En systematisk oversikt over risikofaktorer for utvikling av nevroendokrine tynntarmssvulster
Ibrahim Basim Ibrahim
Prosjektoppgave ved Det medisinske fakultet Universitetet i Oslo
2017
© Ibrahim Basim Ibrahim 2017
En systematisk oversikt over risikofaktorer for utvikling av nevroendokrine tynntarmssvulster http://www.duo.uio.no
Innholdsfortegnelse
Forord ... 4
Abstract ... 6
Introduksjon ... 7
Metoder ... 9
Inklusjon- og eksklusjonskriterier ... 10
Målt utfall og eksponering ... 10
Resultater ... 11
Forest plot-resultater ... 14
Diskusjon ... 18
Konklusjon ... 22
Litteraturliste ... 23
Appendiks ... 25
Vedlegg 1: Definisjon av litteratursøk i PubMed ... 25
Vedlegg 2: Manuskript av artikkelen som er sendt inn til Scandinavian Journal of Gastronenterology ... 26
Forord
Jeg var i mars 2015 for første gang i kontakt med dr. med. Sven-Petter Haugvik vedrørende min prosjektoppgave. Jeg ble informert av mine medstudenter om muligheten for å skrive oppgave med dr. Haugvik i fagfeltet kirurgi, med fokus på nevroendokrine svulster i tynntarm.
Dr. Haugvik introduserte meg for min hovedveileder, prof. Ivar Prydz Gladhaug. På grunn av min store interesse for kirurgi så jeg på dette som en god mulighet til å gjøre meg kjent med en sjelden kreftsykdom som det ikke er så mye fokus på i den kliniske undervisningen i legestudiet, sammenlignet med mer prevalente svulster i gastrointestinal-traktus.
Denne prosjektoppgaven består av en forskningsartikkel som ble til gjennom et samarbeid mellom forskere fra Norge, Italia, Storbritannia, Slovenia og Sverige. Artikkelen forventes publisert i løpet av 2017. Vi gjennomførte en systematisk litteraturgjennomgang med mål om å definere risikofaktorer for utvikling av nevroendokrine svulster i tynntarm. Vi utførte et veldefinert litteratursøk (se Vedlegg 1) for å identifisere relevante publikasjoner som omhandlet risikofaktorer for utvikling av nevroendokrine svulster i tynntarm. Søket ble gjennomført i den elektroniske søkemotoren PubMed tilhørende United States National Library of Medicine (www.ncbi.nlm.nih.gov/pubmed). Vi uthentet også abstrakter fra de årlige konferansene til European Neuroendocrine Tumor Society (ENETS) og North American Neuroendocrine Tumor Society (NANETS). Vi sorterte studiene i ulike grupper avhengig av deres relevans.
Publikasjonene/abstraktene ble enten markert som «1 - Ikke aktuell for våre undersøkelser», «2 - Mulig aktuell», «3 - Aktuell, men oppfyller ikke alle inklusjonskriteriene» eller «4 - Aktuell artikkel som oppfyller alle inklusjonskriteriene».
Jeg bidro i gjennomgangen av litteratursøket, tolkningen av resultatene, utarbeidelsen av manuskriptet og revisjonen av manuskriptet.
Jeg vil rette en stor takk til mine veiledere; dr. med. Sven-Petter Haugvik og professor Ivar P.
Gladhaug for hjelp til å skrive min oppgave. Jeg har lært mye i løpet av denne arbeidsperioden, og fått en innføring i bruken av, og søk i ulike databaser. Jeg har i tillegg fått et verdifullt innsyn i medisinsk forskning.
Artikkelen er sendt inn til tidsskriftet Scandinavian Journal of Gastroenterology (Vedlegg 2).
Abstract
Her følger abtraktet fra forskningsartikkelen på engelsk.
Background & Aims: Risk factors for small intestinal neuroendocrine tumors (SI-NETs) are not well understood. The aim of this systematic literature review was to identify risk factors of SI-NET and to further assess these by meta-analysis.
Methods: PubMed and abstracts from the ENETS and NANETS were searched for studies published until May 2015. Eligible studies were selected according to the PRISMA statement.
Results: Seven studies evaluating six individual populations were included (study accrual period 1980-2012) in the meta-analysis, involving 765 (range 17-325) cases and 502,282 (range 52-498,376) controls. All studies were case-control by design. The following risk factors were reported in ≥2 studies: family history of any cancer, family history of colorectal cancer, ever alcohol use, and ever smoking. The pooled OR was 1.34 (95% CI 1.12-1.60; p<0.01; I2=0.0%) for family history of any cancer, 1.43 (95% CI 1.15-1.79; p<0.01; I2=0.0%) for family history of colorectal cancer, 1.04 (95% CI 0.63-1.72; p=0.87; I2=65.0%) for ever alcohol use, and 1.40 (95% CI 1.06-1.86; p<0.05; I2=49.3%) for ever smoking.
Conclusions: Family history of any cancer, family history of colorectal cancer and history of ever smoking were associated with an increased risk of SI-NET by meta-analysis. Alcohol consumption was not a significant risk factor for SI-NET. However, the studies reporting smoking and alcohol had a high degree of heterogeneity. Therefore, further studies are needed for clarification of smoking and alcohol as risk factors for the occurrence of SI-NET.
Introduksjon
Nevroendokrine svulster i tynntarmen (small intestinal neuroendocrine tumors, si-NET) er en sjelden kreftsykdom som utgår fra nevroendokrine celler i tynntarmen, hovedsakelig i ileum (1). Insidensen av si-NETs er estimert til ca. 0,9-1,2 per 100 000. Selv om disse svulstene kun utgjør en liten del av øvrige gastrointestinale svulster, er insidensen av disse svulstene økende i befolkningen (2). En studie har vist at insidensen av si-NET i Norge mellom 1993 og 2004 har økt med omtrent 69% (3). Årsakene til denne økning kan skyldes økende interesse for nevroendokrine svulster de siste årene og økende bruk av radiologiske undersøkelser (1).
Typisk forekommer denne formen for svulster rundt 50-års alderen (4,5). Det kan likevel tenkes at svulstene oppstår tidligere uten at de nødvendigvis er erkjent, for eksempel på grunn av manglende eller uspesifikke symptomer. Det er undersøkelser som tyder på at si-NET utgår fra multipotente celler (6), men den molekylære patofysiologien bak utviklingen av disse svulstene er enda ikke kartlagt i detalj (7). De fleste si-NET forekommer sporadisk, det vil si at det ikke er noen underliggende kjente genetiske tilstander for utvikling av disse svulstene. Det finnes likevel noen som er assosierte med genetiske syndromer (8).
Vi skiller mellom nevroendokrine svulster som vi kaller «funksjonelle» og nevroendokrine svulster som vi kaller for «ikke-funksjonelle». Funksjonelle NETs gir symptomer som knyttes til hormonet de utskiller. Ikke-funksjonelle NETs kan produsere og utskille hormoner, men ikke i stå store mengder at de vil gi kliniske symptomer. Det er likevel viktig å være klar over at selv om ikke-funksjonelle NETs ikke utskiller hormoner av klinisk relevant mengde, kan de likevel gi symptomer lokalt der de vokser, for eksempel lokaliserte smerter og utvikling av ileus.
Når det gjelder andre gastrointestinale svulster, som kolorektale adenocarsinomer, er det veletablert at røyking, overforbruk av alkohol, manglende fysisk aktivitet, overvekt og kosthold spiller en viktig rolle for utviklingen av kreft (9-12). Selv om risikofaktorene for denne type kreft er velkjent, foreligger svært begrenset kunnskap om risikofaktorene for utvkikling av si- NET.
For å øke vår forståelse av etiologien til si-NET er det viktig å kunne kartlegge sykdommens risikofaktorer. Det er i litteraturen tidligere undersøkt flere mulige risikofaktorer for si-NET.
Det er rapportert at det er en sammenheng mellom utvikling av si-NET og røyking (13-15), kreft i familien (16), tidligere cholecystektomi (17) og inflammatorisk tarmsykdom (18).
Likevel er dette relativt få studier. Det kan derfor være en utfordring å undersøke dette basert på de få studiene som er publisert.
Det har nylig også kommet frem at bruk av acetylsalisylsyre er en mulig beskyttende faktor mot utvikling av si-NET. Vi tar ikke videre for oss de beskyttende faktorer mot utvikling av si-NET da det etter vår kjennskap kun er én studie som undersøker dette.
Metoder
Vi gjennomførte et systematisk litteratursøk gjennom PubMed-databasen med søk til og med 15. oktober 2015, i tillegg til å manuelt undersøke abstraker fra European Neuroendocrine Tumor Society (ENETS), og North American Neuroendocrine Tumor Society (NANETS). Vi spesifiserte litteratursøket, slik det kommer frem i Vedlegg 1, basert på PRISMA-metoden (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) (19). Studienes titler ble screenet for deres relevans. Relevante studier ble undersøkt videre. Et søk gjennom litteraturlisten av potensielle relevante artikler ble også foretatt for å inkludere funn som ikke var blitt funnet gjennom PubMed-søket.
Fire uavhengige undersøkere var ansvarlige for å finne relevante artikler. Dersom uenigheter oppsto ble disse diskutert med en uavhengig tredjepart i studiegruppen. Likeledes undersøkte to andre uavhengige kolleger abstrakter fra ENETS og NANETS.
Inklusjon- og eksklusjonskriterier
Alle relevante studier ble undersøkt med tanke på våre inklusjonskriterier, og dernest enten inkludert eller ekskludert. Vi inkluderte studier som var case-control eller kohort-studier.
Begrensning av publikasjonsstatus var ikke inkludert. Kun artikler som var skrevet på engelsk ble inkludert.
Studier som på generell basis undersøkte gastrointestinale nevroendokrine svulster, eller nevroendokrine svulster generelt, uten mulighet å uthente spesifikke data på si-NETs, ble ikke inkludert i studien. Når det gjelder dupliserte studier, er det mest informative eller den nyeste som er blitt brukt.
Målt utfall og eksponering
Utfallet var definert som diagnosen si-NET. Eksponeringen som ble undersøkt var: røyking (definert som noen gang røykt, eller aldri røykt), noen sinne bruk av alkohol, kjent familiær (førstegrads slektning) anamnese med enhver type kreft, og kjent familiær (førstegrads slektning) anamnese med kolorektal kreft.
Resultater
Figur 1 viser et PRISMA-diagram for hvordan våre artikler ble selektert. Gjennom vårt søk i PubMed fant vi 3686 artikler. I tillegg identifiserte vi fire studier fra NANETS-abstraktene.
Dette ga oss til sammen 3690 potensielle artikler som var relevante for våre undersøkelser.
Majoriteten av artiklene ble ekskludert, gjennom deres tittel og/eller abstrakt da de ikke var relevante i forhold til vår analyse. Videre ble 94 artikler ekskluderte da de ikke oppfylte alle inklusjonskriterier. Av de gjenværende 7 artiklene, ble én artikkel ekskludert, da det ikke var mulig å kvantitativt uthente data fra studien.
Tabell 1 gir en oversikt over artiklene som ble inkludert i meta-analysen.
Figur 1: PRISMA-diagram som viser seleksjonen av artiklene som ble funnet i litteratursøket.
Records identified through database search
n = 3686
Additional records identified from conference abstracts
n = 4
Records screened n = 3690
Records assessed for eligibility n = 101
Studies included in qualitative synthesis n = 7
Records excluded (not related to study topic)
n = 3589
Excluded (did not fulfill inclusion criteria)
n = 94
Studies included in quantitative synthesis (meta-analysis)
n = 6
Tabell 1: Tabellen viser en oversikt over artiklene som ble inkludert i meta-analysen. CCS, case-control study. OR, odds ratio.
Author (Reference)
Year Single-
/Multi- center
Study accrual period
Setting and design
Number of Cases Male
sex (%) Mean age
(years) Number of Controls
Investigated Exposures Outcome Measures
Chen et al.
[4]
1994 USA Single 1980-
1987
CCS 17 41 65.3 52 Ever smoking, ever alcohol use OR
Cross et al.
[5] 2013 USA Multi 1995-
2006 CCS 124 57 63.5 498,376 Ever smoking, family history of any
cancer, family history of colorectal cancer
OR
Hassan et al.
[6]* 2008 USA Single 2000-
2006 CCS 325 48 54.1 924 Ever smoking, ever alcohol use,
family history of any cancer OR
Hassan et al.
[7]*
2008 USA Single 2000-
2006
CCS 325 48 54.1 924 Family history of colorectal cancer OR
Kaerlev et al. [8]
2002 Europe Multi 1995- 1997
CCS 84 61 60.0 2070 Ever smoking OR
Rinzivillo et al. [10]
2015 Italy Single 2009- 2012
CCS 215 54 50.4 860 Ever smoking, ever alcohol use,
family history of any cancer, family history of colorectal cancer
OR
Forest plot-resultater
Røyking noensinne
Figur 2: Forest plot som viser odds ratio (OR) og 95% konfidensintervall (CI) for røyking noensinne og risiko for utvikling av si-NET. I2 = 49.3%.
Det ble identifisert fem studier som rapporterer risiko for utvikling av si-NETs. Vi ser at meta-analysen gir en OR på 1,40 (p<0.05). Dette indikerer at det er en forhøyet risiko for si- NET utvikling hos pasienter som har røkt noensinne.
Alkohol noensinne
Figur 3: Forest plot som viser odds ratio (OR) og 95% konfidensintervall (CI) for alkoholkonsum noensinne og risiko for utvikling av si-NET. I2 = 65.0%.
Det ble identifisert tre studier som rapporterer alkoholkonsum noensinne som risikofaktor. Vi ser at OR er 1.04 (p>0.05). Alkohol er i denne analysen dermed ingen risikofaktor for
utvikling av si-NET.
Kreft i familieanamnesen
Figur 4: Forest plot som viser odds ratio (OR) og 95% konfidensintervall (CI) for positiv familiær anamnese for enhver type kreft. I2 = 0.0%.
Det ble identifisert tre studier som rapporterer familiær forekomst av kreft og risiko for utvikling av si-NET. Vi ser at OR = 1,34 (p<0.05). Kreft i familieanamnesen er i denne analysen dermed en risikofaktor for utvikling av si-NET.
Kolorektal kreft i familieanamnesen
Figur 5: Forest plot som viser odds ratio (OR) og 95% konfidensintervall (CI) for positiv familiær anamnese for kolorektalkreft. I2 = 0.0%.
Det ble identifisert tre studier som rapporterer familiær anamnese med kolorektalkreft og risiko for utvikling av si-NET. Vi ser at OR=1,43 (p<0.05). Kolorektal kreft i
familieanamnesen er i denne analysen dermed en risikofaktor for utvikling av si-NET.
Diskusjon
Vi gjennomførte en meta-analyse med mål om å undersøke risikofaktorer for utvikling av si- NET. Vi fant studier som rapporterte røyking, alkoholkonsum, familiær anamnese med kreft og familiær anamnese med kolorektalkreft, og forekomst av si-NET. Dette resulterte i en meta- analyse som omfattet seks studier med til sammen 765 pasienter med si-NET og 502.282 kontroller. Våre resultater viser at kolorektal kreft hos en førstegrads slektning (OR 1,43) og kreft generelt hos en førstegrads slektning (OR 1,34) er knyttet opp mot økt risiko for å utvikle si-NET. Effekten av røyking noensinne (OR 1,40) og alkohol-bruk noensinne (OR 1,04) var usikker. Det forelå betydelig heterogenitet blant de inkluderte studiene i henhold til røyking og alkohol-bruk som risikofaktorer for uvikling av si-NET.
For pasienter med positiv familieanamnese for enhver type kreft, ser vi fra Figur 4 at vi finner en samlet OR 1,34 (KI 1,12 - 1,60, p < 0,05, I2 = 0.0%). For kolorektalkreft finner vi; samlet OR 1,43 (KI 1,15 - 1,79, p < 0,05, I2 = 0.0%). Vi identifiserer den sterkeste risikofaktoren for si-NET utvikling i vår undersøkelse til å være kjent kolorektalkreft i familien. Disse resultatene er interessante fordi de kan vekke mistanke om at genetisk predisposisjon for si-NET kan ha en stor rolle i patogenesen og utviklingen av si-NET, og kanskje en større rolle enn miljøfaktorer (3,20). Rinzivillo et al. (14) fant i deres meta-analyse ikke sammenheng mellom familiære kolorektalkreft-syndromer, som Familiær Adenomatøs Polypose (FAP) eller Hereditær non- polypøs kolorektalpreft (hereditary non polyposis colorectal cancer, HNPCC). Det betyr at det er mulig at andre gener spiller en rolle i karsinogenesen for si-NET.
Det er velkjent at røyking er en risikofaktor for flere typer gastrointestinal kreft, blant annet ventrikkelkreft og kolorektalkreft (22, 23). Også nevroendokrin kreft i pankreas ser ut til å være assosiert med røyking som årsak (24, 25). Vi kan av Figur 2 se at røykere har en samlet OR på 1,40 (KI 1,06 - 1,86, p < 0,05, I2 = 49.3%) for utvikling av si-NET. En meta-analyse av Leoncini et. al. (25) som har tatt i bruk samme artikler som vi bruker i vår meta-analyse trekker frem to kasus-kontroll studier fra Nord-Amerika av Chen et al. (13) og Hassan et al. (4) som viser at røyking noensinne er en risikofaktor for utvikling av si-NETs. Det trekkes også frem en kasus- kontroll studie fra Europa; Kaerlev et al. (15) som også viser at røyking noensinne er en risikofaktor. Basert på disse kasus-kontroll studiene viser meta-analysen av Leoncini et al. (25) en samlet OR 1,59 (KI 1,07 - 2,37, p = 0.23, I2 = 32,9%), og er dermed ikke statistisk signifikant, men justert for dose-effekt for røyking viser resultatet at pasienter som røyker mye har en signifikant høyere risiko for utvikling av si-NET med OR 1,38 (KI 0,55-3,44, p < 0,05, I2 = 79,1%). Hvordan ”mye røyking” defineres kommer ikke eksplisitt frem. Meta-analysen inkluderte likevel ikke studien fra Cross et al. (16) som vi undersøkte, som viser at røyking ikke er en uavhengig risikofaktor.
Et problem som vi ser både fra våre resultater, men også fra Leoncini et al. (25) er at vi har høye I2 - verdier, som tyder på at det er betydelig heterogenitet i studiene. Derfor kan resultatene være upålitelige, og andre undersøkelser, med artikler av liknende studiedesign bør gjøres for å kaste mer lys på dette.
Når det gjelder noensinne bruk av alkohol, finner vi en samlet OR 1,04 (KI 0,63 - 1,72, p >
0,05, I2 = 65.0%). OR er lav. Ser vi på dette i lys av en ikke-signifikant p-verdi, finner vi at noensinne inntak av alkohol ikke utgjør en risikofaktor for utvikling av si-NET. Det vi likevel
må være oppmerksomme på er en stor I2-verdi, slik som for røyking. Dette betyr at det er stor variasjon mellom studiene, og at variasjonen ikke kan tilskrives tilfeldigheter alene. Det er derfor viktig med videre undersøkelser for å påvise alkoholens eventuelle rolle som risikofaktor for utvikling av si-NET.
Chen et al. (13) finner i deres studie at alkohol (OR 5,8) og røyking (OR 4,4) er risikofaktorer for utvikling av malign si-NET . Men, når alkohol og røyking justeres for hverandre, finner man ikke en økt risiko for malign si-NET utvikling; OR 4,2 for røyking justert for alkoholkonsum og OR 3,1 for alkoholkonsum, justert for røyking, begge med p > 0,05.
Det finnes flere svakheter i vår meta-analyse. Først og fremst er si-NET er relativt sjeldne, og en vil derfor forvente å finne færre studier enn for neoplasmer som forekommer hyppigere i befolkningen. Det kan følgelig være vanskelig å si noe om den reelle forekomst av risikofaktorer i befolkningen basert på et begrenset antall studier.
Når det gjelder risikofaktorene som noensinne drukket alkohol, eller noensinne røykt, ser vi at vi får høy heterogenitet blant studiene. Våre resultater angir en estimert heterogenitet. Likevel kan det tenkes det at den reelle heterogeniteten sannsynligvis er høyere, da det er tendens til å underestimere heterogeniteten (26).
Et annet viktig moment å trekke frem er at studiene omfatter erkjente krefttilfeller i familien.
Det er flere problemer som kan dukke opp i denne sammenheng; for det første kan det være at pasienter med si-NET kan ha familiemedlemmer med samtidig kreft, uten at dette nødvendigvis er erkjent før en innhenter data. For det andre, er alder i seg selv en risikofaktor for å utvikle kreft (25), likevel, ser vi at si-NET typisk forekommer hos relativt unge pasientgrupper, rundt 50-års alder, men også yngre (4,5). Det kan derfor tenkes at kreft som oppstår senere i pasientens familie, ikke erkjennes ved diagnosetidspunktet av si-NET hos pasienten, noe som kan gi en bias i forhold til risikofaktorens reelle verdi. Dette gjelder spesielt for kolorektalkreft av ikke-syndrom type, der insidensen øker med økende alder (17), og som vi har funnet utgjør en risikofaktor for si-NET.
Et annet problem som vi møter ved disse studiene er at noen ikke har justert for samtidig røyking og bruk av alkohol. Vi finner at kun Hassan et al. (4) og Chen et al. (13) har tatt høyde for dette. Det vil også gi en bias i forhold til resultatene, fordi det kan tenkes at pasienter som røyker, også samtidig drikker alkohol. Røyke- og drikkemønsteret kan da variere ved at noen pasienter drikker mye alkohol, men røyker relativt lite, og motsatt.
Det er videre viktig å merke seg at familiemedlemmer av pasienter som får diagnosen si-NET, kan tenkes a ha få tettere oppfølging, med for eksempel jevnlig screening for å detektere si- NET, slik at det vil kunne gi en surveillance bias. Dette har blitt trukket frem av både Chen et al. (13) og av Kharazmi et al. (20), der det kun er sistnevnte forfattere som har justert for dette i deres undersøkelser.
Konklusjon
Kjent kolorektalkreft hos førstegrads slektning gir en signifikant økt risiko for utvikling av si- NET, og vi identifiserer dette som den sterkeste risikofaktoren i forhold til de øvrige risikofaktorene vi har undersøkt. Kjent kreft i familien hos førstegrads slektning synes også å øke risikoen for utvikling av si-NET. Røyking noensinne ser også ut til å være en risikofaktor, men på grunn av høy heterogenitet blant studiene, bør det gjøres ytterligere studier for å belyse dette nærmere, slik at det kan gi et tydeligere svar. Alkohol ser ikke ut til å være en risikofaktor for utvikling av si-NET. Alkohol er likevel beskrevet som en risikofaktor i én studie og det foreligger høy heterogenitet blant studiene inkludert i meta-analysen. Det er derfor nødvendig med ytterligere studier for å avklare dette nærmere, og trekke endelige konklusjoner.
Litteraturliste
1. Scherubl H, Jensen RT, Cadiot G, Stolzel U, Kloppel G. Neuroendocrine tumors of the small bowels are on the rise: Early aspects and management. World J Gastrointest Endosc.
2010;2(10):325-34.
2. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, et al. 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(18):3063-72.
3. Hauso O, Gustafsson B, Kidd M, Waldum H, Drozdov I, Chan A et al.
Neuroendocrine tumor epidemiology. Cancer. 2008;113(10):2655-2664.
4. Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC. Risk factors associated with neuroendocrine tumors: A U.S.-based case-control study. Int J Cancer. 2008;123(4):867- 73.
5. Merola E, Rinzivillo M, Cicchese N, Capurso G, Panzuto F, Delle Fave G. Digestive neuroendocrine neoplasms: A 2016 overview. Dig Liver Dis. 2016;48(8):829-35.
6. Boutzios G, Kaltsas G. Clinical Syndromes Related to Gastrointestinal Neuroendocrine Neoplasms. Front Horm Res. 2015;44:40-57.
7. Hallet J, Law CHL, 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(4):589-97.
8. Öberg K. The Genetics of Neuroendocrine Tumors. Seminars in Oncology.
2013;40(1):37-44.
9. Botteri E, Iodice S, Bagnardi V, Raimondi S, Lowenfels AB, Maisonneuve P.
Smoking and colorectal cancer: a meta-analysis. JAMA2008;300:2765-78.
10. Ma Y, Yang Y, Wang F, et al. Obesity and risk of colorectal cancer: a systematic review of prospective studies. PLoS One2013;8:e53916.
11. Chan DS, Lau R, Aune D, et al. Red and processed meat and colorectal cancer incidence: meta-analysis of prospective studies. PLoS One2011;6:e20456.
12. Wolin KY, Yan Y, Colditz GA, Lee IM. Physical activity and colon cancer prevention: a meta-analysis. Br J Cancer2009;100:611-6
13. Chen CC, Neugut AI, Rotterdam H. Risk factors for adenocarcinomas and malignant carcinoids of the small intestine: preliminary findings. Cancer Epidemiol Biomarkers Prev.
1994;3(3):205-7.
14. Rinzivillo M, Capurso G, Campana D, Fazio N, Panzuto F, Spada F, et al. Risk and Protective Factors for Small Intestine Neuroendocrine Tumors: A Prospective Case-Control Study. Neuroendocrinology. 2016;103(5):531-7.
15. Kaerlev L, Teglbjaerg PS, Sabroe S, Kolstad HA, Ahrens W, Eriksson M, et al. The importance of smoking and medical history for development of small bowel carcinoid tumor:
a European population-based case-control study. Cancer Causes Control. 2002;13(1):27-34.
16. Cross A, Hollenbeck A, Park Y. A large prospective study of risk factors for adenocarcinomas and malignant carcinoid tumors of the small intestine. Cancer Causes &
Control. 2013;24(9):1737-1746.
17. Lagergren J, Ye W, EkbomA Intestinal Cancer After Cholecystectomy: Is Bile Involved in Carcinogenesis? Gastroenetrology2001;121:542–547
18. West NE, Wise PE, Herline AJ Muldoon RL, Chopp WV, Schwartz DA.Carcinoid Tumors are 15 Times more common in patients with Crohn’s Disease.Inflamm Bowel Dis2007; 13: 1129-1134
19. Moher D, Liberati A, Tetzlaff J, Altman D. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339(jul21 1):b2535-b2535.
20. Kharazmi E, Pukkala E, Sundquist K, Hemminki K. Familial risk of small intestinal carcinoid and adenocarcinoma. Clin Gastroenterol Hepatol. 2013;11(8):944-9
21. Rinzivillo M, Capurso G, Campana D, Fazio N, Panzuto F, Spada F, et al. Risk and Protective Factors for Small Intestine Neuroendocrine Tumors: A Prospective Case-Control Study. Neuroendocrinology. 2016;103(5):531-7.
22. Liang PS, Chen T-Y, Giovannucci E. Cigarette smoking and colorectal cancer incidence and mortality: systematic review and meta-analysis. Int J Cancer.
2009;124(10):2406-15.
23. Praud D, Rota M, Pelucchi C, Bertuccio P, Rosso T, Galeone C, et al. Cigarette smoking and gastric cancer in the Stomach Cancer Pooling (StoP) Project. Eur J Cancer Prev.
2016.
24. Haugvik S, Hedenström P, Korsæth E, Valente R, Hayes A, Siuka D et al. Diabetes, Smoking, Alcohol Use, and Family History of Cancer as Risk Factors for Pancreatic
Neuroendocrine Tumors: A Systematic Review and Meta-Analysis. Neuroendocrinology.
2015;101(2):133-142.
25. Leoncini E, Carioli G, La Vecchia C, Boccia S, Rindi G. Risk factors for neuroendocrine neoplasms: a systematic review and meta-analysis. Ann Oncol.
2016;27(1):68-81.
26. 9.5.1 What is heterogeneity? [Internet]. Handbook.cochrane.org. 2017 [sitert 26.
Januar 2017]. Tilgjengelig fra:
http://handbook.cochrane.org/chapter_9/9_5_1_what_is_heterogeneity.htm
Appendiks
Vedlegg 1: Definisjon av litteratursøk i PubMed
(Small intestinal neoplasms OR small bowel tumor OR carcinoid OR midgut carcinoid OR small intestinal neuroendocrine tumor OR small intestinal
neuroendocrine tumors OR small bowel neuroendocrine tumor OR small bowel neuroendocrine tumors OR small intestinal endocrine tumor OR ileal
neuroendocrine tumor OR ileal neuroendocrine tumors OR jejunal neuroendocrine tumor OR jejunal neuroendocrine tumors)
AND (risk factor OR risk factors OR cause OR causalities OR causality OR causation OR predisposing factors OR etiology OR cigarette OR cigarette smoking OR cigarette smoke OR smokers OR smoking habits OR alcohol consumption OR alcohol OR ethanol OR alcohol induced cancer OR family history OR familial OR aspirin OR acetylsalicylic acid OR ASA OR IBD OR inflammatory bowel disease OR Crohn’s disease OR Ulcerative colitis OR collagenous colitis OR lymphocytic colitis)
AND (case-control OR case-control study OR cohort study OR cohort)
Limits: Publication date until 24.10.2015
Entries = 3686
Vedlegg 2: Manuskript av artikkelen som er sendt inn til Scandinavian Journal of Gastronenterology
Smoking, alcohol and family history of cancer as risk factors for small intestinal neuroendocrine tumors: a systematic review and meta-analysis
Sven-Petter Haugvik*1,2, Ibrahim Basim Ibrahim3, Per Hedenström4, Roberto Valente5, Alastair J Hayes6, Darko Siuka7, Ivar Prydz Gladhaug1,3, Gabriele Capurso5.
1) Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital; 2) Department of Surgery, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway; 3) Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 4) Unit of Gastroenterology,
Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden; 5) Digestive and Liver Disease Unit, II Medical School, University "La Sapienza," S. Andrea Hospital, Rome, Italy; 6) Department of General Surgery, Royal Infirmary of Edinburgh, Edinburgh, Scotland; 7) Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia.
Short title: Risk factors for small intestinal NET
Keywords: SI-NET; NET; small intestinal neuroendocrine tumor; epidemiology; meta- analysis; risk factor
*Corresponding author: Sven-Petter Haugvik, Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway, Phone: (0047) 47 44 00 90, Fax: (0047) 23 07 25 26, E-mail: [email protected].
Abstract
Background & Aims: Risk factors for small intestinal neuroendocrine tumors (SI-NETs) are not well understood. The aim of this systematic literature review was to identify risk factors of SI-NET and to further assess these by meta-analysis.
Methods: PubMed and abstracts from the ENETS and NANETS were searched for studies published until May 2015. Eligible studies were selected according to the PRISMA statement.
Results: Seven studies evaluating six individual populations were included (study accrual period 1980-2012) in the meta-analysis, involving 765 (range 17-325) cases and 502,282 (range 52-498,376) controls. All studies were case-control by design. The following risk factors were reported in ≥2 studies: family history of any cancer, family history of colorectal cancer, ever alcohol use, and ever smoking. The pooled OR was 1.34 (95% CI 1.12-1.60;
p<0.01; I2=0.0%) for family history of any cancer, 1.43 (95% CI 1.15-1.79; p<0.01; I2=0.0%) for family history of colorectal cancer, 1.04 (95% CI 0.63-1.72; p=0.87; I2=65.0%) for ever alcohol use, and 1.40 (95% CI 1.06-1.86; p<0.05; I2=49.3%) for ever smoking.
Conclusions: Family history of any cancer, family history of colorectal cancer and history of ever smoking were associated with an increased risk of SI-NET by meta-analysis. Alcohol consumption was not a significant risk factor for SI-NET. However, the studies reporting smoking and alcohol had a high degree of heterogeneity. Therefore, further studies are needed for clarification of smoking and alcohol as risk factors for the occurrence of SI-NET.
Introduction
Gastroenteropancreatic neuroendocrine tumors (GEP-NET) make up over half of all NETs, and are the most common subgroup of neuroendocrine tumors. Approximately 20-25% of GEP-NETs originate in the small intestine, and are referred to as small intestinal
neuroendocrine tumors (SI-NETs) (1). SI-NETs are rare neoplasms that arise in
neuroendocrine cells, predominantly in the ileum (2). Whilst there is evidence to suggest a possible increasing incidence, SI-NETs currently arise in approximately 0.9-1.3 per 100,000 in Western populations (3;4).
The pathogenesis of SI-NET and the contributing factors that increase risk within the population are not well defined. More common intestinal malignancies, such as colorectal adenocarcinoma, have received greater attention in this regard. It is known that a personal history of inflammatory bowel disease (IBD) (5;6), family history of colorectal cancer (7), smoking and alcohol consumption (8) each infer an increased risk for colorectal
adenocarcinoma. It is also known that the aspirin use is a protective factor for the development of colorectal adenocarcinoma (9). Environmental and non-modifiable risk factors for SI-NETs are less well characterized as there has been little research in this area.
Based on the limited number of studies available, it has been suggested that smoking (10), alcohol consumption (10), family history of any cancer (11;12), and family history of colorectal cancer (11;12) are risk factors for SI-NET occurrence.
Given that the incidence of SI-NETs may be increasing (4), there is an emerging need for clarification and further investigation of factors that might increase the risk of the
development of SI-NET within the population. Accordingly, we report a systematic literature review and meta-analysis of risk factors for the development of SI-NET.
Material and Methods Literature search strategy
A computerized literature search of PubMed and the Cochrane Database of Systematic Reviews for a prior systematic review concerning risk factors for the occurrence of SI-NETs revealed no previous publication on this topic. In our search for original studies we performed a PubMed search (until 15 October, 2015), and a hand-search of conference abstracts
presented at the European Neuroendocrine Tumor Society (ENETS) meeting, from 2009 to 2015, and the North American Neuroendocrine Tumor Society (NANETS) meeting, from 2008 to 2015. Specific search terms were defined and are detailed in Appendix S1. The methodology was developed from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (13).
The titles of all identified articles were screened to ascertain their relevance. Abstracts and/or full texts of selected potentially relevant papers were further evaluated. Further articles were identified by hand-searching reference lists of all the articles retrieved to identify potentially relevant studies.
Inclusion and exclusion criteria
We included studies related with our research question if they were either cohort or case- control studies with available data for a quantitative synthesis, meaning that they included a minimum of information necessary to estimate the relative risk (RR) or odds ratio (OR) for the occurrence of SI-NETs associated with any of the investigated exposures. Thus, included studies had to: 1) evaluate exposure to the reported risk factor in a cohort or population that included internal controls; 2) evaluate the occurrence or diagnosis of SI-NET; and 3) report the RR or OR with confidence interval, or original raw data sufficient to evaluate the
hypothesized effect. Publication status limitation was not included. Only articles written in the English language were included. In the event of duplicate publications, the most recent or more complete publication was used.
Four independent reviewers (R.V., D.S., I.B.I. and S.P.H.) completed a study identification and selection search in PubMed, and disagreements were discussed with another reviewer (G.C.). Similarly, another two reviewers (P.H. and A.H.) selected suitable conference proceeding abstracts from the ENETS and NANETS. Excluded studies and reasons for exclusion were recorded.
Outcome and exposure measures
The outcome measured was the diagnosis of SI-NET. The exposures measured were smoking, defined as ever smoked or not, and all other more specific definitions; alcohol; as defined as ever consumed alcohol or not, and all other more specific definitions; family history of cancer, defined as first-degree history of any cancer; and family history of colorectal cancer, defined as first-degree history of colorectal cancer.
Data extraction
From the studies that met the eligibility criteria, the following data were collected: 1) Study:
year of publication, nationality, study accrual period, study design, and type of interview; 2) Cases: definition (i.e. clinical charts, histological diagnosis or other means), number, gender, and age; 3) Controls: number and source of controls, matching design; 4) Type of exposure:
definition, dosage, and length of exposure; 5) Type of outcome measures. We developed a summary table of the relevant studies listing the population characteristics, exposures and outcome (Table 1).
Statistical analysis
The agreement between reviewers for the assessment of eligibility was calculated. A meta- analysis of all eligible studies identified was planned using the software package
Comprehensive Meta-Analysis (Biostat, Englewood, NJ, USA) with the following methods:
Calculation of the pooled estimates (OR and 95% confidence interval) using the
DerSimonian-Laird method and a random-effects model. In addition to within-study variance, the random effects model considers heterogeneity among studies and gives estimates that are more conservative. We preferred the random-effects model because we believe that the relevant variation in the risk is most likely a consequence of inter-study differences. The quantity of heterogeneity was assessed by means of the I2 value (14-16). We considered an I2 value of 25% or lower as trivial heterogeneity, and an I2 value of 75% or higher as important heterogeneity. A p-value <0.05 was accepted as statistically significant.
Results
Search result and study selection
A total of 3686 references were identified by the PubMed search (Figure 1). After evaluation of all ENETS abstracts in the period 2009-2015 and all NANETS abstracts in the period 2008-2015, four relevant studies were identified. Together, the overall 3690 records were screened and 3589 studies were excluded as they were unrelated to the study topic. Thus, the remaining 101 studies were examined in detail, leaving seven as potentially appropriate for inclusion in the meta-analysis (10-12;17-20). Two studies reported different risk factors on the same study population, and were both included separately in the meta-analysis (17;21).
Therefore, seven studies, which comprised of six independent study populations remained for qualitative analysis. One study was excluded from the quantitative analysis (19) as it did not
report the RR or OR with confidence interval, or original raw data sufficient to evaluate the hypothesized effect, thus leaving six studies with five independent study populations for quantitative analysis (Table 1) (10-12;17;18;20). Agreement amongst reviewers for the assessment of eligibility and selection of studies was unanimous.
Study characteristics
Table 1 shows the descriptive characteristics of the six studies identified from the systematic search. All studies reported history of smoking, four studies reported history of alcohol use (10;12;17;20), whereas four studies reported family history of cancer (11;12;17;20). Data collection was performed retrospectively in three studies (10;12;17), prospectively with standardized questionnaires in one study (11), with face-to-face interviews in one study (20), and with face-to-face interviews or telephone interviews in the remaining study (18). Controls were defined as patients diagnosed with benign disease at a hospital during the same period (10), patients without small-intestinal malignancy within a large defined national patient cohort (11), healthy individuals who accompanied patients at a hospital and who were
genetically unrelated family members (12;17), randomly selected individuals from population registries or electoral rolls from the regions from which cases arose during the study period (18), and patients visiting a Gastrointestinal outpatient clinic during the same period, with specific exclusion criteria (20). Inclusion and exclusion criteria for cases and controls are summarized in Table 2.
The six studies that were included in the meta-analysis included five study cohorts with 765 (range, 17-325) cases and 502,282 (range, 52-498,376) controls, with accrual periods between 1980 and 2012. Table 1 shows the descriptive characteristics of the six included studies.
Risk of SI-NET: history of smoking
Figure 2 shows the OR for the individual studies reporting history of ever smoking. The pooled estimated OR of the five study populations (10-12;17;18;20) reporting ever smoking as an exposure was 1.40 (95% CI 1.06-1.86; p<0.05), indicating ever smoking as a risk factor for the development of SI-NET. The I2 value was 49.3%.
Risk of SI-NET: history of alcohol use
Figure 3 shows the OR for the individual studies reporting a history of ever alcohol
consumption. The pooled estimated OR of the three study populations (10;12;17;20) reporting history of ever alcohol consumption as an exposure was 1.04 (95% CI 0.63-1.72; p=0.87), indicating that ever alcohol consumption is not a significant risk factor for the development of SI-NET. The I2 value was 65.0%, suggesting strong heterogeneity among the studies
analyzed.
Risk of SI-NET: family history of any cancer
Figure 4 shows the OR for the individual studies reporting a family history of any cancer.
The pooled estimated OR of the three study populations (11;12;17;20) reporting a family history of any cancer as a risk factor was 1.34 (95% CI 1.12-1.60; p<0.01). The I2 value was 0.0%.
Risk of SI-NET: family history of colorectal cancer
Figure 5 shows the OR for the individual studies reporting a family history of colorectal cancer. The pooled estimated OR of the three study populations (11;12;17;20) reporting
family history of colorectal cancer as a risk factor was 1.43 (95% CI 1.15-1.79; p<0.01), indicating family history of colorectal cancer as a risk factor for development of SI-NET. The I2 value was 0.0%.
Discussion
The present study was aimed to systematically reviewing the literature for risk factors for development of SI-NET. The resulting pooled meta-analysis included five study populations with data from 765 cases and 502,282 controls, which found that a family history of colorectal cancer (OR 1.43) and a family history of any cancer (OR 1.34) were associated with an
increased risk of developing a SI-NET, while the role of smoking (OR 1.40) and alcohol (1.04) were less clear. Considerable heterogeneity between primary studies was observed in the analysis with regard to the risk associated with smoking and alcohol consumption.
In the present analysis, family history of colorectal cancer was identified as the strongest risk factor for developing SI-NET, with an OR of 1.43 (Figure 5). In all the three cohorts that investigated the role of colorectal cancer, it was found to be associated with an increased risk (11;12;17;20). Family history of cancer was also associated with an increased risk of SI-NET (pooled OR=1.34), this result being consistent among all the included studies, without
heterogeneity (Figure 4). These results suggest that SI-NETs may share inherited genetic predisposing factors with other neoplasms, such as colorectal cancer, or that certain causative factors common within the family living environment may be important. A recent case-cohort study found no correlation between SI-NETs and familial colorectal cancer syndromes (20), suggesting that it is not the classical germline mutations known to cause colorectal cancer syndromes (i.e. DNA mismatch repair gene mutations) that are responsible for increasing SI- NET risk.
The role of smoking and alcohol drinking seemed less clear in the present analysis. A history of ever smoking seems to be associated with an increased risk of SI-NET (pooled OR=1.40, Figure 2), but with a quite high heterogeneity among the included studies. A history of ever alcohol consumption was not associated with an increased risk of SI-NET (pooled OR=1.04, Figure 3). The authors of one of the included studies concluded that alcohol and smoking, separately, do not seem to increase the risk of SI-NET (10). However, when combining both alcohol and smoking, there was a significant increase in the risk of developing SI-NET.
Whether smoking and alcohol are independent risk factors for the occurrence of SI-NETs is unclear, and further research would be required to clarify this issue. In a recent meta-analysis on risk factors for development of neuroendocrine tumors, which was published after
completion of the data synthesis of this study, heavy smoking was reported as a risk factor for SI-NET (22). This could indicate a dose-effect-relationship regarding smoking as a risk factor.
The present study carries a number of limitations. First, as we have been able to include only a limited number of studies, conducted on some relatively small series, the evidence obtained by the present results might be limited and further studies on this topic seem necessary. As for any analysis of this kind, the observed heterogeneity is also related to possible differences concerning patient and control groups among the individual studies (see Table 2). The definition of the control groups varied between studies. We employed one strategy to deal with the observed heterogeneity, namely, we used a random-effect model for all analyses.
Using a random-effect model, however, might produce wider confidence intervals. Moreover, most tests for heterogeneity tend to underestimate the magnitude of heterogeneity, and the observed results, given the paucity of studies, should therefore be interpreted with some
caution and mainly be employed to design further investigations. Surveillance bias is also an important factor to consider. Another important issue is that when considering a family history of cancer, we are only limited to any known cancers, meaning that family members with indolent cancers that have yet to be diagnosed were not counted for in the studies.
Secondly, we know that SI-NETs tend to be diagnosed at a mean age of 50, but they could also appear at a much younger age (17;23). It is known that age itself is a risk factor for cancer development. Therefore, this implies that there might be a cancer development in the future in family members of patients diagnosed with SI-NET, who were included in the studies, without them having any current cancer. This might give a biased result, and the true importance of a family history of any cancer, or colorectal cancer, as risk factors for SI-NETs might be underestimated. Another limitation is the possibility of confounding biases in patients who smoke and consume alcohol and vice versa. We found that only two studies adjusted for both smoking and alcohol consumption (10;17). The results from the remaining studies could therefore be biased, as there is a possibility that patients that smoke, also consume alcohol, and vice versa. There would then be great differences even among this group in regards to smoking and drinking frequency, which could make it difficult to
distinguish these potential risk factors. Finally, we only focused our attention on risk factors for which there was a biological plausibility, and for which we were aware of available literature data.
In conclusion, this systematic review and meta-analysis has identified a family history of any cancer and a family history of colorectal cancer to be associated with an increased risk of SI- NET. Whether smoking and alcohol are independent risk factors for the occurrence of SI- NETs is unclear, and further research would be required to clarify this issue.
Acknowledgements
This study was conducted through Pancreas 2000, which is a European educational and scientific pancreatology programme initiated by the Karolinska Institute in Stockholm, Sweden, and the European Pancreatic Club.
References
(1) Hauso O, Gustafsson BI, Kidd M, Waldum HL, Drozdov I, Chan AK, Modlin IM.
Neuroendocrine tumor epidemiology: contrasting Norway and North America.
Cancer 2008 November 15;113(10):2655-64.
(2) Scherubl H, Jensen RT, Cadiot G, Stolzel U, Kloppel G. Neuroendocrine tumors of the small bowels are on the rise: Early aspects and management. World J
Gastrointest Endosc 2010 October 16;2(10):325-34.
(3) Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, Caplin M, Delle FG, Kaltsas GA, Krenning EP, Moss SF, Nilsson O, Rindi G, Salazar R, Ruszniewski P, Sundin A. Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 2008 January;9(1):61-72.
(4) Boyar CR, Aagnes B, Thiis-Evensen E, Tretli S, Bergestuen DS, Hansen S. Trends in Incidence of Neuroendocrine Neoplasms in Norway: A Report of 16,075 Cases from 1993 through 2010. Neuroendocrinology 2017;104(1):1-10.
(5) Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001 April;48(4):526-35.
(6) von Roon AC, Reese G, Teare J, Constantinides V, Darzi AW, Tekkis PP. The risk of cancer in patients with Crohn's disease. Dis Colon Rectum 2007 June;50(6):839- 55.
(7) Butterworth AS, Higgins JP, Pharoah P. Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer 2006 January;42(2):216-27.
(8) Tsong WH, Koh WP, Yuan JM, Wang R, Sun CL, Yu MC. Cigarettes and alcohol in relation to colorectal cancer: the Singapore Chinese Health Study. Br J Cancer 2007 March 12;96(5):821-7.
(9) Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, Meade TW.
Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 2010 November 20;376(9754):1741-50.
(10) Chen CC, Neugut AI, Rotterdam H. Risk factors for adenocarcinomas and malignant carcinoids of the small intestine: preliminary findings. Cancer Epidemiol
Biomarkers Prev 1994 April;3(3):205-7.
(11) Cross AJ, Hollenbeck AR, Park Y. A large prospective study of risk factors for adenocarcinomas and malignant carcinoid tumors of the small intestine. Cancer Causes Control 2013 September;24(9):1737-46.
(12) Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC. Family history of cancer and associated risk of developing neuroendocrine tumors: a case-control study. Cancer Epidemiol Biomarkers Prev 2008 April;17(4):959-65.
(13) Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009 July 21;6(7):e1000097.
(14) DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986 September;7(3):177-88.
(15) Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002 June 15;21(11):1539-58.
(16) Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997 September 13;315(7109):629-34.
(17) Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC. Risk factors associated with neuroendocrine tumors: A U.S.-based case-control study. Int J Cancer 2008 August 15;123(4):867-73.
(18) Kaerlev L, Teglbjaerg PS, Sabroe S, Kolstad HA, Ahrens W, Eriksson M, Guenel P, Gorini G, Hardell L, Cyr D, Zambon P, Stang A, Olsen J. The importance of
smoking and medical history for development of small bowel carcinoid tumor: a European population-based case-control study. Cancer Causes Control 2002 February;13(1):27-34.
(19) Kharazmi E, Pukkala E, Sundquist K, Hemminki K. Familial risk of small intestinal carcinoid and adenocarcinoma. Clin Gastroenterol Hepatol 2013 August;11(8):944- 9.
(20) Rinzivillo M, Capurso G, Campana D, Fazio N, Panzuto F, Spada F, Cicchese N, Partelli S, Tomassetti P, Falconi M, Delle FG. Risk and Protective Factors for Small Intestine Neuroendocrine Tumors: A Prospective Case-Control Study.
Neuroendocrinology 2016;103(5):531-7.
(21) Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC. Family history of cancer and associated risk of developing neuroendocrine tumors: a case-control study. Cancer Epidemiol Biomarkers Prev 2008 April;17(4):959-65.
(22) Leoncini E, Carioli G, La VC, Boccia S, Rindi G. Risk factors for neuroendocrine neoplasms: a systematic review and meta-analysis. Ann Oncol 2016
January;27(1):68-81.
(23) Merola E, Rinzivillo M, Cicchese N, Capurso G, Panzuto F, Delle FG. Digestive neuroendocrine neoplasms: A 2016 overview. Dig Liver Dis 2016
August;48(8):829-35.
Table 1: Characteristics of studies included in the meta-analysis
Author (Reference)
Year Country Single- /Multi- center
Study accrual period
Setting and design
Number of Cases
Male sex (%) Mean age (years)
Number of Controls
Investigated Exposures Outcome
Measures
Chen et al. (10) 1994 USA Single 1980-1987 CCS 17 41 65.3 52 Ever smoking, ever alcohol use OR
Cross et al. (11) 2013 USA Multi 1995-2006 CCS 124 57 63.5 498376 Ever smoking, family history of any cancer, family history of colorectal cancer
OR
Hassan et al.
(17)*
2008 USA Single 2000-2006 CCS 325 48 54.1 924 Ever smoking, ever alcohol use, family history of any cancer
OR
Hassan et al.
(12)*
2008 USA Single 2000-2006 CCS 325 48 54.1 924 Family history of colorectal cancer OR
Kaerlev et al.
(18)
2002 Europe Multi 1995-1997 CCS 84 61 60.0 2070 Ever smoking OR
Rinzivillo et al.
(20)
2015 Italy Single 2009-2012 CCS 215 54 50.4 860 Ever smoking, ever alcohol use, family history of any cancer, family history of colorectal cancer
OR
*The two studies by Hassan et al. report different risk factors on the same study population. CCS, case-control study. F, functioning. NF, nonfunctioning. MEN-1, multiple endocrine neoplasia type 1. OR, odds ratio. NA, not available.
1
Table 2: Inclusion and exclusion criteria for cases and controls in the different studies
Cases Inclusion criteria Exclusion criteria
Chen et al. (10) Confirmed histological SI-NET Not specified Cross et al. (11) Confirmed SI-NET in the same patient in other
US state cancer registries
Not specified
Hassan et al. (12;17) Confirmed histological well-differentiated low/intermediate grade SI-NET
Not specified
Kaerlev et al. (18) Confirmed histological SI-NET Not specified
Rinzivillo et al. (20) Confirmed histological SI-NET Diagnosis of hereditary malignant syndromes
Controls Inclusion criteria Exclusion criteria
Chen et al. (10) Patients diagnosed with benign disease at a hospital over the study period
Past history of cancer
Cross et al. (11) Individuals included in a large national US registry without SI-NET
Not specified
Hassan et al. (12;17) Genetically unrelated and healthy family members, who accompanied cancer patients who had cancers other than gastrointestinal, lung or head and neck cancer, US residents
Past history of cancer
Kaerlev et al. (18) Individuals randomly selected from population registries or electoral rolls from the regions from which cases arose during the study period
Not specified
Rinzivillo et al. (20) Outpatients for evaluation of different gastrointestinal disorders
Current or previous diagnosis of cancer or chronic disorders (liver cirrhosis,
inflammatory bowel disease, chronic obstructive bronchial disease, kidney failure), genetic relationship with study patients, and specific referral for evaluation of a possible cancer familial syndrome
NA, not available.
2
(Figures)
Figure 1: PRISMA diagram showing selection of articles for review.
Records identified through database search
n = 3686
Additional records identified from conference abstracts
n = 4
Records screened n = 3690
Records assessed for eligibility n = 101
Studies included in qualitative synthesis
n = 7
Records excluded (not related to study topic)
n = 3589
Excluded (did not fulfill inclusion criteria)
n = 94
Studies included in quantitative synthesis (meta-analysis)
n = 6
3
Figure 2: Forest plot, summary odds ratio (OR) and 95% confidence intervals for history of
ever smoking and risk of SI-NET. OR < 1: risk of SI-NET reduced; OR > 1, risk of SI-NET increased. I2 = 49.3%.
Figure 3: Forest plot, summary odds ratio (OR) and 95% confidence intervals for history of ever alcohol consumption and risk of SI-NET. OR < 1: risk of SI-NET reduced; OR > 1, risk of SI-NET increased. I2 = 65.0%.
4
Figure 4: Forest plot, summary odds ratio (OR) and 95% confidence intervals for family
history of any cancer and risk of SI-NET. OR < 1: risk of SI-NET reduced; OR > 1, risk of SI-NET increased. I2 = 0.0%.
Figure 5: Forest plot, summary odds ratio (OR) and 95% confidence intervals for family history of colorectal cancer and risk of SI-NET. OR < 1: risk of SI-NET reduced; OR > 1, risk of SI-NET increased. I2 = 0.0%.
5
(Supporting information)
Appendix S1: Search strategy for the literature search in PubMed
(Small intestinal neoplasms OR small bowel tumor OR carcinoid OR midgut carcinoid OR small intestinal neuroendocrine tumor OR small intestinal neuroendocrine tumors OR small bowel neuroendocrine tumor OR small bowel neuroendocrine tumors OR small intestinal endocrine tumor OR ileal neuroendocrine tumor OR ileal neuroendocrine tumors OR jejunal neuroendocrine tumor OR jejunal neuroendocrine tumors)
AND (risk factor OR risk factors OR cause OR causalities OR causality OR causation OR predisposing factors OR etiology OR cigarette OR cigarette smoking OR cigarette smoke OR smokers OR smoking habits OR alcohol consumption OR alcohol OR ethanol OR alcohol induced cancer OR family history OR familial OR aspirin OR acetylsalicylic acid OR ASA OR IBD OR inflammatory bowel disease OR Crohn’s disease OR Ulcerative colitis OR collagenous colitis OR lymphocytic colitis)
AND (case-control OR case-control study OR cohort study OR cohort)
Limits: Publication date until 24.10.2015
Entries = 3686
