination therapy with SSA. In graphical pattern analysis, there was no clear pattern visible after first line therapy.

CONCLUSIONIn this study, 60% of patients initiated treatment with SSA alone or in combination. The relatively long time to discontinuation suggests possible sustained effectiveness and tolerability.

Key words: Gastrointestinal neuroendocrine tumors; Treatment patterns; Insurance claims; Somatostatin analogue; Targeted therapy; Chemotherapy

© The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.

Core tip: In this retrospective study of real-world treatment patterns, somatostatin analogues were the most common initial pharmacologic treatment in patients with gastrointestinal neuroendocrine tumors, and most of the remaining patients began treatment with chemotherapy. However, despite the many treatment options, over half of the patients discontinued treatments after first line and only less than 10% of patients received any second-line pharmacotherapy. Given limitations of claims data to elucidate reasons for this lack of continued treatment, a study using more detailed clinical information such as medical charts or physician surveys is warranted.

Benson III AB, Broder MS, Cai B, Chang E, Neary MP, Papoyan E. Real-world treatment patterns of gastrointestinal neuroendocrine tumors: A claims database analysis. World J Gastroenterol 2017; 23(33): 6128-6136 Available from: URL: http://www.wjgnet.com/1007-9327/full/v23/i33/6128.htm DOI: http://dx.doi.org/10.3748/wjg.v23.i33.6128

INTRODUCTIONNeuroendocrine tumors (NET) comprise a broad family of rare and often slow growing malignancies. NET can develop anywhere in the body and arise from neuroendocrine cells throughout the endocrine system[1,2]. Approximately two-thirds of NET tumors occur in the gastrointestinal (GI) tract. These sites include the stomach, small intestine, appendix, colon, and rectum[3]. NET secrete peptides and neuroamines that cause distinct syndromes (e.g., carcinoid syn-drome), in which case they are referred to as “functional” tumors. Clinical presentation depends on the site of the primary tumor and whether they are functional. Surgery may be curative in the early stages, but delayed diagnosis is typical.

While rare, the incidence and prevalence of NET appear to be increasing worldwide[4-8]. The incidence of NET in the United States increased from 10.9 cases per million person-years (PMPY) in 1973 to 52.5 PMPY in 2004, and to 69.8 PMPY in 2012 as reported using the United States Surveillance Epidemiology and End Results database[4,9]. Prevalence also increased and was reported as 216 per million per year for GI NET in the United States.

The management of GI NET is based on a variety of factors including stage, anatomic location, and the presence and type of symptoms. The most recent NCCN guidelines for unresectable and metastatic GI NET recommend somatostatin analogues (SSA) as first-line treatment, but do not recommend a particular treatment sequence for the remaining therapies[10]. Considering the heterogeneity of GI NET tumors and the resultant lack of specificity in guidelines, we aimed to describe the current real-world treatment patterns of GI NET in a large sample of patients.

MATERIALS AND METHODSData sourceWe conducted a longitudinal, retrospective cohort analysis of newly pharmacologically treated GI NET patients using two large United States commercial claims databases. Data from the Truven Health Analytics MarketScan database and the IMS Phar-Metrics database (both using dates from January 1, 2009 to December 31, 2014) were combined to increase sample size. To prevent duplicate records, patients with the same age, gender, region, and date of first GI NET diagnosis in a calendar year found in both databases were randomly removed from one of the databases. Both databases are Health Insurance Portability and Accountability Act compliant administrative claims databases that contain de-identified adjudicated medical claims (e.g., inpatient and outpatient services) and pharmacy claims (e.g., outpatient prescriptions) submitted for payment by


Benson III AB et al . GI NET treatment patterns

providers, healthcare facilities, and pharmacies. For both data sources, claims include information on each physician visit, medical procedure, hospitalization, drug dispensed, date of service, number of days of medication supplied, test performed, and complete payment information. Each medical claim has a principal diagnosis and secondary diagnoses codes associated with it. Available patient demographic information includes age, gender, and geographic region. Dates of enrollment and disenrollment are also recorded. As the data were fully de-identified, this study was considered exempt from approval by the Institutional Review Board.

Cohort selectionPatients at least 18 years of age were identified from each dataset if they had at least 1 inpatient or 2 outpatient claims with an International Statistical Classification of Disease-9-Clinical Modification (ICD-9-CM) for GI NET (209.00-209.03, 209.10-209.17, 209.23, 209.24-209.27, 209.40-209.43, 209.50-209.57, 209.62, 209.65-209.67) during the study period (1/1/2009-12/31/2014). The first GI NET pharmacologic treatment claim on or after the appearance of the GI NET diagnosis code and within the ID period (7/1/2009 to 6/30/2014) was considered to be the index date. Patients were required to be enrolled for a baseline period of at least six months before the index date. To ensure new treatment, patients with any evidence of pharmacologic treatment during this baseline period were excluded. In order not to include the same patient twice, we searched for any patients with the same age, gender, region, and date of GI NET diagnosis who could be found in both databases, but we found none. Patient follow-up was variable and continued until the end of enrollment or the study end date (12/31/2014), whichever was first (Figure 1).

Study variables and measuresThe primary outcome measure was the use of pharmacologic or liver directed therapy. Pharmaco-therapy was divided into four groups: SSA, TT, CC and IF. SSA included octreotide and lanreotide, TT included everolimus and sunitinib, and CC included

temozolomide, streptozotocin, doxorubicin, liposomal doxorubicin, fluorouracil, capecitabine, dacarbazine, oxaliplatin and thalidomide. Pharmacologic therapy was identified in claims using both the Healthcare Common Procedure Coding System (HCPCS) and National Drug Codes (NDC). Liver directed therapies comprised liver resection, transplant, lesion ablation (using radiotherapy, cryotherapy, microwave and thermal energy, and including laparoscopic, open and percutaneous routes), embolization (including bland, radioisotope, and chemotherapy), and radiation therapy. Liver directed therapies were identified in claims using HCPCS, ICD-9-CM, and Current Procedural Terminology (CPT) codes. Chemotherapy observed only once and on the same date as embolization was considered chemoembolization and not part of a pharma-cologic regimen.

First-line therapy was defined as the pharmacologic treatment regimen observed on, or within three months of, the index date. Therapy included mono-therapy or combination therapies. A three-month period after the index date was used to identify pharmacologic therapy intended as first-line but not administered on the index date. This would include, for example, combination chemotherapy where the second agent is given after some delay. Second-line therapy was defined as beginning when treatment was switched from one category of pharmacotherapy to another (e.g., from SSA alone to CC alone), or when a new category of treatment was added (e.g., from SSA alone to SSA plus CC). Changes from one cytotoxic agent to another, or one SSA to another, were not considered a switch. The first day of treatment switch or addition was defined as the initiation date of second-line therapy.

Statistical analysisMeans and proportions were presented in tabular analyses. An inverse Kaplan-Meier curve was used to show duration of first-line therapy. All data transformations and statistical analyses were performed using SAS® version 9.4 (SAS Institute, Cary, NC). Graphical analyses were conducted using GRAPHx™, a proprietary graphics-based algorithm. The GRAPHx method uses multi-colored line segments to represent


Figure 1 Study timeline. The first gastrointestinal neuroendocrine tumors (GI NET) pharmacologic treatment claim on or after the appearance of the GI NET diagnosis code and within the ID period (7/1/2009 to 6/30/2014) was considered to be the index date. Patients were required to be enrolled for a baseline period of at least six months before the index date. Patient follow-up was variable and continued until the end of enrollment or the study end date (12/31/14), whichever was first.

Day 1(first GI NET pharmacologic treatment)

6/30/14

Follow-up period(Until the end of enrollment or 12/31/14)

Identification period

7/1/09

1/1/09

6-mo washout period (No GI NET treatment)

12/31/14



Mean duration of first-line therapy was 361 d (SD = 385) for all newly treated patients. The mean observed duration of treatment for first-line SSA monotherapy users was 449 d (SD = 434.2). It was 215 d (SD = 228.8) for first-line CC monotherapy and 267 d (SD = 325.7) for first-line TT monotherapy (Table 2). By 588 d of treatment (1.61 years), half of SSA initiators had discontinued treatment, compared to 182 d (0.498 years) for half of CC users and 171 d (0.47 years) for half of TT users to discontinue treatment (Figure 3). Liver directed therapy was used by 12.5% during first-line pharmacologic therapy; another 3.7% received it sometime after the first-line (Table 2).

By the end of the study follow-up period [mean (SD, median) of 576 d (447.1, 454)] 58.9% (n = 1331) patients had stopped pharmacologic therapy completely. These patients continued to be enrolled in one of the databases but no longer had claims for pharmacologic treatment. In Figure 4, these patients can be identified as colored line segments that terminate in gray segments of variable length, with the gray representing the period of no treatment. An additional 32.7% (n = 738) continued their initial therapy until the end of their enrollment; these patients were still receiving their first-line therapy at the time they left a covered plan or reached the end of study. This pattern is shown in Figure 4 as a colored segment terminating in white. The remaining 8.4% (n = 189) were observed to change pharmacologic treatment during the follow-up period (a colored segment terminating in different colored segment)

various treatments, plotting them over time. The images are reviewed visually for the presence and length of segments and change in colors and patterns over time.

RESULTSThere were 2900 and 2453 patients meeting the definition of GI NET who also had a claim for pharma-cologic treatment between 7/1/2009 and 6/30/2014 in the MarketScan and PharMetrics databases, respectively. After excluding patients who had treatment during a 6-mo pre-index period (and therefore were considered to be continuing, rather than initiating, treatment); received treatment before receiving a diagnosis of GI NET; were < 18 years old; or were not continuously enrolled in the 6-mo pre-index period, there remained 2258 newly treated GI NET patients who were included in the study (Figure 2).

Gender was evenly split with n = 1103 (48.8%) female patients and n = 1155 (51.2%) male. The average age was 55.6 years (SD = 9.7) and 47.2% of the patients were between 55 and 64 years. All regions of the United States were represented. More than half of patients, n = 1345 (59.6%), were treated with SSA as first-line monotherapy, 964 with octreotide LAR, 380 with octreotide SA, and 1 with lanreotide. An additional 75 patients (3.3%) received SSA in combination with other either CC, TT or IF. The second largest group, n = 752 (33.3%), was treated with CC monotherapy, and n = 81 (3.6%) received TT monotherapy (Table 1).

Figure 2 Patient identification. There were 2900 and 2453 gastrointestinal neuroendocrine tumors (GI NET) patients who also had a claim for pharmacologic treatment between 7/1/2009 and 6/30/2014 in the MarketScan and PharMetrics databases, respectively. After excluding patients who had treatment during a 6-mo pre-index period (and therefore were considered to be continuing, rather than initiating, treatment); received treatment before receiving a diagnosis of GI NET; were < 18 yr old; or were not continuously enrolled in the 6-mo pre-index period, there remained 2258 newly treated GI NET patients who were included in the study. 1Somatostatin analogues (SSAs), targeted therapy, cytotoxic chemotherapy, or interferon; 2324 (34.8%) within 3 mo, and 516 (55.4%) within 6 mo; 3249 (35.0%) within 3 mo, and 380 (53.4%) within 6 mo.

MarketScan database PharMetrics database

2900 GI NET patients received pharmacologic treatment1 in ID period

(7/1/2009-6/30/2014)

2453 GI NET patients received pharmacologic treatment1 in ID period

(7/1/2009-6/30/2014)

1 was < 18 yr old

430 had treatment in the 6mo pre-index period

9322 started treatment before the first GI NET diagnosis

7 were < 18 yr old

315 were not continuously enrolled in 6 mo pre-index period

264 were not continuously enrolled in 6 mo pre-index period

7113 started treatment before the first GI NET diagnosis

435 had treatment in the 6 mo pre-index period

2258 Newly treated GI NET patients

n = 2470

n = 1538

n = 1531

n = 1216 n = 1042

n = 1306

n = 1307

n = 2018



(Fig

ure

4 an

d Ta

ble

2).

Am

ong

thes

e 18

9 pa

tient

s w

ho w

ere

obse

rved

to

begi

n se

cond

-lin

e th

erap

y, 1

28 (

67.7

%)

had

initi

ally

bee

n tr

eate

d w

ith S

SA.

Am

ong

thes

e 12

8 fir

st-lin

e SSA u

sers

, 89

(69

.5%

) ad

ded

addi

tiona

l th

erap

y (e

.g., C

C o

r TT

) as

the

ir s

econ

d-lin

e tr

eatm

ent. I

n pa

tient

s w

ho d

id n

ot b

egin

the

rapy

with

SSA,

mos

t re

ceiv

ed S

SA m

onot

hera

py o

r co

mbi

natio

n th

erap

y as

sec

ond-

line

(Tab

le 3

). L

iver

direc

ted

ther

apy

(sho

rt, re

d se

gmen

ts)

appe

ars

disp

erse

d th

roug

hout

per

iods

of bo

th

phar

mac

olog

ic tre

atm

ent (c

olor

ed s

egm

ents

) an

d pe

riod

s of

no

phar

mac

olog

ic tre

atm

ent (g

ray

segm

ents

) (F

igur

e 4)

. Am

ong

1331

pat

ient

s w

ho s

topp

ed p

harm

acol

ogic

tr

eatm

ent an

d di

d no

t be

gin

a se

cond

-lin

e tr

eatm

ent, 5

.5%

wer

e tr

eate

d w

ith li

ver-

dire

cted

the

rapy

with

in 3

0 d

befo

re o

r af

ter th

ey s

topp

ed.

DIS

CU

SSIO

NTh

is s

tudy

use

d tw

o ve

ry la

rge,

nat

iona

lly r

epre

sent

ativ

e cl

aim

s da

taba

ses,

whi

ch t

oget

her

repr

esen

t up

to

100

millio

n co

vere

d liv

es, to

des

crib

e re

al-w

orld

tre

atm

ent

of G

I N

ET. Th

ree

findi

ngs

wer

e of

par

ticul

ar in

tere

st. Fi

rst, the

mos

t co

mm

on in

itial

pha

rmac

olog

ic tre

atm

ent w

as w

ith S

SA, w

ith a

vera

ge d

urat

ion

of u

se o

f ju

st o

ver

18

mo.

Sec

ond,

alth

ough

60%

of pa

tient

s in

itiat

ed t

reat

men

t w

ith S

SA a

lone

or

in c

ombi

natio

n, m

ost

of t

he r

emai

nder

beg

an t

reat

men

t w

ith C

C, th

erap

y re

com

men

ded

Tabl

e 1 Pa

tien

t de

mog

raph

ics

by fi

rst-

line

trea

tmen

t n (

%)

Firs

t-lin

e tr

eatm

ent

All

new

ly t

reat

ed

patien

tsSS

AC

CTT

SSA

+ C

CSS

A +

TT

TT +

CC

IFSS

A +

IF

SSA

+ T

T +

CC

n13

451

752

81

42

31

3

2

1

1

2258

59.6

%33

.3%

3.6%

1.9%

1.4%

0.1%

0.1%

0.0

0.0

100.

0%A

ge (m

ean

± SD

, yr)

56.3

± 9

.554

.7 ±

9.9

54.9

± 1

0.5

53.5

± 1

0.9

53.8

± 1

0.1

59.3

± 3

.858

.5 ±

3.5

N/A

N/A

55.6

± 9

.7

18-2

46

(0.4

)2

(0.3

)0

(0)

1 (2

.4)

0 (0

)0

(0)

0 (0

)0

(0)

0 (0

)9

(0.4

)

25-3

420

(1.5

)25

(3.3

)4

(4.9

)3

(7.1

)0

(0)

0 (0

)0

(0)

0 (0

)0

(0)

52 (2

.3)

35

-44

121

(9.0

)92

(12.

2)9

(11.

1)4

(9.5

)4

(12.

9)0

(0)

0 (0

)0

(0)

0 (0

)23

0 (1

0.2)

45

-54

371

(27.

6)22

5 (2

9.9)

18 (2

2.2)

12 (2

8.6)

12 (3

8.7)

0 (0

)0

(0)

0 (0

)0

(0)

638

(28.

3)

55-6

465

1 (4

8.4)

338

(44.

9)39

(48.

1)20

(47.

6)11

(35.

5)3

(100

.0)

2 (1

00.0

)1

(100

.0)

1 (1

00.0

)10

66 (4

7.2)

65

+17

6 (1

3.1)

70 (9

.3)

11 (1

3.6)

2 (4

.8)

4 (1

2.9)

0 (0

)0

(0)

0 (0

)0

(0)

263

(11.

6)Fe

mal

e67

7 (5

0.3)

341

(45.

3)40

(49.

4)26

(61.

9)17

(54.

8)1

(33.

3)1

(50.

0)0

(0.0

)0

(0.0

)11

03 (4

8.8)

Regi

on

Mid

wes

t32

1 (2

3.9)

183

(24.

3)20

(24.

7)13

(31.

0)7

(22.

6)0

(0)

1 (5

0.0)

0 (0

)0

(0)

545

(24.

1)

Nor

thea

st26

1 (1

9.4)

150

(19.

9)12

(14.

8)11

(26.

2)7

(22.

6)1

(33.

3)0

(0)

0 (0

)0

(0)

442

(19.

6)

Sout

h56

3 (4

1.9)

323

(43.

0)36

(44.

4)12

(28.

6)15

(48.

4)2

(66.

7)1

(50.

0)0

(0)

1 (1

00.0

)95

3 (4

2.2)

W

est

200

(14.

9)96

(12.

8)13

(16.

0)6

(14.

3)2

(6.5

)0

(0)

0 (0

)1

(100

.0)

0 (0

)31

8 (1

4.1)

Year

of t

reat

men

t ini

tiatio

n13

0 (9

.7)

41 (5

.5)

4 (4

.9)

2 (4

.8)

1 (3

.2)

0 (0

)0

(0)

1 (1

00.0

)0

(0)

179

(7.9

)

2009

20

1027

1 (2

0.1)

122

(16.

2)4

(4.9

)11

(26.

2)7

(22.

6)0

(0)

1 (5

0.0)

0 (0

)0

(0)

416

(18.

4)

2011

282

(21.

0)15

9 (2

1.1)

15 (1

8.5)

17 (4

0.5)

5 (1

6.1)

0 (0

)0

(0)

0 (0

)0

(0)

478

(21.

2)

2012

270

(20.

1)16

8 (2

2.3)

33 (4

0.7)

4 (9

.5)

10 (3

2.3)

0 (0

)1

(50.

0)0

(0)

1 (1

00.0

)48

7 (2

1.6)

20

1326

8 (1

9.9)

174

(23.

1)16

(19.

8)3

(7.1

)4

(12.

9)2

(66.

7)0

(0)

0 (0

)0

(0)

467

(20.

7)

2014

124

(9.2

)88

(11.

7)9

(11.

1)5

(11.

9)4

(12.

9)1

(33.

3)0

(0)

0 (0

)0

(0)

231

(10.

2)D

ays

of fo

llow

-up

M

ean

621

514

454

588

425

244

675

836

496

576

(S

D)

(468

.5)

(409

.1)

(403

.6)

(424

.1)

(269

.6)

(140

.7)

(145

.7)

N/A

N/A

(447

.1)

M

edia

n50

039

329

045

536

021

667

583

649

645

4

1 964

with

oct

reot

ide

LAR,

380

with

oct

reot

ide

SA, a

nd 1

with

lanr

eotid

e. S

SA: S

omat

osta

tin a

nalo

gues

; CC

: Cyt

otox

ic c

hem

othe

rapy

; TT:

Tar

gete

d th

erap

y; IF

: Int

erfe

ron.



1.0

0.8

0.6

0.5

0.4

0.2

0.0

Failu

re p

roba

bilit

y

0 0.47 0.498 1 1.61 2 3 4 5 Duration of first-line treatment, yr

Log-rank test: P < 0.001

CC

TTSSA

Point estimate (95%CI)SSA CC TT

75 percentile 3.35 (3.13-3.71) 0.75 (0.67-0.87) 1.70 (0.93-2.97)Median 1.61 (1.36-1.80) 0.498 (0.496-0.507) 0.47 (0.27-0.90)25 percentile 0.44 (0.36-0.52) 0.23 (0.19-0.27) 0.20 (0.16-0.24)

No. of patients at riskIndex date 0.5 yr 1 yr 1.5 yr 2 yr 2.5 yr 3 yr 3.5 yr 4 yr 4.5 yr 5 yr

SSA 1345 871 606 426 291 195 133 89 53 26 10CC 752 320 107 52 31 21 13 5 1 1 0TT 81 34 16 11 9 8 4 1 0 0 0

Figure 3 Time to discontinuation of first-line treatment. By 588 d of treatment (1.61 yr), half of SSA initiators had discontinued treatment, compared to 182 d (0.498 yr) for half of CC users and 171 d (0.47 yr) for half of TT users to discontinue treatment. SSA: Somatostatin analogues; CC: Cytotoxic chemotherapy; TT: Targeted therapy.

Day 1: First date of treatmentCopyright 2016. PHAR. LLC GRAPHx Version 1.0

500

1000

1500

2000

Day 1 Year 1 Year 2 Year 3 Year 4 Year 5

SSATTCCIFSSA + TTSSA + CCSSA + IFTT + CCSSA + TT + CCSSA + CC + IFLiver directed TxtNo treatmentNo data

Figure 4 Pharmacologic treatment. By end of study follow-up [mean (SD, median) of 576 d (447.1, 454)], 58.9% (n = 1331) patients had stopped pharmacologic therapy completely. These patients (no pharmacologic treatment claims, but remained enrolled in one of the databases) can be identified as colored line segments that terminate in gray segments of variable length, with the gray representing the period of no treatment. An additional 32.7% (n = 738) continued their initial therapy until the end of their enrollment; these patients were still receiving their first-line therapy at the time they left a covered plan or reached the end of study. This pattern is shown as a colored segment terminating in white. The remaining 8.4% (n = 189) were observed to change pharmacologic treatment during the follow-up period (a colored segment terminating in different colored segment). Liver directed therapy (short, red segments) appears dispersed throughout periods of both pharmacologic treatment (colored segments) and periods of no pharmacologic treatment (gray segments). SSA: Somatostatin analogues; CC: Cytotoxic chemotherapy; TT: Targeted therapy; IF: Interferon.



by N

CCN

onl

y if

no o

ther

opt

ions

(SSA, TT

, or

liv

er d

irec

ted

trea

tmen

t) a

re fea

sibl

e. T

hird

, de

spite

the

man

y av

aila

ble

trea

tmen

t op

tions

, le

ss t

han

one

in 1

0 pa

tient

s w

as o

bser

ved

to rec

eive

tre

atm

ent w

ith s

econ

d-lin

e ph

arm

acot

hera

py o

f an

y ty

pe.

Each

of th

ese

findi

ngs

mus

t be

con

side

red

in lig

ht o

f w

hat

is k

now

n ab

out

the

dise

ase

as w

ell as

the

inh

eren

t lim

itatio

ns o

f th

e da

ta s

ourc

e. T

reat

ing

NET

pat

ient

s is

a c

ompl

ex p

roce

ss.

Trea

tmen

ts a

re ind

ivid

ualiz

ed b

ased

on

tum

or s

ize,

loc

atio

n, a

nd p

atho

logy

, as

wel

l as

whe

ther

the

tum

or is

func

tiona

l, ty

pe a

nd e

xten

t of

sy

mpt

oms,

and

spe

ed o

f pr

ogre

ssio

n. O

ur d

ata

did

not

incl

ude

this

lev

el o

f de

tail.

Ins

uran

ce c

ompa

nies

agg

rega

te inf

orm

atio

n on

inp

atie

nt a

nd o

utpa

tient

ser

vice

s (g

ener

ally

rep

orte

d as

ICD

-9-C

M o

r IC

D-1

0), pr

oced

ures

(IC

D-9

pro

cedu

re c

odes

and

CPT

cod

es)

and

phar

mac

y cl

aim

s (N

DC)

as c

laim

s ar

e su

bmitt

ed for

pay

men

t by

pr

ovid

ers,

hea

lthca

re fac

ilitie

s, a

nd p

harm

acie

s. S

o fo

r ex

ampl

e, w

hile

GI

NET

can

be

iden

tified

by

usin

g a

list

of I

CD

-9-C

M c

odes

, pr

esen

ce o

f ad

vanc

ed d

isea

se m

ust

be in

ferr

ed b

y ob

serv

ing

the

use

of p

harm

acol

ogic

tre

atm

ent. A

noth

er li

mita

tion

of t

he d

ate

sour

ce is

tha

t th

e av

aila

ble

leng

th o

f tim

e fo

r an

alys

is is

rel

ativ

ely

brie

f, so

co

nclu

sion

s re

gard

ing

aver

age

dura

tion

of u

se m

ay n

ot b

e re

pres

enta

tive

of lo

ng-t

erm

tre

atm

ent pa

tter

ns.

Our

prim

ary

findi

ng tha

t 60

% o

f pa

tient

s in

itiat

ed p

harm

acol

ogic

the

rapy

with

SSA is

con

sist

ent w

ith the

NCCN

rec

omm

enda

tion

of the

se d

rugs

for

initi

al tre

atm

ent

of c

linic

ally

sig

nific

ant

and

prog

ress

ive

NET

. Con

sist

ent

with

the

clin

ical

obs

erva

tion

that

SSA t

end

to b

e w

ell t

oler

ated

, pa

tient

s in

itiat

ing

trea

tmen

t w

ith S

SA r

emai

ned

on fi

rst-

line

ther

apy

long

er tha

n th

e pa

tient

s w

ho b

egan

tre

atm

ent w

ith C

C a

nd T

T. T

he s

econ

d fin

ding

not

ed a

bove

, th

at 1

/3 o

f G

I N

ET p

atie

nts

bega

n tr

eatm

ent w

ith

CC, is

mor

e su

rprisi

ng. CC is

rel

ativ

ely

inef

fect

ive

in the

se p

atie

nts,

and

as

a re

sult

is rec

omm

ende

d on

ly if

oth

er o

ptio

ns a

re n

ot fea

sibl

e.

Ther

e ar

e se

vera

l po

ssib

le e

xpla

natio

ns for

the

fre

quen

t us

e of

CC.

Patie

nts

obse

rved

to

initi

ate

cyto

toxi

c tr

eatm

ent

may

hav

e be

en t

reat

ed in

the

past

with

oth

er

agen

ts a

nd e

ither

pro

gres

sed

or w

ere

into

lera

nt t

o th

ose

agen

ts.

We

revi

ewed

dat

a fo

r 6

mo

befo

re t

he fi

rst

phar

mac

olog

ic t

reat

men

t, b

ut t

reat

men

ts m

ore

than

6

mo

in the

pas

t w

ould

hav

e be

en m

isse

d. I

t m

ay a

lso

be tha

t so

me

of the

pat

ient

s ha

d a

path

olog

y fin

ding

sug

gest

ing

chem

othe

rapy

wou

ld b

e be

nefic

ial,

or a

diff

eren

t ty

pe o

f G

I tu

mor

tha

t w

as in

corr

ectly

cod

ed a

s N

ET. O

ur d

ata

wer

e de

-ide

ntifi

ed, m

eani

ng w

e co

uld

not

confi

rm t

he d

iagn

osis

in m

edic

al r

ecor

ds, ph

ysic

ian

or p

atie

nt

surv

eys,

or

by o

ther

mea

ns.

Fina

lly,

som

e cl

inic

ians

may

hav

e be

en u

nfam

iliar

with

eith

er b

est

prac

tice

reco

mm

enda

tions

or

the

avai

labl

e, a

lbei

t lim

ited,

dat

a on

GI

NET

tre

atm

ent. O

ur fi

ndin

gs a

re c

onsi

sten

t w

ith a

rec

ent la

rge

case

ser

ies

from

a ter

tiary

ref

erra

l cen

ter

that

fou

nd S

SA a

nd C

C w

ere

the

two

mos

t co

mm

on tre

atm

ent

stra

tegi

es u

sed

for ga

stro

ente

ropa

ncre

atic

NET

[11].

Prev

ious

stu

dies

hav

e fo

und

sign

ifica

nt d

iver

genc

e be

twee

n cl

inic

al g

uide

lines

and

tre

atm

ent

in o

ther

, m

ore

com

mon

, ca

ncer

s. C

hagp

ar a

nd c

olle

ague

s fo

und

that

w

hile

Sta

ge I

col

on c

ance

r pa

tient

s w

ere

trea

ted

acco

rdin

g to

gui

delin

es b

y 95

%, hi

gher

sta

ge p

atie

nts

wer

e le

ss li

kely

to

be t

reat

ed a

ccor

ding

to

guid

elin

es. Sta

ge I

I

Tabl

e 2 U

se o

f fir

st-li

ne t

reat

men

t n (

%)

Firs

t-lin

eA

ll ne

wly

tre

ated

pa

tien

tsSS

AC

CTT

SSA

+ C

CSS

A +

TT

TT +

CC

IFSS

A +

IF

SSA

+ T

T +

CC

n13

4575

281

4231

32

11

2258

59.6

%33

.3%

3.6%

1.9%

1.4%

0.1%

0.1%

0.0%

0.0%

100.

0%D

urat

ion

of fi

rst-l

ine

trea

tmen

t (m

ean

± SD

, d)

449

± 43

4.2

215

± 22

8.8

267

± 32

5.7

408

± 32

7.9

276

± 18

9.5

208

± 16

5.6

251

± 28

5.0

836

± 0

426

± 0

361

± 38

5.0

Firs

t-lin

e en

ding

sta

tus

635

(47.

2)60

9 (8

1.0)

44 (5

4.3)

26 (6

1.9)

14 (4

5.2)

1 (3

3.3)

1 (5

0.0)

0 (0

)1

(100

.0)

1331

(58.

9)

Stop

Sw

itch

128

(9.5

)33

(4.4

)14

(17.

3)5

(11.

9)7

(22.

6)1

(33.

3)1

(50.

0)0

(0)

0 (0

)18

9 (8

.4)

End

of e

nrol

lmen

t58

2 (4

3.3)

110

(14.

6)23

(28.

4)11

(26.

2)10

(32.

3)1

(33.

3)0

(0)

1 (1

00.0

)0

(0)

738

(32.

7)Li

ver d

irec

ted

ther

apy

timin

gD

urin

g fir

st-li

ne17

1 (1

2.7)

87 (1

1.6)

9 (1

1.1)

10 (2

3.8)

4 (1

2.9)

1 (3

3.3)

0 (0

.0)

0 (0

.0)

0 (0

.0)

282

(12.

5)A

fter fi

rst-l

ine

36 (2

.7)

39 (5

.2)

7 (8

.6)

0 (0

.0)

2 (6

.5)

0 (0

.0)

0 (0

.0)

0 (0

.0)

0 (0

.0)

84 (3

.7)

+/- 3

0 d

afte

r sto

ppin

g fir

st li

ne

ther

apy1

635

609

4426

141

10

113

3129

(4.6

)42

(6.9

)2

(4.5

)0

(0.0

)0

(0.0

)0

(0.0

)0

(0.0

)0

(0.0

)0

(0.0

)73

(5.5

)

1 Am

ong

patie

nts

who

sto

pped

.



high-risk patients showed the lowest concordance with only 36% being treated per recommendation[12]. In a prospective study of women with breast cancer, Giorano and colleagues found that 83% of patients 55-64 years old received care concordant with chemotherapy guidelines compared with 29% of patients 75 or older[13].

The finding that only a small proportion of patients are observed to receive second-line treatment is also surprising. The 5-year survival of patients with advanced GI NET is more than 70%. Most surviving patients would be expected to receive continued treatment, whether in the form of liver-directed treatment or pharmacotherapy. We considered multiple explanations for this finding. First, although median follow-up was over 15 mo, many patients were eventually lost to follow-up when they disenrolled from a plan included in our databases. One third of patients were continuing to use their index treatment when they were lost to follow-up. Whether (or when) these individuals progressed to second-line treatment cannot be determined using these databases. If these patients were systematically different from the ones who remained under observation, our results would be biased.

Despite this significant loss to follow-up, nearly 60% of patients were observed to continue enrollment but stop therapy. That is, they survived and remained in the data set, but no second-line pharmacotherapy use could be identified. We considered the possibility that these patients received some liver-directed treatment that alleviated their symptoms or controlled their disease, obviating the need for second-line treatment. However, we found no evidence of this: liver-directed treatment was observed in only 5.5% of patients around the time they stopped first-line treatment. We also considered whether some patients may have had a secondary source of payment, such that their claims for pharmacotherapy did not appear in our databases. Just over 11% of patients were 65

and older and would have been eligible for Medicare. Payment rules regarding patients with both commercial coverage and Medicare are complex[14] but generally require the commercial payer (for which we did have data) to be primarily responsible for payment. In cases where Medicare had primary responsibility, we would have missed claims for pharmacologic or liver-directed therapy and thus underestimated treatment. The magnitude of this problem is impossible to know using our current data source. A study using Medicare data and examining patients over 65 only might be less likely to suffer from this bias. Finally, it may indeed be the case that some patients stop therapy completely. Such patients may be terminal and choose not to undergo further treatment, or they may be relatively asymptomatic and decline to be treated on that basis. Further research with detailed clinical data would be needed to confirm which, if any, of these explanations is the most accurate.

In this large, claims-based, retrospective study of real-world pharmacologic treatment patterns, we found that 60% of GI NET patients began therapy with SSA and about one-third with CC. The relatively long time to discontinuation of SSA, as well as their use in combination with other agents, suggests they may be well tolerated and potentially have sustained effectiveness. We also found that over half of the patients discontinued treatment after first-line and only less than 10% of the patients received second-line treatment despite the availability of a number of different options. To address the limitations of this study and expand knowledge of real-world treat-ment patterns, a study using more detailed clinical information such as medical charts or physician surveys is warranted. In addition, future studies should consider using databases that would allow for greater longitudinal follow-up, such as registries, to assist in the further understanding of treatment patterns and length of therapy.

Table 3 Second-line treatment, stratified by first-line treatment n (%)

First-line treatment Patients with second-line treatmentSSA CC TT SSA + CC SSA + TT TT + CC IF

n 128 33 14 5 7 1 1 18967.7% 17.5% 7.4% 2.6% 3.7% 0.5% 0.5% 100.0%

Second-line treatment SSA + TT 51 (39.8) 4 (12.1) 4 (28.6) 3 (60.0) 0 (0) 1 (100.0) 63 (33.3) SSA + CC 33 (25.8) 6 (18.2) 0 (0) 5 (71.4) 0 (0) 0 (0) 44 (23.3) CC 24 (18.8) 4 (28.6) 0 (0) 1 (14.3) 0 (0) 0 (0) 29 (15.3) SSA 16 (48.5) 5 (35.7) 0 (0) 0 (0) 1 (100.0) 0 (0) 22 (11.6) TT 12 (9.4) 7 (21.2) 2 (40.0) 0 (0) 0 (0) 0 (0) 21 (11.1) SSA + IF 3 (2.3) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 3 (1.6) IF 2 (1.6) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 2 (1.1) TT + CC 1 (0.8) 0 (0) 1 (7.1) 0 (0) 0 (0) 0 (0) 2 (1.1) SSA + TT + CC 1 (0.8) 0 (0) 0 (0) 0 (0) 1 (14.3) 0 (0) 0 (0) 2 (1.1) SSA + CC + IF 1 (0.8) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (0.5)

SSA: Somatostatin analogues; CC: Cytotoxic chemotherapy; TT: Targeted therapy; IF: Interferon.



COMMENTSBackgroundNeuroendocrine tumors (NET) comprise a broad set of rare tumors. Almost 2/3 arise in the gastrointestinal (GI) tract. The management of GI NET is based on a variety of factors including stage, anatomic location, and the presence and type of symptoms. The most recent NCCN guidelines for unresectable and metastatic GI NET recommend somatostatin analogues (SSA) as first-line treatment, but do not recommend a particular treatment sequence for the remaining therapies.

Research frontiersThis study’s results add to the limited knowledge about real-world treatment patterns for GI NET, which is especially significant in light of the lack of treatment guidelines regarding treatment sequences beyond first-line therapy.

Innovations and breakthroughsThis study used two very large, nationally representative claims databases to describe real-world treatment of GI NET. The three key findings were: first, the most common initial pharmacologic treatment was with SSA, with average duration of use of just over 18 mo; second, although 60% of patients initiated treatment with SSA alone or in combination, most of the remainder began treatment with cytotoxic chemotherapy, therapy recommended by NCCN only if no other options (SSA, targeted therapy, or liver directed treatment) are feasible; and third, despite the many available treatment options, less than one in 10 patients was observed to receive treatment with second-line pharmacotherapy of any type. The authors findings are consistent with a recent large case series from a tertiary referral center that found SSA and CC were the two most common treatment strategies used for gastroenteropancreatic NET. Previous studies have also found significant divergence between clinical guidelines and treatment in other, more common, cancers.

ApplicationsThis study suggests that there is frequent use of CC in GI NET treatment, although CC is relatively ineffective in these patients and recommended only if other options are not feasible. This may be a result of clinicians unfamiliarity with either best practice recommendations or the available, albeit limited, data on GI NET treatment. To address the limitations of this study and expand knowledge of real-world treatment patterns, a study using more detailed clinical information such as medical charts or physician surveys is warranted. In addition, future studies should consider using databases that would allow for greater longitudinal follow-up, such as registries, to assist in the further understanding of treatment patterns and length of therapy.

TerminologyNET arise from cells that release hormones in response to nerve stimulation. Insurance claims databases compile coded information related to charges for medical care for large populations, but they do not contain clinically detailed records.

Peer-reviewThe article aims to describe real-world treatment patterns of GI NET.

REFERENCES1 Korse CM, Taal BG, van Velthuysen ML, Visser O. Incidence and

survival of neuroendocrine tumours in the Netherlands according to histological grade: experience of two decades of cancer registry. Eur J Cancer 2013; 49: 1975-1983 [PMID: 23352435 DOI:

10.1016/j.ejca.2012.12.022]2 Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW,

Thakker RV, Caplin M, Delle Fave G, Kaltsas GA, Krenning EP, Moss SF, Nilsson O, Rindi G, Salazar R, Ruszniewski P, Sundin A. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008; 9: 61-72 [PMID: 18177818 DOI: 10.1016/S1470-2045(07)70410-2]

3 Tsikitis VL, Wertheim BC, Guerrero MA. Trends of incidence and survival of gastrointestinal neuroendocrine tumors in the United States: a seer analysis. J Cancer 2012; 3: 292-302 [PMID: 22773933 DOI: 10.7150/jca.4502]

4 Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008; 26: 3063-3072 [PMID: 18565894 DOI: 10.1200/JCO.2007.15.4377]

5 Ito T, Igarashi H, Nakamura K, Sasano H, Okusaka T, Takano K, Komoto I, Tanaka M, Imamura M, Jensen RT, Takayanagi R, Shimatsu A. Epidemiological trends of pancreatic and gastrointestinal neuroendocrine tumors in Japan: a nationwide survey analysis. J Gastroenterol 2015; 50: 58-64 [PMID: 24499825 DOI: 10.1007/s00535-014-0934-2]

6 Hallet J, Law CH, Cukier M, Saskin R, Liu N, Singh S. Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes. Cancer 2015; 121: 589-597 [PMID: 25312765 DOI: 10.1002/cncr.29099]

7 Tsai HJ, Wu CC, Tsai CR, Lin SF, Chen LT, Chang JS. The epidemiology of neuroendocrine tumors in Taiwan: a nation-wide cancer registry-based study. PLoS One 2013; 8: e62487 [PMID: 23614051 DOI: 10.1371/journal.pone.0062487]

8 Fraenkel M, Kim M, Faggiano A, de Herder WW, Valk GD; Knowledge NETwork. Incidence of gastroenteropancreatic neuroendocrine tumours: a systematic review of the literature. Endocr Relat Cancer 2014; 21: R153-R163 [PMID: 24322304 DOI: 10.1530/ERC-13-0125]

9 Shen C, Zhao B, Zhou S, Halperin D, Xu Y, Shih Y, Yao J. Incidence and Prevalence of Neuroendocrine Tumors in the United States 1973-2012. Poster presentation at the 2016 North American Neuroendocrine Tumor Society (NANETS) Annual Symposium; 2016 Sep 30-Oct 1; Jackson Hole, Wyoming: 2016

10 NCCN. Neuroendocrine Tumors. National Comprehensive Cancer Network; 2016 Available from: URL: https://www.nccn.org/professionals/physician_gls/PDF/neuroendocrine.pdf

11 Jalbert JJ, Casciano R, Tao B, Dutton T, Brais LK, Pulgar SJ, Berthon A, Gabriel S, Dinet J, Kulke M. Treatment Patterns Among Metastic GEP-NET Patients Treated at a Tertiary Referral Center. Poster presentation at the 2017 Gastrointestinal Cancers Symposium; 2017 Jan 19-21; San Francisco, CA: 2017

12 Chagpar R, Xing Y, Chiang YJ, Feig BW, Chang GJ, You YN, Cormier JN. Adherence to stage-specific treatment guidelines for patients with colon cancer. J Clin Oncol 2012; 30: 972-979 [PMID: 22355049 DOI: 10.1200/JCO.2011.39.6937]

13 Giordano SH, Hortobagyi GN, Kau SW, Theriault RL, Bondy ML. Breast cancer treatment guidelines in older women. J Clin Oncol 2005; 23: 783-791 [PMID: 15681522 DOI: 10.1200/JCO.2005.04.175]

14 Centers for Medicare & Medicaid Services. Which insurance pays first [Internet]. Medicare.gov Available from: URL: https://www.medicare.gov/supplement-other-insurance/how-medicare-works-with-other-insurance/who-pays-first/which-insurance-pays.html

P- Reviewer: Amornyotin S, Gazouli M S- Editor: Ma YJ L- Editor: A E- Editor: Zhang FF


COMMENTS

© 2017 Baishideng Publishing Group Inc. All rights reserved.

Published by Baishideng Publishing Group Inc7901 Stoneridge Drive, Suite 501, Pleasanton, CA 94588, USA

Telephone: +1-925-223-8242Fax: +1-925-223-8243

E-mail: [email protected] Desk: http://www.f6publishing.com/helpdesk

http://www.wjgnet.com

I S S N 1 0 0 7 - 9 3 2 7

9 7 7 1 0 07 9 3 2 0 45

3 3

new issn 1007-9327 (print) issn 2219-2840 (online) world journal of · 2017. 9. 14. · world...

Documents