Report in English with a French summary (KCE reports 75B)

Guideline pour la prise en charge du
cancer oesophagien et gastrique :
éléments scientifiques à destination du
Collège d’Oncologie
KCE reports 75B
Federaal Kenniscentrum voor de Gezondheidszorg
Centre fédéral d’expertise des soins de santé
2008
Le Centre fédéral d’expertise des soins de santé
Présentation :
Le Centre fédéral d’expertise des soins de santé est un parastatal, créé le 24
décembre 2002 par la loi-programme (articles 262 à 266), sous tutelle du
Ministre de la Santé publique et des Affaires sociales, qui est chargé de réaliser
des études éclairant la décision politique dans le domaine des soins de santé et
de l’assurance maladie.
Conseil d’administration
Membres effectifs :
Gillet Pierre (Président), Cuypers Dirk (Vice-Président), Avontroodt Yolande,
De Cock Jo (Vice-Président), Demeyere Frank, De Ridder Henri, Gillet JeanBernard, Godin Jean-Noël, Goyens Floris, Maes Jef, Mertens Pascal, Mertens
Raf, Moens Marc, Perl François, Van Massenhove Frank, Vandermeeren
Philippe, Verertbruggen Patrick, Vermeyen Karel.
Membres suppléants :
Annemans Lieven, Bertels Jan, Collin Benoît, Cuypers Rita, Decoster
Christiaan, Dercq Jean-Paul, Désir Daniel, Laasman Jean-Marc, Lemye Roland,
Morel Amanda, Palsterman Paul, Ponce Annick, Remacle Anne, Schrooten
Renaat, Vanderstappen Anne.
Commissaire du gouvernement : Roger Yves
Direction
Directeur général :
Dirk Ramaekers
Directeur général adjoint :
Jean-Pierre Closon
Contact
Centre fédéral d’expertise des soins de santé (KCE).
Rue de la Loi 62
B-1040 Bruxelles
Belgium
Tel: +32 [0]2 287 33 88
Fax: +32 [0]2 287 33 85
Email : [email protected]
Web : http://www.kce.fgov.be
Guideline pour la prise en
charge du cancer oesophagien
et gastrique :
éléments scientifiques à
destination du Collège
d’Oncologie
KCE reports 75B
M. PEETERS, T. LERUT, J. VLAYEN, F. MAMBOURG,
N. ECTORS, P. DEPREZ, T. BOTERBERG, J. DE MEY,
P. FLAMEN, J.-L. VAN LAETHEM, B. NEYNS, P. PATTYN
Federaal Kenniscentrum voor de Gezondheidszorg
Centre fédéral d’expertise des soins de santé
2008
KCE REPORTS 75B
Titre :
Auteurs :
Experts externes :
Acknowledgements
Validateurs :
Conflict of interest :
Disclaimer:
Guideline pour la prise en charge du cancer oesophagien et gastrique:
éléments scientifiques à destination du Collège d’Oncologie
M. Peeters (UZ Gent; College Oncologie), T. Lerut (UZ Leuven), J. Vlayen
(KCE), F. Mambourg (KCE), N. Ectors (UZ Leuven), P. Deprez (UCL), T.
Boterberg (UZ Gent), J. De Mey (UZ Brussel), P. Flamen (Institut Jules
Bordet), J.-L. Van Laethem (ULB), B. Neyns (UZ Brussel), P. Pattyn (UZ
Gent)
Michel Buset (Belgian Society of Gastrointestinal Endoscopy), Wim
Ceelen (Belgian Society of Surgical Oncology), Paul Cheyns (Upper GI
sectie van het Koninklijk Belgisch Genootschap Heelkunde), Jean-Marie
Collard (Belgian Society of Surgical Oncology), Jochen Decaestecker
(Vlaamse Vereniging voor Gastro-enterologie), Jacques De Grève
(Président Working Party Manual and Guidelines, College Oncologie),
Pierre Demetter (Belgian Digestive Pathology Club), Louis Ferrant
(Domus Medica), Roland Hustinx (Belgische Genootschap voor Nucleaire
Geneeskunde), Anne Jouret-Mourin (Belgian Digestive Pathology Club),
Cathy Mahin (Belgische Vereniging voor Radiotherapie-Oncologie), Max
Mano (Société Belge d’Oncologie Medicale), Hubert Piessevaux (Société
Royale Belge de Gastro-enterologie), Daniel Urbain (Belgian Society of
Gastrointestinal Endoscopy), Eric Van Cutsem (Vlaamse Vereniging voor
Gastro-enterologie), Bart Van den Eynden (Domus Medica), Didier
Verhoeven (Belgische Vereniging voor Medische Oncologie), Joseph
Weerts (Upper GI section de l’Association Royale Belge de Chirurgie)
Liesbet Van Eycken (Stichting Kankerregister), Kris Henau (Stichting
Kankerregister)
Harry Bleiberg (Jules Bordet Instituut), Marc De Man (OLV Ziekenhuis
Aalst), Hugo W. Tilanus (Erasmus MC Rotterdam)
La plupart des auteurs, des experts externes et des validateurs
travaillent pour un centre spécialisé dans le traitement des cancers de
l'oesophage et de l'estomac. Joseph Weerts a reçu une bourse destinée à
couvrir les frais de participation à cours organisé dans le cadre
d'un postgraduat (IRCAD Stasbourg). D'autres conflits d'intérêt n'ont pas
été mentionnés
Les experts externes ont collaboré au rapport scientifique qui a ensuite
été soumis aux validateurs. La validation du rapport résulte d’un
consensus ou d’un vote majoritaire entre les validateurs. Le KCE reste
seul responsable des erreurs ou omissions qui pourraient subsister de
même que des recommandations faites aux autorités publiques.
Ine Verhulst
Mise en Page :
Bruxelles, 21 mars 2008
Etude n° 2007-28-01
Domaine : Good Clinical Practice (GCP)
MeSH : Esophageal Neoplasms ; Stomach Neoplasms ; Gastrointestinal Stromal Tumors ; Lymphoma,
B-Cell, Marginal Zone
NLM classification : WI 149
Langage : français, anglais
Format : Adobe® PDF™ (A4)
Dépôt légal : D/2008/10.273/17
La reproduction partielle de ce document est autorisée à condition que la source soit mentionnée. Ce
document est disponible en téléchargement sur le site Web du Centre fédéral d’expertise des soins
de santé.
Comment citer ce rapport ?
Peeters M, Lerut T, Vlayen J, Mambourg F, Ectors N, Deprez P, et al. Guideline pour la prise en
charge du cancer oesophagien et gastrique : éléments scientifiques à destination du Collège
d’Oncologie. Bruxelles: Centre fédéral d'expertise des soins de santé (KCE); 2008. KCE Reports 75B
(D/2008/10.273/17)
KCE Reports 75B
Cancer oesophagien et gastrique
i
PREFACE
Chaque année, environ deux mille belges sont confrontés au diagnostic de cancer de
l’oesophage ou de l’estomac. Le pronostic défavorable de ces cancers leur donne la
cinquième place dans les causes de mortalité par cancer les plus fréquentes après le
cancer du poumon, du colon, du sein et de la prostate. Une importante proportion des
patients ne peut espérer guérir et bénéficiera d’emblée d’un traitement palliatif.
Il était donc justifié de présenter des recommandations de bonne pratique à l’intention
des praticiens et des patients concernés. Ils trouveront dans ce rapport les meilleures
recommandations de bonne pratique internationales mises à jour en fonction de la
littérature récente.
Ce rapport est le quatrième à s’inscrire dans une collaboration de plus en plus confiante
entre le Collège d’Oncologie et le KCE. De nombreux experts parmi lesquels des
représentants de la société scientifique néerlandophone des médecins généralistes ont
collaboré à ce rapport. Leur enthousiasme et leur participation furent à nouveau
remarquables et ont largement contribué à la bonne qualité du document. Qu’ils en
soient remerciés.
La rédaction de ces recommandations constitue la première étape d’un processus long
et continu. Leur mise à disposition en ligne via le site web du Collège d’Oncologie
contribuera à leur diffusion et à leur mise en pratique. La toute première pierre de la
construction d’indicateurs de qualité a également été posée dans ce rapport. Certains
projets en cours, comme le projet PROCARE, apporteront incontestablement un
éclairage utile pour la stratégie à suivre dans ce domaine
La prise en charge du cancer est actuellement d’actualité puisqu’un plan national de lutte
contre le cancer est en cours de développement. Puissent les recommandations
présentées ci-dessous, s’intégrer dans les développements ultérieurs de ce plan.
Jean-Pierre Closon
Dirk Ramaekers
Directeur general adjoint
Directeur général
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Résumé exécutif
INTRODUCTION
Des recommandations décrivant la prise en charge du cancer de l’œsophage et du
cancer de l’estomac (y compris le lymphome primaire de l’estomac et les tumeurs
stromales gastro-intestinales [GIST]) ont été élaborées dans le cadre de la collaboration
entre le Collègue d’Oncologie et le Centre Fédéral d’Expertise des Soins de Santé
(KCE). Ces recommandations concernent l’intégralité du trajet de ces patients, du
diagnostic au follow-up. Elles s’adressent à l’ensemble des prestataires de soins
impliqués dans leur prise en charge.
MÉTHODOLOGIE
La méthodologie ADAPTE a été utilisée pour le développer cette directive. Les
membres de l’équipe formulent d’abord les questions cliniques principales avec l’aide
des experts. Les directives (inter)nationales existantes sont ensuite recherchées dans
Medline, Embase, National Guideline Clearinghouse et les sites Web des organisations
qui rédigent des directives et sont actives en oncologie. La qualité des 17 directives
répertoriées a été évaluée au moyen de l’instrument AGREE par deux évaluateurs
travaillant de manière indépendante. Sept directives ont été sélectionnées sur base de
cette évaluation. Elles ont été actualisées pour chaque question clinique, en recherchant
les données probantes les plus récentes dans Medline et la Cochrane Database of
Systematic Reviews. Un niveau d’évidence a été attribué à chaque recommandation
originelle et à chaque étude au moyen de la classification GRADE.
Ensuite, des recommandations ont été formulées par le groupe de développement
multidisciplinaire sur base des données probantes. Elles ont finalement été évaluées de
manière formelle par des représentants des associations professionnelles et
scientifiques. Les conflits d’intérêt des experts ont été répertoriés.
DÉFINITIONS
DÉFINITIONS TOPOGRAPHIQUES
De nombreuses discussions concernant la classification des tumeurs de la jonction
gastro-oesophagienne sont en cours. Les définitions suivantes sont utilisées dans ce
rapport :
•
Si plus de 50 % de la tumeur se situe dans la partie gastrique du cardia,
celle-ci est classée comme tumeur de l'estomac.
•
Si la masse tumorale se situe principalement dans l'œsophage, elle est
classée comme tumeur de l’œsophage.
•
Les tumeurs de la jonction gastro-oesophagienne doivent être
considérées comme des tumeurs de l’œsophage et traitées comme
telles.
LÉSIONS PRÉCOCES
La définition d’une lésion de Barrett ne fait pas l’objet d’aucun consensus. La définition la
plus courante est la suivante : il s’agit d’une modification de l’épithélium œsophagien
visible à l’endoscopie et présentant des lésions de métaplasie intestinale confirmées par
la biopsie.
Plusieurs classifications de la dysplasie sont disponibles. La pertinence clinique est le
critère principal à prendre en compte pour choisir l’une d’entre elles.
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Cancer oesophagien et gastrique
RECOMMANDATIONS FINALES
1. CANCER DE L’ŒSOPHAGE
COM: Concertation Multidisciplinaire
PET : Tomographie par Emission de Positrons
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Diagnostic
Après l’anamnèse et l’examen clinique, le diagnostic du cancer de l’œsophage est établi
par une endoscopie de l’œsophage comportant des biopsies. Les patients présentant
les symptômes d’alarme suivants devraient être orientés le plus rapidement possible
vers une endoscopie : dysphagie, vomissements incessants, anorexie, perte de poids et
hémorragies gastro-intestinales.
Une endoscopie haute résolution et une chromo-endoscopie ne sont pas indiquées en
routine, mais peuvent être utiles pour le suivi des patients présentant un risque élevé
de cancer de l’œsophage, comme les patients ayant un œsophage de Barrett ou une
dysplasie de haut grade.
Approche des lésions de dysplasie
Chez les patients présentant une lésion de Barrett, le protocole de biopsie sera
structuré ainsi : réaliser des biopsies tous les 2 centimètres en 4 quadrants et biopsier
chaque lésion visible. En cas de présomption de dysplasie de haut grade, il convient de
tenir compte en outre des conclusions cliniques et endoscopiques. En cas de
confirmation d’une dysplasie de haut grade et si une intervention thérapeutique est
envisagée, une évaluation endoscopique (endoscopie haute résolution +/- chromoendoscopie, avec biopsies tous les centimètres en 4 quadrants) et une évaluation
pathologique (confirmation du diagnostic par un deuxième pathologiste, avec biopsies
additionnelles éventuelles ou une résection endoscopique (REM) de la muqueuse à visée
diagnostique seront réalisées. Le traitement doit être discuté en concertation
pluridisciplinaire et avoir lieu de préférence dans un centre possédant des installations
endoscopiques et chirurgicales ainsi que l’expertise requises.
Staging
Les patients atteints d’un cancer de l’œsophage bénéficieront d’un CT du thorax
(incluant la région basse du cou) et de l’abdomen pour exclure les métastases. Si un
traitement curatif est jugé possible, la détermination du stade au moyen d’une échoendoscopie (EUS) avec ou sans aspiration cytologique à l’aiguille fine (FNAC) sera
réalisée. En complément, un PET(/CT) scan peut être envisagé pour l’évaluation des
métastases lymphatiques et autres. Des analyses additionnelles, comme une résonance
magnétique nucléaire (RMN), une bronchoscopie (+/- échographie des bronches +/biopsie), une thoracoscopie ou une laparoscopie sont envisageables en cas d’indication
précise.
Traitement des cancers de la muqueuse
Chez les patients présentant une lésion T1a, le diagnostic doit être confirmé par un
deuxième pathologiste. Des biopsies additionnelles ou une RMN à visée diagnostique
peuvent être indiqués en cas de doute. Le traitement doit être discuté en concertation
pluridisciplinaire où la REM sera préférée à la chirurgie, compte tenu du stade, de la
taille, de la longueur de la lésion de Barrett, du type histologique, du degré de
différenciation et de l’invasion lymphovasculaire.
Traitement des cancers sous-muqueux
Traitement néoadjuvant
Le traitement néoadjuvant n’est pas indiqué en routine chez les patients atteints d’un
cancer de l’œsophage et doit être discuté durant une concertation pluridisciplinaire. La
radiothérapie néoadjuvante n'est pas indiquée.
Si, toutefois, un traitement combiné (traitement néoadjuvant et chirurgie) était réalisé,
ses résultats cliniques et ses effets secondaires doivent être enregistrés de manière
prospective.
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Chirurgie
La chirurgie est le traitement standard des patients atteints d’un cancer de l’œsophage
résécable et a lieu de préférence au moyen d’une résection transthoracique ‘en bloc’
avec lymphadénectomie étendue à deux champs. L’objectif de la chirurgie consiste en
l’élimination totale de la tumeur (résection R0). La chirurgie du cancer de l’œsophage
est effectuée de préférence au sein de services spécialisés ayant un volume d’actes
élevé et par un chirurgien ayant l’expérience et/ou la formation requises.
Traitement adjuvant
Le traitement adjuvant n’est pas indiqué chez les patients atteints d’un cancer de
l’œsophage.
Traitement non chirurgical à but curatif
Un traitement par radio et chimiothérapie exclusive est envisageable pour les patients
présentant un cancer de l'œsophage étendu non résécable ou pour les patients ayant un
cancer de l’œsophage localement étendu, inopérables pour des raisons médicales ou qui
refusent la chirurgie.
Traitement palliatif et maladie métastatique
Le placement d’un stent, le traitement au laser ou la coagulation au plasma d’argon
(APC) sont indiqués pour lever l’obstruction de l’œsophage par une tumeur. Le choix
de la technique sera fait en fonction de sa disponibilité et de l’expertise locales. Le
traitement de la dysphagie causée par une tumeur œsophagienne sera effectué de
préférence avec des stents en métal auto-déployables ou des stents déployables en
plastique. En cas de recouvrement du stent par la tumeur, un traitement par laser,
l’APC ou un re-stenting sont envisageables. La radiothérapie (externe ou endoluminale)
sera utilisée pour les patients atteints de dysphagie ayant une espérance de vie
relativement longue.
La chimiothérapie avec ou sans radiothérapie est une solution qui doit être discutée en
concertation pluridisciplinaire pour les patients atteints d’un cancer de l'œsophage
localement étendu ou métastasé. La chirurgie palliative, comme l’oesophagectomie ou le
bypass substernal, n’est plus indiquée dans ces situations.
Il convient que les patients atteints d’un cancer de l’œsophage aient accès à une équipe
palliative spécialisée, laquelle apportera une attention spécifique au contrôle des
symptômes, à l’alimentation et à la qualité de vie. Le médecin traitant assurera le rôle
de coordinateur dans l’organisation des soins palliatifs à domicile.
Follow-up
Chez les patients qui ont été traités pour un cancer de l’œsophage, un examen clinique
tous les 3 mois sera réalisé. Il est recommandé de réaliser un CT scan tous les 6 mois
au cours de la première année, puis chaque année par la suite. Les patients qui ont été
traités par REM subiront une endoscopie de contrôle après 3 mois, puis tous les 6 mois
pendant 2 ans, et ensuite chaque année.
Traitement de la récidive
Les options thérapeutiques envisageables pour les patients présentant une récidive de
cancer de l’œsophage seront discutées en concertation pluridisciplinaire. La répétition
d’un traitement local fait partie des options envisageables pour les patients ayant une
récidive localisée ou une deuxième tumeur révélées par la RMN.
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2. CANCER DE L’ESTOMAC
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Diagnostic
Après une anamnèse et un examen clinique, le diagnostic du cancer de l’estomac est
établi par une endoscopie de l’œsophage comportant des biopsies. Les patients
présentant les symptômes d’alarme suivants devraient être orientés le plus rapidement
possible vers une endoscopie : dysphagie, vomissements incessants, anorexie, perte de
poids et hémorragie gastro-intestinales. Un test de positivité au H. pylori doit être
réalisé de manière systématique et confirmé par un deuxième test.
Une endoscopie haute résolution et une chromo-endoscopie ne sont pas indiquées en
routine, mais peuvent se révéler utiles dans le suivi des patients présentant un risque
élevé de cancer de l’estomac, comme c’est le cas pour les patients présentant une
dysplasie de haut grade.
Approche des lésions de dysplasie
Chez les patients présentant une dysplasie de haut grade pour lesquels une intervention
thérapeutique est envisagée, une évaluation endoscopique et pathologique approfondie
est indiquée (confirmation du diagnostic par un deuxième pathologiste, biopsies
additionnelles éventuelles). Le traitement doit faire l’objet de discussions en
concertation pluridisciplinaire et sera effectué de préférence au sein de services
spécialisés ayant un volume d’actes endoscopiques élevé et par un chirurgien ayant
l’expérience et/ou la formation requises.
Staging
Les patients atteints d’un cancer de l’estomac, bénéficieront d’un CT du thorax et de
l’abdomen pour exclure les métastases. Si un traitement curatif est jugé possible, la
déterminations du stade par EUS (écho-endoscopie) avec ou sans FNAC est indiquée.
Des examens additionnels comme un PET scan, une RMN ou une laparoscopie seront
envisagés en fonction des nécessités.
Traitement du cancer de la muqueuse
Les biopsies d’un cancer des muqueuses seront évaluées par un pathologiste ayant une
expérience suffisante. Le traitement doit être discuté en concertation pluridisciplinaire
où la REM sera préférée à la chirurgie, compte tenu du stade, de la taille, du type
histologique, du degré de différentiation.
Traitement du cancer sous-muqueux
Traitement néoadjuvant
Le traitement néoadjuvant n’est pas indiqué en routine chez les patients atteints d’un
cancer de l’estomac, mais constitue une option devant être discutée en concertation
pluridisciplinaire.
En cas de traitement combiné (traitement néoadjuvant et chirurgie), les résultats
cliniques et les effets secondaires seront enregistrés de manière prospective.
Chirurgie
La chirurgie est le traitement standard des patients atteints d’un cancer de l’estomac
résécable. Les tumeurs distales sont traitées au moyen d’une gastrectomie partielle, les
tumeurs proximales, par gastrectomie totale. Une lymphadénectomie D2 doit être
réalisée de manière standard. L’objectif de la chirurgie consiste en l’élimination totale de
la tumeur (résection R0). La chirurgie du cancer de l’estomac a lieu de préférence au
sein de services spécialisés avec un volume élevé par un chirurgien ayant l’expérience
et/ou la formation requises.
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Traitement adjuvant
Le traitement adjuvant n’est pas indiqué chez les patients atteints d’un cancer de
l’estomac. La chimiothérapie adjuvante n’est pas conseillée de manière routinière, mais
peut être envisagée après discussion en concertation pluridisciplinaire.
Traitement palliatif et maladie métastatique
La chirurgie palliative est limitée aux patients présentant des sténoses symptomatiques,
des tumeurs qui saignent ou une perforation. Chez les patients présentant une
obstruction maligne de l’estomac, le choix existe entre un stenting endoscopique ou
une gastroentérostomie chirurgicale.
Chez les patients atteints d’un cancer étendu ou métastatique ayant une bonne
condition physique générale, une chimiothérapie combinée est envisageable.
Il convient que les patients atteints d’un cancer de l’estomac aient accès à une équipe
palliative spécialisée, laquelle apportera une attention spécifique au contrôle des
symptômes, à l’alimentation et à la qualité de vie. Le médecin traitant devra remplir un
rôle de coordination dans l’organisation des soins palliatifs à domicile.
Follow-up
Chez les patients qui ont été traités pour un cancer de l’estomac, un examen clinique et
une analyse de sang sont conseillés tous les 3 mois. Un CT scan est indiqué tous les 6
mois au cours de la première année, et ensuite chaque année. Les patients qui ont été
traités par REM subiront une endoscopie de contrôle après 3 mois, puis tous les 6 mois
durant 2 ans, et ensuite chaque année.
Traitement de la récidive
Les options thérapeutiques envisageables pour les patients présentant une récidive de
cancer de l’estomac seront discutées en concertation pluridisciplinaire. Pour les patients
présentant une récidive locale ou une nouvelle tumeur après la REM, un deuxième
traitement local fait partie des options.
3. LYMPHOME PRIMAIRE DE L’ESTOMAC
Diagnostic et staging
En cas de suspicion d’un lymphome primaire de l’estomac, la réalisation de 8 à 12
biopsies (au minimum) est indiquée. Les biopsies seront conservées de manière telle
qu’un diagnostic moléculaire soit possible. Chez les patients pour lesquels un lymphome
primaire de l’estomac a été confirmé par l’histologie, un EUS (sans FNAC) est indiqué. Il
est inutile de procéder à d’autres investigations pour les patients présentant un
lymphome de type MALT (mucosa-associated lymphoid tissue) de faible malignité, à
moins qu’il ne soit nécessaire d’établir un diagnostic différentiel.
Traitement
L’éradication de l’H. pylori est le traitement de premier choix des patients présentant
un lymphome MALT de faible malignité à petites cellules. Ensuite, un suivi rigoureux
avec endoscopie et biopsies est nécessaire. L’évaluation de l’éradication de l’ H. pylori
aura lieu dans les 3 mois. Les patients présentant une éradication réussie de l’ H. pylori,
mais pas de régression tumorale après 1 an ou présentant une progression tumorale
seront dirigés vers un centre spécialisé en hématologie.
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4. TUMEURS STROMALES GASTRO-INTESTINALES DE L’ESTOMAC
Diagnostic et staging
Un EUS avec FNAC et un test immunohistochimique du CD117 sont recommandés
pour les patients présentant une suspicion de tumeur stromale gastro-intestinale
(GIST). . Si une thérapie est envisagée, un CT de l’abdomen est conseillé..
Traitement
GIST résécable non-métastatique
La résection chirurgicale est indiquée pour les patients présentant une bonne condition
physique générale avec un GIST non-métastatique histologiquement confirmé. Celle-ci
est également indiquée pour les patients présentant une bonne condition physique
générale et une tumeur de l’estomac > à 5 cm suggestive d’un GIST sans métastases.
Le choix entre une résection chirurgicale et l’expectative sera discuté en concertation
pluridisciplinaire pour les patients présentant une bonne condition physique générale et
une tumeur de l’estomac de 2 à 5 cm suggestive d’un GIST sans métastases.
L’expectative est indiquée pour les patients présentant une tumeur de l’estomac de < 2
cm suggestive d’un GIST sans métastases.
GIST métastatique et/ou non-résécable
Le traitement à l’imatinib est conseillé pour les patients atteints d’un GIST métastatique
et/ou non-résécable. Un PET/CT est recommandé pour évaluer la réponse à l’imatinib.
Pour les patients résistants à l’imatinib ou présentant une intolérance à ce produit, le
sunitinib peut être considéré comme traitement de deuxième ligne.
IMPLEMENTATION ET REVISION DE LA
RECOMMANDATION
Il convient que l’implémentation de cette directive soit facilitée par la mise en ligne d’un
algorithme basé sur ces recommandations. Cet outil sera mis à disposition sur le site
web du Collège d’Oncologie.
Des indicateurs de qualité appropriés seront développés sur base des principales
recommandations.
En raison de l’évolution
des données probantes, une actualisation de cette
recommandation sera probablement nécessaire dans 5 ans, au terme d’une préévaluation de la littérature.
KCE Reports 75
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1
Scientific summary
Table of contents
1
INTRODUCTION ................................................................................................... 5
1.1
SCOPE.................................................................................................................................................. 5
1.2
EPIDEMIOLOGY .................................................................................................................................. 5
1.2.1 Oesophageal cancer ............................................................................................................ 5
1.2.2 Gastric cancer ...................................................................................................................... 6
2
METHODOLOGY................................................................................................... 8
2.1
GENERAL APPROACH ........................................................................................................................ 8
2.2
CLINICAL QUESTIONS ....................................................................................................................... 8
2.3
SEARCH FOR EVIDENCE ..................................................................................................................... 9
2.3.1 Clinical practice guidelines................................................................................................. 9
2.3.2 Additional evidence...........................................................................................................10
2.4
QUALITY APPRAISAL ........................................................................................................................10
2.4.1 Clinical practice guidelines...............................................................................................10
2.4.2 Additional evidence...........................................................................................................10
2.5
DATA EXTRACTION AND SUMMARY ............................................................................................10
2.6
FORMULATION OF RECOMMENDATIONS .....................................................................................10
2.7
EXTERNAL REVIEW ..........................................................................................................................10
3
DEFINITIONS ...................................................................................................... 12
3.1
TOPOGRAPHIC DEFINITIONS .........................................................................................................12
3.2
EARLY LESIONS .................................................................................................................................13
3.2.1 Histology of the normal oesophagus ............................................................................13
3.2.2 Barrett’s oesophagus ........................................................................................................13
3.2.3 Dysplasia in squamous epithelium .................................................................................15
3.2.4 Dysplasia in columnar epithelium ..................................................................................15
4
FINAL RECOMMENDATIONS ON OESOPHAGEAL CANCER ................................. 18
4.1
FLOWCHART ....................................................................................................................................18
4.2
DIAGNOSIS .......................................................................................................................................19
4.3
WORK-UP OF DYSPLASTIC LESIONS ..............................................................................................20
4.4
STAGING ...........................................................................................................................................22
4.5
TREATMENT OF MUCOSAL CANCER .............................................................................................23
4.6
TREATMENT OF CANCER BEYOND THE MUCOSA .......................................................................24
4.6.1 Neoadjuvant treatment....................................................................................................24
4.6.2 Surgical treatment .............................................................................................................25
4.6.3 Adjuvant treatment ...........................................................................................................27
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KCE reports 75
4.6.4 Non-surgical treatment with curative intent ..............................................................27
4.7
PALLIATIVE TREATMENT & METASTATIC DISEASE ........................................................................28
4.8
FOLLOW-UP .....................................................................................................................................30
4.9
RECURRENT DISEASE .......................................................................................................................30
5
FINAL RECOMMENDATIONS ON GASTRIC CANCER............................................ 31
5.1
FLOWCHART ....................................................................................................................................31
5.2
DIAGNOSIS .......................................................................................................................................32
5.3
WORK-UP OF DYSPLASTIC LESIONS ..............................................................................................33
5.4
STAGING ...........................................................................................................................................34
5.5
TREATMENT OF MUCOSAL CANCER .............................................................................................35
5.6
TREATMENT OF CANCER BEYOND THE MUCOSA .......................................................................36
5.6.1 Neoadjuvant treatment....................................................................................................36
5.6.2 Surgical treatment .............................................................................................................37
5.6.3 Adjuvant treatment ...........................................................................................................38
5.7
PALLIATIVE TREATMENT & METASTATIC DISEASE ........................................................................39
5.8
FOLLOW-UP .....................................................................................................................................40
5.9
RECURRENT DISEASE .......................................................................................................................41
5.10 TREATMENT OF GASTRIC LYMPHOMA ..........................................................................................41
5.10.1 Introduction ........................................................................................................................41
5.10.2 Diagnosis and staging ........................................................................................................41
5.10.3 Treatment............................................................................................................................42
5.11 TREATMENT OF GASTROINTESTINAL STROMAL TUMOURS ........................................................43
5.11.1 Introduction ........................................................................................................................43
5.11.2 Diagnosis and staging ........................................................................................................43
5.11.3 Treatment............................................................................................................................44
6
IMPLEMENTATION AND UPDATING OF THE UPPER GI CANCER GUIDELINE ...... 46
6.1
IMPLEMENTATION ............................................................................................................................46
6.2
QUALITY CONTROL ........................................................................................................................46
6.3
GUIDELINE UPDATE .........................................................................................................................46
7
REFERENCES ...................................................................................................... 47
8
APPENDICES ...................................................................................................... 65
KCE Reports 75
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3
ABBREVIATIONS
95% CI
95 percent confidence interval
5-FU
5-fluorouracil
AFE
Autofluorescence endoscopy
AGA
American Gastroenterological Association
APC
Argon plasma coagulation
ASCO
American Society of Clinical Oncology
BUS
Bronchoscopic ultrasound
CBO
Dutch Institute for Healthcare Improvement
CCO
Cancer Care Ontario
CODG
Conventional open distal gastrectomy
CPG
Clinical Practice Guideline
CRT
Chemoradiotherapy
CT
Computed tomography
EMR
Endoscopic mucosal resection
ESD
Endoscopic submucosal dissection
EUS
Endoscopic ultrasound
FNA(C
Fine needle aspiration (cytology)
FNCLCC
Fédération Nationale des Centres de Lutte Contre le Cancer
GI
Gastrointestinal
GIST
Gastrointestinal stromal tumours
GOJ
Gastro-oesophageal junction
GRADE
Grading of
Evaluation
HR
Hazard ratio
HRE
High-resolution endoscopy
IARC
International Agency for Research on Cancer
IBD
Inflammatory bowel disease
IUAC
International Union Against Cancer
LN
Lymph node
MALT
Mucosa-associated lymphoid tissue
MDCT
Multidetector row CT
MDT
Multidisciplinary team
MeSH
Medical Subject Headings
MRI
Magnetic resonance imaging
NBI
Narrow band imaging
NICE
National Institute for Health and Clinical Excellence
OR
Odds ratio
PDT
Photodynamic therapy
PET
Positron-emission tomography
Recommendations
Assessment,
Development
and
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Upper GI Cancer
RCT
Randomised Controlled Trial
RR
Risk ratio
SCJ
Squamo-columnar junction
SEMS
Self-expanding metal stents
SIGN
Scottish Intercollegiate Guidelines Network
SSBE
Short-segment Barrett’s oesophagus
UK
United Kingdom
US
United States of America
WHO
World Health Organisation
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INTRODUCTION
1.1
SCOPE
5
In the present report, a clinical practice guideline (CPG) on upper gastrointestinal
cancer is presented, which is the result of a collaboration of the College of Physicians
for Oncology and the KCE. This clinical practice guideline will cover a broad range of
topics: diagnosis, staging, treatment, supportive therapy, and follow-up. The guideline
primarily concerns individuals with oesophageal or gastric cancer, and is intended to be
used by all care providers involved in the care for these patients.
1.2
EPIDEMIOLOGY
1.2.1
Oesophageal cancer
Oesophageal cancer is the eighth most common cancer in the world and one of the
most lethal [1]. Incidence rates of oesophageal cancer show well-known regional
disparities. Overall, incidence rates for all types of oesophageal cancer range from four
to nine cases per 100.000 males per year (1975 – 1997) in Western countries [2].
Lower incidence rates are found in Northern Europe (Finland, Norway, and Sweden),
whereas the French regions of Burgundy and Calvados have incidence rates of > 14 per
100.000 males per year.
In the Netherlands, Crane et al. found an increase in age standardised incidence by 3.4%
and 1.9% per year (1989 – 2003) for males and females respectively [3]. This increase
was almost exclusively caused by oesophageal adenocarcinomas. In 14 years, age
standardised mortality increased 2.5% per year among males and 1.7% per year among
females. Similar trends were found in the UK and the US, but not in France [4]. Relative
survival in the Netherlands improved significantly from 8.1% in 1989-1993 to 12.6% in
1999-2003 (p<0.001) [3].
Differences in incidence trends of the two main histological types of oesophageal cancer
– squamous cell carcinoma and adenocarcinoma – are noteworthy. The incidence rate
of squamous cell carcinoma of the oesophagus has been relatively stable in most
countries from 1975 to 1995 according to the International Agency for Research on
Cancer (IARC), although increasing trends were observed in Denmark and the
Netherlands among men and in Canada, Scotland and Switzerland among women [5]. A
significant increase in the incidence of oesophageal adenocarcinomas was found in both
sexes in Canada and South Australia and in 6 European countries (Scotland, Denmark,
Iceland, Finland, Sweden and Norway). In France the increase was limited to men and in
Switzerland the increase was observed only in women [5].
In Belgium, the crude incidence rate of oesophageal cancer rose from 8.8 per 100.000
males in 1997 to 10.8 per 100.000 males in 2003, and from 2.2 per 100.000 females in
1997 to 3.5 per 100.000 females in 2003 (Belgian Cancer Registry, personal
communication). Age standardised incidence increased by 2.9% and 11.7% per year
(1997 – 2003) for males and females respectively (Table 1).
Table 1. Age standardised incidence$ of oesophageal cancer in Belgium, 1997
– 2003 (n/100.000 person years) (Belgian Cancer Registry, personal
communication).
Year
Males
Belgium
5.8
5.5
5.8
6.3
7.0
6.9
6.8
1997
1998
1999
2000
2001
2002
2003
$using
a world standard population.
Females
Flanders
6.5
6.2
5.7
6.8
8.0
7.3
7.0
Belgium
1.0
1.1
1.4
1.6
1.6
1.6
1.7
Flanders
1.2
1.2
1.5
1.7
1.5
1.3
1.9
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KCE reports 75
The differences in incidence trends of oesophageal squamous cell carcinoma and
adenocarcinoma are less pronounced in Belgium (Table 2 and Figure 1). This is probably
due to the fact that the Belgian cancer registration is of recent years (only going back
until 1997). During the first registration years a high percentage of tumours with
unspecified histology were registered. However, recently the quality of the cancer
registration markedly improved. This lead to an increase in incidence of both squamous
cell carcinoma and adenocarcinoma and a decrease in the incidence of tumours with
unspecified histology (Table 2 and Figure 1) (Belgian Cancer Registry, personal
communication).
Table 2. Age standardised incidence$ of oesophageal cancer in Belgium
according to histological type, 1997 – 2003 (n/100.000 person years) (Belgian
Cancer Registry, personal communication).
Males
• SCC#
• Adenocarcinoma
• Unspecified tumour
Females
• SCC#
• Adenocarcinoma
• Unspecified tumour
$using
1997
1998
1999
2000
2001
2002
2003
4.0
2.7
1.0
3.9
2.8
0.6
4.2
2.9
0.5
4.4
3.6
0.4
4.9
4.5
0.2
5.2
4.0
0.1
4.7
4.3
0.2
0.9
0.4
0.1
1.0
0.4
0.1
1.3
0.4
0.2
1.4
0.7
0.0
1.6
0.6
0.1
1.5
0.5
0.1
1.5
0.8
0.1
a European standard population. #SCC: squamous cell carcinoma.
Figure 1. Age standardised incidence$ of oesophageal cancer in Belgium for
males according to histological type, 1997 – 2003 (n/100.000 person years)
(Belgian Cancer Registry, personal communication).
$using
1.2.2
a European standard population.
Gastric cancer
With an estimated 934.000 new cases per year in 2002 worldwide (8.6% of all new
cancer cases), gastric cancer is in fourth place behind cancers of the lung, breast, and
colon and rectum, with almost two-third of the cases occurring in developing countries
[1]. It is the second most common cause of death from cancer.
Gastric cancer incidence rates vary by up to ten-fold throughout the world. Japan and
Korea have the highest gastric cancer incidence rates in the world.
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High-incidence areas for non-cardia gastric adenocarcinoma include East Asia, Eastern
Europe, and Central and South America. Low incidence rates are found in South Asia,
North and East Africa, North America, Australia, and New Zealand [6]. Survival is
moderately good only in Japan (52%), where mass screening by photofluoroscopy has
been practiced since the 1960s. Survival is also relatively high in North America
(approximatively 21%), possibly due to early diagnosis following a higher number of
endoscopic examinations performed for gastric disorders. Estimated survival is 27% in
Western Europe [1].
In the Netherlands, age standardised incidence of gastric cancer declined from 21.6 to
15.9 per 100.000 person years in males and from 10.4 to 6.2 per 100.000 person years
in females since 1978 [7]. The age standardised mortality rates decreased from 20.7 to
12.8 per 100.000 person years in males and from 8.2 to 4.2 per 100.000 person years in
females.
In Belgium, the crude incidence rate of gastric cancer rose from 12.9 per 100.000 males
in 1997 to 14.9 per 100.000 males in 2003, and from 8.0 per 100.000 females in 1997 to
8.4 per 100.000 females in 2003 (Belgian Cancer Registry, personal communication).
Age standardised incidence increased by 2.6% and 0.8% per year (1997 – 2003) for
males and females respectively (Table 3). However, in these rates tumours of the
gastro-oesophageal junction (GOJ) are also included.
While the incidence rates of these GOJ tumours recently increased, the incidence rates
of ‘real’ gastric tumours (see chapter 3.1) declined [8].
Table 3. Age standardised incidence$ of gastric cancer in Belgium, 1997 –
2003 (n/100.000 person years) (Belgian Cancer Registry, personal
communication).
Year
Males
Belgium
7.4
7.3
7.9
7.5
8.2
8.5
8.2
1997
1998
1999
2000
2001
2002
2003
$using
a world standard population.
Females
Flanders
9.2
8.3
9.1
9.0
9.8
9.8
9.1
Belgium
3.1
3.4
3.5
3.9
3.5
3.9
3.2
Flanders
4.3
4.1
4.4
4.5
4.2
4.5
3.6
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2
METHODOLOGY
2.1
GENERAL APPROACH
KCE reports 75
As for the previous CPGs developed within the collaboration between the College and
the KCE, the present CPG was developed by adapting (inter)national CPGs to the
Belgian context [9]. This approach is currently being structured in a formal
methodology by the ADAPTE group, an international group of guideline developers and
researchers [10]. The ADAPTE methodology generally consists of three major phases:
1. Set-up Phase: Outlines the necessary tasks to be completed prior to
beginning the adaptation process (e.g., identifying necessary skills and
resources).
2. Adaptation Phase: Assists guideline developers in moving from selection of
a topic to identification of specific clinical questions; searching for and
retrieving guidelines; assessing the consistency of the evidence therein, their
quality, currency, content and applicability; decision making around
adaptation; and preparing the draft adapted guideline.
3. Finalization Phase: Guides guideline developers through getting feedback
on the document from stakeholders who will be impacted by the guideline,
consulting with the source developers of guidelines used in the adaptation
process, establishing a process for review and updating of the adapted
guideline and the process of creating a final document.
2.2
CLINICAL QUESTIONS
The clinical practice guideline addresses the following clinical questions:
1. Which diagnostic techniques should be used for the diagnosis of oesophageal
and gastric cancer?
2. What are the best treatment options for dysplastic lesions of the oesophagus
and stomach?
3. What staging techniques should be used for oesophageal and gastric cancer?
4. What are the best treatment options for mucosal oesophageal and gastric
cancer?
5. What are the best treatment options for oesophageal and gastric cancer
beyond the mucosa?
a. neoadjuvant treatment
b. surgical treatment
c. adjuvant treatment
d. non-surgical treatment with curative intent
6. What are the best palliative treatment options for extensive disease?
7. What are the best follow-up strategies for oesophageal and gastric cancer?
8. What are the best treatment options for gastric lymphoma?
9. What are the best treatment options for gastrointestinal stromal tumours?
KCE Reports 75
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2.3
SEARCH FOR EVIDENCE
2.3.1
Clinical practice guidelines
2.3.1.1
Sources
9
A broad search of electronic databases (Medline, EMBASE), specific guideline websites
and websites of oncologic organisations (Table 4) was conducted in July 2007.
Table 4: Searched guideline websites and websites of oncologic
organisations.
Alberta Heritage Foundation For Medical
Research (AHFMR)
American Society of Clinical Oncology (ASCO)
American College of Surgeons (ACS)
CMA Infobase
Guidelines International Network (GIN)
National Comprehensive Cancer Network
(NCCN)
National Guideline Clearinghouse
National Cancer Institute
Haute Autorité de Santé (HAS)
BC Cancer Agency
Institute for Clinical Systems Improvement (ICSI)
National Health and Medical Research Council
(NHMRC)
Scottish Intercollegiate Guidelines Network
(SIGN)
New Zealand Guidelines Group (NZGG)
Fédération Nationale des Centres de Lutte
Contre le Cancer (FNCLCC)
National Institute for Health and Clinical
Excellence (NICE)
2.3.1.2
http://www.ahfmr.ab.ca/
http://www.asco.org/
http://www.facs.org/cancer/coc/
http://mdm.ca/cpgsnew/cpgs/index.asp
http://www.g-i-n.net/
http://www.nccn.org/
http://www.guideline.gov/
http://www.cancer.gov/
http://bfes.hassante.fr/HTML/indexBFES_HAS.html
http://www.bccancer.bc.ca/default.htm
http://www.icsi.org/index.asp
http://www.nhmrc.gov.au/
http://www.sign.ac.uk/
http://www.nzgg.org.nz/
http://www.fnclcc.fr/sor/structure/indexsorspecialistes.html
http://www.nice.org.uk/
Search terms
For Medline the following MeSH terms were used in combination: stomach neoplasms,
esophageal neoplasms. For EMBASE the following Emtree terms were used in
combination: stomach tumor, esophagus tumor. These MeSH and Emtree terms were
combined with a standardised search strategy to identify CPGs (Table 5).
Table 5: Standardised search strategy for CPGs.
Database
Medline
Search strategy
guideline [pt] OR practice guideline [pt] OR
recommendation* [ti] OR standard* [ti] OR
guideline* [ti]
'practice guideline'/exp
EMBASE
2.3.1.3
In- and exclusion criteria
Both national and international CPGs on oesophageal and gastric cancer were searched.
A language (English, Dutch, French) and date restriction (2001 – 2007) were used.
CPGs without references were excluded, as were CPGs without clear
recommendations.
10
2.3.2
Upper GI Cancer
KCE reports 75
Additional evidence
For each clinical question, the evidence – identified through the included CPGs – was
updated by searching Medline and the Cochrane Database of Systematic Reviews from
the search date of the CPG on (search date August – September 2007). A combination
of appropriate MeSH terms and free text words was used (see appendix).
For therapeutic interventions, only systematic reviews and randomized controlled trials
(RCT) were included. However, for diagnostic interventions we also searched for
observational studies in case no systematic review or RCT was found. The identified
studies were selected based on title and abstract. For all eligible studies, the full-text
was retrieved. In case no full-text was available, the study was not taken into account
for the final recommendations.
2.4
QUALITY APPRAISAL
2.4.1
Clinical practice guidelines
In total, 17 CPGs were identified. All were quality appraised by two independent
reviewers (JV, FM) using the AGREE instrument. Disagreement was discussed face-toface. At the end, agreement was reached for all CPGs, and 7 CPGs were included (see
appendix).
2.4.2
Additional evidence
The quality of the retrieved systematic reviews and RCTs was assessed using the
checklists of the Dutch Cochrane Centre (www.cochrane.nl).
2.5
DATA EXTRACTION AND SUMMARY
For each included CPG the following data were extracted: search date & publication
year, searched databases, availability of evidence tables, recommendations and
referenced evidence.
For each systematic review, the search date, publication year, included studies and main
results were extracted. For RCTs, the following data were extracted: publication year,
study population, study intervention, and outcomes.
For each clinical question, the recommendations from the identified CPGs and the
additional evidence were summarized in evidence tables. A level of evidence was
assigned to each recommendation and additional study using the GRADE system (see
appendix).
2.6
FORMULATION OF RECOMMENDATIONS
Based on the retrieved evidence, a first draft of recommendations was prepared by a
small working group (JV, FM). This first draft together with the evidence tables was
circulated to the guideline development group 2 weeks prior to the first face-to-face
meeting. The guideline development group met on several occasions (October 1st 2007,
November 5th 2007, December 10th 2007 and January 9th 2008) to discuss the first draft.
Recommendations were changed if important evidence supported this change. Based on
the discussion meetings a second draft of recommendations was prepared. A grade of
recommendation was assigned to each recommendation using the GRADE system (see
appendix). The second draft was once more circulated to the guideline development
group for final approval.
2.7
EXTERNAL REVIEW
The recommendations prepared by the guideline development group were circulated to
the Professional Associations (Table 6). Each association was asked to assign 2 key
persons to discuss the recommendations during an open meeting.
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11
These panellists received the recommendations one week prior to this open meeting.
As a preparation of the meeting all invited panellists were asked to score each
recommendation on a 5-point Likert-scale to indicate their agreement with the
recommendation, with a score of ‘1’ indicating ‘completely disagree’, ‘2’ indicating
‘somewhat disagree’, ‘3’ indicating ‘unsure’, ‘4’ indicating ‘somewhat agree’, and ‘5’
indicating ‘completely agree’ (the panellists were also able to answer ‘not applicable’ in
case they were not familiar with the underlying evidence). In case a panellist disagreed
with the recommendation (score ‘1’ or ‘2’), (s)he was asked to provide appropriate
evidence. All scores (n = 15) were than anonymized and summarized into a mean score,
standard deviation and % of ‘agree’-scores (score ‘4’ and ‘5’) to allow a targeted
discussion (see appendix). The recommendations were then discussed during a face-toface meeting on January 23rd 2008. Based on this discussion a final draft of the
recommendations was prepared, and discussed by the guideline development group by
email. In appendix, an overview is provided of how the comments of the experts were
taken into account.
Table 6: List of Professional Associations to which the recommendations
were communicated.
Belgian Society of Medical Oncology (BSMO)
Belgian Society of Radiotherapy (BVRO – ABRO)
Belgian Society of Nuclear Medicine
Belgian Society of Surgical Oncology (BSSO)
Upper GI section of the Royal Belgian Society of Surgery
Flemish Society of Gastroenterology (VVGE)
Belgian Group of Digestive Oncology (BGDO)
Royal Belgian Society of Gastroenterology (SRBGE)
Domus Medica (Scientific association of Flemish general practitioners)
Belgian Society of Gastrointestinal Endoscopy (BSGIE)
Belgian Digestive Pathology Club
Belgian Society of Pathology
Royal Belgian Radiological Society
Scientific Society of General Medicine (SSMG)
Belgian Group for Endoscopic Surgery (BGES)
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3
DEFINITIONS
3.1
TOPOGRAPHIC DEFINITIONS
KCE reports 75
Traditionally, when discussing cancer of the oesophagus, cancer of the gastrooesophageal junction (GOJ) is also included. Clinicians are very often confronted with
adenocarcinomas that straddle the GOJ. Various criteria have been used to categorize
tumours situated at the GOJ. In most classification systems, the anatomic location of the
epicentre or predominant mass of the tumour is used to determine whether the
neoplasm is oesophageal or gastric (cardia) in origin.
Siewert and Stein proposed a topographic classification for cardia carcinomas [11].
According to these authors, epidemiologic, clinical, and pathologic data support a
subclassification of adenocarcinomas arising into the vicinity (i.e. that have their centre
within 5 cm proximal and distal of the anatomical cardia) of the GOJ into:
1. adenocarcinoma of the distal oesophagus, which usually arises from an area with
specialized intestinal metaplasia (i.e. Barrett oesophagus) and may infiltrate
the GOJ from above (type I);
2. true carcinoma of the cardia arising immediately at the GOJ (type II);
3. subcardial carcinoma that infiltrates the GOJ and distal oesophagus from below
(type III).
In contrast to previously described classification systems, Siewert and Stein attempted
to solve the problem of splitting up GOJ tumours into oesophageal and gastric tumours
by creating a third entity [11]. This third entity, the so-called cardiacarcinoma, is
lumping a large group of tumours and ‘squeezes’ the true GOJ tumours between the
type I and type II tumours. Their effort seems rather adding to the confusion than
helping to solve the true problem. This classification is entirely based on identifying the
“anatomical” cardia and measuring the centre of the tumour in relation to this
anatomical cardia on the resected specimen (i.e. pathological staging). However,
measuring the centre of the tumour is impractical if not impossible for clinical staging
purposes, which need to be as accurate as possible for making appropriate therapeutic
decisions.
In 2000, the World Health Organization Classification of Tumours published Pathology
and Genetics of Tumours of the Digestive System [12]. The authors formulated
diagnostic criteria based on the following definition of the GOJ: “the GOJ is the
anatomical region at which the tubular oesophagus joins the stomach”. According to
these authors, adenocarcinomas that cross the GOJ are called adenocarcinomas of the
GOJ, regardless of where the bulk of the tumour lies. Adenocarcinomas located entirely
above the GOJ, as defined above, are considered oesophageal carcinomas.
Adenocarcinomas located entirely below the GOJ are considered gastric in origin. The
use of the ambiguous and often misleading term ‘carcinoma of the gastric cardia’ is
discouraged. Depending on their size, these tumours should instead be referred to as
carcinoma of the body of the stomach [12].
In the most recent recommendations of the International Union Against Cancer (IUAC)
[13], according to the advice formulated in the supplement on the TNM classification,
adenocarcinomas situated at the GOJ are to be classified into oesophageal, GOJ or
cardiac adenocarcinomas using a single major criterion, i.e. the localization of the bulk of
the tumour. If more than 50% of the mass of the tumour is situated in the cardia, the
tumour should be considered to be of cardiac origin and classified as a gastric tumour. If
the mass of the tumour is predominantly found in the oesophagus, it is to be classified
as an oesophageal tumour. Furthermore, it is specified that a tumour situated on the
GOJ is likely to be of oesophageal origin when the neoplastic lesion was associated with
a Barrett oesophagus of the specialized or intestinal type. Unfortunately, the
recommendations in the most recent Cancer Staging Manual on how to handle these
tumours may not always be compatible with this classification, again creating confusion.
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13
The chapter on stomach refers to the 50% rule, whereas the chapter on oesophagus
indicates that “tumours arising within the GOJ and gastric cardia that have minimal
involvement (2 cm or less) of the oesophagus are considered primary gastric cancers”.
A continuing increase in the incidence of cardia cancer has been reported since the mid
1970s [14]. The output of scientific publications on cardia and cardiac cancer has
evolved in parallel internationally. Today, the vast majority of data available on cardia
and cardiac cancer are not comparable because of lack/variability of diagnostic criteria.
This may result in therapeutic approaches based on loose (and non-scientific) grounds.
Uniformity in classification, terminology and diagnostic criteria is urgently needed. At
present, at least in our experience, it would appear that the similarities between
adenocarcinoma of the GOJ or cardia and Barrett adenocarcinoma outnumber the
dissimilarities and are to be differentiated from gastric (including “subcardia”) cancer
[15, 16].
Since the ‘50% rule’ as proposed by the IUAC [13] is practical from a clinical staging
point of view, easily being applicable on endoscopic ultrasonography (EUS) (the top of
the longitudinal gastric mucosal folds being the endoscopic landmark between
oesophagus and stomach), this rule will be used in the present CPG. “True” GOJ
tumours should be classified and treated as oesophageal tumours.
Key points
• If more than 50% of the mass of the tumour is situated in the cardia, the
tumour should be considered to be of cardiac origin and classified as a
gastric tumour.
• If the mass of the tumour is predominantly found in the oesophagus, it
should be classified as an oesophageal tumour.
• Tumours of the gastro-oesophageal junction should be classified and have
the same concept of treatment as oesophageal tumours.
3.2
EARLY LESIONS
3.2.1
Histology of the normal oesophagus
The luminal side of the normal oesophagus is lined by mucosa composed of epithelium,
lamina propria and the muscularis mucosae. Except for a short segment of columnar
epithelium in the distal oesophagus at the gastro-oesophageal junction the normal
oesophageal epithelium is a tough non-keratinizing stratified squamous epithelium. This
epithelium consists of a dynamic cell population which is renewed continuously. The
different cell layers in the squamous epithelium - basal, intermediate or prickle cell
layers and superficial layers (functional and surface) - are the morphological expression
of processes of proliferation, differentiation or maturation and dying cells. A variety of
cell types such as neuroendocrine cells (Merkel cells), rare melanocytes, lymphocytes
and Langerhans cells are normally present within the squamous epithelium of the
oesophagus. The lamina propria rests on a muscularis mucosae. The lamina propria
contains lymphatics, blood vessels, nerve fibres and occasional inflammatory cells. The
three remaining layers of the oesophageal wall are the submucosa, an area of loose
connective tissue containing mucus-secreting glands that open into the lumen via ducts,
the muscularis propria with an inner circular and an outer longitudinal layer, and the
adventitia. The oesophagus lacks a defining layer of mesothelial cells.
3.2.2
Barrett’s oesophagus
3.2.2.1
Anatomy
The muscular GOJ is the site at which the most distal portion of the oesophagus (the
most distal segment of the lower oesophageal sphincter [LOS]) meets the proximal
stomach. Endoscopically, one can closely approximate the muscular GOJ by identifying
the proximal margin of the gastric folds.
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The mucosal GOJ, also known as the mucosal squamo-columnar junction (SCJ) or Zline, is the site at which the squamous mucosa of the oesophagus meets columnar- lined
mucosa. It is important to understand, however, that the SCJ may be at the same level
as the muscular GOJ or may lie 1-2 cm above the muscular GOJ in ‘normal’ individuals.
In order to avoid confusion between Barrett’s mucosa and normal – gastric – junctional
columnar mucosa, especially in cases further complicated by the presence of hiatus
hernia, an arbitrary minimal length of 3 cm of Barrett’s mucosa from the GOJ was
required before the diagnosis of Barrett’s mucosa could be made [17]. Short-segment
Barrett’s oesophagus (SSBE) was later defined as Barrett’s mucosa <2-3 cm in length
and an ultrashort segment as a microscopically Barrett’s mucosa at a normal looking
GOJ, both in contrast to the classical ‘long’ segment Barrett’s oeosophagus.
3.2.2.2
Histology
THE EPITHELIUM
Barrett’s mucosa is a type of metaplasia (replacement of one mature tissue type by
another mature tissue type) aimed at better withstanding the gastro-oesophageal reflux.
Since its first description, three types of columnar epithelium were described in
Barrett’s mucosa: the specialized intestinal epithelium (SIM), the junctional epithelium
(or cardia-antral type) and the fundic (or oxyntic) epithelium, the two latter both being
gastric types [18]. The malignant potential of Barrett’s mucosa was subsequently
described and specifically attributed to the specialized intestinal epithelium and not to
the two gastric types of metaplasia [19-22].
Over time, the following ‘adapted’ definitions of Barrett’s mucosa – combining
endoscopy and histology – were proposed:
- A change in the oesophageal epithelium of any length that can be recognized at
endoscopy and is confirmed to have intestinal metaplasia by biopsy [23] (which is the
most commonly accepted definition);
- A displacement of the SCJ proximal to the GOJ with the presence of specialized
intestinal epithelium [24];
- An apparent area above the GOJ that is suggestive of Barrett’s, which is supported
by the finding of columnar lined oesophagus on histology. The finding of intestinal
metaplasia, although often present, is not a requirement for diagnosis. If a sufficient
number of biopsies are taken over an adequate period of time, intestinal metaplasia can
usually be demonstrated in the majority of these patients [25].
The fact that the definition of Barrett’s mucosa has evolved and is adapted over time
and that these ‘adapted’ definitions show (minor) differences, does hamper the
interpretation of data published in the literature.
Conceptually, intestinal metaplasia in Barrett’s mucosa is an integral part of the
‘metaplasia-dysplasia-carcinoma’ sequence. Pragmatically, it was thought that the finding
of specialized intestinal mucosa was the ultimate hallmark of biopsies taken in a Barrett’s
mucosa. Therefore, these biopsies would have to be taken in the oesophagus and not in
the stomach, i.e. taken in the cardia (especially, when considering an ultrashort Barrett’s
oesophagus). In the meantime, it has been shown that intestinal metaplasia does develop
in the cardia too. Thus, the finding of intestinal cells at the GOJ is an abnormal feature.
It is not clear whether this metaplastic epithelium originates from the oesophagus (socalled ultrashort Barrett) or from the stomach
(intestinal metaplasia of the gastric cardia), the latter arguably being the result of gastrooesophageal reflux disease and subsequent carditis [26].
THE MUSCULARIS MUCOSAE
Patients with Barrett’s oesophagus often develop a new (superficial), more luminally
situated, layer of muscularis mucosae [27]. Important to know is that endoscopic
biopsies may contain some limited fragments of muscle. These may originate from a
newly formed muscularis mucosae or from the original muscularis mucosae. However,
light microscopic distinction towards origin is impossible.
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The ‘double’ muscularis mucosae can only be visualized in (good quality) endoscopic
mucosal resection (EMR) and operation specimens. Only invasion through the original,
deeper muscularis mucosae is defined as “submucosal” invasion [28, 29].
3.2.3
Dysplasia in squamous epithelium
In squamous epithelium dysplasia is classified as mild, moderate, or severe. With
increasing grades of dysplasia there is a progressive increase in dysplastic cells from the
basal layer onwards untill the entire thickness of the epithelium is replaced. The latter
state is described as carcinoma in situ [30]. When dysplastic cells reach the luminal
aspect of the epithelium without cytoplasmic maturation the term carcinoma in situ can
be used.
Some authors use a simplified classification for non-invasive squamous neoplastic
lesions: low-grade intraepithelial neoplasia, which includes mild and moderate dysplasia,
and high-grade intraepithelial neoplasia, which includes severe dysplasia and carcinoma
in situ.
By definition, the basement membrane is intact in dysplasia. However, the junction of
the epithelium with the underlying stroma may become irregular [31].
3.2.4
Dysplasia in columnar epithelium
From a biological point of view, the progression of precursors and precursor lesions
into carcinomas is driven by the evolution and proliferation of clones of cells with
accumulated genetic errors related to control of cell proliferation, intercellular
adhesion, tumour suppression, etc., resulting in genomic instability.
Dysplasia is defined as ‘an unequivocal neoplastic epithelium confined within its
basement membrane [32]. Furthermore, dysplasia has the potential to progress into
invasive malignancy. Although morphological detection in mucosal biopsy specimens is
still the best method of detecting patients at risk of developing cancer, it has its
limitations:
INTRA-OBSERVER AND INTER-OBSERVER VARIABILITY
Numerous articles have been published on this topic demonstrating specific areas of
discordance at the lower and higher end of the spectrum of early lesions. There is a
significant degree of intra-observer and inter-observer variability in the diagnosis of
dysplasia (unequivocal neoplastic atypia) versus reactive atypia even among experienced
gastrointestinal pathologists [33-35]. Similarly, it has become apparent, especially from
comparative studies between Western and Japanese pathologists, that the differential
diagnosis between high-grade dysplasia, carcinoma in situ and intramucosal carcinoma is
prone to intra-observer and inter-observer variability [36-38].
CLASSIFICATIONS
Diagnosis of dysplasia is based on the detection of morphological changes. According to
the severity of histological changes, dysplasia has been graded using either a three tier
system or a two tier system (Table 7). The changes were initially described as mild,
moderate and severe dysplasia (morphological classification, 3-tier). In 1983, the
Inflammatory Bowel Disease (IBD) study group classified dysplasia as negative, indefinite
or positive, i.e. low and high-grade (clinical classification, 2-tier: low-grade = mild and
moderate dysplasia; high-grade = severe dysplasia) (Table 7)) [32].
Grading in a two tier system would seem to be easier and more reproducible, and
moreover to correlate with clinical implications. In the US and Western Europe, there
was a general agreement that this clinically based classification was applicable to
neoplastic changes in Barrett’s mucosa too [35, 39, 40]. In 2000, three new
classifications for gastrointestinal dysplasia have been proposed: the Padova classification
(gastric) [41], the Vienna classification [42] and the revised Vienna classification [43]
(Table 7).
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These new classifications aimed at : 1) changing the terminology used, i.e. replacing
dysplasia by (intra)epithelial neoplasia; 2) including not only dysplasia but also (invasive)
carcinomas; and 3) distinguishing ‘mucosal high-grade neoplasia’ into high-grade
dysplasia, suspicion for non-invasive or invasive carcinoma, non-invasive carcinoma,
intramucosal carcinoma and carcinoma invading submucosa or beyond. The major
differences amongst these classifications reside in the subcategories included/grouped
and the figures attributed. Comparative studies using the new classifications have shown
an improvement of the inter-observer variability especially between the Western and
Japanese pathologists [36-38, 44]. Finally, a revision of the WHO classification of
tumours of the digestive system was published at the end of 2000 [45]. The latter
introduced ‘high-grade intraepithelial neoplasia’ (including severe dysplasia and
carcinoma in situ), but did not recommend one or another of the previously mentioned
classifications. Up till now, these new classifications have not yet gained widespread
acceptance [25, 46]. Moreover, the authors of the Vienna classification stressed that the
subdivisions related to ‘mucosal high-grade neoplasia’ (high-grade dysplasia, suspicion for
invasive carcinoma, non-invasive carcinoma and intramucosal carcinoma) may be
important for research purposes and may not be needed for clinical purposes [42].
Moreover, for resection specimens, only specific histological diagnoses should be given.
Group classifications such as ‘mucosal high-grade neoplasia’ should not be used [44].
In conclusion, especially concerning the higher end of the spectrum of early lesions and
in view of the importance of a multidisciplinary approach, it is important for a
pathologist to have a clear understanding of the particular treatment regimens available
and to be applied under particular circumstances. Classification is a chosen arrangement
of elements in relation to a purpose. For the physician, a classification should be
clinically relevant. Currently, the main clinical options are no follow-up, follow-up, local
treatment by endoscopy, minimally invasive (laparoscopic) surgery and extensive
surgery including lymph node dissection (see below). Many studies have evaluated the
potential utility of immunohistochemical or molecular markers as additional techniques
in detecting dysplasia, however with limited success. Additional confirmation by an
expert pathologist (second opinion) is advocated, especially when therapeutic
intervention is considered [25]. Today, the new classifications should be taken for what
they are, i.e. attempts at an international level to reach consensus on histological
diagnosis of dysplasia in ‘chosen arrangements of elements’ which may eventually
generate guidelines for the development of diagnostic and management strategies.
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Table 7. Overview of classifications for dysplasia.
IBD
Negative for
dysplasia
Indefinite for
dysplasia
Low-grade
dysplasia
High-grade
dysplasia
Padova
1. Negative for dysplasia
1.0. Normal
1.1. Reactive foveolar
hyperplasia
1.2. Intestinal metaplasia (IM)
1.2.1. IM complete type
1.2.1. IM incomplete type
2. Indefinite for dysplasia
2.1. Foveolar hyperplasia
2.2. Hyperproliferative IM
3. Non-invasive neoplasia (flat
or elevated)
3.1. Low-grade
3.2. High-grade
3.2.1. High-grade including
suspicious carcinoma without
invasion (intraglandular)
3.2.2. High-grade including
carcinoma without invasion
(intraglandular)
4. Suspicious for invasive
carcinoma
5. Invasive adenocarcinoma
Vienna
1. No neoplasia
Revised Vienna
1. No neoplasia
2. Indefinite for dysplasia
2. Indefinite for dysplasia
3. Low-grade
adenoma/dysplasia
3. Low-grade
adenoma/dysplasia
4. Non-invasive highgrade neoplasia
4.1. High-grade
adenoma/dysplasia
4. High-grade neoplasia
4.2. Non-invasive
carcinoma (carcinoma in
situ)
4.3. Suspicious for
invasive carcinoma
5. Invasive neoplasia
5.1. Intramucosal
carcinoma
5.2. Submucosal
carcinoma (or deeper
infiltration)
TNM
4.1. High-grade
adenoma/dysplasia
4.2. Non-invasive
carcinoma (carcinoma in
situ)
4.3. Suspicious for
invasive carcinoma
Tis
4.4. Intramucosal
carcinoma
T1a
Key points
• There is no consensus about the definition of Barrett’s oesophagus.
• Several classifications are available for dysplasia. For the physician, the used
classification should be clinically relevant.
T1b
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FINAL RECOMMENDATIONS ON
OESOPHAGEAL CANCER
4.1
FLOWCHART
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4.2
Upper GI Cancer
19
DIAGNOSIS
The diagnosis of oesophageal cancer should include a history and clinical examination.
However, a diagnosis purely based on clinical grounds is unreliable [47]. Two diagnostic
procedures, i.e. flexible upper gastrointestinal (GI) endoscopy and barium contrast
radiology, are available. However, barium studies are less sensitive than endoscopy for
the diagnosis of early malignancy and they cannot reliably diagnose premalignant lesions
including dysplasia. Therefore, flexible upper GI endoscopy with at least biopsies of all
suspicious lesions is recommended as the diagnostic procedure of choice in patients
with suspected oesophageal cancer [47]. Nevertheless, barium studies can be useful to
determine the oesophageal or gastric extent of a tumour, to confirm the presence of a
tracheo-oesophageal fistula or to document complete luminal obstruction [48].
The following alarm symptoms are associated with oesophageal (and gastric) cancer and
should lead to a referral for early endoscopy and biopsies: dysphagia, recurrent
vomiting, anorexia, weight loss and gastrointestinal blood loss [47, 49]. The general
practitioner has an important role in recognizing these symptoms. In a recent
prospective study, Bowrey et al. found a sensitivity of 85% using alarm symptoms for
the referral for endoscopy [49]. This means that 15% of patients with oesophageal
cancer would not have been referred for initial endoscopic assessment because of the
absence of alarm symptoms. Importantly, patients with alarm symptoms had a
significantly more advanced tumour stage (metastatic disease in 47% vs. 11%; p < 0.001),
were less likely to undergo surgical resection (50% vs. 95%; p<0.001), and had a poorer
survival (median, 11 vs. 39 months; p = 0.01) than patients without such symptoms [49].
Although odynophagia was not discussed in this study, it can be used as an additional
alarm symptom of oesophageal cancer warranting endoscopic evaluation [50].
Patients at high risk for developing oesophageal cancer (Table 8) may benefit from
screening and follow-up with chromoendoscopy (methylene blue, indigo carmine, lugol,
etc.) [47, 51]. In a recent RCT, diagnostic accuracy of autofluorescence endoscopy
(AFE) combined with four-quadrant biopsies was higher than the diagnostic accuracy of
conventional endoscopy with four-quadrant biopsies (one additional high grade
dysplasia or adenocarcinoma for every 23 patients undergoing AFE vs. 1 in 93 patients
undergoing conventional endoscopy) [52]. On the other hand, methylene-blue directed
biopsies were found to be less sensitive in detecting dysplasia than random fourquadrant biopsies in Barrett’s esophagus [53].
High-resolution endoscopy (HRE) is a fairly new endoscopic imaging technique with the
potential to improve the detection of early neoplasia in Barrett’s oesophagus [48]. One
RCT was identified comparing indigo carmine chromoendoscopy and narrow band
imaging as adjuncts to HRE [54]. Both techniques were found to have a comparable
diagnostic accuracy. No studies were found comparing HRE to conventional techniques
[48].
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Table 8. Features associated with high risk for developing oesophageal
cancer.
Clinical features:
•
Alcohol and tobacco abuse
•
Longstanding gastro-oesophageal reflux disease
•
Neck, mouth and head cancer
•
Previous oesophageal cancer
•
Barrett’s oesophagus
•
Caustic injury
•
Papilloma
•
Genetic diseases
•
Various: Achalasia, Plummer-Vinson, Celiac disease
Endoscopic features:
•
stricture
•
ulceration
•
nodularity
Histological features:
•
high-grade dysplasia
•
multifocal dysplastic lesions, persisting after adequate conservative
treatment for 6-8 weeks
Recommendations
1. Patients presenting with any of the following alarm symptoms within
the clinical context of potential oesophageal pathology should be
referred for early endoscopy and biopsies: dysphagia, recurrent
vomiting, anorexia, weight loss, gastrointestinal blood loss (1C
recommendation).
2. Flexible upper gastrointestinal endoscopy with at least biopsies of all
suspicious lesions is recommended as the diagnostic procedure of
choice in patients with suspected oesophageal cancer (1C
recommendation).
3. High-resolution endoscopy (HRE) and chromoendoscopy is not
routinely recommended, but may be of value in screening and
follow-up of high-risk patients (2C recommendation).
4.3
WORK-UP OF DYSPLASTIC LESIONS
Evidence from a few RCTs [47] and one low-quality systematic review [55] suggests
that anti-reflux surgery is not indicated in patients with Barrett’s oesophagus to reduce
the risk of progression to adenocarcinoma.
Patients diagnosed with high-grade dysplasia should have careful endoscopic assessment
[47]. However, dysplastic lesions in patients with Barrett’s oesophagus are difficult to
detect using conventional endoscopy. Recent studies suggest that high-resolution
endoscopy (HRE) – with or without chromoendoscopy –, narrow band imaging (NBI)
or autofluorescence may improve the detection of dysplastic lesions (see above) [56].
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In patients with Barrett's oesophagus, a structured biopsy protocol with quadrantic
biopsies every two centimetres and biopsy of any visible lesion is recommended. In the
presence of dysplasia, quadrantic biopsies should be taken every 1 cm during
surveillance and control endoscopies [57, 58]. In addition to the endoscopic assessment,
patients with high-grade dysplasia should have a careful pathological assessment [47].
Evaluation of suspected high-grade dysplasia in Barrett's oesophagus biopsies should be
undertaken with knowledge of the clinical and endoscopic background. Pathologists
should follow a classification for reporting dysplasia that the multidisciplinary team is
familiar with. An overview of classifications is already provided in chapter 3.2.4. Where
therapeutic intervention is contemplated on the basis of high-grade dysplasia, the
diagnosis should be validated by a second pathologist experienced in this area because
of the significant inter- and intra-observer variation [47, 56]. Further biopsies or
diagnostic endoscopic mucosal resection (EMR) should be done if there is uncertainty.
Biopsies should also be reviewed at a multidisciplinary meeting with access to the
clinical information.
Finally, as the diagnosis, treatment and follow-up of patients with oesophageal highgrade dysplastic lesions is very specific and new techniques rapidly become available,
these patients should be referred to centres or network reference centres with the
appropriate endoscopic and surgical expertise and facilities [47]
Recommendations
4. Reduction of risk of progression to adenocarcinoma is not an
indication for anti-reflux surgery in patients with Barrett's
oesophagus (2A recommendation).
5. In patients with Barrett's oesophagus there should be a structured
biopsy protocol with quadrantic biopsies every two centimetres and
biopsy of any visible lesion (1C recommendation).
6. Pathologists should follow a classification for reporting dysplasia that
the multidisciplinary team is familiar with (1C recommendation).
7. Evaluation of suspected high-grade dysplasia in Barrett's oesophagus
biopsies should be undertaken with knowledge of the clinical and
endoscopic background (1C recommendation).
8. Patients confirmed with high-grade dysplasia should have careful
endoscopic and pathological assessment (1C recommendation).
9. High-resolution endoscopy +/- chromoendoscopy as well as every 1
cm qaudrantic biopsies is recommended in patients with a dysplastic
or neoplastic lesion in a Barrett's oesophagus (1C recommendation).
10. Where therapeutic intervention is contemplated on the basis of
high-grade dysplasia, the diagnosis should be validated by a second
pathologist experienced in this area and further biopsies or
eventually diagnostic endoscopic mucosal resection (EMR) should be
done if there is uncertainty (1C recommendation).
11. Treatment options for patients with high-grade dysplasia should be
discussed at a multidisciplinary meeting with access to the clinical
and pathological information (expert opinion).
12. Patients with high-grade dysplasia should be referred to centres or
network reference centres with the appropriate endoscopic and
surgical expertise and facilities (1C recommendation).
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STAGING
In patients with oesophageal cancer, CT scan of the chest and abdomen with
intravenous contrast and gastric distension with oral contrast or water should be
performed routinely. The liver should at least be imaged in the arterial and portal
venous phase [47]. Slice thickness should be 5 mm or less [56]. The main contribution
of CT scan to the staging of oesophageal cancer is the detection of distant metastases
and gross invasion of adjacent structures/organs [47, 56, 59]. If metastatic disease is
detected with CT scan, curative treatment is excluded and additional staging with EUS
and/or PET scan is unnecessary. CT scan has also an acceptable diagnostic accuracy for
locoregional staging (T and N), although EUS is clearly more sensitive (see below) [47,
56]. Given the high incidence of cervical lymph node metastasis [60], CT scan should
also include the cervical region.
EUS has emerged as the imaging technique of choice for locoregional staging [47, 56],
with a diagnostic accuracy ranging from 53-94% (median 83%) for T-staging and from
54-94% for N-staging (median 76%) [61]. In stenotic tumours, the accuracy of EUS is
further improved with the use of dilation, which in most cases permits passage of the
endoscope [62, 63]. However, this is associated with a risk of perforation [64].
Importantly, most studies dealing with the accuracy of N-staging only assess the yes-no
possibility of positive lymph nodes, without correlating the EUS findings of a positive
lymph node to the histopathological findings of that particular node. As a result,
although a final pathology report may conclude N1 disease to be present, a node with
positive EUS findings may be histopathologically negative and vice versa. Therefore, the
diagnostic accuracy of EUS for N-staging may be overestimated.
The accuracy of N staging with EUS is further improved with fine needle aspiration
cytology (FNAC) [47, 56]. FNAC needs to be interpreted by an experienced
pathologist.
Neck imaging with ultrasonography or CT enables the detection of metastatic lymph
nodes that are clinically not palpable [47] or can be used to guide fine needle aspiration
of suspicious lymph nodes with very high accuracy and specificity [56, 65].
In the absence of clear metastatic disease on conventional CT/EUS/cervical US,
PET(/CT) may provide valuable additional information, in particular when considering
multimodality treatment with curative option. In such cases, baseline PET(/CT) allows
better response assessment as compared to conventional CT/EUS/cervical US.
FNCLCC made specific recommendations on the use of PET scan in the diagnosis and
staging of oesophageal cancer [66]. In addition, the KCE recently published an HTA
report on the use of PET scan [67]. Since this HTA report, numerous observational
studies of variable quality have been published [68-75]. For initial staging of patients
without apparent metastases on CT scan, especially in locally advanced disease (cT>2 or
cN1 or cN doubtful), PET(/CT) is useful for detecting positive lymph nodes and distant
metastatic disease [67]. However, in early-stage disease (cT1-2N0) the probability that
PET(/CT) will significantly upstage disease is low.
Magnetic resonance imaging (MRI) was not found to be superior to conventional
imaging techniques such as CT scan ([47, 56]. Therefore, MRI should be reserved for
those patients who cannot undergo CT or used for additional investigation following CT
and/or EUS.
In patients with clinical or imaging features suspicious of tracheobronchial invasion (e.g.
cough aggravated by swallowing in case of a fistula) or extrinsic compression,
bronchoscopy combined with bronchoscopic ultrasound (BUS)
and/or biopsy can be useful [47, 76, 77]. The underlying evidence, however, is weak to
very weak. Observational data also provide weak evidence for the occurrence of
synchronous neoplasms of the bronchial tree in patients with squamous cell carcinoma
of the oropharynx and the oesophagus, which is an indication for bronchoscopy [78].
Few studies are available to support the use of invasive staging with thoracoscopy and
laparoscopy (+/- peritoneal cytology and/or laparoscopic ultrasound) [47, 56, 79].
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Thoracoscopy can be useful for the detection of positive mediastinal lymph nodes, while
laparoscopy can be considered in patients with oesophageal tumours with a gastric
component [47]. Laparoscopy has a higher specificity for M staging in comparison with
CT scan, but obviously carries a higher risk of morbidity [56].
Recommendations
13. In patients with oesophageal cancer, CT scan of the chest (including
lower neck region) and abdomen with intravenous contrast and
gastric distension with oral contrast or water should be performed
routinely. The liver should at least be imaged in the arterial and
portal venous phase (1C recommendation).
14. Patients with oesophageal or gastro-oesophageal junction cancers
who are candidates for any curative therapy should have their
tumours staged with endoscopic ultrasonography +/- fine needle
aspiration cytology (FNAC) and ultrasonography of the neck (1B
recommendation).
15. Fine needle aspiration cytology (FNAC) needs to be interpreted by
an experienced pathologist (expert opinion).
16. In patients with oesophageal cancer and an option for curative
treatment
after
conventional
staging
(CT/endoscopic
ultrasonography), PET(/CT) scan may be considered for the staging
of lymph nodes (loco-regional, distal or all lymph nodes) and distant
sites other than lymph nodes (1C recommendation).
17. The following examinations can be considered for specific
indications: MRI, bronchoscopy +/- bronchial ultrasonography (BUS)
+/- biopsy, thoracoscopy, or laparoscopy (1C recommendation).
4.5
TREATMENT OF MUCOSAL CANCER
The principles of anatomopathological evaluation of mucosal cancer are similar to those
of high-grade dysplasia, including validation of the diagnosis by a second pathologist,
additional biopsies or diagnostic EMR in case of uncertainty, and discussion of treatment
options at the MDT [47].
Only observational studies are available comparing endoscopic mucosal resection (EMR)
to surgery for the treatment of superficial oesophageal cancer [56]. Both treatments
were found to be equally effective, but EMR was associated with less complications.
Therefore, superficial oesophageal cancer limited to the mucosa should be treated with
EMR, taking into account the stage, size, length of Barrett, histological type,
differentiation grade, and lymphovascular invasion [47]. For example, in case of mucosal
cancer in a long Barrett’s segment, complete resection of the Barrett’s area with EMR is
unlikely. In these cases, surgery (e.g. gastric pull-up or vagal sparing oesophagectomy
with colon interposition) may remain the treatment of choice.
En-bloc resection – allowing better pathology staging of deep and lateral margins –
should be aimed at with the appropriate technique (EMR for lesions less than 12 mm)
[80-82].
Mucosal ablative techniques, such as argon plasma coagulation (APC), photodynamic
therapy (PDT) or laser, are investigational [47, 56]. Only small observational studies
showed the benefits of these techniques, and they should therefore be limited to units
with appropriate expertise.
Moreover, APC was associated with buried neoplastic glands and should not be
considered for curative treatment. Importantly, PDT is associated with a risk of
stricture formation in up to 30% of patients [83]. Above this, mucosal ablative
techniques make an anatomopathological control of the staging results impossible.
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Recommendations
18. Where therapeutic intervention is considered for a supposedly T1a
mucosal cancer, the diagnosis should be validated by a second
pathologist experienced in this area. Further biopsies or eventually
diagnostic endoscopic mucosal resection (EMR) should be done if
there is uncertainty (1C recommendation).
19. Treatment options for patients with mucosal cancer should be
discussed at a multidisciplinary meeting with access to the clinical
and pathological information (expert opinion).
20. Superficial oesophageal cancer limited to the mucosa should be
treated with endoscopic mucosal resection (EMR), taking into
account well-defined criteria relating to stage, size, length of Barrett,
histological type, differentiation grade, and lymphovascular invasion
(1C recommendation).
21. Mucosal ablative techniques, such as argon plasma coagulation
(APC), photodynamic therapy (PDT) or laser, are investigational and
should be limited to units with appropriate expertise (1C
recommendation).
4.6
TREATMENT OF CANCER BEYOND THE MUCOSA
4.6.1
Neoadjuvant treatment
In 2006, Cancer Care Ontario (CCO) published a high-quality CPG (including metaanalyses) on the use of neoadjuvant treatment for oesophageal cancer [84]. Three
additional meta-analyses [85-87] and one systematic review [88] have been published
since then. Only Gebski et al. found new evidence in addition to that presented by
CCO [86].
CCO identified 6 RCTs comparing preoperative radiotherapy and surgery vs. surgery
alone [84]. No significant difference was detected in the risk of death at one year (RR
1.01; 95%CI 0.88 – 1.16; p=0.90). These results are in line with those of Arnott et al.,
who found a hazard ratio (HR) of 0.98 (95%CI 0.78 – 1.01), suggesting a small but nonsignificant absolute survival benefit of 3% at 2 years and 4% at 5 years in favour of
preoperative radiotherapy [85].
Nine different RCTs were identified by CCO comparing preoperative chemotherapy
and surgery vs. surgery alone [84]. In addition, two RCTs were identified comparing
preoperative and postoperative chemotherapy and surgery vs. surgery alone. All eleven
trials were also included in a recent Cochrane review [87]. A meta-analysis of the first 9
RCTs found a pooled RR of 1.00 (95%CI 0.83 – 1.19; p=0.97), detecting no difference in
survival at one year [84]. These results are in line with the Cochrane review (HR 0.88;
95%CI 0.75 – 1.04). Trials also reported risks of toxicity with chemotherapy that ranged
from 11% to 90% [87].
Gebski et al. identified 10 RCTs (of which one was an unpublished thesis, and two were
published as an abstract) comparing preoperative CRT and surgery vs. surgery alone
[86]. A HR for all-cause mortality of 0.81 (95%CI 0.70 – 0.93; p=0.002) in favour of
preoperative CRT was found, corresponding to a 13% absolute difference in survival at
2 years. Patients with adenocarcinoma seemed to obtain the highest benefit, although
conflicting evidence is available.
These results are not in line with those presented by CCO, who found no difference in
one-year survival between the 2 treatment arms (RR 0.91; 95%CI 0.79 – 1.06; p=0.21)
[84]. CCO also identified 1 RCT comparing preoperative CRT (bleomycin +
radiotherapy) to preoperative radiotherapy alone. No significant difference in survival
between the two treatment groups was found [84].
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25
In a systematic review of 6 RCTs by Graham et al., a RR of 0.81 (95%CI 0.64 – 1.02)
compared to surgery alone was found. This corresponded to an additional 40 days of
quality-adjusted life expectancy [88].
Since the literature search of CCO and Gebski et al., results of two additional small
RCTs became available, comparing preoperative CRT (cisplatin + 5-FU) to surgery
alone [89, 90]. No significant difference in survival was found.
Based on the evidence presented, the advantage of neoadjuvant treatment is small and
although neoadjuvant treatment is frequently used, it cannot be considered as a routine
practice in patients with oesophageal cancer. It is clear that for each individual patient
the need for neoadjuvant treatment should be discussed during a multidisciplinary
meeting. If neoadjuvant treatment is part of the treatment plan, it should be
administered according to a predefined protocol. This protocol should also specify the
role of PET(/CT) scan in the evaluation of treatment response to neoadjuvant
treatment. In a previous KCE report, some evidence was identified supporting the role
of PET scan in the assessment of treatment response to neoadjuvant treatment, using
the initial staging PET results as a comparison [67]. These conclusions are confirmed by
subsequent prospective trials [74, 91]. Finally, in all trials, a complete pathological
response was associated with the most favourable prognosis.
Since the use of neoadjuvant treatment for patients with oesophageal cancer still is
controversial, it is recommended to prospectively register clinical outcomes and
adverse events of the combined treatment. In fact, besides the mandatory cancer
registration, prospective registration of clinical outcomes and adverse events is
mandatory for all oncologic patients according to the Royal Decree of March 21st 2003
settling the norms for the healthcare programme in oncology [92].
Recommendations
22. Preoperative radiotherapy alone is not recommended for patients
with oesophageal cancer (2A recommendation).
23. Neoadjuvant treatment is not routinely indicated for patients with
oesophageal cancer (2A recommendation).
24. The need for neoadjuvant treatment should be discussed during a
multidisciplinary meeting (expert opinion).
25. Prospective registration of clinical outcomes and adverse events of
combined treatment is recommended (expert opinion).
4.6.2
Surgical treatment
Surgical resection remains the standard treatment for patients with resectable
oesophageal cancer [47, 56, 84, 88]. Patients are considered to have unresectable
disease in case of metastatic disease, positive lymph nodes outside the region of surgery
and/or radiotherapy (i.e. the cervical, thoracic and upper abdominal compartment),
advanced locoregional disease (e.g. tracheo-oesophageal fistula), or severe comorbidity.
Until now, only few studies are available comparing surgery to other treatment
modalities [56, 93, 94]. One moderate-quality eastern RCT compared primary
chemoradiotherapy (CRT) and salvage surgery to primary ‘standard’ oesophagectomy
[94]. No significant difference in 2-year survival and disease-free survival was found
between the 2 treatment groups. Six out of 36 patients (17%) assigned to primary CRT
were treated with salvage oesophagectomy [94]. A French study compared CRT
followed by surgery to CRT alone in patients with operable oesophageal cancer that
responded to CRT [93]. Two-year survival and 2-year local recurrence rate did not
differ significantly.
The results of these two RCTs need to be interpreted with caution, since they had
important methodological limitations (no accurate information on randomisation
procedure, absence of blinding). Above this, as in many other trials, surgery was not
standardized [93, 94].
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Surgery for oesophageal cancer should be aimed at achieving an R0 resection, and
should be considered preferentially through an en bloc resection (i.e. with systematic
abdominal and mediastinal lymph node dissection, the so-called two field
lymphadenectomy) [47, 56]. This recommendation is mainly based on the results of 1
RCT that compared extended transthoracic resection with two-field lymphadenectomy
to limited transhiatal resection without two-field lymphadenectomy [95]. A trend
towards improved 5-year survival was found in favour of the extended thoracic group.
The goal of lymphadenectomy is to optimize staging and to improve long-term
outcomes by decreasing the risk for local recurrence and increasing the probability of
an R0 resection [47, 56]. Two-field lymphadenectomy involves the clearance of
mediastinal (1st field) and abdominal (2nd field) lymph nodes, while three-field
lymphadenectomy also involves cervical lymph node clearance (3rd field). The extent of
two-field lymphadenectomy is specified in relation to the extent of the mediastinal part
of the lymphadenectomy. Standard two-field lymphadenectomy involves the clearance of
lymph nodes from the carina down to the diaphragm. In extended two-field
lymphadenectomy, clearance is expanded to the right paratracheal and recurrent nerve,
while in total two-field lymphadenectomy clearance is further extended to the left
recurrent nerve [96]. Extensive two-field lymphadenectomy should be standard during
oesophagectomy [47]. Three-field lymphadenectomy is considered strictly
investigational, especially in distal third adenocarcinoma [60]. Indeed, data from
Western studies with three-field lymphadenectomy are scarce and are based on
relatively small sample sizes [60, 97].
Many studies have shown a relationship between patient outcomes (e.g. 30-day
mortality) and surgeon or hospital volume [47, 56, 98, 99]. Recently, a meta-analysis of
13 studies calculated that the experience of 20 oesophagectomies per year is needed to
significantly reduce postoperative mortality [100]. Therefore, oesophageal cancer
surgery should be carried out in high volume specialist surgical units by surgeons with
experience in oesophageal and GOJ cancer [47]. Recently, it was shown that specialty
training in thoracic surgery has an independent association with lower mortality after
oesophageal resection (adjusted mortality 12.4% vs. 16.5%; p = 0.01), although specialty
training appeared to be less important than hospital and surgeon volume [101]. Of
course, specialty training and high volume are closely related.
Recommendations
26. Surgical resection is considered standard treatment for patients with
resectable oesophageal cancer (1A recommendation).
27. Surgery for oesophageal cancer should be aimed at achieving an R0
resection, and should be considered preferentially through a
transthoracic en bloc resection (1A recommendation).
28. Extensive two-field lymphadenectomy should be standard during
oesophagectomy to improve staging, local disease control and
potentially cure rate (1C recommendation).
29. Three-field lymphadenectomy
recommendation).
is
strictly
investigational
(2C
30. Oesophageal cancer surgery should be carried out in high volume
specialist surgical units by surgeons with experience and/or specialist
training in oesophageal and gastro-oesophageal junction cancer (1C
recommendation).
KCE Reports 75
4.6.3
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27
Adjuvant treatment
CCO provided an excellent overview of the literature concerning adjuvant treatment
for resectable oesophageal cancer [84]. Three RCTs of postoperative chemotherapy (all
cisplatin-based regimens) and surgery vs. surgery alone were identified. Pooled results
of 2 RCTs [102, 103] showed no significant difference in the risk of death at 3 years (RR
0.94; 95%CI 0.74 – 1.18; p=0.60) [84]. A third RCT also found no survival benefit for
postoperative chemotherapy, but 3-year survival was not reported [104].
CCO identified 5 RCTs of postoperative radiotherapy and surgery vs. surgery alone
[84]. Meta-analysis of these trials showed no significant difference in the risk of death
with postoperative radiotherapy and surgery at one year compared with surgery alone
(RR 1.23; 95%CI 0.95 – 1.59; p=0.11). The rate of local recurrence with radiotherapy
was lower in two RCTs, but this benefit was achieved at the expense of increased
morbidity [105, 106]. The most recent RCT found significantly improved 5-year survival
rates with adjuvant radiotherapy for stage III patients (35% vs. 13%; p=0.0027) [107].
However, this trial was hampered by some important methodological drawbacks (no
informed consent, no intention-to-treat analysis).
No RCTs on postoperative combined chemoradiotherapy vs. surgery alone were
identified by CCO [84]. A search for RCTs published since the CCO report also did
not identify new evidence.
There is also no available evidence on whether adjuvant therapy is of real benefit in R1
or R2 resection.
Recommendations
31. Postoperative adjuvant chemotherapy is not recommended for
patients with oesophageal cancer (2A recommendation).
32. Postoperative adjuvant radiotherapy is not recommended for
patients with oesophageal cancer (2A recommendation).
33. Postoperative adjuvant chemoradiotherapy is not recommended for
patients with oesophageal cancer (expert opinion).
4.6.4
Non-surgical treatment with curative intent
Definitive CRT should be considered in patients with oesophageal cancer who have
locally advanced disease and are unfit for surgery, or in patients who decline surgery
[47, 108]. Recently, a moderate-quality eastern RCT found no difference in survival at 2
years between primary CRT (and salvage surgery) and primary surgery in patients with
potentially resectable oesophageal cancer (see above) [94]. Bedenne et al. also found no
difference in survival at 2 years between CRT followed by surgery and CRT alone in
patients with operable oesophageal cancer that responded to CRT (see above) [93].
Once again, the need for an adequate method to predict treatment response is
highlighted.
Definitive CRT should also be considered for patients with cervical oesophageal cancer,
for whom it offers the benefit of preserving the larynx [56]. However, no RCTs are
available comparing surgery to CRT for these patients.
Concomitant CRT is recommended over radiotherapy alone. In their systematic review,
CCO included 8 RCTs of concomitant CRT vs. radiotherapy alone, of which 7 RCTs
had 1-year mortality rates available. Pooled analysis showed an odds ratio (OR) of 0.61
(95%CI 0.44 – 0.84; p<0.00001) in favour of concomitant CRT [108]. When only
concomitant CRT trials using cisplatin-based chemotherapy regimens were included, a
statistically significant survival benefit was detected at one year (OR 0.54; 95%CI 0.36 –
0.82; p=0.003) [108, 109]. Zhao et al. recently published 5-year results of a trial
comparing late course accelerated hyperfractionation (LCAF) radiotherapy combined
with chemotherapy vs. LCAF radiotherapy alone [110]. A trend toward better survival
was found in patients who received combination therapy.
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Sequential radiotherapy and chemotherapy is not recommended as standard practice
[108]. CCO identified 5 RCTs of sequential radiotherapy and chemotherapy vs.
radiotherapy alone. Pooled analysis revealed no significant difference in survival between
the treatment groups at one year.
Patients should be made aware of the increased acute toxicity associated with the use
of concomitant CRT. Therefore, the decision to use concomitant CRT should only be
made after careful consideration of the potential risks, benefits, and the patient’s general
condition [108].
In patients with locally advanced infracarinal oesophageal tumours that do not respond
to primary CRT, curative salvage surgery remains an option provided the patient is fit
for surgery [111]. Piessen et al. found a R0 resection rate of 62.2% in these patients.
Overall survival was significantly higher in the R0 resection group compared with the
incomplete resection group (18.4 vs. 8.6 months, p<0.001). Tumours < 5 cm and with <
90° aortic contact had the highest chance of obtaining an R0 resection.
Recommendation
34. Definitive chemoradiotherapy should be considered in patients with
oesophageal cancer who have locally advanced disease that is
considered unresectable, in patients who are unfit for surgery, or in
patients who decline surgery (1A recommendation). It can also be
considered for patients with cervical oesophageal cancer in order to
preserve the larynx (1C recommendation).
4.7
PALLIATIVE TREATMENT & METASTATIC DISEASE
Endoscopic therapy has an important role in the control of obstruction caused by
oesophageal cancer. Different treatment options are available, such as stent placement,
laser or argon plasma coagulation (APC) therapy. Treatment must be individualized and
should depend on the local availability and expertise [47].
Partially covered self-expanding metal stents (SEMS) or plastic expandable stents are the
best options for palliation of dysphagia caused by oesophageal cancer, especially in
patients with a short life expectancy [47, 112, 113]. Both types have a highly successful
insertion rate, but SEMS are associated with fewer procedure-related complications and
a trend toward better quality of life [48]. On the other hand, plastic stents are
associated with lower costs. In case of tumour ingrowth or overgrowth in stented
patients, laser therapy, APC therapy or re-stenting should be considered [47].
However, the use of APC therapy is supported by observational studies only.
The use of oesophageal dilatation alone should be avoided [47]. Dilation can be used as
an adjunct to other treatment modalities, such as by facilitating placement of an
oesophageal stent.
No RCTs are available to support the use of palliative surgery in patients with
oesophageal cancer [47]. Observational studies showed associated high morbidity and
decreased quality of life in selected patients. Therefore, oesophagectomy (transthoracic
or transhiatal) should not be performed routinely with palliative intent in patients with
oesophageal cancer [47]. In carefully selected patients that are fit for surgery and having
recurrent upper GI bleeding or a covered perforation that induces severe back pain that
is unlikely to be relieved by any other therapy, oesophagectomy can be considered.
Since substernal bypass is also associated with high morbidity and mortality, it should
not be performed with palliative intent in patients with oesophageal cancer [47].
In a recent Cochrane review, 7 RCTs on chemotherapy for patients with metastatic
oesophageal cancer were identified [114]. No survival benefit was found in the 2 RCTs
comparing chemotherapy with best supportive care. In the five RCTs comparing
different chemotherapy regimens, no consistent benefit of any specific regimen was
found [114]. No RCTs or systematic reviews were identified supporting the use of CRT
in the palliative setting of oesophageal cancer [47].
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29
Therefore, in patients with locally advanced or metastatic cancer of the oesophagus,
chemotherapy or CRT are treatment options that should be discussed in the MDT [56,
114].
The use of external-beam radiotherapy for the palliation of dysphagia and pain is
supported by observational studies only [47]. In 1 RCT, endoluminal brachytherapy
resulted in better dysphagia control than stent placement in patients who lived longer
than 140 days [47]. Therefore, it should be considered in patients with dysphagia from
oesophageal cancer with the perspective of a more prolonged survival.
Patients with oesophageal cancer should have access to a specialist (outpatient and/or
inpatient) palliative care team, in particular in relation to comfort and symptom control,
and quality of life [47]. This team clearly should involve the general practitioner, who
should have a coordinating role in the organisation of the palliative home care.
Evidence specific to control of symptoms, such as pain, anorexia and bleeding, in these
cancers is limited. Some evidence exists for the use of celiac axis plexus block for the
palliation of pain and for the use of corticosteroids in patients with oesophageal cancer
who are anorexic or who have symptoms of bowel obstruction [47]. Nutritional
support in the palliative setting should take into account the comfort of the patient, in
that quality of life is much more important than the long-term effects [56].
Limited evidence (coming from a secondary analysis of 1 RCT) is also available for
psychotherapeutic support during hospital stay [115].
Recommendations
35. Control of obstruction caused by oesophageal cancer should be
obtained with stent placement or laser/ argon plasma coagulation
(APC) therapy, depending on the local availability and expertise (1A
recommendation).
36. Partially covered self-expanding metal stents or plastic expandable
stents are the best options for palliation of dysphagia caused by
oesophageal cancer (1B recommendation).
37. Laser therapy, argon plasma coagulation (APC) therapy or restenting should be considered for control of tumour ingrowth or
overgrowth in stented patients (1C recommendation).
38. The use of oesophageal dilatation alone should be avoided (2C
recommendation).
39. Oesophagectomy (transthoracic or transhiatal) should not be
performed with palliative intent in patients with oesophageal cancer
(1C recommendation).
40. Substernal bypass for oesophageal cancer should not be performed
with palliative intent (1C recommendation).
41. In patients with locally advanced or metastatic cancer of the
oesophagus, chemotherapy or chemoradiotherapy are treatment
options that should be discussed in the multidisciplinary team (2A
recommendation).
42. Palliative external-beam radiotherapy or endoluminal brachytherapy
should be considered in patients with dysphagia from oesophageal
cancer and with the perspective of a more prolonged survival (2C
recommendation).
43. Patients with oesophageal cancer should have access to a specialist
palliative care team, in particular in relation to comfort and
symptom control, nutrition and quality of life (1C recommendation).
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FOLLOW-UP
In patients that underwent treatment for oesophageal cancer, follow-up is needed to
detect recurrent disease (in case of curative treatment), progressive disease, symptoms
that warrant treatment, or nutritional problems. However, evidence about the duration,
frequency and type of follow-up is unavailable [56]. Therefore, published guidelines on
the follow-up of patients with oesophageal cancer are always consensus-based.
A physical examination is recommended every three months, and should give special
attention to nutritional status, weight loss, fatigue, etc. Vitamin B12 evaluation can be
done, but deficiency after oesophagectomy occurs less frequently than after total
gastrectomy. A CT scan of the chest and abdomen is recommended every six months in
the first year and afterwards annually until the fifth year. However, it should be stressed
that no evidence is available to support regular imaging in the follow-up of these
patients [47].
After endoscopic treatment of dysplastic lesions or mucosal cancer, endoscopic followup is similar to that of patients with Barrett’s oesophagus [56]: three months after
endoscopic treatment, then every six months in the first two years, and then annually.
Recommendations
44. It is recommended that the follow-up of patients treated for
oesophageal cancer includes a physical examination every three
months, and a CT scan every six months in the first year and
afterwards annually until the fifth year (expert opinion).
45. Patients treated with endoscopic mucosal resection (EMR) should
have a follow-up endoscopy after three months, then every six
months in the first two years, and then annually (expert opinion).
4.9
RECURRENT DISEASE
In a small number of patients, recurrent disease can be successfully treated with curative
intent [116-118]. In patients with a localised lymph node recurrence [119-121] or a
localised anastomotic recurrence [122], a combined chemoradiotherapy regimen or
occasionally redo-surgery can be considered after discussion by the MDT. Patients who
develop a solitary lung or liver metastasis can also be considered for resection. The
evidence for these treatments, however, is weak and coming from small observational
studies only.
When patients are confronted with a local recurrence or a new tumour after EMR for a
mucosal cancer, treatment options include local treatment or multimodality treatment
[123]. These options should be discussed in the MDT. Again, only small observational
studies are available to support these treatments.
Recommendations
46. In patients with recurrent oesophageal cancer, treatment options
should be discussed in the multidisciplinary team (expert opinion).
47. In patients with a local recurrence or new tumour after endoscopic
mucosal resection (EMR), treatment options, including local
treatment, should be discussed in the multidisciplinary team (expert
opinion).
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5
FINAL RECOMMENDATIONS ON GASTRIC
CANCER
5.1
FLOWCHART
31
32
5.2
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KCE reports 75
DIAGNOSIS
As for oesophageal cancer, in addition to a history and clinical examination, flexible
upper GI endoscopy with at least biopsies of all suspicious lesions is recommended as
the diagnostic procedure of choice in patients with suspected gastric cancer [47]. The
same alarm symptoms are associated with gastric cancer and should lead to a referral
for early endoscopy and biopsies: dysphagia, recurrent vomiting, anorexia, weight loss
and gastrointestinal blood loss (see above) [47, 49].
In a prospective trial involving 202 consecutive patients (including 47 with oesophageal
or gastric carcinomas), seven biopsy and cytology specimens were found to yield the
correct diagnosis in all patients [124]. However, in patients with large gastric folds
(suggestive of linitis plastica or gastric lymphoma), at least 10 biopsies are
recommended, together with an additional technique, such as large forceps biopsy.
As in patients at high risk for oesophageal cancer, patients at high risk for developing
gastric cancer (Table 9) may also benefit from screening and follow-up with HRE and/or
chromoendoscopy [47], although the supporting evidence is scarce. No recent RCTs
were identified. Mainly Japanese observational studies have shown that
chromoendosocpy increases the rate of superficial and “early” lesions detection [125].
Patients with a familial history of gastric cancer should be referred to a centre for
genetic counselling.
No evidence was found on the most appropriate frequency of surveillance. Frequency of
surveillance endoscopy depends on specific risk factors, e.g. every 3-5 years in patients
with autoimmune chronic gastritis, annual follow-up for patients with low-grade
dysplasia in atrophic gastritis, etc.
Table 9. Features associated with high risk for developing gastric cancer.
Histological features:
•
Dysplasia
•
Gastric atrophy with or without intestinal metaplasia
•
Adenomatous polyps
Patient’s history:
•
Previous gastric cancer
•
History of partial gastrectomy
•
Familial history of gastric cancer
Clinical features:
•
Refractory gastric ulcer
•
Pernicious anaemia
In patients with suspected gastric cancer or at high risk for developing gastric cancer, H.
pylori testing should be systematically done on histology and ideally with a second test
(rapid urease test, urea breath test, culture or serology) [126-128]. In case of a negative
histology and negative additional testing, a positive serological test suggests the
presence of an unrecognised H. pylori infection, and additional investigations to confirm
whether the serological test is false positive or reflects active or recent infection should
be carried out [128].
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Recommendations
1. Patients presenting with any of the following alarm symptoms within
the clinical context of potential gastric pathology should be referred
for early endoscopy and biopsies: dysphagia, recurrent vomiting,
anorexia,
weight
loss,
gastrointestinal
blood
loss
(1C
recommendation).
2. Flexible upper gastrointestinal endoscopy with at least biopsies of all
suspicious lesions is recommended as the diagnostic procedure of
choice in patients with suspected gastric cancer (1C
recommendation).
3. High-resolution endoscopy and chromoendoscopy may be of value in
screening and follow-up of high-risk patients (2C recommendation).
4. H. pylori testing should be systematically done on histology and
ideally with a second test. Serology should be considered if gastric
sampling remains negative (2C recommendation).
5.3
WORK-UP OF DYSPLASTIC LESIONS
Patients diagnosed with high-grade dysplasia should have careful endoscopic and
pathological assessment [47]. Pathologists should follow a classification for reporting
dysplasia that the multidisciplinary team is familiar with. An overview of classifications is
already provided in chapter 3.2.4. Where therapeutic intervention is contemplated on
the basis of high-grade dysplasia, the diagnosis should be validated by a second
pathologist experienced in this area because of the significant inter- and intra-observer
variation [47]. Further biopsies or EMR should be done if there is uncertainty. Biopsies
should also be reviewed at a multidisciplinary meeting with access to the clinical
information.
Finally, as the diagnosis, treatment and follow-up of patients with gastric high-grade
dysplastic lesions is very specific and new techniques rapidly become available, these
patients should be referred to centres or network reference centres with the
appropriate endoscopic and surgical expertise and facilities [47].
Recommendations
5. Patients confirmed with high-grade dysplasia should have subsequent
careful
endoscopic
and
pathological
assessment
(1C
recommendation).
6. Pathologists should follow a classification for reporting dysplasia that
the multidisciplinary team is familiar with (1C recommendation).
7. Where therapeutic intervention is contemplated on the basis of
high-grade dysplasia, the diagnosis should be validated by a second
pathologist experienced in this area. Further biopsies should be done
if there is uncertainty (1C recommendation).
8. Biopsies should be reviewed at a multidisciplinary meeting with
access to the clinical information (expert opinion).
9. Patients with high-grade dysplasia should be referred to centres or
network reference centres with the appropriate endoscopic and
surgical expertise and facilities (1C recommendation).
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STAGING
As for patients with oesophageal cancer, the main contribution of CT scan to the
staging of gastric cancer is the detection of distant metastases [47, 129]. If metastatic
disease is detected with CT scan, curative treatment is excluded and additional staging
with EUS is unnecessary. A recent systematic review identified five observational studies
examining the diagnostic accuracy of multidetector row CT (MDCT) for the T staging
of gastric tumours [130]. It was concluded that both EUS and MDCT achieved similar
results in terms of diagnostic accuracy in T staging and in assessing serosal involvement.
Only one of the five included studies made a direct comparison between EUS and
MDCT [130]. A more recent prospective study of MDCT (with multiplanar reformation
images) found an overall diagnostic accuracy of 89% for T staging and of 78% for N
staging [131].
Kwee et al. identified 23 studies examining the diagnostic accuracy of EUS for the T
staging of gastric tumours [130]. Diagnostic accuracy varied between 65% and 92%.
Sensitivity and specificity for assessing serosal involvement varied between 78% and
100% and between 68% and 100%, respectively.
PET(/CT) is not routinely recommended in the staging of gastric cancer. However, it
can be considered in locally advanced mass-forming tumours (intestinal type a ) in a
curative setting [134].
Kwee et al. identified 3 observational studies examining the diagnostic accuracy of MRI
for the T staging of gastric tumours [130]. Diagnostic accuracy varied between 71% and
83%. Sensitivity and specificity for assessing serosal involvement varied between 90%
and 93% and between 94% and 100%, respectively. Overall, there is no anatomical area
where MRI is superior to CT. Therefore, MRI should be reserved for those patients
who cannot undergo CT. It can also be used for additional investigation following CT
and/or EUS [47].
Laparoscopy can be considered in patients with gastric tumours being considered for
surgery where full thickness gastric wall involvement is suspected [47]. There are
insufficient data to confirm benefit for laparoscopic ultrasound [47, 79].
Sentinel lymph node mapping has been the subject of several observational studies [135139]. Overall sensitivity ranged from 71 – 89% [136-138]. In patients with a pT1
tumour, sensitivity ranged from 88 – 100% [136, 138].
a
Gastric carcinomas can be classified according to different classification systems (Lauren [132],
Goseki [133], WHO, etc.) based on different criteria. The Lauren classification combines
etiopathological, clinical and pathological (macro- and microscopic) features [132]. The most
common type, the intestinal type, generates a tumoral mass and has convincingly been
demonstrated to arise through a Helicobacter pylori infection, gastritis, intestinal metaplasia,
dysplasia, carcinoma sequence. The less common type, the signet ring cell carcinoma, often
presents with a characteristic macroscopic appearance called “linitis plastica” and will often be
negative on PET.
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Recommendations
10. In patients with gastric cancer, CT scan of the chest and abdomen
with IV contrast and gastric distension with oral contrast or water
should be performed routinely. The liver should at least be imaged in
the arterial and portal venous phase (1C recommendation).
11. Endoscopic ultrasonography with or without fine-needle aspiration
cytology can be considered in patients to be treated with curative
intent based on clinical presentation and/or CT (1C
recommendation).
12. The following examinations can be considered for specific indications
(as explained in the text above): PET scan, Magnetic Resonance
Imaging, laparoscopy (1C recommendation).
5.5
TREATMENT OF MUCOSAL CANCER
Treatment options for patients with mucosal cancer should be discussed at a
multidisciplinary meeting, taking into account clinical and histological information.
Superficial gastric cancer limited to the mucosa can be treated with endoscopic mucosal
resection (EMR), taking into account the stage, size, histological type and differentiation
grade (Table 10) [47]. Large Japanese series of hundreds of patients treated
endoscopically with EMR or ESD showed the advantages and success rates of
endoscopic management for mucosal cancer [140-143]. However, a recent Cochrane
review failed to identify RCTs of early gastric cancer patients involving a treatment arm
of EMR and a comparison arm of gastrectomy [144]. Therefore, the potential harms
(incomplete resection, recurrence, perforation) and benefits (quality of life, utility in
patients unfit for surgery) of EMR must be weighed against the harms/benefits of surgical
treatment.
En-bloc resection – allowing better pathology staging of deep and lateral margins –
should be aimed at during mucosectomy with the appropriate technique (EMR for
lesions less than 12 mm and ESD for larger lesions) [145].
Mucosal ablative techniques, such as photodynamic therapy (PDT), laser or argon
plasma coagulation (APC), cannot be recommended as a curative option.
Table 10. Criteria associated with low risk of lymph node metastasis in
patients with mucosal gastric cancer [47, 144] (based on Japanese
Classification of Gastric Carcinoma [146]).
•
Lesion < 2 cm in size in elevated types
•
Lesion < 1 cm in size in depressed types
•
Well or moderately differentiated histology
•
No macroscopic ulceration
•
Invasion limited to mucosa and certainly no deeper than the superficial
submucosa
•
No residual invasive disease after EMR
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Recommendations
13. Biopsies should be reviewed by an experienced pathologist in this
area and discussed at a multidisciplinary meeting with access to the
clinical information (expert opinion).
14. Superficial gastric cancer limited to the mucosa can be treated with
endoscopic mucosal resection (EMR), taking into account the stage,
size,
histological
type
and
differentiation
grade
(2C
recommendation).
15. Mucosal ablative techniques, such as photodynamic therapy (PDT),
laser or argon plasma coagulation (APC), cannot be recommended
as a curative option (expert opinion).
5.6
TREATMENT OF CANCER BEYOND THE MUCOSA
5.6.1
Neoadjuvant treatment
In a recent Cochrane review, 4 RCTs were identified comparing neoadjuvant
chemotherapy and surgery to surgery alone, including 2 Japanese trials using oral
fluoropyrimidines [147]. Meta-analysis of these 4 trials showed no statistically significant
difference in mortality between the two treatment groups (OR 1.05; 95%CI 0.73 – 1.50;
p = 0.29). The MAGIC trial, which was excluded from the Cochrane review because it
also included postoperative chemotherapy, found a higher likelihood of overall survival
in patients receiving perioperative chemotherapy (ECF) as compared to surgery alone
(HR 0.75; 95%CI 0.60 – 0.93; p = 0.009) [148]. However, the trial received some
criticism because of a lack of standardisation of surgery, the absence of separate data
for gastric cancer, and some methodological shortcomings (e.g. lack of staging accuracy,
no blinding).
One abstract was found presenting the results of an RCT comparing preoperative
chemotherapy (5-FU/cisplatin) to surgery alone in adenocarcinoma of stomach and
lower oesophagus [149]. HR of death was 0.69 (95%CI 0.50 – 0.95; p=0.02) with 3 and
5- year overall survival of 35% and 24% respectively in the surgery alone group vs. 48%
and 38% respectively in the neoadjuvant chemotherapy group.
CCO identified three RCTs comparing preoperative radiotherapy and surgery to
surgery alone [150]. However, inconsistent results were found, making it difficult to
draw unambiguous conclusions. Three additional RCTs were identified comparing
neoadjuvant immunotherapy and surgery to surgery alone [150]. No significant survival
benefit was found. A recent small trial of neoadjuvant immunotherapy with interleukin-2
found a trend towards better overall and disease-free survival in the neoadjuvant
treatment group [151].
As for oesophageal cancer, since the use of neoadjuvant treatment for patients with
gastric cancer still is controversial, it is recommended to prospectively register clinical
outcomes and adverse events of the combined treatment [92].
Recommendations
16. Neoadjuvant treatment is not routinely indicated for patients with
gastric cancer, but is an option to be discussed during a
multidisciplinary meeting (2A recommendation).
17. Prospective registration of clinical outcomes and adverse events of
combined treatment is recommended (expert opinion).
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5.6.2
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37
Surgical treatment
Surgical treatment remains the standard treatment for patients with resectable gastric
cancer, and should aim at achieving an R0 resection [47, 129]. For distal tumours (lower
third, antrum) a partial gastrectomy with sparing of the proximal stomach is indicated.
Proximal tumours (upper two third) should be treated with a total gastrectomy [129].
Figure 2 gives an overview of the extent of lymphadenectomy for subtotal gastrectomy
in terms of dissection of lymph nodes. McCulloch et al. identified 2 RCTs comparing
limited (D1) versus extended (D2) node dissection (including splenectomy and distal
pancreatectomy) during gastrectomy for gastric cancer [152]. Meta-analysis did not
reveal any survival benefit for extended lymph node dissection (RR 0.95; 95%CI 0.83 –
1.09), but showed increased postoperative mortality (RR 2.23; 95%CI 1.45 – 3.45).
Figure 2. The extent of lymphadenectomy for subtotal gastrectomy in terms
of dissection of lymph nodes (figure reprinted from Roukos et al. [153].
D1 requires the dissection of the first-tier nodes (N1, nodal stations no. 1-6). D2 includes the N1
and second-tier nodes (N2, no. 7-11). D3 requires the dissection of N1, N2 and third-tier nodes
(N3, no. 12-15). D4 requires the dissection of N1, N2, N3 and fourth-tier para-aortic nodes (N4,
no. 16).
Since this Cochrane review, numerous trials have been published examining the extent
of lymph node dissection. An interim analysis of the Italian Gastric Cancer Study Group
(IGCSG) randomised surgical trial showed no statistically significant difference in
postoperative morbidity and mortality between D1 and D2 gastrectomy [154]. In this
trial, only a minority of patients received a splenectomy (in case of clinical T > 1 on the
greater curvature of the proximal and middle thirds of the stomach) or a distal
pancreatectomy (suspicion of tumour involvement). However, a subsequent
multicentric phase II study by the same group evaluating pancreas-preserving D2
gastrectomy suggested a survival benefit with an overall 5-year survival of 55% and a
postoperative in-hospital mortality of 3.1% [155]. Hartgrink et al. also compared D1
with D2 lymph node dissection [156]. Postoperative morbidity (25% vs. 43%; p = 0.001)
and mortality (4% vs. 10%; p = 0.004) were significantly higher in the D2 dissection
group, but after 11 years no overall difference in survival was found (30% vs. 35%; p =
0.53).
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As compared to Degiuli et al. [154], the amount of splenectomies and distal
pancreatectomies was higher in the Randomized Dutch Gastric Cancer Group Trial
[156].
Three trials recently compared standard D2 vs. extended D2 (D2+, i.e. D2 with paraaortic nodal dissection) lymph node dissection [157-159]. No statistically significant
differences in postoperative morbidity and mortality were found in two trials [157, 158],
while postoperative morbidity was higher in the extended D2 group in the third trial
[159].
Reconstruction after gastrectomy can be with or without pouch formation and with
(Billroth I and II) or without (Roux-en-Y, jejunal interposition) maintenance of duodenal
passage [47]. Evidence suggests that pouch procedures may be associated with a higher
earlier weight gain [160, 161] and some improvement in long-term quality of life [162].
Several articles have compared laparoscopic surgery to conventional surgery for gastric
cancer [163-166]. One SR identified 4 RCTs comparing laparoscopy-assisted distal
gastrectomy (LADG) to conventional open distal gastrectomy (CODG) [164]. LADG
was found to be a longer procedure, but was associated with a lower postoperative
morbidity. No difference was found in postoperative mortality. These results were
confirmed by an RCT published subsequently [166]. Hayashi et al. also found a shorter
operation time with CODG, but no differences in postoperative morbidity and
mortality [163]. Huscher et al. found no differences in duration of surgery and
postoperative morbidity and mortality between laparoscopic-assisted and open radical
subtotal gastrectomy [165]. Overall, duration of analgesic administration was shorter
after laparoscopic surgery [163, 164, 166].
As for oesophageal cancer, several studies have shown a relationship between patient
outcomes (e.g. 30-day mortality) and surgeon or hospital volume for gastric cancer
surgery [47, 98, 99]. However, this relationship is less profound than for oesophageal
cancer surgery [98]. Nevertheless, based on these results, gastric cancer surgery should
be carried out in high volume specialist surgical units by surgeons with experience in
gastric cancer [47]. Subspecialty training is also associated with lower postoperative
mortality, although this relationship is not statistically significant [167].
Recommendations
18. Surgical resection should be considered standard treatment for
patients with resectable gastric cancer (1A recommendation).
19. Surgery for gastric cancer should aim at achieving an R0 resection
(1A recommendation).
20. D2 lymphadenectomy (with a minimum of 15 lymph nodes removed
and examined) should be standard during gastrectomy to improve
staging and local disease control (1B recommendation).
21. Gastric cancer surgery should be carried out in high volume
specialist surgical units by surgeons with experience and/or specialist
training in this area (1C recommendation).
5.6.3
Adjuvant treatment
Numerous RCTs and systematic reviews have been published comparing postoperative
adjuvant chemotherapy to surgery alone [47, 150]. Most meta-analyses found small
statistically significant differences in survival favouring adjuvant chemotherapy, although
only a minority of the included RCTs were of high quality. Subgroup analyses in one
meta-analysis showed a trend towards a larger magnitude of the effect for trials in which
at least two thirds of the patients had node-positive disease (OR 0.74; 95%CI 0.59 –
0.95) [150]. Therefore, CCO concluded that adjuvant chemotherapy alone may be of
benefit in particular for patients with lymph node metastases. However, this is not in
line with SIGN, that did not recommend postoperative chemotherapy outside a clinical
trial [47].
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One meta-analysis of 4 Japanese RCTs comparing adjuvant oral fluorinated pyrimidines
to surgery alone found a survival benefit in favour of adjuvant chemotherapy (HR 0.73;
95%CI 0.60 – 0.89; p = 0.002) [168]. Other trials failed to demonstrate a benefit in
favour of adjuvant chemotherapy [169-172]. The optimum chemotherapy regimen has
also not yet been defined.
CCO identified two RCTs comparing adjuvant radiotherapy to surgery alone [150]. No
differences in survival were found. However, addition of postoperative chemotherapy to
radiotherapy may result in better outcomes. Three RCTs were identified by the CCO,
of which one found no statistically significant difference in survival. The two other trials
detected improved survival with postoperative CRT, but received considerable criticism
[150]. For example, the surgery performed in the RCT of McDonald et al. was often not
up to the desired standards [173].
Several RCTs and meta-analyses compared adjuvant intraperitoneal chemotherapy to
surgery alone [150, 174, 175]. A recent meta-analysis found a significant survival benefit
in favour of hyperthermic intraoperative intraperitoneal chemotherapy with or without
early postoperative intraperitoneal chemotherapy [175]. However, in general survival
results have been conflicting, and some trials even reported harm from intraperitoneal
therapy [150].
CCO identified 9 RCTs comparing adjuvant immunochemotherapy to surgery alone
[150]; one meta-analysis on immunochemotherapy with polysaccharide K [176] and one
RCT [177] were published subsequently. Overall, inconsistent results were found,
making it difficult to draw definite conclusions.
Recommendations
22. Postoperative adjuvant chemotherapy is not recommended for
patients with gastric cancer (2A recommendation).
23. Postoperative adjuvant radiotherapy is not recommended for
patients with gastric cancer (2A recommendation).
24. Postoperative adjuvant chemoradiotherapy is not routinely
recommended for patients with gastric cancer, but can be
considered after discussion in the multidisciplinary team (2A
recommendation).
5.7
PALLIATIVE TREATMENT & METASTATIC DISEASE
Palliative gastric surgery is limited to symptomatic stenoses, bleeding tumours and
perforation [129]. It should be avoided in patients who have disseminated peritoneal
disease [47, 129]. In comparison to palliative gastrectomy, gastric bypass has a higher
mortality [47]. However, reported mortality after laparoscopic gastrojejunostomy is
lower than for open bypass.
For patients with malignant gastric outlet obstruction, treatment options include
endoscopic stenting or surgical gastroenterostomy [178, 179]. Two systematic reviews,
that mainly comprised observational studies, found a higher initial clinical success after
endoscopic stenting. However, inconsistent results were found for associated morbidity
[178, 179]. No significant survival benefit was found. Endoscopic stenting was associated
with a shorter hospital stay.
Several RCTs compared palliative chemotherapy to best supportive care for patients
with advanced or metastatic gastric cancer [180, 181]. A clear survival benefit was found
in favour of palliative chemotherapy. Above this, palliative chemotherapy was associated
with a better quality of life [180]. Wagner et al. also found a significant survival benefit in
favour of combination chemotherapy as compared to single agent chemotherapy (HR
0.83; 95%CI 0.74 – 0.93) [181]. Therefore, in patients with locally advanced or
metastatic cancer of the stomach with good performance status combination
chemotherapy should be considered [47, 181].
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Patients with gastric cancer should have access to a specialist (outpatient and/or
inpatient) palliative care team, in particular in relation to comfort and symptom control,
and quality of life [47]. This team clearly should involve the general practitioner, who
should have a coordinating role in the organisation of the palliative home care.
However, as for oesophageal cancer, evidence specific to control of symptoms, such as
pain, anorexia and bleeding, in these cancers is limited. Some evidence exists for the use
of celiac axis plexus block for the palliation of pain and for the use of corticosteroids in
patients with gastric cancer who are anorexic or who have symptoms of bowel
obstruction [47]. Nutritional support in the palliative setting should take into account
the comfort of the patient, in that quality of life is much more important than the longterm effects.
Limited evidence (coming from a secondary analysis of 1 RCT) is also available for
psychotherapeutic support during hospital stay [115].
Recommendations
25. Palliative gastric surgery is limited to symptomatic stenoses,
bleeding tumours and perforation (2C recommendation).
26. For patients with malignant gastric outlet obstruction, treatment
options include endoscopic stenting or surgical gastroenterostomy
(2C recommendation).
27. In patients with locally advanced or metastatic cancer of the
stomach with good performance status combination chemotherapy
should be considered (1A recommendation).
28. Patients with gastric cancer should have access to a specialist
palliative care team, in particular in relation to comfort and
symptom control, and quality of life (1C recommendation).
5.8
FOLLOW-UP
In patients that underwent treatment for gastric cancer, follow-up is needed to detect
recurrent disease (in case of curative treatment), progressive disease, symptoms that
warrant treatment, or nutritional problems resulting from total gastrectomy (e.g. iron
and vitamin deficiency, maldigestion with steathorroea, etc). However, evidence about
the duration, frequency and type of follow-up is lacking [182] (one retrospective study
was published after our literature search [183]). Therefore, these recommendations are
made in line with those for oesophageal cancer.
A physical examination is recommended every three months, and should give special
attention to nutritional status, weight loss, fatigue, etc. Above this, a blood analysis
(routine chemistry and haematology, completed with serum ferritine and vitamin B12
dosing in case of anaemia) is recommended. Vitamin B12 deficiency is a frequent
phenomenon after total gastrectomy, and should be adequately treated. CT scan of the
abdomen is recommended every six months in the first year and afterwards annually
until the fifth year. However, it should be stressed that no evidence is available to
support regular imaging in the follow-up of these patients [47]. For patients that
underwent partial gastrectomy, lifelong endoscopic surveillance is indicated because of
the high risk of developing gastric stump carcinoma [184].
Patients treated with endoscopic mucosal resection (EMR) should have strict
endoscopic surveillance [144] with a follow-up endoscopy after three months, then
every six months in the first two years, and then annually.
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Recommendations
29. It is recommended that the follow-up of patients treated for gastric
cancer includes a physical examination and blood analysis every
three months, and a CT scan every six months in the first year and
afterwards annually until the fifth year (expert opinion).
30. Patients treated with endoscopic mucosal resection (EMR) should
have a follow-up endoscopy after three months, then every six
months in the first two years, and then annually (expert opinion).
5.9
RECURRENT DISEASE
In a small number of patients, recurrent disease can be successfully treated with curative
intent. In patients with cancer of the gastric stump after distal gastrectomy, R0 resection
can be achieved in a relatively high number of patients [185, 186]. Patients who develop
a solitary lung or liver metastasis can also be considered for resection [187, 188]. When
patients are confronted with a local recurrence after EMR for a mucosal cancer, local
treatment can be reconsidered [145, 189]. The evidence for these treatments, however,
is weak and coming from small observational studies only. Treatment options for
recurrent disease should therefore be discussed in the MDT.
Recommendations
31. In patients with recurrent gastric cancer, treatment options should
be discussed in the multidisciplinary team (expert opinion).
32. In patients with a local recurrence or new tumour after endoscopic
mucosal resection (EMR), treatment options, including local
treatment, should be discussed in the multidisciplinary team (expert
opinion).
5.10
TREATMENT OF GASTRIC LYMPHOMA
5.10.1
Introduction
Primary gastric lymphoma is a rare tumour, accounting for less than 5% of primary
gastric neoplasms. However, it is the most common extranodal lymphoma, representing
4-20% of all extranodal lymphomas [190]. Helicobacter pylori infection,
immunosuppression after solid-organ transplantation, celiac disease, inflammatory bowel
disease, and human immunodeficiency virus (HIV) infection are known risk factors for
GI lymphoma. A significant proportion of gastric lymphomas is of low-grade histology
and arises from mucosa-associated lymphoid tissue (MALT) [191].
According to the most recent WHO classification, the term ‘MALT lymphoma’ should
only be applied to tumours previously defined as low-grade MALT lymphomas
composed mostly by small cells. High-grade lymphomas are known as large B-cell
lymphoma [192]. Patients with low-grade B-cell lymphoma or MALT lymphoma have a
better prognosis than patients with diffuse large B-cell lymphoma (DLBCL) [193].
Tumours of T-cell origin are rare [190]. Patients with gastric lymphomas are currently
staged using the Ann Arbor staging system with the Cotswold modification. This has
largely replaced the older International Workshop staging system [194].
5.10.2
Diagnosis and staging
There is no consensus regarding the diagnostic work-up and staging of primary gastric
lymphomas. Evidence is scarce and exclusively based on observational studies. As for all
patients with suspected gastric cancer, upper GI endoscopy is indicated in case of
suspected gastric lymphoma.
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Dedicated endoscopic-bioptic techniques are recommended, including a minimum of 8 –
12 biopsies from visible lesions, mapping of macroscopically normal-appearing areas, and
repeated examinations in the individual case. Biopsies should be preserved in such a way
to allow molecular diagnostic investigation [195, 196].
Several classifications of lymphomas are available [197, 198]. It is recommended to
diagnose and classify gastric lymphomas according to the most recent appropriate
classification.
In patients with histologically confirmed gastric lymphoma, endoscopic ultrasonography
is indicated [199, 200]. EUS-guided FNA of suspicious LN is not recommended. For
other staging procedures, such as CT scan or PET scan, even less evidence is available
[201-203]. Therefore, for patients with low-grade MALT lymphoma no further staging
procedures are recommended, unless otherwise required for differential diagnostic
reasons.
Recommendations
1. In patients with suspected gastric lymphoma, subtle endoscopicbioptic techniques are needed, including a minimum of 8–12
biopsies from visible lesions, mapping of macroscopically normalappearing areas, and repeated examinations in the individual
case. Biopsies should be preserved in such a way to allow
molecular diagnostic investigation (expert opinion).
2. Lymphomas should be diagnosed and classified according to the
most recent appropriate classification (expert opinion).
3. In patients with histologically confirmed gastric lymphoma,
endoscopic ultrasonography is indicated. Endoscopic ultrasoundguided fine needle aspiration of suspicious lymph nodes is not
recommended (1C recommendation).
4. For patients with low-grade MALT lymphoma no further staging
procedures are recommended, unless otherwise required for
differential diagnostic reasons (expert opinion).
5.10.3
Treatment
In the past, surgery was thought to be necessary for the diagnosis, staging, and
treatment of low-grade gastric lymphomas. However, as mentioned above, most
patients now can be adequately diagnosed with biopsy and appropriately staged with
non-invasive studies. Furthermore, gastrectomy can be associated with significant
morbidity [194]. Numerous observational studies have demonstrated successful
treatment of gastric MALT lymphomas with H. pylori eradication alone [204-208].
Complete remission rates ranged from 62 – 95%. No trials were found comparing H.
pylori eradication to surgical treatment.
In one RCT, 245 previously untreated patients with gastric low-grade MALT lymphoma
(stage IE and IIE) were randomised to surgery, radiotherapy or chemotherapy [209]. No
statistically significant differences were found in overall survival, but event-free survival
was significantly higher in the group randomised to chemotherapy.
Because the time from H. pylori eradication to lymphoma regression ranges from 1-28
months, close follow-up is required with upper GI endoscopy including biopsy [128,
194]. No evidence is available on the most appropriate duration of this follow-up, but
an annual control during the first three years seems rational. Patients beyond stage I
have a significantly decreased response to H. pylori eradication therapy [206, 207].
These patients, and patients without tumour regression after successful H. pylori
eradication, should be referred to a specialized haematology centre [205].
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Recommendations
5. H. pylori eradication is the treatment of first choice for H. pylori
infected patients with stage I low grade gastric MALT lymphoma
(1C recommendation).
6. In patients with low-grade MALT lymphoma treated with
antibiotic eradication, close follow-up with upper GI endoscopy
and biopsies is required, including evaluation of H. pylori
eradication within 3 months (expert opinion).
7. Patients with successful H. pylori eradication but without tumour
regression after 1 year or with tumour progression should be
referred to a specialized haematology centre (expert opinion).
5.11
TREATMENT OF GASTROINTESTINAL STROMAL
TUMOURS
5.11.1
Introduction
Gastrointestinal stromal tumours (GIST) are relatively rare tumours, representing less
than 1% of all tumours of the gastrointestinal tract. They are most common in the
stomach (39% to 70%) and the small intestine (20% to 32%), whereas the colon, rectum
and oesophagus are affected in less than 15% of cases [210]. GISTs predominantly occur
in individuals over 40 years of age, with the majority occurring between the ages of 55
to 65. Estimates of incidence vary widely from 4 to 14 cases per million populations
[211].
Presenting features of these tumours include abdominal discomfort or pain, a feeling of
abdominal fullness and the presence of a palpable mass. However, many people with
GISTs are asymptomatic during early stages of the disease until tumours reach a large
size, at which time the tumours rupture and bleed or obstruct the gastrointestinal tract
[211].
Overall, literature on GIST is relatively scarce and of low quality. Most studies are
observational studies or case series without an adequate control. Therefore, the
recommendations presented below often have a low level of evidence or are based on
expert opinion.
5.11.2
Diagnosis and staging
In patients with clinical suspicion of GIST, endoscopic ultrasonography (EUS) and EUSguided FNA are recommended for differential diagnostic reasons and to confirm the
presence of positive lymph nodes or malignancy in adjacent organs [212]. Findings on
EUS of a diameter > 3 cm, irregular extraluminal border, cystic spaces, echogenic foci,
and adjacent malignant-appearing lymph nodes are features that can suggest malignancy.
Unfortunately, EUS findings do not accurately predict the malignant potential of a small
GIST (< 3 cm).
Most GISTs (80 – 100%) express the tyrosine kinase growth factor receptor c-KIT,
which is detected by immunostaining with the antibody for the cell-surface marker
CD117. This immunohistochemical test (performed on tissue) is now considered to be
an appropriate diagnostic marker for the diagnosis of GIST [212].
In patients with a (suspected) GIST tumour, a CT abdomen is recommended if
treatment is considered [213-217]. However, the evidence supporting this
recommendation is observational and of low quality.
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Recommendations
1. In patients with clinical suspicion of GIST, endoscopic
ultrasonography and endoscopic ultrasound-guided fine needle
aspiration can be recommended for differential diagnostic
reasons and to confirm the presence of positive lymph nodes or
malignancy in adjacent organs (2C recommendation).
2. In patients with a (suspected) GIST, immunohistochemical
testing of CD117 is recommended (1C recommendation).
3. In patients with a (suspected) GIST tumour, a CT abdomen is
recommended if treatment is considered (expert opinion).
5.11.3
Treatment
5.11.3.1
Non-metastatic resectable GIST
Discrepancies were found in the literature on the strategy to predict malignant
behaviour of GISTs. AGA proposed criteria including size (>3 cm), mitotic count on
histology, and several EUS criteria (size; irregularity of the extraluminal border; the
presence of cystic spaces, echogenic foci, and heterogeneity) [212]. The National
Institutes of Health proposed a strategy for predicting malignant behaviour of GISTs
based on size (>2cm, 2-5cm, 5-10 cm, or >10) and mitotic count on histology (<5, 6–10,
or >10 per 50 high-power field), with the understanding that no GIST can be defined as
benign on the basis of currently available diagnostic testing [218].
Debate also exists as to whether the potential morbidity and mortality associated with
surgical resection are acceptable for removing a lesion with low potential for
malignancy. Given the overall lack of evidence to guide management, it is recommended
to perform surgical resection in patients that are fit for surgery and with a histologically
confirmed non-metastatic GIST or with a gastric tumour of >5 cm that is highly
suspicious of a GIST (and without evidence for metastatic disease) [211, 212, 219]. For
lesions of 2 – 5 cm that are highly suspicious of GIST and without evidence for
metastatic disease, the choice between surveillance and surgical resection should be
discussed at the MDT, taking into consideration histology, size, margins, age,
comorbidities and fitness for surgery. In patients with a gastric tumour of <2 cm that is
highly suspicious of a GIST and without evidence for metastatic disease, surveillance is
indicated.
The use of imatinib (see below), a targeted therapy aimed specifically at blocking the
phosphorylation of tyrosine kinase receptors, as adjuvant treatment is investigational
[210]. One abstract was identified comparing adjuvant imatinib to surgery alone for
primary GIST measuring at least 3 cm and expressing c-kit [220]. Recurrence-free
survival was significantly higher in the group assigned to adjuvant imatinib (HR 0.33;
95%CI 0.20 – 0.53).
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Recommendations
4. In patients with a histologically confirmed non-metastatic GIST
and who are fit for surgery, resectional surgery is indicated
(expert opinion).
5. In patients with a gastric tumour of >5 cm that is highly suspicious
of a GIST, without evidence for metastatic disease, and who are
fit for surgery, resectional surgery is indicated (expert opinion).
6. In patients with a gastric tumour of 2-5 cm that is highly
suspicious of a GIST, without evidence for metastatic disease, and
who are fit for surgery, the choice between surveillance and
resectional surgery should be discussed at the multidisciplinary
team (expert opinion).
7. In patients with a gastric tumour of <2 cm that is highly suspicious
of a GIST and without evidence for metastatic disease,
surveillance is indicated (expert opinion).
8. The use of imatinib as adjuvant treatment is investigational
(expert opinion).
5.11.3.2
Metastatic or unresectable GIST
Imatinib clearly represents an important advance in the treatment of metastatic GISTs.
A recent systematic review identified 2 RCTs comparing 2 doses of imatinib [210]. An
initial dose of 400 mg daily is recommended, as a higher dose (800 mg) is not associated
with a survival benefit, but leads to a significant increase in side effects [210].
Nevertheless, a dose of 400 mg twice daily may be considered in patients who
demonstrate progression with 400 mg daily [211]. No RCTs comparing imatinib to no
treatment or best supportive care have been published so far, making it difficult to state
with statistical certainty whether treatment with imatinib confers a definite survival
advantage as such. However, worldwide imatinib is considered standard treatment for
these patients.
The optimal duration of imatinib treatment in responding patients or in those patients
who achieve a complete clinical and/or radiological remission has not yet been defined,
but continuation seems to be more favourable [219]. Low-quality observational studies
show that PET/CT can be used to evaluate treatment response to imatinib [221-224]. In
patients with imatinib resistance or intolerance sunitinib can be considered as secondline treatment [225]. So far, no RCTs have been published to compare sunitinib to
imatinib or no treatment.
Recommendations
9. In patients with inoperable or metastatic (suspected) GIST
imatinib is recommended (1C recommendation).
10. PET/CT is indicated to evaluate treatment response to imatinib
(expert opinion).
11. In patients with imatinib resistance or intolerance sunitinib can be
considered as second-line treatment (2A recommendation).
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6
IMPLEMENTATION AND UPDATING OF THE
UPPER GI CANCER GUIDELINE
6.1
IMPLEMENTATION
The implementation of the present guideline will be led by the College of Oncology. An
online implementation tool – similar to the tools accompanying previous guidelines
(https://portal.health.fgov.be/portal/page?_pageid=56,10338450&_dad=portal&_schema=
PORTAL) – will be developed. The tool will be based on the general algorithms of this
guideline.
6.2
QUALITY CONTROL
The implementation of the guideline has to be evaluated with appropriate quality
control criteria. These criteria should at least assess the following items of the general
algorithms:
•
diagnostic work-up
•
staging
•
treatment according to stage
•
follow-up
•
multidisciplinary approach
For each of these steps, quality indicators should be developed, which should be
preferentially based on the recommendations with a high level of evidence. Additionally,
a literature search for existing quality indicators should be done. However, a preassessment of the literature (Medline and the National Quality Measures Clearinghouse,
http://www.qualitymeasures.ahrq.gov/) only identified a limited number of exisiting
quality indicators (Table 11).
Table 11. Existing quality indicators for oesophageal and gastric cancer,
identified through pre-assessment of the literature.
Quality Indicator
Oesophageal resection mortality rate
Oesophageal resection: volume
6.3
Source
Agency for Healthcare Research and Quality
Agency for Healthcare Research and Quality
GUIDELINE UPDATE
In view of the changing evidence, and based on a pre-assessment of the literature, this
guideline should be fully updated in 5 years. In the meanwhile, when important evidence
becomes available, this will be mentioned on the website of the College of Oncology
(https://portal.health.fgov.be/portal/page?_pageid=56,10338450&_dad=portal&_schema=
PORTAL).
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Crane, L.M., et al., Oesophageal cancer in The Netherlands: increasing incidence and mortality but
improving survival. Eur J Cancer, 2007. 43(9): p. 1445-51.
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Qiu, D. and S. Kaneko, Comparison of esophageal cancer mortality in five countries: France, Italy,
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KCE Reports 75
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Tentes, A.-A.K., et al., Intraarterial chemotherapy as an adjuvant treatment in locally advanced
gastric cancer. Langenbecks Archives of Surgery, 2006. 391(2): p. 124-9.
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Tsuburaya, A., et al., A randomized phase III trial of post-operative adjuvant oral fluoropyrimidine
versus sequential paclitaxel/oral fluoropyrimidine; and UFT versus S1 for T3/T4 gastric carcinoma: the
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Yu, W., A review of adjuvant therapy for resected primary gastric cancer with an update on Taegu's
phase III trial with intraperitoneal chemotherapy. European Journal of Surgical Oncology, 2006.
32(6): p. 655-60.
310.
Chen, D.W., et al., Role of enteral immunonutrition in patients with gastric carcinoma undergoing
major surgery. Asian Journal of Surgery, 2005. 28(2): p. 121-4.
311.
Farreras, N., et al., Effect of early postoperative enteral immunonutrition on wound healing in patients
undergoing surgery for gastric cancer. Clinical Nutrition, 2005. 24(1): p. 55-65.
312.
Sato, Y., et al., A randomized controlled study of immunochemotherapy with OK-432 after curative
surgery for gastric cancer. Journal of Immunotherapy, 2004. 27(5): p. 394-7.
313.
Di Cosimo, S., et al., Docetaxel in advanced gastric cancer--review of the main clinical trials. Acta
Oncologica, 2003. 42(7): p. 693-700.
314.
Wohrer, S.S., M. Raderer, and M. Hejna, Palliative chemotherapy for advanced gastric cancer.
Annals of Oncology, 2004. 15(11): p. 1585-95.
315.
Ajani, J.A., et al., Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without
fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma.[see
comment]. Journal of Clinical Oncology, 2005. 23(24): p. 5660-7.
316.
Bouche, O., et al., Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and
leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously
untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study-FFCD 9803. Journal of Clinical Oncology, 2004. 22(21): p. 4319-28.
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Cocconi, G., et al., Cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) is more active than 5fluorouracil, doxorubicin and methotrexate (FAMTX) in advanced gastric carcinoma. Annals of
Oncology, 2003. 14(8): p. 1258-63.
318.
Koizumi, W., et al., Randomized phase II study comparing mitomycin, cisplatin plus doxifluridine with
cisplatin plus doxifluridine in advanced unresectable gastric cancer. Anticancer Research, 2004.
24(4): p. 2465-70.
319.
Lutz, M.P., et al., Weekly infusional high-dose fluorouracil (HD-FU), HD-FU plus folinic acid (HDFU/FA), or HD-FU/FA plus biweekly cisplatin in advanced gastric cancer: randomized phase II trial
40953 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group
and the Arbeitsgemeinschaft Internistische Onkologie. Journal of Clinical Oncology, 2007. 25(18): p.
2580-5.
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Moehler, M., et al., Randomised phase II evaluation of irinotecan plus high-dose 5-fluorouracil and
leucovorin (ILF) vs 5-fluorouracil, leucovorin, and etoposide (ELF) in untreated metastatic gastric cancer.
British Journal of Cancer, 2005. 92(12): p. 2122-8.
321.
Ohtsu, A., et al., Randomized phase III trial of fluorouracil alone versus fluorouracil plus cisplatin
versus uracil and tegafur plus mitomycin in patients with unresectable, advanced gastric cancer: The
Japan Clinical Oncology Group Study (JCOG9205). Journal of Clinical Oncology, 2003. 21(1): p. 549.
322.
Park, S.H., et al., Paclitaxel versus docetaxel for advanced gastric cancer: a randomized phase II trial
in combination with infusional 5-fluorouracil. Anti-Cancer Drugs, 2006. 17(2): p. 225-9.
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323.
Pozzo, C., et al., Irinotecan in combination with 5-fluorouracil and folinic acid or with cisplatin in
patients with advanced gastric or esophageal-gastric junction adenocarcinoma: results of a randomized
phase II study. Annals of Oncology, 2004. 15(12): p. 1773-81.
324.
Sadighi, S., et al., Quality of life in patients with advanced gastric cancer: a randomized trial
comparing docetaxel, cisplatin, 5-FU (TCF) with epirubicin, cisplatin, 5-FU (ECF). BMC Cancer, 2006.
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325.
Takahashi, Y., et al., A randomized phase II clinical trial of tailored CPT-11 + S-1 vs S-1 in patients
with advanced or recurrent gastric carcinoma as the first line chemotherapy. Japanese Journal of
Clinical Oncology, 2004. 34(6): p. 342-5.
326.
Thuss-Patience, P.C., et al., Docetaxel and continuous-infusion fluorouracil versus epirubicin, cisplatin,
and fluorouracil for advanced gastric adenocarcinoma: a randomized phase II study. Journal of
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Bonnetain, F., et al., Longitudinal quality of life study in patients with metastatic gastric cancer.
Analysis modalities and clinical applicability of QoL in randomized phase II trial in a digestive oncology.
Gastroenterologie Clinique et Biologique, 2005. 29(11): p. 1113-24.
328.
Van Cutsem, E., et al., Phase III study of docetaxel and cisplatin plus fluorouracil compared with
cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study
Group. Journal of Clinical Oncology, 2006. 24(31): p. 4991-7.
329.
Dormann, A., et al., Self-expanding metal stents for gastroduodenal malignancies: systematic review
of their clinical effectiveness. Endoscopy, 2004. 36(6): p. 543-50.
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endoscopic stenting. A randomized prospective trial. Anticancer Research, 2004. 24(1): p. 269-71.
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stenting for malignant gastric outflow obstruction. Surgical Endoscopy, 2006. 20(2): p. 239-42.
332.
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APPENDICES
APPENDIX 1
GRADE SYSTEM
Grade of Recommendation/
Description
1A/ Strong recommendation, high
quality evidence
Benefit vs. Risk and Burdens
1B/ Strong recommendation, moderate
quality evidence
Benefits clearly outweigh risk and
burdens, or vice versa
1C/ Strong recommendation, low quality
evidence
Benefits clearly outweigh risk and
burdens, or vice versa
2A/ Weak recommendation, high quality
evidence
Benefits closely balanced with risks and
burden
2B/ Weak recommendation, moderate
quality evidence
Benefits closely balanced with risks and
burden
2C/ Weak recommendation, low quality
evidence
Benefits closely balanced with risks and
burden
Benefits clearly outweigh risk and
burdens, or vice versa
Methodological Quality of
Supporting Evidence
RCTs without important limitations or
overwhelming evidence from
observational studies
RCTs with important limitations
(inconsistent results, methodological
flaws, indirect, or imprecise) or
exceptionally strong evidence from
observational studies
Observational studies or case series
RCTs without important limitations or
overwhelming evidence from
observational studies
RCTs with important limitations
(inconsistent results, methodological
flaws, indirect, or imprecise) or
exceptionally strong evidence from
observational studies
Observational studies or case series
Implications
Strong recommendation, can apply to
most patients in most circumstances
without reservation
Strong recommendation, can apply to
most patients in most circumstances
without reservation
Strong recommendation, but may
change when higher quality evidence
becomes available
Weak recommendation, best action may
differ depending on circumstances or
patients’ or societal values
Weak recommendation, best action may
differ depending on circumstances or
patients’ or societal values
Very weak recommendation, other
alternatives may be equally reasonable
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APPENDIX 2
IDENTIFIED GUIDELINES AND THEIR QUALITY APPRAISAL
Source
American Gastroenterological
Association [212]
American Gastroenterological
Association [48]
American Society for
Gastrointestinal Endoscopy [226]
American Society for
Gastrointestinal Endoscopy [64]
National Comprehensive Cancer
Network [227]
National Comprehensive Cancer
Network [228]
Scottish Intercollegiate Guidelines
Network [47]
Kwaliteitsinstituut voor de
Gezondheidszorg [56]
Cancer Care Ontario [84]
Cancer Care Ontario [108]
Cancer Care Ontario [150]
Fédération Nationale des Centres
de Lutte Contre le Cancer [129]
Fédération Nationale des Centres
de Lutte Contre le Cancer [66]
European Society for Medical
Oncology [229]
European Society for Medical
Oncology [230]
American College of
Gastroenterology [231]
Allum W et al. [232]
Title
American Gastroenterological Association Institute Technical Review on the Management
of Gastric Subepithelial Masses
American Gastroenterological Association Technical Review on the Role of the
Gastroenterologist in the Management of Esophageal Carcinoma
The role of endoscopy in the assessment and treatment of esophageal cancer
Standardised Methodology Score
22%
Final Appraisal
Not recommended
31%
Not recommended
33%
Not recommended
Esophageal dilation
29%
Not recommended
Esophageal Cancer
57%
Not recommended
Gastric Cancer
57%
Not recommended
Management of oesophageal and gastric cancer
95%
Recommended
Diagnostiek en behandeling oesofaguscarcinoom
93%
Recommended with alterations
Neoadjuvant or Adjuvant Therapy for Resectable Esophageal Cancer. Practice Guideline
Report #2-11.
Combined Modality Radiotherapy and Chemotherapy in the Non-surgical Management of
Localized Carcinoma of the Esophagus. Practice Guideline Report #2-12.
Neoadjuvant or Adjuvant Therapy for Resectable Gastric Cancer. Practice Guideline
Report #2-14.
Recommandations pour la pratique clinique: Standards, Options et Recommandations 2003
pour la prise en charge des patients atteints
d’adénocarcinomes de l’estomac (cancers du cardia, autres types histologiques exclus)
(rapport intégral)
Recommandations pour la pratique clinique: Standards, Options et Recommandations 2003
pourl’utilisation de la tomographie par émission de positons au [18F]-FDG (TEP-FDG) en
cancérologie (rapport intégral)
ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of
gastric cancer
ESMO Minimal Clinical Recommendations for diagnosis, treatment and follow-up of
esophageal cancer
Updated Guidelines for the Diagnosis, Surveillance, and Therapy of Barrett’s Esophagus
93%
Recommended with alterations
93%
Recommended with alterations
93%
Recommended with alterations
86%
Recommended with alterations
86%
Recommended with alterations
24%
Not recommended
24%
Not recommended
27%
Not recommended
Guidelines for the management of oesophageal and gastric cancer
46%
Not recommended
KCE Reports 75
APPENDIX 3
OVERVIEW OF SCORES OF EXTERNAL EXPERTS
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67
68
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69
70
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72
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74
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76
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APPENDIX 4
EVIDENCE TABLES OF OESOPHAGEAL CANCER BY CLINICAL QUESTION
Diagnosis of oesophageal cancer.
CPG ID
Search
date
Alarm symptoms
SIGN
[47] 2004
CBO
Ref
[56]
July 2003
Oesophagogastroscopy
SIGN
[47] 2004
Barium X-ray
SIGN
[47]
Biopsy
SIGN
[47]
Recommendation
Supporting evidence
Level of
evidence
Patients presenting with any of the following alarm symptoms should be referred for early endoscopy:
dysphagia, recurrent vomiting, anorexia, weight loss, gastrointestinal blood loss.
Meineche-Schmidt V 2002
Numans ME 2001
Wallace MB 2001
Kapoor N 2005
Gillen D 1999
Meineche-Schmidt V 2002
Numans ME 2001
Wallace MB 2001
Low
Graham DY 1982
Abbas SZ 2004
Inone H 2001
Ragunath K 2003
Kiesslich R 2001
Canto MI 2001
Low
Lal N 1992
Low
Alarmsymptomen, zoals haematemesis en/of melaena, en maagklachten in combinatie met aanhoudend
braken, passagestoornissen, ongewild gewichtsverlies of anemie, vormen een indicatie voor een
endoscopie.
Bij het besluit om een endoscopie te laten verrichten speelt leeftijd een beperkte rol.
Flexible upper GI endoscopy is recommended as the diagnostic procedure of choice in patients with
suspected oesophageal cancer.
Routine use of chromoendoscopy during upper GI endoscopy is not recommended, but may be of value
in selected patients at high risk of oesophageal malignancy.
2004
No recommendation, only discussion
2004
A minimum of eight biopsies should be taken to achieve a diagnosis of oesophageal malignancy.
Low
High
78
Study ID
Upper GI Cancer
Ref
Search
date
Population
Alarm symptoms
Bowrey DJ 2006 [49]
NA
Marmo R 2005
NA
Patients referred for
Application of referral guidelines Gastroscopy
identified
oesophagogastric
open-access gastroscopy using alarm symptoms
carcinoma in 123 (3%) of the 4,018 subjects. Of
these
123
patients,
104
(85%)
with
oesophagogastric cancer had
‘‘alarm’’ symptoms (anemia, mass, dysphagia,
weight loss, vomiting) and would have satisfied
the referral criteria. The remaining 15% would
not have been referred for initial endoscopic
assessment because their symptoms were those
of uncomplicated ‘‘benign’’ dyspepsia.
The patients with ‘‘alarm’’ symptoms had a
significantly more advanced tumor stage
(metastatic disease in 47% vs 11%; p < 0.001),
were less likely to undergo surgical resection
(50% vs 95%; p<0.001), and had a poorer survival
(median, 11 vs 39 months; p = 0.01) than their
counterparts without such symptoms.
Patients with
Endoscopy
A total of 5,224 patients with uncomplicated
uncomplicated dyspepsia Identification of risk factors
dyspepsia were considered (training sample).
Twenty-two (16 males) had malignancy at
endoscopy. These patients were about 20 yr
older than patients with no malignancy (p <
0.001). The mean age of females with cancer was
almost 10 yr higher compared to males (p= 0.08).
Such differences in age were confirmed in a split
sample of 3,684 patients (p < 0.001 and p < 0.05,
respectively). The age cut-offs identified were 35
yr for males and 56 yr for females.
[233]
Oesophagogastroscopy
No additional studies found
Barium X-ray
No additional studies found
Biopsy
No additional studies found
Intervention
Results
KCE reports 75
Comments
Study type
Level of
evidence
Prospective
study
Low
Prospective
study
Low
KCE Reports 75
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79
Staging of patients with oesophageal cancer.
CPG ID
Ref
Search
date
Recommendation
Supporting evidence
Level of
evidence
CT scan
SIGN
[47]
2004
Kamel IR 2004
Low
CBO
July 2003
In patients with oesophageal cancer, CT scan of the chest and abdomen with IV contrast and gastric
distention with oral contrast or water should be performed routinely. The liver should be imaged in the
portal venous phase.
CT van de thoraxapertuur tot en met de bovenbuik kan worden gebruikt om de aanwezigheid van
mediastinale en/of truncale lymfkliermetastasen, alsook mogelijke metastasen in longen, lever, bijnieren of
skelet vast te stellen. Hierbij dient zowel gering oraal contrast ter markering van het oesofaguslumen als
intraveneus contrast te worden toegepast. De coupedikte dient kleiner dan of gelijk aan 5 mm te zijn.
Romagnuolo J 2002
Wakelin SJ 2002
van Overhagen H 1993
van den Hoed RD 1997
Low
[56]
Endoscopic
ultrasonography
SIGN
[47] 2004
CBO
[56]
July 2003
Patients with oesophageal or oesophagogastric junction cancers who are candidates for any curative
therapy should have their tumours staged with endoscopic US +/- fine needle aspiration.
Kelly S 2001 (SR)
Vazquez-Sequeiros E 2003
Weaver SR 2004
Endoscopische ultrasonografie is zinvol om de uitbreiding van de laesie in de diepte en mogelijke ingroei in Eloubeidi MA 2001
omgevende structuren (bijvoorbeeld aorta) (T-status) en de aanwezigheid van vergrote mediastinale en/of Catalano MF 1995
truncale lymfklieren te bepalen (N- en M-status).
Vazquez-Sequeiros E 2003
Heidemann J 2000
Wiersema MJ 1997
Williams DB 1999
Laparoscopy
SIGN
[47]
2004
Laparoscopy should be considered in patients with oesophageal tumours with a gastric component.
CBO
July 2003
Minimaal invasieve chirurgische stadiëring met behulp van thoracoscopie en laparoscopie is geïndiceerd bij
afwijkingen in de oesofagus van onduidelijke aard, gevonden bij niet-invasieve stadiëring. Voorts kan
laparoscopie worden overwogen bij carcinomen op de gastro-oesofageale overgang en cardiacarcinomen
die als T3/T4 worden gestadieerd met een niet-invasieve techniek.
Suspecte cervicale, mediastinale en truncale klieren dienen onder beeldvorming ((endoscopische)
ultrasonografie) cytologisch te worden gepuncteerd indien de status van de desbetreffende lymfklieren
voor beleidsbepaling relevant is.
[56]
Magnetic resonance
imaging
SIGN
[47] 2004
MRI should be reserved for those patients who cannot undergo CT or used for additional investigation
following CT/EUS.
Moderate
Low
Clements DM 2004
Molloy RG 1995
Wilkiemeyer MB 2004
Krasna MJ 1995 & 2002
Whyte RI 2001
Wakelin SJ 2002
Romijn MG 1998
Bonvalot S 1996
Natsugoe S 1999
van Overhagen H 1993
Low
Sohn KM 2000
Wu LF 2003
Kersjes 1997
Lauenstein TC 2004
Wong R 2000
Low
Low
Low
80
CPG ID
Upper GI Cancer
Ref
Search
date
Recommendation
Supporting evidence
Level of
evidence
Bronchoscopy +/- bronchoscopic US +/- biopsy should be undertaken in patients with clinical or imaging
features suspicious of tracheobronchial invasion.
Aggarwal AN 2003
Nguyen NT 2001
Nishimura Y 2002
Riedel M 2001
Baisi A 1999
Choi TK 1984
Low
Krasna MJ 2002
Low
Krasna MJ 1995 & 2002
Whyte RI 2001
Wakelin SJ 2002
Romijn MG 1998
Bonvalot S 1996
Natsugoe S 1999
van Overhagen H 1993
Low
van Westreenen HL 2004
van Westreenen HL 2004
Low
Low
October
2002
PET is not routinely indicated in the staging of oesophageal cancers.
FDG-PET bij T3-oesofaguscarcinomen kan worden overwogen om eventuele afstandsmetastasen vast te
stellen.
La TEP-FDG est indiquée, est complémentaire du scanner et de l’écho-endoscopie, pour l’évaluation
préthérapeutique du statut ganglionnaire et métastatique des cancers de l’oesophage.
Kinkel 2002
Depotter 2002
McAteer 1999
Hoffmann 1999
Couper 1998
Low
2004
July 2003
Neck imaging either by US or CT is recommended as part of the staging of oesophageal cancer.
Echografie van de hals is nuttig om cervicale lymfkliermetastasen te bepalen.
Griffith JF 2000
Bonvalot S 1996
Natsugoe S 1999
van Overhagen H 1993
Bonvalot S 1996
Natsugoe S 1999
van Overhagen H 1993
Low
Low
Bronchoscopy
SIGN
[47] 2004
CBO
[56]
July 2003
Thoracoscopy
SIGN
[47] 2004
CBO
[56]
PET scan
SIGN
[47]
CBO
[56]
FNCLCC [66]
Neck imaging
SIGN
[47]
CBO
[56]
KCE reports 75
July 2003
2004
July 2003
Bronchoscopie, inclusief brush-cytologie, van suspecte gebieden is onderdeel van de stadiëring van
oesofaguscarcinomen op of craniaal van het niveau van de carina.
Thoracoscopy may be considered for patients where a tissue diagnosis of suspicious nodes (not possible
by either EUS or CT guided techniques) is required to determine optimum management.
Minimaal invasieve chirurgische stadiëring met behulp van thoracoscopie en laparoscopie is geïndiceerd bij
afwijkingen in de oesofagus van onduidelijke aard, gevonden bij niet-invasieve stadiëring. Voorts kan
laparoscopie worden overwogen bij carcinomen op de gastro-oesofageale overgang en cardiacarcinomen
die als T3/T4 worden gestadieerd met een niet-invasieve techniek.
Suspecte cervicale, mediastinale en truncale klieren dienen onder beeldvorming ((endoscopische)
ultrasonografie) cytologisch te worden gepuncteerd indien de status van de desbetreffende lymfklieren
voor beleidsbepaling relevant is.
Suspecte cervicale, mediastinale en truncale klieren dienen onder beeldvorming ((endoscopische)
ultrasonografie) cytologisch te worden gepuncteerd indien de status van de desbetreffende lymfklieren
voor beleidsbepaling relevant is.
Low
Low
Low
KCE Reports 75
Upper GI Cancer
Study ID
Ref
Search date Population
CT scan
Kim SH 2006
[234]
NA
Umeoka S 2006
[235]
NA
Panebioanco V 2006
[236]
NA
Onbas O 2006
[237]
NA
Lowe VJ 2005
[59]
NA
Intervention
Patients with suspected or 3D Multidetector CT and CT
known oesophageal
oesophagography (n = 23)
neoplasms (n = 23)
Conventional barium study (n
= 20)
Conventional endoscopy (n =
23)
Histology (surgery: n = 12;
endoscopic biopsy: n = 11)
28 consecutive patients
Triple-phase dynamic
with oesophageal cancer
contrast-enhanced CT
histopathologically proved Standard: histopathology (23
at endoscopic biopsy (31
lesions) or EUS (8 lesions)
lesions)
39 patients with
Dynamic CT of the chest and
oesophageal cancer
abdomen with the aid of 3D
proved by means of
rendering
Standard: histopathology (26
endoscopy
patients)
Multidetector CT (n = 24)
44 patients with
oesophageal cancer
Virtual endoscopy (n = 27)
diagnosed by conventional Standard: histopathology (n =
endoscopy and biopsy
24)
specimens
69 patients with newly
FDG-PET
diagnosed oesophageal
CT
cancer
EUS
Histology (endoscopic biopsy:
n = 55; surgery n = 14)
Results
81
Comments
Study type
Level of
evidence
Sensitivity MDCT: 91%
Not very clear if
Overall accuracies for T and N staging prospective
were 42.9% and 85.7% respectively
Observationa Very low
l study
One lesion not identifiable at CT
Insufficient data to calculate accuracy
Same standard not
applied to all patients
Prospective
observational
study
Very low
T staging: sensitivity 92%, accuracy 88%
N staging: sensitivity 85%, specificity
58%, accuracy 69%
Standard not applied to
all patients
Prospective
observational
study
Very low
Prospective
observational
study
Very low
Prospective
observational
study
Low
MDCT: correct T staging in 22/24
patients, overstaging in 1 pt and
understaging in 1 pt; correct N staging in
20/24 patients, overstaging in 2 pts and
understaging in 2 pts
Correct T staging: 42% with PET and
CT, 71% with EUS
Sensitivity and specificity for nodal
involvement: 84% and 67% for CT, 86%
and 67% for EUS, 82% and 60% for PET
Sensitivity and specificity for distant
metastasis: 81% and 82% for CT, 73%
and 86% for EUS, and 81% and 91% for
PET
82
Upper GI Cancer
KCE reports 75
Study ID
Ref
Search date Population
Intervention
Results
Comments
Study type
Weaver SR 2004
[238]
NA
Spiral CT
EUS
Standard: histology
Sensitivity for T and N stages was 58%
and 79% for CT, and 72% and 91% for
EUS. Specificity for T and N stages was
80% and 84% for CT, and 85% and 68%
for EUS.
Included in SIGN
guideline
Prospective
observational
study
Yoon YC 2003
[239]
NA
60 consecutive patients
with histologically proven
cancer of the oesophagus,
established by endoscopy
and biopsy, that
underwent surgery
81 patients with squamous
cell carcinoma of the
oesophagus
CT and FDG-PET
Standard: histopathology
T staging: primary tumour was correctly
detected in 65 patients (80%) at CT and
in 74 patients (91%) at FDG PET
N staging:
CT: sensitivity 11%, specificity 95%
PET: sensitivity 30%, specificity 90%
Strong selection of 136
Prospective
patients with oesophageal observational
cancer
study
Included in SR of Van
Westreenen et al.
Very low
Patients with oesophageal
cancer
EUS
54 articles included
Medline search only
English only
No quality appraisal
Low
Patients (n = 144) with
adenocarcinoma or
squamous-cell carcinoma
of the oesophagus, M0
(helical CT) and who
were candidates for
surgical resection; no
neoadjuvant treatment
Patients with a suspicion
of early oesophageal
adenocarcinoma (n = 81)
or squamous cell
carcinoma (n = 19)
Helical CT
EUS (standard vs. modified
criteria)
EUS-FNAC
Standard: surgical pathology
result (n = 47) or malignant
cytology result (n = 97)
T staging: median accuracy 83% (5394%)
N staging: median accuracy 76% (5494%), median sensitivity 77% (37-100%),
median specificity 74% (50-90%)
No evidence for publication bias
Presence of all 7 modified criteria:
specificity and PPV of 100%
Presence of no modified criteria:
sensitivity and NPV of 100%
Blinded evaluation
Prospective
Standard not the same for observational
all patients
study
Low
Accuracy of staging:
HR-E 83.4% vs. HR-EUS 79.6%
Blinded evaluation
Low
Endoscopic ultrasonography
van Vliet EP 2007
[61]
February
2006
Vazquez-Sequeiros E
2006
[240]
NA
May A 2004
[241]
NA
Yanai H 2004
[242]
NA
Patients with
endoscopically staged
High-resolution video
endoscopy
HR-EUS with a 20 MHz
miniprobe
Standard: histological
examination of the
endoscopically or surgically
resected tumour
Systematic
review
Prospective
observational
study
Level of
evidence
Low
Mucosal tumours:
Sensitivity HR-E 94.1% vs. HR-EUS
91.2%
Submucosal tumours:
Sensitivity HR-E 56% vs. HR-EUS 48%
Combination of HR-E and HR-EUS: 60%
20-MHz thin ultrasound probe Invasion depth correctly staged in 20/31
EUS
pts (64.5%)
In calculation exclusion of Prospective
2 dysplasia pts and 2 non- observational
Very low
KCE Reports 75
Study ID
Ref
Upper GI Cancer
Search date Population
Intervention
Comments
Study type
resection cases
study
Standard not applied to
all patients
2 pts lost-to-follow-up
Prospective
observational
study
Very low
Patient survival was significantly related
to tumour (EUS T), node (EUS N) and
Union Internacional Contra la Cancrum
classification (EUS UICC) stage
according to sonographic findings (P =
0·003, P = 0·009 and P = 0·004
respectively), and the presence of
stenosis determined by EUS (P = 0·004).
EUS T stage was a prognostic factor for
survival (RR 1.7, 95%CI 1.1 to 3.0; P =
0·046). Complete surgical resection (R0)
was also significantly related to EUS T,
N and UICC classification (P < 0·001).
EUS UICC stage was a factor predictive
of R0 resection (RR 2.6, 95%CI 1.4 to
4.8; P = 0·003).
Doubts about prospective
design
Not enough data to
calculate staging accuracy
Prospective
(?)
observational
study
Very low
The combination of EUS and LUS
correctly predicted R0 resection in
90.6%, R1–R2 in 91% and irresectability
in 91.4% of patients. Ten patients (2.4%)
had explorative laparotomy only. There
were no complications associated with
the EUS and LUS procedures.
To avoid false-positive
findings with regard to
local irresectability
ultrasonographic criteria
were adjusted so that
only a combination of
several ultrasonographic
criteria with a 100 per
cent predictive value for
local
irresectability were used
Standard is not identical
Prospective
study
Very low
superficial oesophageal
cancer (n = 31)
Chang KJ 2003
[243]
NA
Mariette C 2003
[244]
NA
Laparoscopy
Mortensen MB 2006
[79]
NA
Standard: histological
examination of the
endoscopically or surgically
resected tumour
Patients with oesophageal CT
cancer (n = 60)
EUS
EUS-FNAC if positive FNAC
would upstage the tumour
Standard: surgical pathology
result
150 patients who
EUS
underwent EUS for staging Standard: surgical pathology
of tumours of the
result
oesophagus (out of 372
patients who underwent
surgery with curative
intent)
Results
411 patients with upper
gastrointestinal tract
cancer, of which 95 had
biopsy-proven
oesophageal cancer
Combined endoscopic
ultrasonography (EUS) and
laparoscopic ultrasonography
(LUS)
‘Standard’: treatment actually
undertaken
83
T staging: accuracy EUS 83%
N staging:
Accuracy EUS 83%
Accuracy EUS-FNAC 89%, PPV 100%
Level of
evidence
84
Upper GI Cancer
Study ID
Ref
Search date Population
Menon KV 2003
[245]
NA
Magnetic resonance imaging
Riddell AM 2006
[246] NA
Bronchoscopy
Wakamatsu T 2006
[77]
NA
Intervention
133 out of 320
Multiport laparoscopy
consecutive patients with Standard: histology or
histologically proven
subsequent surgery
carcinoma of the
oesophagus or cardia,
without clinical or
radiological evidence (CT)
of metastases and deemed
fit for potential excisional
surgery
Results
KCE reports 75
Comments
for all patients
Laparoscopy detected incurable disease Standard is not identical
in 31 patients (24%), some of whom had for all patients
more than one contraindication to
surgery, including hepatic metastases (n
= 10), peritoneal metastases (n = 12)
and
malignant small volume ascites (n = 5).
Lymph node metastases were confirmed
histologically by biopsy at laparoscopy in
26 patients (fixed nodes, n = 14; mobile
nodes, n = 12). Sensitivity for the
detection of liver and peritoneal
metastases was 100%, and lymph node
metastases were 83%. Specificity for
detection of hepatic metastases was
99%, 100% for peritoneal metastases
and 82% for lymph node metastases.
Ninety-nine patients proceeded to
definitive surgery and only two were
unresectable.
Study type
Level of
evidence
Prospective
study
Very low
10 patients with
confirmed oesophageal
carcinoma (7 with
adenocarcinoma, 2 with
squamous cell carcinoma,
and 1 with spindle-cell
melanoma),
who were deemed
medically fit for surgery
and shown to have
resectable disease using
endoscopic sonography
and CT
High-resolution MRI of
primary tumour
Standard: histology
50 MRI images (5 per patient)
Very small sample size
7 images underestimated, 20 images
overestimated
Tumor position was correctly diagnosed
by MRI in 5 patients
Extramural extension: 2 false negatives
Prospective
study
Very low
54 surgical patients with
suspected thyroid or
oesophageal cancer (n =
CT neck/upper mediastinum
MRI neck/upper mediastinum
Bronchoscopy with EBUS
The sensitivity and specificity of CT, MRI No separate numbers for
and EBUS for invasion were 59 and 56,
oesophageal cancer
75 and 73, and 92 and 83%, respectively. patients
Prospective
study
Very low
KCE Reports 75
Study ID
Ref
Upper GI Cancer
Search date Population
Intervention
24) and a mass adjacent to Standard: histology and/or
the tracheobronchial wall clinical follow-up
on chest or neck CT or
MRI
Osugi H 2003
[76]
NA
Thoracoscopy
No additional diagnostic studies found
PET scan
Meyers BF 2007
[247] NA
Ott K 2006
[72]
NA
Patients with advanced
squamous cell carcinoma
in contact with the
trachea, the main bronchi,
or both (n = 66)
BUS
CT
50 thoracotomies
Patients with resectable,
biopsy-proven carcinoma
of the thoracic
oesophagus (n = 189)
FDG-PET
Chest and abdominal CT
Additional study or biopsy if
positive PET finding
65 patients with biopsy
proven adenocarcinoma
of the distal oesophagus
or cardia (stage uT3)
PET before preoperative
chemotherapy and on day 14
of first chemotherapy cycle
85
Results
Comments
Study type
Level of
evidence
The accuracy of EBUS was significantly
greater than that of CT in the present
study (p = 0.0011). The accuracy of
EBUS was significantly different from
that of CT and MRI in the surgically
treated patients (p = 0.005 and p =
0.032, respectively).
BUS: sensitivity 91%, specificity 89%,
accuracy 90%
CT: sensitivity 69%, specificity 55%,
accuracy 62%
Standard not same for all
patients
Sensitivity and specificity
calculated with 50
thoracotomy patients
Prospective
study (?)
Very low
The reasons for no resection included
the following: M1 disease found by PET
and confirmed (9), M1 disease found by
PET and not confirmed (2), M1 disease
at exploration not found by PET (7),
decline or death before surgery (10),
patient refusal of surgery (7),
unresectable local tumour at
exploration (5), and extensive N1
disease precluding operation (2). Eight
(4.2%) patients undergoing resection had
a recurrence in the first 6 months.
Metabolic responders showed a high
histopathologic response rate (44%)
with a 3-year survival rate of 70%. In
contrast, prognosis was poor for
metabolic nonresponders with a
histopathologic response rate of 5% (P =
0.001) and a 3-year survival rate of 35%
(P = 0.01). A multivariate analysis
(covariates: ypT-, ypN-category,
histopathologic response) demonstrated
that metabolic response was the only
factor predicting recurrence (P = 0.018)
Standard not applied to
all patients
Prospective
study
Very low
9 patients excluded from
analysis (8 too low FDG
uptake, 1 with
hyperglycemia)
Prospective
study
Low
86
Study ID
Upper GI Cancer
Ref
Search date Population
Intervention
Yuan S 2006
[75]
NA
Patients with a first
PET/CT
diagnosis of biopsy-proven Standard: histology
squamous cell cancer of
the thoracic oesophagus,
operable (including M1a),
not refusing surgery, and
willing to pay at least 30%
of the charge for PET/CT
(n = 45)
Van Baardwijk A
2006
[248]
August 2005
Patients with oesophageal
cancer
Leong T 2006
[70]
NA
Patients with histologically PET/CT for radiotherapy
planning vs. CT
proven squamous or
adenocarcinoma of the
oesophagus stages I–III
and ECOG performance
status 0–2, where the
treatment intent was
radical chemoradiotherapy
(radiation dose 50 Gy)
following completion of all
non-PET staging
investigations that did not
reveal evidence of
metastatic disease (n =
23)
PET for radiotherapy
treatment planning
Results
KCE reports 75
Comments
in the subgroup of completely resected
(R0) patients.
The sensitivity, specificity, accuracy,
positive predictive value, and negative
predictive value of PET/CT were 93.90%
(77/82 nodal groups), 92.06% (290/315),
92.44% (367/397), 75.49% (77/102), and
98.31% (290/295), respectively, whereas
those of PET were 81.71% (67/82),
87.30% (275/315), 86.15% (342/397),
62.62% (67/107), and 94.83% (275/290),
respectively. P values were 0.032, 0.067,
0.006, 0.063, and 0.037, respectively.
The differences in sensitivity, accuracy,
and negative predictive value between
PET and PET/CT were statistically
significant.
In oesophageal cancer, PET scan can be Medline only
used to include PET positive lymph
No information on study
nodes in the target volume.
selection and quality
appraisal
The addition of PET information altered Patients with PET
detected metastatic
the clinical stage in 8 of 21 eligible
disease came off study
patients enrolled on the study (38%); 4
with no further data
patients had distant metastatic disease
collection, while patients
and 4 had unsuspected regional nodal
who did not have
disease. Sixteen patients proceeded to
metastatic disease on PET
the radiotherapy planning phase of the
and were deemed suitable
study and received definitive
for radical treatment
chemoradiation planned with the
PET/CT data set. The GTV based on CT proceeded to the
radiotherapy planning
information alone excluded PET-avid
phase of the study.
disease in 11 patients (69%), and in five
patients (31%) this would have resulted Two patients excluded
in a geographic miss of gross tumour.
The discordance between CT and
PET/CT was due mainly to differences in
defining the longitudinal extent of
disease in the oesophagus. The cranial
extent of the primary tumour as defined
Study type
Level of
evidence
Prospective
study
Low
SR
Low
Prospective
study
Low
KCE Reports 75
Study ID
Ref
Upper GI Cancer
Search date Population
Levine EA 2006
[249]
NA
Kato H 2005
[250]
NA
Moureau-Zabotto L
2005
[71]
NA
Song SY 2005
[74]
NA
Intervention
Results
by CT vs. PET/CT differed in 75% of
cases, while the caudal extent differed in
81%.
64 consecutive
PET pre- and postResponse was as follows: pCR 27%,
patients, with potentially
chemoradiation (of the 44
pathologic residual microscopic
curable, locally advanced
patients undergoing
(pCRmicro) 14.5%, partial response
oesophageal cancer
oesophagectomy following
19%, and stable or progressive disease
chemoradiation, 31 patients
39.5%. A pretreatment standardized
had both a preuptake value
chemoradiation and post(SUVmax1 hour) ≥15 was associated
chemoradiation PET, while 13 with an observed 77.8% significant
patients had a single PET scan: response (pCR + pCRmicro) compared
10 patients of which
with 24.2% for patients with a
had a pre-chemoradiation
pretreatment SUVmax1 hour <15 (P =
study and 3 of which had post- 0.005). Significant response was
chemoradiation imaging)
observed in 71.4% of patients with a
decrease in SUVmax1 hour ≥10
compared with 33.3% when the
SUVmax1 hour decreased<10 (P =
0.004).
44 patients with thoracic
FDG-PET
PET: sensitivity 92%, specificity 94%
oesophageal cancer
Bone scintigraphy
Bone scintigraphy: sensitivity 77%,
specificity 84%
Thirty-four oesophageal
PET-CT vs. CT for
PET identified previously undetected
carcinoma patients
radiotherapy treatment
distant metastatic disease in 2 patients,
referred for concomitant planning
making them ineligible for curative
radiotherapy and
conformal radiotherapy. Modifications of
chemotherapy with radical
the GTV affected the planning treatment
intent
volume in 18 patients. Modifications of
the delineation of the GTV and
displacement of the isocenter of the
planning treatment volume by FDG-PET
also affected the percentage of total lung
volume receiving >20 Gy in 25 patients
(74%), with a dose reduction in 12
patients and dose increase in 13.
PET before and after
Patients with locally
Five patients (16%) were PET negative
advanced but resectable
neoadjuvant chemoradiation
before chemoradiotherapy, which
oesophageal cancer (n =
indicates a sensitivity of 84% as a
32)
diagnostic procedure for both the
87
Comments
Study type
Level of
evidence
Patients not treated
similarly (different
chemotherapy schedule,
surgery not for all
patients, etc.)
Standard not similar for
all patients
Prospective
study (?)
Very low
Not clear if prospective
Prospective
(?) study
Very low
Prospective
study
Low
Prospective
study
Low
88
Upper GI Cancer
Study ID
Ref
Search date Population
Intervention
Van Westreenen HL
2005
[251]
NA
Ten patients with biopsyproven cancer of the
oesophagus or gastrooesophageal junction
18F-FLT PET vs.
18F-FDG PET
Standard: histology
Vrieze O 2004
[252]
NA
30 patients with an
advanced oesophageal
carcinoma (cT4 based on
EUS and/or CT), M0
PET before neoadjuvant
chemoradiation therapy (25
patients treated with surgery)
Sihvo EI 2004
[73]
NA
Routine staging with
endoscopy, CT and EUS
FDG-PET
Histopathology
Choi JY 2004
[68]
NA
Patients with histologically
proves adenocarcinoma of
the oesophagus (n = 20)
or the EG junction (n =
35)
Eighty-nine consecutive
patients having newly
diagnosed oesophageal
cancer, undergoing
curative surgery
PET preoperatively
Results
oesophagus and lymph nodes.
18F-FDG PET was able to detect all
oesophageal cancers, whereas 18FFLT
PET visualized the tumor in 8 of 10
patients. Both 18F-FDG PET and 18FFLT PET detected lymph node
metastases in 2 of 8 patients. 18F-FDG
PET detected 1 cervical lymph node that
was missed on 18F-FLT PET, whereas
18F-FDG PET showed uptake in benign
lesions in 2 patients.
In 14 of the 30 patients (47%)
discordances were found in detection of
the pathological lymph nodes between
CT/EUS and FDGPET. In 8 patients, 9
lymph node regions were found with
pathologic nodes on conventional
imaging only. In three of these patients
the influence of FDG-PET findings would
have led to a decrease of the irradiated
volume. In 6 patients, 8 lymph node
regions were found with a normal
CT/EUS and pathologic nodes on FDGPET. In three of these patients (10%) the
influence of the FDG-PET would have
led to enlargement of the irradiated
volume.
Accuracy N staging: PET 60%, EUS 72%,
CT 58%
Accuracy M staging: PET 76%, CT 75%
There were 130 malignant nodal groups
of 554 dissected nodal groups in 43 of
69 patients on pathologic examination.
Ninety-six positive lymph nodes in 43
patients were evident on 18F-FDG PET.
Only 30 lymph nodes were positive in
24 patients on CT. EUS revealed lymph
KCE reports 75
Comments
Study type
Level of
evidence
Small sample size
Prospective
study
Very low
Included in SR of Van
Baardwijk et al.
One centre analysis of
prospective study of 36
patients
No comparison with
histology
Prospective
study
Very low
Prospective
study
Low
Prospective
study
Low
KCE Reports 75
Upper GI Cancer
Study ID
Ref
Search date Population
Intervention
Kneist W 2004
[69]
NA
PET and computer
tomography
(CT) of the chest and
abdomen (and of the neck in
45 patients) within 45 days.
The findings of the
histopathological examination
for 31 suspicious lesions from
28 patients served as the basis
for the diagnosis of distant
metastasis.
Neck imaging
No additional diagnostic studies found
Patients with biopsyproved oesophageal
carcinoma (n = 81)
Results
node metastases in 27 patients.
The PET findings had a higher specificity
(89% vs 11%) but a lower sensitivity
(38% vs 63%) than CT findings in the
detection of metastatic sites. The CT
results showed greater agreement with
histopathological findings than did PET
results. In 8 patients (10%), PET
detected distant metastases that were
not identified with CT. In 4 patients
(5%), PET detected bone metastases
only, but in all of these patients
metastases in other locations were
detected by CT. Although PET led to
upstaging (M1) in 2 patients (2%), it did
not enable the exclusion of oesophageal
resection.
89
Comments
Study type
Level of
evidence
Prospective
study
Low
90
Upper GI Cancer
KCE reports 75
Diagnosis and treatment of early lesions.
CPG ID
Ref
SIGN
[47]
Search
date
2004
Recommendation
Supporting evidence
Reduction of risk of progression to adenocarcinoma is not an indication for anti-reflux surgery in patients
with Barrett’s oesophagus.
Spechler SJ 2001
Corey KE 2003
Parrilla P 2003
Inone H 2001
Ragunath K 2003
Kiesslich R 2001
Canto MI 2001
Mitooka H 1995
Garside R 2006
Fitzgerald RC 2001
Conio M 2003
Macdonald CE 2000
Montgomery E 2001a
Schlemper RJ 2000
Montgomery E 2001a
Baak JP 2002
Montgomery E 2001b
Baak JP 2002
Montgomery E 2001b
Routine use of chromoendoscopy during upper GI endoscopy is not recommended, but may be of value
in selected patients at high risk of oesophageal malignancy.
In patients with Barrett’s oesophagus there should be a structured biopsy protocol with quadrantic
biopsies every two centimetres and biopsy of any visible lesion.
Pathologists should follow the revised Vienna classification for reporting dysplasia.
Where radical intervention is contemplated on the basis of high-grade dysplasia or early adenocarcinoma
the diagnosis should be validated by a second pathologist experienced in this area and further biopsies
should be taken if there is uncertainty.
Evaluation of suspected high-grade dysplasia in Barrett’s oesophagus biopsies should be undertaken with
knowledge of the clinical and endoscopic background and biopsies should be reviewed at a
multidisciplinary meeting with access to the clinical information.
Patients diagnosed with high-grade dysplasia should have careful assessment (CT, EUS, rigorous biopsy
protocol +/- EMR) to exclude coexisting cancer.
In the absence of invasive cancer, patients with high-grade dysplasia should be offered endoscopic
treatment.
The assessment and management of patients with high-grade dysplasia should be centralised to units with
the appropriate endoscopic facilities and expertise.
Superficial oesophageal cancer limited to the mucosa should be treated with EMR.
Mucosal ablative techniques, such as PDT, APC, or laser should be reserved for the management of
residual disease after EMR and not for initial management if invasive disease is present in patients fit for
surgery.
CBO
[56]
July 2003
Ondanks de relatief lage interobserveerdersvariatie verdient het aanbeveling dat de histopathologische
diagnose van hooggradige dysplasie (carcinoma in situ) en vroegcarcinoom in de oesofagus door een
patholoog met ervaring op dit gebied wordt gesteld.
Level of
evidence
High
Moderate
Low
Low
Low
Low
Schnell TG 2001
Levine DS 1993
May A 2002
May A 2002
Ell C 2000
Pacifico RJ 2003
Ell C 2000
Low
Fujita H 2001
Inoue H 1991
Takekoshi T 1994
May A 2002
Ell C 2000
Pacifico RJ 2003
Attwood SE 2003
Schlemper 2000a
Schlemper 2000b
Montgomery 2001
Low
Low
Low
Low
Low
KCE Reports 75
CPG ID
Ref
Upper GI Cancer
Search
date
Recommendation
Chromoscopie met lugolkleuring is geïndiceerd bij patiënten met een neoplastische afwijking in het
plaveiselepitheel van de oesofagus waarbij endoscopische therapie wordt overwogen.
Bij patiënten met een neoplastische afwijking in een Barrett-oesofagus gelden de volgende aanbevelingen in
de endoscopische work-up voor eventuele endoscopische therapie:
Endoscopische inspectie geschiedt bij voorkeur in een centrum met endoscopische expertise in
de detectie van vroege afwijkingen in Barrett-oesofagus.
Hierbij wordt bij voorkeur gebruikgemaakt van hoge-resolutie-endoscopie, eventueel aangevuld
met chromoscopie.
Geadviseerd wordt om biopten te nemen uit alle zichtbare mucosale onregelmatigheden en at
random uit vier kwadranten voor elke centimeter Barrett-oesofagus, te beginnen 1 cm boven de
bovenrand van de maagplooien en doorlopend tot aan de overgang van cilindrisch naar
plaveiselepitheel.
Bij alle patiënten met een neoplastische afwijking in de oesofagus bij wie endoscopische therapie wordt
overwogen, dient een endoscopische ultrasonografie te worden verricht om diepte-infiltratie van de
afwijking en verdachte lokale lymfklieren uit te sluiten.
Aanvullende stadiëring met CT-scan is optioneel.
91
Supporting evidence
Skacel 2000
Dawsey 1998
Dave U 2001
Endo T 2002
Guelrud M 2001
Sharma P 2003
Reid BJ 2000
Scotiniotis IA 2001
Hasegawa N 1996
Natsugoe S 1996
Bergman JJ 1999
Scotiniotis IA 2001
Voor patiënten met hooggradige dysplasie en/of vroegcarcinoom in plaveiselepitheel van de oesofagus
Shimizu Y 2002
heeft endoscopische behandeling de voorkeur. Hierbij zijn de volgende voorwaarden van belang:
Fujita H 2001
Voorafgaande aan de behandeling worden een endoscopische beoordeling en stadiëring verricht. Narahara H 2000
Nijhawan PK 2000
Het betreft een solitaire, vlakke afwijking met een maximale diameter van 2-3 cm.
Als endoscopische resectietechniek verdient de endoscopische mucosale resectie-cap-techniek de
Inoue H 1991
voorkeur, zodat histologisch onderzoek van de verwijderde afwijking mogelijk is.
Het besluit om de endoscopische behandeling als curatief te beschouwen, kan pas worden genomen nadat
het endoscopische mucosale resectiepreparaat histologisch is beoordeeld.
Bij patiënten met evidente submucosale ingroei en/of positieve resectieranden van het endoscopische
mucosale resectiepreparaat dient in principe een chirurgische resectie te worden verricht.
Er vindt initieel een endoscopisch onderzoek plaats dat specifiek dient om in de Barrett-oesofagus een
Cfr supra
eventueel invasief carcinoom te detecteren:
- Hierbij geniet hoge-resolutie-endoscopie, eventueel aangevuld met chromoscopie, de voorkeur.
- Er worden biopten genomen uit alle zichtbare mucosale onregelmatigheden en random uit vier
kwadranten voor elke centimeter Barrett-oesofagus, te beginnen 1 cm boven de bovenrand van de
maagplooien en doorlopend tot aan de overgang tussen cilinder- en plaveiselepitheel.
Na de work-up wordt de endoscopische surveillance als volgt verricht:
No evidence
- Frequentie surveillance: in het eerste jaar elke drie maanden, in het tweede jaar elke zes maanden en
daarna tenminste jaarlijks.
- Indien er tijdens surveillance sprake is van nieuwe afwijkingen zoals erosies of een onregelmatig
oppervlak, dienen opnieuw biopten te worden genomen en/of dient dit te worden uitgebreid met een
Level of
evidence
Low
Low
Low
Low
Low
Low
92
CPG ID
Upper GI Cancer
Ref
Search
date
Recommendation
KCE reports 75
Supporting evidence
diagnostische endoscopische mucosale resectie.
Endoscopische surveillance (ten minste gedurende het eerste jaar) wordt bij voorkeur verricht in een
centrum met ervaring.
Voor geselecteerde patiënten met hooggradige dysplasie en/of vroegcarcinoom in een Barrett-oesofagus
heeft endoscopische behandeling de voorkeur. Hierbij gelden de volgende voorwaarden:
Voorafgaande aan de behandeling zijn endoscopische beoordeling en stadiëring verricht.
Het betreft een solitaire verheven en/of vlakke afwijking met een maximale grootte van 2 cm.
De endoscopische behandeling omvat als primaire behandeling een endoscopische resectietechniek (bij
voorkeur de endoscopische mucosale resectie-cap-techniek), waardoor histologisch onderzoek van de
verwijderde afwijking mogelijk is.
Het besluit om endoscopische behandeling als in opzet curatieve behandeling te beschouwen, kan pas
worden genomen nadat het endoscopische mucosale resectiepreparaat is beoordeeld.
Bij geselecteerde patiënten kan aanvullende ablatietherapie na voorafgaande endoscopische mucosale
resectie worden overwogen.
Bij afwijkingen groter dan 2 cm en/of de helft van de circumferentie is ‘piece-meal-resectie vereist.
De histopathologische beoordeling van de endoscopische mucosale resectiepreparaten dient door een
patholoog met ervaring op dit gebied te geschieden. Referentiepanels voor een ‘second opinion’ zijn in
Nederland aanwezig.
Bij submucosale ingroei van een vroegcarcinoom in plaveiselcelepitheel dient alsnog een chirurgische
resectie te worden overwogen gezien de hoge kans (26-47%) op lokale lymfkliermetastasen.
Bij submucosale ingroei van een vroegcarcinoom in een Barrett-oesofagus dient alsnog een chirurgische
resectie te worden overwogen gezien de hoge kans (tot 50%) op lokale lymfkliermetastasen.
Na endoscopische behandeling van hooggradige dysplasie/vroegcarcinoom in de oesofagus gelden de
aanbevelingen voor de endoscopische follow-up conform de aanbevelingen voor endoscopische
surveillance van Barrett-oesofagus.
Level of
evidence
Cfr supra
Buttar NS 2001
May A 2002
Low
Buttar NS 2001
May A 2002
Low
Ell C 2000
Schlemper 2000a
Schlemper 2000b
Low
Low
Multiple studies
Low
Multiple studies
Low
May A 2002
Low
Study ID
Ref
Search date Population
Intervention
Results
Comments
Study type
Level of
evidence
Diagnosis
Pohl J 2007
[253]
NA
Conventional
chromoendoscopy with acetic
acid vs. computed virtual
chromoendoscopy
At each examination targeted
biopsies from all detected
lesions, followed by random
four-quadrant biopsies
In 24/57 patients, 30 lesions with
HGIN/early cancer were detected. The
sensitivity of targeted biopsies for
HGIN/early cancer on a 'per lesion'
basis was 87 % (26/30) for both CAA
and CVC. The positive predictive value
was 39 % (26/66) for CAA and 37 %
(26/70) for CVC. In the 'per patient'
analysis, sensitivity was 83 % (20/24) and
Cross-over design
Randomization with
sealed envelopes
(blinded??)
Blinded assessors
RCT
Moderate
Patients withBarrett’s
oesophagus and possible
high-grade intraepithelial
neoplasia or early cancer,
having discrete mucosal
alterations or
macroscopically occult
lesions (n = 57)
KCE Reports 75
Study ID
Ref
Upper GI Cancer
Search date Population
Borovicka J 2006 [52]
NA
Patients with
endoscopically
documented Barrett’s
oesophagus (n = 187)
Lim CH 2006
NA
Patients with a diagnosis
of dysplasia identified in
Barrett's oesophagus (n =
35)
[53]
Intervention
Results
92 % (22/24) for CAA and CVC,
respectively ( P = 0.617). Stepwise
random four-quadrant biopsies identified
only one patient with HGIN/early
cancer that was missed by both, CAA
and CVC.
Phase 1: Autofluorescence
In study phase 1, the AFE and
endoscopy with targeted
conventional approaches yielded
biopsy followed by fouradenocarcinoma/HGD rates of 12% and
quadrant biopsies vs.
5.3%, respectively, on a per-patient
conventional endoscopic
basis. With AFE, four previously
surveillance, also including
unrecognized adenocarcinoma/HGD
four-quadrant biopsies.
lesions were identified (4.3% of the
Phase 2: After exclusion of
patients); with the conventional
patients with early cancer or
approach, one new lesion (1.1%) was
high-grade dysplasia, who
identified. Of the 19
underwent endoscopic or
adenocarcinoma/HGD lesions detected
surgical treatment, as well as
during AFE endoscopy in study phase 1,
those who declined to
eight were visualized, while 11 were
participate in phase 2 of the
only detected using untargeted fourstudy, 130 patients remained. quadrant biopsies (sensitivity 42%). Of
These patients were examined the 766 biopsies classified at histology as
again with the alternative
being non-neoplastic, 58 appeared
method after a mean of 10
suspicious (specificity 92%, positive
weeks, using the same
predictive value 12%, negative predictive
methods described.
value 98.5%). In study phase 2, AFE
detected two further lesions in addition
to the initial alternative approach in
3.2% of cases, in comparison with one
lesion with conventional endoscopy
(1.7%).
Overall, dysplasia was identified in 17 of
4 random quadrant biopsies
taken every 2 cm through the 18 patients by RB and in 9 of 18 by
MBDB (McNemar test, p = 0.02).
length of the Barrett's
esophagus (n = 18) vs.
methylene blue (MB)
chromoendoscopy directed
biopsies from unstained or
heterogenously stained
mucosa (n = 17)
93
Comments
Study type
Level of
evidence
Cross-over design
Blinded assessors
Computer-generated
randomization list with
block randomization
RCT
High
Cross-over design
No ITT
RCT
Moderate
94
Upper GI Cancer
KCE reports 75
Study ID
Ref
Search date Population
Intervention
Results
Comments
Study type
Kara MA 2005
[54]
NA
Patients with Barrett’s
oesophagus and recently
diagnosed but
endoscopically
inconspicuous high-grade
dysplasia or early cancer
(n = 28)
High-resolution endoscopy
with indigo carmine
chromoendoscopy or narrowband imaging
Cross-over design
Randomization with
sealed opaque envelopes
(blinded??)
Blinded assessors
RCT
Ragunath K
2003
[254]
NA
Patients with Barrett's
oesophagus segments 3
cm or more in length
without macroscopic
evidence of dysplasia or
cancer (n = 75)
Methylene blue-directed
biopsies vs. random biopsy (4
random quadrant biopsies
taken every 2 cm)
Fourteen patients were diagnosed with
HGD/EC. The sensitivity for HGD/EC
was 93 % and 86 % for HRE-ICC and
HRE-NBI, respectively. Targeted
biopsies had a sensitivity of 79 % with
HRE alone. HGD was diagnosed from
random biopsies alone in only one
patient. ICC and NBI detected a limited
number of additional lesions occult to
HRE, but these lesions did not alter the
sensitivity for identifying patients with
HGD/EC.
Analysis of the results by per-biopsy
protocol showed that the MBDB
technique diagnosed significantly more
specialized intestinal metaplasia (75 %)
compared to the random biopsy
technique (68 %; P = 0.032). The
sensitivity and specificity rates of MBDB
for diagnosing specialized intestinal
metaplasia were 91 % (95 % CI, 88 - 93
%) and 43 % (95 % CI, 36 - 51 %),
respectively. The sensitivity and
specificity rates of MBDB for diagnosing
dysplasia or carcinoma were 49 % (95 %
CI, 38 - 61 %) and 85 % (95 % CI, 82 88 %), respectively. There were no
significant differences in the diagnosis of
dysplasia and carcinoma - MBDB 12 %,
random biopsy 10 %. The methylene
blue staining pattern appeared to have
an influence on the detection of
specialized intestinal metaplasia and
dysplasia/carcinoma. Dark blue staining
was associated with increased detection
of specialized intestinal metaplasia (P <
0.0001), and heterogeneous staining (P =
0.137) or no staining (P = 0.005) were
associated with dysplasia and/or
carcinoma detection. The MBDB
Level of
evidence
Moderate
Cross-over design
Blinding
RCT
High
KCE Reports 75
Study ID
Ref
Upper GI Cancer
Search date Population
Intervention
Results
95
Comments
Study type
Level of
evidence
technique prolonged the endoscopy
examination by an average of 6 min.
Staging
Pech O 2006
[255]
NA
Patients with suspected
early cancer in Barrett’s
oesophagus referred for
endoscopic treatment (n
= 100)
EUS
Helical CT of chest and upper
abdominal organs
Abdominal US examination
Histology (n = 62)
Larghi A 2005
[256]
NA
EUS
Standard: surgical pathology
result (n = 8) or EMR
pathology result
Waxman I 2006
[257]
NA
Patients (n = 48) with
Barrett’s oesophagus and
biopsy specimen proven
high-grade dysplasia and
adenocarcinoma in focal
nodular lesions or in
endoscopically unapparent
flat lesions in shortsegment Barrett’s
oesophagus
9 consecutive patients
with Barrett’s oesophagus
and high-grade dysplasia (n
= 7) or intra-mucosal
carcinoma (n = 2)
Treatment
Overholt BF
2005
[83]
NA
Patients with Barrett’s
oesophagus and highgrade dysplasia
For staging of T1 tumours, the
Histology not available in
sensitivity of CT was 100%, but its
all patients
specificity was 0%; PPV 89%, NPV 0%.
Differentiation between T1 and>T1
using EUS was possible in all 62 patients.
Sensitivity of CT for N staging was not
acceptable compared with EUS (38% vs.
75%). No extranodal metastases were
found on CT.
Accurate staging in 41/48 patients (85%) Single-center study
Overstaging in 1 pt, understaging in 6
pts
Prospective
Low
observational
study
High-frequency (20 MHz)
probe ultrasonography
(HFPUS)
Standard: histology
Sensitivity 60%
Specificity 75%
Of the 3 true-positives: 1 overstaged
and 1 understaged
Small sample size
Prospective
case series
Very low
Photodynamic therapy with
porfimer sodium +
omeprazole (n = 138) vs.
omeprazole only (n = 70)
There was a significant difference
(p=0.0001) in favour of PORPDT
(106/138 [77%]) compared with OM
(27/70 [39%]) in complete ablation of
HGD at any time during the study
period. The occurrence of
adenocarcinoma in the PORPDT group
(13%) (n=18) was significantly lower
(p=0.006) compared with the OM group
(20%) (n=20). The safety profile showed
94% of patients in the PORPDT group
No information on
randomization procedure
Only partially blinded
(pathology)
RCT
Moderate
Prospective
Low
observational
study
96
Study ID
May A 2003
Upper GI Cancer
Ref
[258]
Search date Population
NA
72 patients with early
stage oesophageal cancer
Intervention
Results
KCE reports 75
Comments
and 13% of patients in the OM group
had treatment-related adverse effects.
Endoscopic resection with
No significant differences were observed Blinded randomization
"suck-and-ligate" device
between the two groups with regard to Blinded evaluation?
without prior submucosa
the maximum diameters and calculated
injection (n = 50) vs. cap
area of the resected specimens (ligation
technique with prior
group: 16.4 [4.0] x 11 [3.1] mm/185 [84]
submucosa injection of a dilute mm(2) vs. cap group: 15.5 [4.1] x 10.7
saline solution of epinephrine [2.7] mm/168 [83] mm(2)), or the
(n = 50)
maximum diameters and calculated area
of the endoscopic resection ulcers after
24 hours (ligation group: 20.6 [4.8] x
14.3 [4.5] mm/314 [160] mm(2) vs. cap
group: 18.9 [5.1] x 12.9 [3.8] mm/260
[145] mm(2)). There was only a slight
advantage (greater diameter of resection
specimens) for the ligation group in
patients who had prior endoscopic
treatment. There was one minor
episode of bleeding in each group; there
was no severe complication. In 41 of 72
patients (57%), further endoscopic
therapy after endoscopic resection was
necessary because of residual neoplasia
at the first follow-up endoscopy after
resection (61 of 100 resection
specimens [61%] had lateral margins that
could not be evaluated because of
coagulation artifact or contained
malignancy but with the base of the
lesion free of tumor).
Study type
Level of
evidence
RCT
Moderate
KCE Reports 75
Upper GI Cancer
97
Neoadjuvant treatment.
CPG ID
Ref
Search
date
Chemotherapy
CCO
[84] January
2005
SIGN
[47]
2004
CBO
[56]
July 2003
Radiotherapy
CCO
[84]
SIGN
CBO
[47]
[56]
January
2005
2004
July 2003
Chemoradiotherapy
CCO
[84] January
2005
SIGN
[47]
2004
CBO
[56]
July 2003
Recommendation
Supporting evidence
Level of
evidence
(In adult patients with resectable and potentially curable thoracic (lower two-thirds of oesophagus)
oesophageal cancer) if surgery is considered appropriate, then surgery alone (i.e., without neoadjuvant or
adjuvant therapy) is recommended as the standard practice for resectable thoracic oesophageal cancer.
Patients with operable oesophageal cancer, who are treated surgically, should be considered for two
cycles of preoperative chemotherapy with cisplatin and 5-fluorouracil or offered entry into a clinical trial.
Patiënten met een potentieel resectabel oesofaguscarcinoom dienen alleen in onderzoeksverband
voorafgaande aan een operatie chemotherapie te krijgen.
Numerous RCTs and SRs
High
Malthaner 2003
High
Malthaner 2003
High
Arnott SJ 2000
Fok 1994
High
Arnott SJ 2000
Arnott SJ 2000
High
High
Numerous RCTs and SRs
High
Urschel 2003
High
Walsh TN 1996 (RCT)
Urba SG 2001 (RCT)
High
(In adult patients with resectable and potentially curable thoracic (lower two-thirds of oesophagus)
oesophageal cancer) if surgery is considered appropriate, then surgery alone (i.e., without neoadjuvant or
adjuvant therapy) is recommended as the standard practice for resectable thoracic oesophageal cancer.
Preoperative radiotherapy is not recommended for patients with oesophageal cancer.
De werkgroep raadt af om patiënten met een potentieel resectabel oesofaguscarcinoom voorafgaand aan
de operatie te bestralen.
(In adult patients with resectable and potentially curable thoracic (lower two-thirds of oesophagus)
oesophageal cancer) if surgery is considered appropriate, then surgery alone (i.e., without neoadjuvant or
adjuvant therapy) is recommended as the standard practice for resectable thoracic oesophageal cancer.
Preoperative chemoradiotherapy for patients with oesophageal cancer is not recommended outside
clinical trials.
De werkgroep adviseert om patiënten met een potentieel resectabel oesofaguscarcinoom voorafgaand
aan een operatie uitsluitend in onderzoeksverband chemoradiotherapie te geven.
98
Study ID
Upper GI Cancer
Ref
Chemotherapy
Graham AH
[88]
2007
Search
date
Population
KCE reports 75
Intervention
Results
Comments
Study
type
Level of
evidence
October Patients with locally
2004
advanced oesophageal
cancer (T2-3N0M0 or T13N1M0)
Surgery vs.
chemoradiotherapy followed
by surgery vs. chemotherapy
followed by surgery vs.
surgery followed by
chemoradiotherapy
For the first year, the relative risk (95%
confidence interval) of death for treatments
compared with surgery were 0.87 (0.75 to
1.02) for chemoradiotherapy followed by
surgery, 0.94 (0.82 to 1.08) for chemotherapy
followed by surgery, and 1.33 (0.93 to 1.93)
for surgery with adjuvant chemoradiotherapy.
The QALYs gained for surgery alone,
chemoradiotherapy followed by surgery,
chemotherapy followed by surgery, and
surgery with adjuvant chemoradiotherapy
strategies were 2.07, 2.18, 2.14, and 1.99,
respectively. If the reduction in utility for
multimodality treatment was increased to 21%,
the QALYs gained for surgery alone,
chemoradiotherapy followed by surgery,
chemotherapy followed by surgery, and
surgery with adjuvant chemoradiotherapy
were 2.07, 2.03, 1.99, and 1.85, respectively.
The hazard ratio for neoadjuvant
chemotherapy was 0.90 (0.81-1.00; p=0.05),
which indicates a 2-year absolute survival
benefit of 7%. There was no significant effect
on all-cause mortality of chemotherapy for
patients with SCC (hazard ratio 0.88 [0.751.03]; p=0.12), although there was a significant
benefit for those with adenocarcinoma (0.78
[0.64-0.95]; p=0.014).
14 RCTs included, of
which 6 RCTs on
neoadjuvant
chemotherapy
NO NEW EVIDENCE
SINCE CCO
GUIDELINE!
SR
High
Only inclusion of RCTs
with ITT analysis
No results of quality
appraisal reported
8 RCTs on neoadjuvant
chemotherapy
2 RCTs in addition to
Graham et al. (Roth
1998 and Schlag 1992)
NO NEW EVIDENCE
SINCE CCO
GUIDELINE!
11 RCTs included
NO NEW EVIDENCE
SINCE CCO
GUIDELINE!
SR
High
SR
High
Gebski V 2007
[86]
2006
Patients with local
operable oesophageal
cancer
Neoadjuvant
chemoradiotherapy or
neoadjuvant
chemotherapy followed by
surgery vs. surgery alone
Malthaner RA
2006
[87]
2006
Patients with localized
potentially resectable
thoracic oesophageal
carcinomas
Neoadjuvant chemotherapy
followed by surgery vs.
surgery alone
There was some evidence to suggest that
preoperative chemotherapy improves survival,
but this was inconclusive (HR 0.88; 95% CI
0.75 to 1.04).
There was no evidence to suggest that the
KCE Reports 75
Study ID
Cunningham D
2006
Radiotherapy
Arnott SJ 2005
Ref
Upper GI Cancer
Search
date
Population
Intervention
[148]
NA
Patients with histologically Perioperative chemotherapy
proven adenocarcinoma
and surgery (n = 250) vs.
of the stomach or lower
surgery alone (n = 253)
third of the oesophagus
that was considered to be
stage II (through the
submucosa) or higher,
with no evidence of
distant metastases, or
locally advanced
inoperable disease, as
evaluated by computed
tomography, chest
radiography,
ultrasonography, or
laparoscopy.
[85]
June
2006
Patients with potentially
resectable carcinoma of
the oesophagus
Chemoradiotherapy
Neoadjuvant radiotherapy
followed by surgery vs.
surgery alone
Results
overall rate of resections (RR 0.96, 95% CI
0.92 to 1.01) or the rate of complete
resections (R0) (RR 1.05; 95% CI 0.97 to 1.15)
differ between the preoperative chemotherapy
arm and surgery alone. There is no evidence
that tumour recurrence (RR 0.81, 95% CI 0.54
to 1.22) or non-fatal complication rates (RR
0.90; 95% CI 0.76 to 1.06) differ for
preoperative chemotherapy compared to
surgery alone. Trials reported risks of toxicity
with chemotherapy that ranged from 11% to
90%.
As compared with the surgery group, the
perioperative-chemotherapy group had a
higher likelihood of overall survival (HR for
death, 0.75; 95%CI 0.60 to 0.93; P=0.009; fiveyear survival rate, 36 percent vs. 23 percent)
and of progression-free survival (HR for
progression, 0.66; 95%CI 0.53 to 0.81;
P<0.001).
No separate date for oesophageal cancer, but
no clear evidence of heterogeneity of
treatment effect according to the site of the
primary tumour
99
Comments
Study
type
Level of
evidence
Randomization
procedure?
No information of
blinding
RCT
Moderate
SR
High
The hazard ratio (HR) of 0.89 (95%CI
Meta-analysis of 5 RCTs
0.78-1.01) suggests an overall reduction in the
risk of death of 11% and an absolute survival
benefit of 3% at 2 years and 4% at 5 years. This
result is not conventionally statistically
significant (p=0.062). No clear differences in
the size of the effect by sex, age or tumor
location were apparent.
100
Upper GI Cancer
Graham AH
2007
[88]
October Patients with locally
2004
advanced oesophageal
cancer (T2-3N0M0 or T13N1M0)
Surgery vs.
chemoradiotherapy followed
by surgery vs. chemotherapy
followed by surgery vs.
surgery followed by
chemoradiotherapy
Gebski V 2007
[86]
2006
Patients with local
operable oesophageal
cancer
Neoadjuvant
chemoradiotherapy or
neoadjuvant
chemotherapy followed by
surgery vs. surgery alone
Geh JI 2006
[259]
2000
Patients with local
operable oesophageal
cancer
Neoadjuvant
chemoradiotherapy followed
by surgery vs. surgery alone
Hao D 2006
[109]
January
2005
Patients with local
operable oesophageal
cancer
Platinum-based neoadjuvant
chemoradiotherapy
See above
14 RCTs included, of
SR
which 6 RCTs on
neoadjuvant
chemoradiotherapy
NO NEW EVIDENCE
SINCE CCO
GUIDELINE!
The hazard ratio for all-cause mortality with
Only inclusion of RCTs
SR
neoadjuvant chemoradiotherapy versus
with ITT analysis
surgery alone was 0.81 (95% CI 0.70-0.93;
No results of quality
p=0.002), corresponding to a 13% absolute
appraisal reported
difference in survival at 2 years, with similar
10 RCTs on neoadjuvant
results for different histological tumour types: chemoradiotherapy
0.84 (0.71-0.99; p=0.04) for squamous-cell
3 RCTs in addition to
carcinoma (SCC), and 0.75 (0.59-0.95; p=0.02) Graham et al. (Tepper
for adenocarcinoma.
2006, Burmeister 2005,
Lee 2004)
Tepper 2006 also not
included in CCO
guideline, but published
as an abstract
The probability of pCR improved with
Medline and meeting
SR
increasing dose of radiotherapy (P=0.006), 5FU abstracts
(P=0.003) and cisplatin (P=0.018). Increasing
Quality appraisal??
radiotherapy treatment time (P=0.035) and
26 RCTs + non-RCTs
increasing median age (P=0.019) reduced the
probability of pCR. The estimated alpha/beta
ratio of oesophageal cancer was 4.9 Gy (95%
confidence interval (CI) 1.5-17 Gy) and the
estimated radiotherapy dose lost per day was
0.59 Gy (95% CI 0.18-0.99 Gy). One gram per
square metre of 5FU was estimated to be
equivalent to 1.9 Gy (95% CI 0.8-5.2 Gy) of
radiation and 100mg/m2 of cisplatin was
estimated to be equivalent to 7.2 Gy (95% CI
2.1-28 Gy). Mitomycin C dose did not appear
to influence pCR rates (P=0.60).
The addition of surgery to CT/RT appeared to Same search as for CCO SR
improve local tumour control but not overall
guideline
survival in patients with locally advanced
oesophageal SCC
KCE reports 75
High
High
Moderate
High
KCE Reports 75
Greer SE 2005
[260]
Upper GI Cancer
January
2003
Patients undergoing
surgery for oesophageal
cancer
Neoadjuvant
chemoradiotherapy followed
by surgery vs. surgery alone
Natsugoe S 2006 [89]
NA
Patients with local
operable squamous cell
oesophageal cancer
Neoadjuvant
chemoradiotherapy (40 Gy,
cisplatin + 5FU) (n = 22) vs.
surgery alone (n = 23)
Burmeister BH
2005
NA
Patients with histologically
confirmed invasive
cancer of the thoracic
oesophagus
Neoadjuvant
chemoradiotherapy (35 Gy,
cisplatin + 5FU) (n = 128) vs.
surgery alone (n = 128)
[261]
Small, non-statistically significant trend toward
improved long-term survival in the NCRT
followed by surgery group (relative risk of
death in the NCRT group 0.86; 95%CI 0.74 to
1.01; P = .07).
Surgical treatment was performed in 20
patients in the CRT group except for two
patients with bone metastasis after CRT.
According to histological effects of primary
tumors, the number of patient with Grades 1,
2 and 3 was 11, 7 and 3, respectively.
Frequency of lymphatic and venous invasion
was significantly lower in the CRT group than
in the Surgery group. The 5-year survival rate
was 57% in the CRT group and 41% in the
Surgery group (P = 0.58). According to the
histological effect in the CRT group, 5-year
survival was 30% for Grade 1, 83% for Grade 2
and 100% for Grade 3 (P = 0.0069).
Neither progression-free survival nor overall
survival differed between groups (HR 0.82
[95%CI 0.61-1.10] and 0.89 [0.67-1.19],
respectively). The chemoradiotherapy-andsurgery group had more complete resections
with clear margins than did the surgery-alone
group (103 of 128 [80%] vs 76 of 128 [59%],
p=0.0002), and had fewer positive lymph
nodes (44 of 103 [43%] vs 69 of 103 [67%],
p=0.003).
101
6 RCTs (same as
Graham 2007)
Quality appraisal??
SR
Moderate
No information on
blinding
RCT
Moderate
Included in CCO
guideline as an abstract
No blinding of patients
and clinicians
RCT
Moderate
Restaging after neoadjuvant treatment.
CPG ID
Ref
Search
date
FNCLCC [66]
SIGN
[47]
2004
Recommendation
Supporting evidence
La place de la TEP-FDG dans l’évaluation de la réponse au traitement reste à déterminer par des études
prospectives.
Patients with locally advanced disease having chemotherapy/chemoradiotherapy should have their
response assessed for an impact on the potential to operate ; following a good response the patient
should be restaged and the role restaged and the role of surgery re-evaluated by the multidisciplinary
team.
Flamen 2002
Level of
evidence
Low
Ross P 1996
Low
102
Upper GI Cancer
Study ID
Ref
Duong CP 2006
[262]
Search
date
NA
Cerfolio RJ 2005 [91]
NA
Song SY 2005
[74]
NA
Brink I 2004
[263]
NA
Nakahara T
2003
[264]
NA
Population
Intervention
53 patients with
oesophageal cancer
referred for PET
evaluation of tumour
response to CRT
Patients with suspected or
biopsy-proved
oesophageal carcinoma
treated with neoadjuvant
chemotherapy (n = 48)
FDG-PET
High PET impact (change in treatment intent or
Standard not
Histology (n = 22) or serial imaging modality) was observed in
the same for
and clinical follow up (n = 26)
19 patients (36%). When PET findings could be
all patients
verified, they were confirmed to be correct in 79%
(38 of 48 cases).
Chest, abdomen, pelvis CT
The accuracy of each test for distinguishing pathologic
EUS-FNA
T4 from T1 to T3 disease is 76%, 80%, and 80% for
FDG-PET/CT
CT scan, EUS-FNA and FDG-PET/CT, respectively.
41 patients underwent surgery
The accuracy for nodal disease was 78%, 78%, and
93% for CT scan, EUS-FNA and FDG-PET/CT,
respectively (p=0.04). FDGPET/
CT correctly identified M1b disease in 4 patients,
falsely suggested it in 4 patients, and missed it in 2
patients, whereas for CT, it was 3, 3, and 3 patients.
Fifteen (31%) patients were complete responders, and
FDG-PET/CT accurately predicted complete response
in 89% compared with 67% for EUS-FNA (p=0.045)
and 71% for CT (p=0.05).
FDG-PET
Sensitivity, specificity, positive predictive value (PPV),
Histology
and negative predictive value (NPV) in the primary
tumours of the preoperative FDG-PET were 27%,
95%, 75%, and 71%, respectively. In regional lymph
nodes, these values were 16%, 98%, 36%, and 93%,
respectively.
FDG-PET
Not enough information to calculate accuracy
CT
Histology
Patients with locally
advanced but resectable
oesophageal cancer
treated with neoadjuvant
chemoradiotherapy (n =
32)
20 patients with
oesophageal cancer
treated with neoadjuvant
chemoradiotherapy
28 patients with squamous Tl-201 SPECT
oesophageal cancer
Barium examination
CT
Ga-67 SPECT
All studies before and after
preoperative chemoradiotherapy
All patients underwent
oesophagectomy (blinded
pathologist)
Results
KCE reports 75
Although thallium-201 SPECT cannot be used to
evaluate the therapeutic effect with acceptable
accuracy, SPECT may be of additional value to barium
swallow and CT in assessing the response of AESCC
to preoperative chemoradiotherapy.
Comments
Study type Level of
evidence
Prospective Very low
study
Prospective
study
Low
Prospective
study
Low
Prospective
study
Very low
Prospective
study
Low
KCE Reports 75
Upper GI Cancer
103
Surgical treatment.
CPG ID
Ref
SIGN
[47]
CBO
[56]
Search
date
2004
Recommendation
Supporting evidence
Oesophageal resectional surgery should be carried out in high volume specialist surgical units by frequent
operators.
Surgery for oesophageal cancer should be aimed at achieving an R0 resection.
Following oesopagectomy, the route of reconstruction and potential use of pyloric drainage procedure
should be determined by the surgeon based on their individual experience.
van Lanschot JJ 2001
Bachmann MO 2002
Hulscher JB 2002
Urschel JD 2001a
Urschel JD 2001b
Urschel JD 2002
Walther B 2003
Dresner SM 2000
Two-field lymphadenectomy should be considered during oesophagectomy to improve staging and local
disease control.
Routine extension of lymphadenectomy into the superior mediastinum or neck should not be carried out.
July 2003 Totdat vergelijkende data tussen chirurgie en andere behandelingsmodaliteiten of data van grote series
van een andere modaliteit dan chirurgie beschikbaar zijn, kan chirurgische resectie als de
standaardbehandeling voor het in opzet curatief resectabele oesofaguscarcinoom worden beschouwd.
Bij grote tumoren zonder metastasen moet worden gestreefd naar een radicale resectie van het
oesofaguscarcinoom. Een palliatieve resectie is in het algemeen gecontraindiceerd.
Tumoren van de proximale oesofagus (gelegen boven de carina) kunnen uitsluitend via een
thoracotomie worden gereseceerd.
Voor type-I-tumoren, die gelegen zijn distaal van de carina, heeft een radicale transthoracale
benadering de voorkeur, mits hiermee voldoende ervaring bestaat en de algemene conditie van
de patiënt dit toelaat.
Gastro-oesofageale type-II-tumoren worden bij voorkeur transhiataal verwijderd.
Voor een proximaal maagcarcinoom type III dat minder dan 1 cm de distale oesofagus ingroeit,
kan een totale maagresectie worden verricht.
Na subtotale en macroscopisch radicale oesofagusresectie gevolgd door reconstructie met een buismaag
en cervicale anastomose heeft positionering van de buismaag in het achterste mediastinum de voorkeur. In
geval van macroscopische irradicaliteit heeft reconstructie via het voorste mediastinum de voorkeur.
Voor tumoren van de cardia of van de cardio-oesofageale overgang is transhiatale resectie met
medenemen van de peri-oesofageale en -cardiale klieren voldoende. Bij carcinomen van de distale
oesofagus bestaat een lichte voorkeur voor een gecombineerde abdominale en transthoracale resectie
met tweevelds-lymfklierdissectie van de abdominale en thoracale lymfklierstations.
Oesofagustumoren boven carinaniveau worden door middel van een gecombineerde abdominale en
transthoracale benadering gereseceerd.
Na subtotale oesofagus- (en cardia)resectie heeft de maag als interponaat de voorkeur. Het colon is
tweede keuze. Slechts in uitzonderingsgevallen kan eventueel van het jejunum gebruik worden gemaakt.
Het is op grond van literatuurgegevens niet mogelijk een keuze te maken tussen een totale maag of een
buismaag als interponaat. Om oncologische redenen kan bij een cardia- of distale oesofagustumor slechts
een buismaag worden gebruikt.
Level of
evidence
Low
High
High
Low
Nishihira T 1998
Hulscher JB 2001
High
High
Hulscher JB 2002
van Lanschot JJ 2001
Sagar PM 1993
High
Urschel JD 2001
van Lanschot JJ 1994
High
Hulscher JB 2002
Nishihira T 1998
Matsubara T 1998
Altorki N 2002
High
Urschel JD 2001
Collard JM 1995
High/low
104
CPG ID
Upper GI Cancer
Ref
Search
date
Recommendation
Supporting evidence
Er is geen duidelijke voorkeur uit te spreken voor een cervicale of thoracale anastomose na
oesofagusresectie en buismaagreconstructie.
Bij de meeste patiënten is de cervicale anastomose de meest aangewezen procedure. Met name
is dit het geval bij patiënten bij wie de chirurg, in geval van een tumor onder het carinaniveau,
kiest voor een transhiatale resectie en halsexploratie voor het verrichten van de
oesofagusresectie. Er is dan geen reden om tot thoracotomie over te gaan voor het leggen van
een intrathoracale anastomose. Wanneer de chirurg bij dit soort tumoren de voorkeur geeft
aan een thoracotomie voor de dissectiefase, kan de anastomose intrathoracaal worden
aangelegd en kan de halsfase achterwege worden gelaten.
Wanneer bij tumoren boven het carinaniveau wordt gekozen voor een thoracotomie, is het om
oncologische redenen ter verkrijging van voldoende proximale marge verstandig ook in dat geval
voor een subtotale oesofagusresectie met cervicale anastomose te kiezen.
Zowel handgelegde als mechanische (gestapelde) anastomosen kunnen worden verricht na subtotale
oesofagectomie, maaginterponaat en oesofagogastrische anastomose.
Hulscher JB 2001
Chasseray VM 1989
Ribet M 1992
Goldminc M 1993
Chu KM 1997
Bij een handgelegde oesofagogastrische anastomose na een subtotale oesofagusresectie met
buismaagreconstructie verdient een enkelrijige doorlopende hechttechniek de voorkeur.
CCO
[84]
January
2005
KCE reports 75
Na oesofagusresectie gevolgd door buismaaginterponaat en oesofagogastrische anastomose is een
pyloroplastiek niet geïndiceerd.
If surgery is considered appropriate, then surgery alone (i.e., without neoadjuvant or adjuvant therapy) is
recommended as the standard practice for resectable thoracic oesophageal cancer.
Urschel JD 2001
Craig SR 1996
Valverde A 1996
Law S 1997
Bardini R 1994a
Zieren HU 1993
Bardini R 1994b
Muller JM 1990
Zieren HU 1995
Level of
evidence
High
High
High
High
KCE Reports 75
Study ID
Ref
Graham AH
2007
[88]
Bedenne L 2007
Bonnetain F
2006
[93]
Upper GI Cancer
Search Population
date
October Patients with locally
2004
advanced oesophageal
cancer (T2-3N0M0 or T13N1M0)
NA
Patients with operable
T3N0-1M0 thoracic
oesophageal cancer, and
with response to
chemoradiation (two
cycles of FU/cisplatin and
either conventional (46
Gy in 4.5 weeks) or splitcourse (15 Gy, days 1 to 5
and 22 to 26) concomitant
radiotherapy) and no
contraindication to either
treatment (n = 444, of
which 259 were randomly
assigned)
105
Intervention
Results
Comments
Study type
Surgery vs.
chemoradiotherapy followed
by surgery vs. chemotherapy
followed by surgery vs.
surgery followed by
chemoradiotherapy
For the first year, the relative risk (95%
confidence interval) of death for
treatments compared with surgery were
0.87 (0.75 to 1.02) for
chemoradiotherapy followed by surgery,
0.94 (0.82 to 1.08) for chemotherapy
followed by surgery, and 1.33 (0.93 to
1.93) for surgery with adjuvant
chemoradiotherapy. The QALYs gained
for surgery alone, chemoradiotherapy
followed by surgery, chemotherapy
followed by surgery, and surgery with
adjuvant chemoradiotherapy strategies
were 2.07, 2.18, 2.14, and 1.99,
respectively. If the reduction in utility
for multimodality treatment was
increased to 21%, the QALYs gained for
surgery alone, chemoradiotherapy
followed by surgery, chemotherapy
followed by surgery, and surgery with
adjuvant chemoradiotherapy were 2.07,
2.03, 1.99, and 1.85, respectively.
Two-year survival rate: 34% in arm A
versus 40% in arm B (HR for arm B vs.
arm A = 0.90; adjusted P = .44).
Median survival time: 17.7 months in
arm A, 19.3 months in arm B.
Two-year local control rate: 66.4% in
arm A, 57.0% in arm B
Stents were less required in the surgery
arm (5% in arm A vs. 32% in arm B; P <
.001).
3-month mortality rate: 9.3% in arm A,
0.8% in arm B (P = .002).
Cumulative hospital stay: 68 days in arm
A, 52 days in arm B (P = .02).
14 RCTs included
The 1 RCT on adjuvant
CRT vs. surgery alone
included patients with
gastric cancer or cancer
of the GEJ
SR
Level of
evidence
High
Two types of
radiotherapy
Not clear if blinded
randomization
No information on
blinding of patients,
clinicians and assessors
RCT
Moderate
Arm A: Surgery (n = 129)
Arm B: Continuation of
chemoradiation (three cycles
of FU/cisplatin and either
conventional [20 Gy] or splitcourse [15 Gy] radiotherapy)
(n = 130)
vs.
106
Upper GI Cancer
Study ID
Ref
Stahl M 2005
[265]
Search
date
NA
Chiu PWY 2005
(CURE)
[94]
Bhat MA 2006
Hsu HH 2004
KCE reports 75
Population
Intervention
Results
Comments
Study type
Patients with locally
advanced squamous cell
carcinoma of the
oesophagus
Induction chemotherapy
followed by
chemoradiotherapy (40 Gy)
followed by surgery (n = 86),
or the same induction
chemotherapy followed by
chemoradiotherapy (at least
65 Gy) without surgery (n =
86).
Unblinded study
RCT
NA
Patients with potentially
resectable squamous cell
carcinoma of the mid or
lower thoracic
oesophagus
No information on
randomization procedure
No information on
blinding of patients,
clinicians and assessors
RCT
Moderate
[266]
NA
238 patients treated for
oesophageal carcinoma
(44 excluded because
inoperable)
Oesophagectomy (n = 44) vs.
chemoradiotherapy
(continuous 5-FU (200
mg/m2/day) from day 1 to 42
and cisplatin (60 mg/m2) on
days 1 and 22; tumour and
regional lymphatics were
concomitantly irradiated to a
total of 50-60 Gy) (n = 36)
Oesophagogastrectomy with
wrapping of the pedicled
omentum around the
esophagogastric anastomosis
(n = 97) vs.
oesophagogastrectomy
without using the omental
graft (n = 97)
Overall survival was equivalent between
the two treatment groups (log-rank test
for equivalence, P < .05). Local
progression-free survival was better in
the surgery group (2-year progressionfree survival, 64.3%; 95%CI 52.1% to
76.5%) than in the chemoradiotherapy
group (2-year progression-free survival,
40.7%; 95%CI 28.9% to 52.5%; hazard
ratio [HR] for arm B v arm A, 2.1; 95%
CI, 1.3 to 3.5; P = .003). Treatmentrelated mortality was significantly
increased in the surgery group than in
the chemoradiotherapy group (12.8% v
3.5%, respectively; P = .03).
No difference in the early cumulative
survival (RR = 0.89; 95%CI 0.37-2.17;
log-rank test P = 0.45).
No difference in the disease-free
survival.
Level of
evidence
Moderate
No information on
blinding of assessors
RCT
Moderate
[267]
NA
Patients with curatively
resectable squamous cell
cancer of the thoracic
oesophagus (T1-3 N0-1)
Anastomotic leaks occurred in 3 group
A patients (3.09%) and in 14 (14.43%)
group B patients. The difference in the
incidence of leakage was statistically
significant (p = 0.005). There was no
complication related to the omental
graft technique nor was there a
significant difference in the mortality
between the two groups.
The mean operating time was longer
when the hand-sewn method was used
(524 vs. 447 min, P < 0.001).
Anastomotic leakage was noted in seven
patients (22%) in the hand-sewn group
and eight patients (26%) in the stapler
group (P = NS). Hospital mortality
Randomization
procedure??
Blinding??
RCT
Moderate
Hand-sewn (n = 32) or
circular stapled (n = 31)
cervical oesophagogastric
anastomosis
KCE Reports 75
Study ID
Walther B 2003
Ref
[268]
Upper GI Cancer
Search
date
NA
Population
Patients with benign or
malignant oesophageal
disease for which a tube
gastroplasty with
anastomotic site in the
proximal chest or in the
neck was deemed suitable
(n = 83, of which 74 had
malignant disease)
Intervention
Manually sutured
oesophagogastric anastomosis
in the neck or an anastomosis
stapled in the right chest
Results
occurred in four patients (13%) of the
hand-sewn group and in three patients
(10%) of the stapler group (P = NS).
After the operation, four patients (14%)
in the hand-sewn group and five patients
(18%) in the stapler group developed a
benign oesophageal stricture (P = NS).
The mean follow-up time was 24
months, and the rates of freedom from
benign stricture and survival were
comparable in each group.
The genuine 5-year survival rate was
29% for chest anastomoses and 30% for
neck anastomoses. The overall leakage
rate was 1.8% (2 cases of 112) with no
relation to mortality or anastomotic
method. All patients in the randomized
group had tumor-free proximal and
distal resection lines, but 1 patient in the
nonrandomized group had tumor
infiltrates in the proximal resection
margin. At 3, 6, and 12 months after
operation, there was no difference in
anastomotic diameter between the
esophagogastric anastomosis in the neck
and in the thorax (P = 0.771), and both
increased with time (P = 0.004, ANOVA
repeated measures). Body weight
development was the same in the two
groups. With similar results in
randomized and nonrandomized
patients, study bias was eliminated.
107
Comments
Study type
Level of
evidence
Randomization with
sealed envelopes
Also 29 non-randomized
patients included in
results
RCT
Moderate
108
Upper GI Cancer
KCE reports 75
Adjuvant treatment.
CPG ID
Ref
Search Recommendation
date
Chemotherapy
SIGN
[47] 2004
CBO
[56] July
2003
CCO
[84] January
2005
Radiotherapy
SIGN
[47]
CBO
[56]
Postoperative adjuvant chemotherapy is not recommended for patients with oesophageal cancer.
Patiënten met een oesofaguscarcinoom komen niet in aanmerking voor postoperatieve chemotherapie.
If surgery is considered appropriate, then surgery alone (i.e., without neoadjuvant or adjuvant therapy) is
recommended as the standard practice for resectable thoracic oesophageal cancer.
2004
July
2003
No recommendation, only discussion
Patiënten met een oesofaguscarcinoom komen niet in aanmerking voor postoperatieve radiotherapie.
January
2005
If surgery is considered appropriate, then surgery alone (i.e., without neoadjuvant or adjuvant therapy) is
recommended as the standard practice for resectable thoracic oesophageal cancer.
Chemoradiotherapy
SIGN
[47] 2004
CCO
[84] January
2005
Postoperative adjuvant chemoradiotherapy is not recommended for patients with oesophageal cancer.
If surgery is considered appropriate, then surgery alone (i.e., without neoadjuvant or adjuvant therapy) is
recommended as the standard practice for resectable thoracic oesophageal cancer.
CCO
Study ID
[84]
Ref
Chemotherapy
Ajani J 2006
[269]
Radiotherapy
No additional studies found
Chemoradiotherapy
No additional studies found
Supporting evidence
Level of
evidence
Lehnert T 1999
Ando N 1997
Pouliquen X 1996
Ando N 1997
Pouliquen X 1996
Ando N 2003
High
High
Fok M 1993
Teniere P 1991
Zieren HU 1995
Xiao ZF 2003
Fok M 1993
Fok M 1994
Teniere P 1991
Zieren HU 1995
Xiao ZF 2003
High
High
High
No evidence
No evidence
Search date Population
Intervention
Results
Comments
Study type
Level of evidence
October
2005
Oral capecitabine
4 trials identified that included patients
with oesophageal cancer
No conclusions to be drawn
Medline search only
No information on
selection, quality
appraisal, etc
SR
Low
Patients oesophageal
cancer
KCE Reports 75
Upper GI Cancer
109
Non-surgical treatment with curative intent.
CPG ID
Ref
SIGN
[47]
CCO
[108]
CBO
[56]
Search
date
2004
February
2005
July 2003
Recommendation
Supporting evidence
Chemoradiotherapy should be considered in patients with esophageal cancer who have locally
advanced disease, those unfit for surgery or those who decline surgery.
(In adult patients with localized (T1-3, small volume N1, M0) carcinoma of the esophagus and good
performance status who are considering a non-surgical approach and for whom combined
radiotherapy and chemotherapy can be tolerated in the judgment of the treating oncologist)
concomitant radiotherapy and chemotherapy is recommended over radiotherapy alone. Based on
considerations of the current clinical practice pattern and the currently available research evidence, a
cisplatin-based chemotherapy regimen is a reasonable chemotherapy regimen to use when
concomitant radiotherapy and chemotherapy is used.
Patients should be made aware of the increased acute toxicity associated with this approach. The
decision to use concomitant radiotherapy and chemotherapy should only be made after careful
consideration of the potential risks, benefits, and the patient’s general condition.
Sequential radiotherapy and chemotherapy is not recommended as standard practice.
Future clinical trials to better define the optimal chemoradiotherapy combination that would improve
outcomes while limiting toxicities are strongly encouraged.
De werkgroep adviseert om patiënten met een oesofaguscarcinoom die niet voor een resectie in
aanmerking komen, indien hun conditie dit toelaat, te behandelen met concomitante
chemoradiotherapie, zo mogelijk in onderzoeksverband.
Wong R '03
Cooper JS '99
Wong R ‘06
Level of
evidence
High
High
Wong R ‘06
High
Wong R ‘06
Wong R ‘06
High
High
Wong R '03
Cooper JS '99
High
110
Upper GI Cancer
Study ID
Ref
Search
date
NA
Bedenne L 2007
[93]
Hao D 2006
[109]
January
2005
Chiu PW 2005
(CURE)
[94]
Zhao KL 2005
[110]
KCE reports 75
Population
Intervention
Results
Comments
Study type
Patients with operable
T3N0-1M0 thoracic
oesophageal cancer, and
with response to
chemoradiation (two
cycles of FU/cisplatin and
either conventional (46
Gy in 4.5 weeks) or splitcourse (15 Gy, days 1 to 5
and 22 to 26) concomitant
radiotherapy) and no
contraindication to either
treatment (n = 444, of
which 259 were randomly
assigned)
Patients with local
operable oesophageal
cancer
Arm B: Continuation of
chemoradiation (three cycles
of FU/cisplatin and either
conventional [20 Gy] or splitcourse [15 Gy] radiotherapy)
(n = 130)
vs.
Arm A: surgery (n = 129)
Two-year survival rate: 34% in arm A
versus 40% in arm B (HR for arm B vs.
arm A = 0.90; adjusted P = .44).
Median survival time: 17.7 months in
arm A, 19.3 months in arm B.
Two-year local control rate: 66.4% in
arm A, 57.0% in arm B
Stents were less required in the surgery
arm (5% in arm A vs. 32% in arm B; P <
.001).
3-month mortality rate: 9.3% in arm A,
0.8% in arm B (P = .002).
Cumulative hospital stay: 68 days in arm
A, 52 days in arm B (P = .02).
Two types of
radiotherapy
Not clear of blinded
randomization
No information on
blinding of patients,
clinicians and assessors
RCT
Level of
evidence
Moderate
Platinum-based
chemoradiotherapy
Same search as for CCO
guideline
SR
High
NA
Patients with potentially
resectable squamous cell
carcinoma of the mid or
lower thoracic
oesophagus
No information on
randomization procedure
No information on
blinding of patients,
clinicians and assessors
RCT
Moderate
NA
Patients with confirmed
SCC of the oesophagus
with clinical stage T1-4,
N0-1, M0 (n = 111)
Oesophagectomy (n = 44) vs.
chemoradiotherapy
(continuous 5-FU (200
mg/m2/day) from day 1 to 42
and cisplatin (60 mg/m2) on
days 1 and 22; tumour and
regional lymphatics were
concomitantly irradiated to a
total of 50-60 Gy) with salvage
surgery (n = 36)
LCAF-RT (n = 57) vs. LCAFRT + chemotherapy (four
cycles of cisplatin 25 mg/m(2)
daily and fluorouracil (5-FU)
600 mg/m(2) daily on Days 1-3
every 4 weeks starting on the
same day that LCAF was
delivered) (n = 54)
To date, no randomized trials have
directly compared CT/RT with
oesophagectomy as primary
locoregional treatment of oesophageal
carcinoma.
No difference in the early cumulative
survival (RR = 0.89; 95%CI 0.37-2.17;
log-rank test P = 0.45).
No difference in the disease-free
survival.
Median survival: 23.9 months (95%CI
20.1-27.7) for the LCAF arm and 30.8
months (95%CI 17.6-44.1) for the
LCAF+CT arm.
Survival rates at 1, 3, and 5 years of the
LCAF arm were 77%, 39%, and 28%,
respectively, while those of the
LCAF+CT arm were 67%, 44%, and
No information on
blinding of patients,
clinicians and assessors
RCT
Moderate
KCE Reports 75
Study ID
Sumpter K 2005
Ref
[270]
Upper GI Cancer
Search
date
NA
Population
Patients with inoperable,
histologically verified
locally advanced or
metastatic
adenocarcinoma,
squamous cell or
undifferentiated
carcinoma of the
oespohagus,
oesophagogastric junction
(OGJ) or stomach
Intervention
ECF (n = 53)
ECX (n = 48)
EOF (n = 55)
EOX (n = 48)
(E = epirubucin, C = cisplatin,
F = 5FU, O = oxaliplatin, X =
capecitabin)
Results
40%, respectively (p = 0.310).
Grades 3 and 4 acute toxicities
occurred in 46% and 25% of the patients
in the LCAF arm and the LCAF+CT
arm, respectively; 6% of the patients in
the combined arm had Grade 5 acute
toxicities, whereas none was noted in
the LCAF alone arm.
First interim analysis was performed
when 80 pts had been randomised.
Doselimiting fluoropyrimidine toxicities
were stomatitis, palmar plantar
erythema (PPE) and diarrhoea; 5.1% of
X-treated pts experienced grade 3/4
toxicity. Protocol planned dose
escalation of X to 625 mg/m² b.i.d. was
instituted and a second interim analysis
has been performed. A total of 204 pts
were randomised at the time of the
protocol planned 2nd interim analysis.
Grade 3/4 fluoropyrimidine-related
toxicity was seen in 13.7% pts receiving
F, 8.4% pts receiving X 500 mg/m² b.i.d.
and 14.7% pts receiving X 625 mg/m²
b.i.d. Combined complete and partial
response rates were ECF 31% (95% CI
18.7–46.3), EOF 39% (95% CI 25.9–
53.1), ECX 35% (95% CI 21.4–50.3),
EOX 48% (95% CI 33.3–62.8). Grade
3/4 fluoropyrimidine toxicity affected
14.7% of pts treated with X 625 mg/m²
b.i.d., which is similar to that observed
with F, confirming this to be the optimal
dose. The replacement of C by O and F
by X does not appear to impair efficacy.
The trial continues to total accrual of
1000 pts.
111
Comments
Study type
RCT
Interim analysis
6 originally randomized
pts not included in results
Noninferiority study
No information on
blinding of randomization
No information on
blinding of patients,
clinicians and assessors
Level of
evidence
Moderate
112
Upper GI Cancer
KCE reports 75
Palliative treatment.
CPG
Ref
ID
General
CBO
[56]
Search Recommendation
date
July
2003
Endoscopic ablation
SIGN
[47] 2004
Afhankelijk van de patiëntkarakteristieken en de tumoruitbreiding zal bij patiënten met een T4oesofaguscarcinoom bij voorkeur worden gekozen voor een korte palliatieve behandeling of een
behandeling gericht op palliatie op de langere termijn, zoals (chemo)radiotherapie. Patiënten met een
fistel komen, afhankelijk van de plaats en de grootte van de fistel, in aanmerking voor stentplaatsing.
Laser or photodynamic therapy should be used for initial control of obstructive symptoms caused by
exophytic tumours in the oesophagus including tumours near the upper oesophageal sphincter.
SIGN
[47]
Dilatation
SIGN
[47]
Surgery
SIGN
[47]
Level of
evidence
Low
Allum WH 2002
O’Donnell CA 2002
Dallal HJ 2001
Lightdale CJ 1995
Carazzone A 1999
Heier SK 1995
Moghissi K 2000
Litle VR 2003
High
Homs MY 2004
High
May A 1998
Dumonceau JM 1999
Siersema PD 2001
Moderate
Moderate
Partially covered self-expanding metal stents should be used to control obstructive oesophageal
symptoms either following or instead of laser therapy, depending on the availability of local expertise.
Homs MY 2004a
Sabharwal T 2003
Vakil N 2001
Bethge N 1996
Homs MY 2004b
2004
The use of oesophageal dilatation alone should be avoided.
Allum WH 2002
Very low
2004
Oesophagectomy (transthoracic or transhiatal) should not be performed with palliative intent in
patients with oesophageal cancer.
Substernal bypass for oesophageal cancer should not be performed with palliative intent.
Blazeby JM 2000
Low
Whooley BP 2002
Alcantara PS 1997
Low
Laser or photodynamic therapy should be considered for control of tumour overgrowth in stented
patients.
Stenting
CBO
[56]
Supporting evidence
July
2003
2004
Indien de levensverwachting korter is dan zes weken, kan allereerst stentplaatsing worden overwogen,
gezien het snelle effect op de verbetering van passageklachten.
Bij patiënten met een fistel tussen de oesofagus en de luchtwegen, patiënten met een inoperabel
oesofaguscarcinoom nabij de bovenste oesofagussfincter en patiënten met een recidief na eerdere
oesofagusresectie in verband met een oesofaguscarcinoom heeft stentplaatsing de voorkeur.
Het verdient aanbeveling om, na stentplaatsing in verband met passageklachten ten gevolge van een
inoperabel oesofaguscarcinoom, rustig te eten, goed te kauwen en veel te drinken om verstopping van
de stent te voorkomen. Bij verstopping van de stent kan deze snel worden gereinigd door middel van
een endoscopie.
Partially covered self-expanding metal stents are the intubation of choice for patients with obstructive
oesophageal symptoms.
Low
Low
KCE Reports 75
Upper GI Cancer
CPG
Ref Search Recommendation
ID
date
Chemotherapy
CBO
[56] July
Chemotherapie is geen standaardbehandeling voor het irresectabele of gemetastaseerde
2003
oesofaguscarcinoom.
SIGN
[47]
2004
Radiotherapy
CBO
[56] July
2003
SIGN
[47]
2004
Supportive care
CBO
[56] July
2003
SIGN
[47]
2004
In patients with locally advanced or metastatic cancer of the oesophagus with good performance status
combination chemotherapy including cisplatin and infusional 5FU (such as ECF or MCF) should be
considered.
Bij oesofaguscarcinoompatiënten met een matige algemene conditie en/of met metastasen op afstand
bestaat een voorkeur voor brachytherapie, eventueel gevolgd door een stentplaatsing indien
brachytherapie onvoldoende effect heeft.
Bij inoperabele patiënten met een levensverwachting langer dan drie maanden kan uitwendige
radiotherapie in combinatie met brachytherapie worden overwogen.
Palliative external-beam radiotherapy is an appropriate option for the treatment of mild dysphagia in
patients with oesophageal cancer.
Endoluminal brachytherapy is an option for patients with dysphagia from oesophageal cancer.
De werkgroep is van mening dat de verpleegkundige zorg voor patiënten met een oesofaguscarcinoom
het beste door een verpleegkundige met specifieke kennis en ervaring kan worden verricht.
Dieetmaatregelen bij patiënten met een inoperabel oesofaguscarcinoom kunnen het beste zijn gericht
op het welbevinden van de patiënt, dat wil zeggen dat de kwaliteit van leven belangrijker is dan de
effecten van voeding op lange termijn.
Patients with oesophageal cancer should have access to a specialist palliative care team.
113
Supporting evidence
Level of
evidence
Schmid EU 1993
Levard H 1998
Mannell A 1986
Webb A 1997
Ross P 2002
Bleiberg H 1997
Janunger KG 2002
Moderate
Homs MY 2004
High
Flores AD 1989
Hishikawa Y 1991
Taal BG 1996
Allum WH 2002
Low
Brewster AE 1995
Homs MYV 2003
Low
Doornik N 2000
Very low
Smeenk FW 1998
Miccinesi G 2003
Costantini M 2003
Costantini M 1993
Low
High
Very low
114
Study ID
Upper GI Cancer
Ref
Search date Population
Endoscopic ablation
No additional studies found
Stenting
Wenger U 2006 [271] NA
Wenger U 2005
Bergquist H
2005
[112]
NA
KCE reports 75
Intervention
Results
Comments
Study type
Level of
evidence
Patients with incurable
cancer of the distal
oesophagus or gastric
cardia (n = 41)
Antireflux stent (n = 19) vs.
standard stent (n = 22)
Interim report
RCT
Central randomization,
but no information on
procedure
Patients were blinded, but
no information on
blinding of clinicians
Moderate
Patients with incurable
cancer of the oesophagus
or gastro-oesophageal
junction
Self-expandable metallic stent
(n = 30) or 3 x 7 Gy
brachytherapy (n = 30)
Fewer patients with complications were
observed in the antireflux stent group (n
= 3) than in the standard group (n = 8),
but no statistically significant difference
was shown (p = 0.14). The survival rates
were similar in the two groups (p =
0.99; hazard ratio, 1.0; 95% confidence
interval, 0.5-2.0). The groups did not
differ significantly in terms of studied
oesophageal or respiratory symptoms
or quality of life. Clinically relevant
improvement in dysphagia occurred in
both groups. Dyspnea decreased after
antireflux stent insertion (mean score
change, -11), and increased after
insertion of standard stent (mean score
change, +21).
The group of patients treated with stent
reported significantly better HRQL
scores for dysphagia (P < 0.05) at the 1month follow-up, but most other HRQL
scores, including functioning and
symptom scales, deteriorated.
There was no difference in survival or
complication rates between the two
treatment strategies. There was a
significant difference in the change of
dysphagia scores between the time of
inclusion and the 1-month follow-up
visit, in favour of the stented group (P =
0.03). This difference had disappeared at
3 months.
Median total lifetime costs were 17,690
for the stented group compared with
Originally 65 randomized, RCT
but 5 withdrew consent
Cost study
No information on
blinding
Moderate
KCE Reports 75
Study ID
Ref
Upper GI Cancer
Search date Population
Intervention
Shim CS 2005
[272]
NA
Patients with cancer at the Newly designed antireflux
oesophagogastric junction stent (n = 12), a Dostent (n =
(n = 36)
12), or a standard open stent
(n = 12)
Shenfine J 2005
[273]
NA
Patients with oesophageal
cancer deemed unsuitable
for surgery (n = 217)
SEMS 18 mm (n = 54)
SEMS 24 mm (n = 54)
Rigid intubation (n = 57)
All other non-SEMS
treatments (n = 52)
Results
33,171 for the brachytherapy group (P =
0.005). This difference was due to higher
costs for the initial treatment (4,615
versus 23,857, P < 0.0001). Sensitivity
analyses showed that the charges for a
brachytherapy session had to be
reduced from 6,092 to 4,222 (31%) to
make this therapeutic concept costcompetitive.
After 1 week, dysphagia had improved in
all patient groups (P < 0.05), but the
degree of improvement did not differ
between the three groups. The
DeMeester score was significantly lower
in the group with the newly designed
antireflux stent than in the other groups.
The fraction of the total recording time
during which oesophageal pH was below
4 was 3.14 +/- 5.78 % using the newly
designed antireflux stent, in comparison
with 29.25 +/- 15.41 % in the Dostent
group and 15.01 +/- 11.72 % in the
standard open stent group (P < 0.001).
Fewer reflux episodes occurred with the
newly designed antireflux stent than
with the Dostent or standard open
stent. There were no complications with
any of the three stents.
There was no difference in cost or
effectiveness between SEMS and nonSEMS therapies, and 18-mm SEMS had
equal effectiveness to, but less
associated pain than, 24-mm SEMS. Rigid
intubation was associated with a worse
quality of swallowing and increased late
morbidity. Bipolar electrocoagulation
and ethanol tumour necrosis were poor
in primary palliation. A survival
advantage was found for non-stent
therapies, but there was a significant
115
Comments
Study type
Level of
evidence
No information on
randomization procedure
or blinding
RCT
Moderate
Secondary randomization
possible after treatment
failure following nonSEMS treatment
Correct randomization
protocol
RCT
Cost study
High
116
Study ID
Polinder S 2004
(SIREC trial)
Upper GI Cancer
Ref
[113]
Search date Population
NA
Dilatation
No additional studies found
Surgery
No additional studies found
Chemotherapy
Homs MY 2006 [114] February
2006
Intervention
Patients with inoperable
oesophagogastric cancer
Ultraflex stent (n=108) or
single-dose brachytherapy (12
Gy, n=101)
Patients with metastatic
carcinoma of the
oesophagus or GEjunction Siewert type I
RCTs comparing
chemotherapy with best
supportive care for patients
with metastatic carcinoma of
the oesophagus and GEjunction, as well as RCTs
comparing different
chemotherapeutic therapies.
Treatments with single
chemotherapeutic agents as
Results
delay to treatment. The length of stay
accounts for the majority of the cost to
the NHS. Patients were found to have
distinct individual treatment preferences.
The initial costs of stent placement were
higher than the costs of brachytherapy
(1500 euro vs 570 euro; P<0.001). Total
medical costs were, however, similar
(stent 11 195 euro vs brachytherapy 10
078 euro, P>0.20). Total hospital stay
during follow-up was 11.5 days after
stent placement vs 12.4 days after
brachytherapy, which was responsible
for the high intramural costs in both
treatment groups (stent 6512 euro vs
brachytherapy 7982 euro, P>0.20).
Costs for medical procedures during
follow-up were higher after stent
placement (stent 249 euro vs
brachytherapy 168 euro, P=0.002), while
the costs of extramural care were
similar (1278 euro vs 1046 euro,
P>0.20).
KCE reports 75
Comments
Study type
Level of
evidence
See also Homs MY 2004,
Lancet
No information on
blinding
RCT
Cost study
Moderate
SR
High
Only two RCTs with a total of 42
7 RCTs included
participants compared chemotherapy
with best supportive care for metastatic
oesophageal cancer. No survival benefit
was shown for chemotherapy treatment
in these RCTs. Five RCTs with a total of
1242 participants compared different
chemotherapy regimes. Due to variation
in patient population and chemotherapy
regimes, it was not possible to perform
KCE Reports 75
Study ID
Ref
Upper GI Cancer
Search date Population
Intervention
Results
well as combination regimes in
all doses and schedules were
included. Studies in which
patients received additional
treatment for dysphagia such
as stent placement or
brachytherapy were not
excluded.
Oral capecitabine
a formal pooled analysis. There was no
consistent benefit of any specific
chemotherapy regimen.
Ajani J 2006
[269]
October
2005
Patients with oesophageal
cancer
Trumper M
2006
[274]
NA
Patients with gastrooesophageal cancer, older
than 70 years (n = 257)
Platinum-containing regimen
(ECF, MCF), PVI 5-FU
(protracted venous infusion of
5-fluorouracil) ± mitomycin C
(MMC), or FAMTX
Duffour J 2006
[275]
NA
232 patients with
histologically proven
carcinoma of the
oesophagus (n = 38),
stomach or pancreas, and
metastatic disease
Cisplatin with continuous 5FU
(n = 19) vs. bolus 5FU and
Leucovorin (n = 19)
4 trials identified that included patients
with oesophageal cancer
117
Comments
Study type
Medline search only
SR
No information on
selection, quality
appraisal, etc
There were no significant differences in Pooled analysis of 3 RCTs MA
the incidence of grades 3/4 toxicity
(retrospective
between the two cohorts. Objective and subanalysis): which trials??
symptomatic response rates, failure-free
and overall survival were not
significantly different. In a multivariate
analysis, independent prognostic factors
for survival were performance status
and locally advanced disease, not age.
Patients >70 years with OGC obtained
similar benefits from palliative
chemotherapy with respect to
symptomatic response, tumour
regression and survival, without
increased toxicities.
All tumours:
Mixed patient population RCT
Safety remained acceptable and
Blinded assessors?
comparable in the two arms except for
the severe grade 3-4 mucositis, which
was lower in arm B (4.5 vs. 16.4%, p <
0.009). Efficacy in terms of tumour
response and survival was similar in the
two arms, showing an objective
response rate (after external review) of
18.6% (95% confidence interval (CI)
11.4-25.8%) in arm A vs. 15% (95% CI
8.5-21.6%) in arm B, an overall median
survival of 24 weeks in arm A vs. 24.7 in
Level of
evidence
Low
Low
Moderate
118
Study ID
Upper GI Cancer
Ref
Search date Population
Intervention
Sumpter K 2005
[270]
NA
Patients with inoperable,
histologically verified
locally advanced or
metastatic
adenocarcinoma,
squamous cell or
undifferentiated carcinoma
of the oespohagus,
oesophagogastric junction
(OGJ) or stomach
ECF (n = 53)
ECX (n = 48)
EOF (n = 55)
EOX (n = 48)
(E = epirubucin, C = cisplatin,
F = 5FU, O = oxaliplatin, X =
capecitabin)
Radiotherapy
Wenger U 2005
Bergquist H
2005
[112]
NA
Patients with incurable
cancer of the oesophagus
or gastro-oesophageal
junction
Self-expandable metallic stent
(n = 30) or 3 x 7 Gy
brachytherapy (n = 30)
Results
arm B (p = 0.83) and a progression-free
median survival of 12.4 weeks vs. 12.1 in
arms A and B, respectively (p = 0.91).
First interim analysis was performed
when 80 pts had been randomised.
Doselimiting fluoropyrimidine toxicities
were stomatitis, palmar plantar
erythema (PPE) and diarrhoea; 5.1% of
X-treated pts experienced grade 3/4
toxicity. Protocol planned dose
escalation of X to 625 mg/m² b.i.d. was
instituted and a second interim analysis
has been performed. A total of 204 pts
were randomised at the time of the
protocol planned 2nd interim analysis.
Grade 3/4 fluoropyrimidine-related
toxicity was seen in 13.7% pts receiving
F, 8.4% pts receiving X 500 mg/m² b.i.d.
and 14.7% pts receiving X 625 mg/m²
b.i.d. Combined complete and partial
response rates were ECF 31% (95% CI
18.7–46.3), EOF 39% (95% CI 25.9–
53.1), ECX 35% (95% CI 21.4–50.3),
EOX 48% (95% CI 33.3–62.8). Grade
3/4 fluoropyrimidine toxicity affected
14.7% of pts treated with X 625
mgm 2 b.i.d. 1, which is similar to
that observed with F, confirming this to
be the optimal dose. The replacement of
C by O and F by X does not appear to
impair efficacy. The trial continues to
total accrual of 1000 pts.
The group of patients treated with stent
reported significantly better HRQL
scores for dysphagia (P < 0.05) at the 1month follow-up, but most other HRQL
scores, including functioning and
symptom scales, deteriorated.
KCE reports 75
Comments
Study type
Level of
evidence
RCT
Interim analysis
6 originally randomized
pts not included in results
Noninferiority study
No information on
blinding of randomization
Moderate
Originally 65 randomized, RCT
but 5 withdrew consent
Cost study
No information on
blinding
Moderate
KCE Reports 75
Study ID
Polinder S 2004
(SIREC trial)
Ref
[113]
Upper GI Cancer
Search date Population
NA
Patients with inoperable
oesophagogastric cancer
Intervention
Ultraflex stent (n=108) or
single-dose brachytherapy (12
Gy, n=101)
Results
There was no difference in survival or
complication rates between the two
treatment strategies. There was a
significant difference in the change of
dysphagia scores between the time of
inclusion and the 1-month follow-up
visit, in favour of the stented group (P =
0.03). This difference had disappeared at
3 months. Median total lifetime costs
were 17,690 for the stented group
compared with 33 171 for the
brachytherapy group (P = 0.005). This
difference was due to higher costs for
the initial treatment (4615 versus 23
857, P < 0.0001). Sensitivity analyses
showed that the charges for a
brachytherapy session had to be
reduced from 6092 to 4222 (31%) to
make this therapeutic concept costcompetitive.
The initial costs of stent placement were
higher than the costs of brachytherapy
(1500 euro vs 570 euro; P<0.001). Total
medical costs were, however, similar
(stent 11 195 euro vs brachytherapy 10
078 euro, P>0.20). Total hospital stay
during follow-up was 11.5 days after
stent placement vs 12.4 days after
brachytherapy, which was responsible
for the high intramural costs in both
treatment groups (stent 6512 euro vs
brachytherapy 7982 euro, P>0.20).
Costs for medical procedures during
follow-up were higher after stent
placement (stent 249 euro vs
brachytherapy 168 euro, P=0.002), while
the costs of extramural care were
similar (1278 euro vs 1046 euro,
P>0.20).
119
Comments
Study type
Level of
evidence
See also Homs MY 2004,
Lancet
No information on
blinding
RCT
Cost study
Moderate
120
Upper GI Cancer
KCE reports 75
Follow up.
CPG ID
Ref
CBO
[56]
SIGN
[47]
Search Recommendation
date
July 2003 In het eerste jaar kan bij patiënten na behandeling van een oesofaguscarcinoom worden gekozen voor
frequente follow-upintervals (drie en eventueel zes weken en daarna driemaandelijks), waarna in de
daarop volgende jaren deze frequentie teruggaat naar elke zes maanden in het tweede jaar en daarna
jaarlijks. Na vijf jaar is er geen indicatie meer voor routinematige follow-up. Er is slechts plaats voor
aanvullend
onderzoek op geleide van klachten.
2004
Follow up of patients with oesophageal cancer should monitor symptoms, signs and nutritional status.
Ref
Search date Population
Study ID
Intervention
Results
Supporting evidence
Level of
evidence
Very low
Virgo KS 1999
Goodnight J 1996
Johnson FE 1997
Marsh JC 1997
Allum WH 2002
Very low
Comments
Study type
Level of
evidence
No additional studies found
Quality of life
CPG ID
Ref
SIGN
[47]
Study ID
Ref
Early lesions
Moraca R 2006
[276]
Surgery
Cense HA 2006
Lagergren
2007
Search
date
2004
Search
date
Recommendation
Supporting evidence
The possibility of reduction in quality of life after surgery should be considered when discussing treatment
options, particularly when preoperative staging suggests that surgery would be unlikely to be curative.
Blazeby 2000
Population
Intervention
Level of
evidence
Low
Results
Comments
Study type
Level of
evidence
36 patients with highEsophagectomy
grade dysplasia (HGD) or
intramucosal cancer (IMC)
28 survivors, significant differences in
postesophagectomy gastrointestinal
symptoms (decrease on heartburn and
slower speed of eating)
Not specific scale :
Medical Outcomes Study
36-Item Short-Form
Health Survey
Prospective
cohort study
Low
[277]
109 patients undergoing a
transthoracic resection
Esophagectomy
Scale : Medical Outcome
Studies Short Form-20
and the Rotterdam
Symptom Check List
Prospective
study
Low
[278]
90 patients who
underwent surgery for
oesophageal cancer.
52% survivors >/=3 years.
Esophagectomy
For survivors, no difference in long-term
(at 2 years) quality of life or survival
between those submitted to the
intensive care unit for a short period vs.
a long period.
Recovery except that scores for physical
function, breathlessness, diarrhea, and
reflux significantly worse than at baseline
(P < .01)
It’s necessary to inform
patients of the long-term
consequences of surgery
Prospective
study
Low
KCE Reports 75
Study ID
Ref
Upper GI Cancer
Search
date
Neoadjuvant treatment
Blazeby 2005
[279]
Palliative treatment
Homs 2004
[280]
121
Population
Intervention
Results
Comments
Study type
Level of
evidence
34 patients undergoing
chemoradiotherapy +
surgery
28 patiens undergoing
chemotherapy + surgery
34 patients undergoing
surgery alone
Quality of life assessment with
QLQ-C30 and QLQ-OES24
(dysphagia scale from the
EORTC)
After neoadjuvant treatment, but before
surgery, HRQL returned to baseline
levels. Recovery of HRQL was not
hampered by preoperative treatment,
and fewer problems with postoperative
nausea, emesis, and dysphagia were
reported by patients who had
undergone neoadjuvant treatment
compared with patients who had
undergone surgery alone.
Recovery of HRQL after
esophagectomy was not
impaired by neoadjuvant
treatment
Prospective
study
Low
Patients with dysphagia
from inoperable
oesophageal carcinoma
Ultraflex stent (n = 108) or
single dose (12 Gy)
brachytherapy (n = 101).
Significant difference in favour of
brachytherapy on four out of five
functional scales of the EORTC QLQC30 (role, emotional, cognitive and
social) (P < 0.05).
Major improvements were seen on the
dysphagia and eating scales of the
EORTC OES-23.
The effects of single dose RCT
brachytherapy on HRQoL
compared favourably to
those of stent placement
for the palliation of
oesophageal cancer.
Inlcuded in SIGN
guideline.
High
Psychological support
Study ID
Ref
Kuchler T
[115]
Search date Population
Patients (N = 271) with a
preliminary diagnosis of
cancer of the oesophagus
(n = 31), stomach,
liver/gallbladder, pancreas,
or colon/rectum
Intervention
Results
Comments
Study type
Standard care as provided on
the surgical wards vs. formal
psychotherapeutic support in
addition to routine care during
the hospital stay
Kaplan-Meier survival curves
demonstrated better survival for the
experimental group than the control
group. The unadjusted significance level
for group differences was P = .0006 for
survival to 10 years. Cox regression
models that took TNM staging or the
residual tumor classification and tumor
site into account also found significant
differences at 10 years. Secondary
analyses found that differences in favor
of the experimental group occurred in
patients with stomach, pancreatic,
primary liver, or colorectal cancer.
Not specifically for
oesophageal cancer.
RCT
Level of
evidence
Moderate
122
Upper GI Cancer
KCE reports 75
Nutritional support
CPG ID
Ref
CBO
[56]
SIGN
[47]
Searc Recommendation
h
date
July
Het verdient aanbeveling gedurende de behandeling met gecombineerde chemoradiotherapie bij een
2003 patiënt met oesofaguscarcinoom de voedselinname te evalueren en zo nodig te starten met
dieetmaatregelen.
Het verdient aanbeveling om reeds in een vroeg stadium bij patiënten met een oesofaguscarcinoom het
lichaamsgewicht te controleren, de voedselinname te evalueren en zo nodig te starten met
voedingsinterventie.
Het verdient aanbeveling bij electieve gastro-intestinale chirurgie terughoudend te zijn met het stimuleren
van orale drinkvoeding gezien het gebrek aan aangetoonde effectiviteit.
Op grond van de beschikbare literatuur is er mogelijk plaats voor het gebruik van immunonutritie in de
perioperatieve fase bij stabiele patiënten met een oesofaguscarcinoom.
Bij ernstig zieke patiënten is terughoudendheid geboden met argininerijke immunonutritie.
In de postoperatieve fase kan men overwegen om gedurende metabole stress te streven naar een inname
van 1,5-1,7 gram eiwitten per kilogram actueel lichaamsgewicht per dag en 25-30 kcal voor mannen en 2025 kcal voor vrouwen per kilogram actueel lichaamsgewicht per dag. Hyperalimentatie dient te worden
voorkomen, omdat dit samen kan gaan met metabole ontregelingen.
Het verdient aanbeveling in de postoperatieve fase langdurig het lichaamsgewicht, de voedselinname en de
aanwezigheid van aan voeding gerelateerde klachten te evalueren. Bij gewichtsverlies, onvoldoende inname
en bij klachten, kan door middel van dieetadviezen zo nodig met orale drinkvoeding dan wel (nachtelijke)
enterale voeding worden geprobeerd gewichtsverlies te voorkomen en de voedingstoestand
te verbeteren.
Het verdient aanbeveling na een oesofagusresectie gebruik te maken van enterale voeding (sondevoeding)
wanneer orale voeding onvoldoende mogelijk is.
Het verdient aanbeveling om in de perioperatieve fase bij patiënten met een oesofaguscarcinoom slechts
gebruik te maken van parenterale voeding indien enterale voeding niet mogelijk is.
Dieetmaatregelen bij patiënten met een inoperabel oesofaguscarcinoom kunnen het beste zijn gericht op
het welbevinden van de patiënt, dat wil zeggen dat de kwaliteit van leven belangrijker is dan de effecten
van voeding op lange termijn.
2004 Patients undergoing surgery for oesophageal cancer who are identified as being at high nutritional risk
should be considered for preoperative nutritional support.
All patients undergoing surgery for oesophageal cancer should be considered for early postoperative
nutritional support preferably by the enteral route.
Corticosteroids or megestrol acetate should be considered for patients with advanced oesophageal
cancer who are anorexic.
Supporting evidence
Level of
evidence
Jeremic B 1998
Safran H 2001
Sikora SS 1998
Low
Gianotti L 2002
Bozzetti F 2000
Braga M 1999 & 2002
Several RCTs
High
High
Observational studies
Low
KCE Reports 75
Study ID
Ref
Lobo DN 2006
[281]
Ryan AM 2006
Gabor S 2005
Upper GI Cancer
Search date Population
123
Intervention
Results
Comments
Study type
120 patients undergoing
resection for cancers of
the pancreas, oesophagus
and stomach
Jejunostomy feeding with an
immune modulating diet
(Group A, n = 60) or an
isonitrogenous, isocaloric feed
(Group B, n = 60) for 10-15
days
12 excluded from
RCT
analysis (3 protocol
violoations, 9
unresectable
disease)
[282]
205 consecutive patients
who underwent
oesophagectomy for
malignancy
Early enteral nutrition via a
needle catheter jejunostomy
[283]
44 consecutive patients
Early enteral feeding
(38 males and 6 females;
compared with parenteral
mean age 62, range 30-82) nutrition
with oesophageal
Feed delivery, although less than targeted, was
similar in both groups. There were 6 (11%)
deaths in each group. Median (IQR)
postoperative hospital stay was 14.5 (12-23)
days in Group A and 17.5 (13-23) days in
Group B (P=0.48). A total of 24 (44%) patients
in each group had infective complications
(P=1.0). A total of 21 (39%) patients in Group
A and 28 (52%) in Group B had non-infective
complications (P=0.18). Jejunostomy-related
complications occurred in 26 (48%) patients in
Group A and 30 (56%) in Group B (P=0.3).
Ninety-two per cent of patients were
successfully fed exclusively by NCJ postoesophagectomy, and 94% of patients were
tolerating a maintenance regimen of 2000 ml
feed over 20 h by day 2 post-operatively.
Patients spent a median of 15 days on
jejunostomy feeding post-surgery (range 2-112
days); however, 26% required prolonged
jejunostomy feeding (>20 days). Minor
gastrointestinal complications were effectively
managed by slowing the rate of infusion, or
administering medication. Three (1.4%) serious
complications of jejunostomy feeding occurred,
all requiring re-laparotomy, one resulting in
death. NCJ feeding was extremely effective in
preventing severe post-operative weight loss in
the majority of oesophagectomy patients postop. However, oral intake was generally poor at
discharge with only 65% of requirements being
met orally. Sixteen patients (8%) patients
required home jejunostomy feeding. By the
first post-operative month, a further 6% (12)
patients were recommenced on jejunostomy
feeding.
There was a significant difference in the
interval until the first bowel movements. No
difference in overall 30 d mortality was
identified. A poor nutritional status was a
Prospective
study
Level of
evidence
High
Low
Observationa Low
l study
124
Upper GI Cancer
Study ID
Ref
Search date Population
Intervention
carcinoma (stages I-III),
who had undergone
radical resection and
reconstruction.
Historical control of 44
patients
KCE reports 75
Results
Comments
Study type
significant prognostic factor for an increased
mortality. Early enteral feeding significantly
reduces the duration of ICU treatment and
total hospital stay in patients who undergo
oesophagectomy or oesophagogastrectomy for
oesophageal carcinoma. The mortality rate is
not affected.
Treatment of recurrent disease
CPG ID
Ref
CBO
[56]
Search
date
July 2003
Recommendation
Bij patiënten met … een recidief na eerdere oesofagusresectie in verband met een oesofaguscarcinoom heeft
stentplaatsing de voorkeur.
Only observational studies were found, but no prospective trials.
Supporting evidence
Level of
evidence
Level of
evidence
KCE Reports 75
Upper GI Cancer
125
APPENDIX 5
EVIDENCE TABLES OF GASTRIC CANCER BY CLINICAL QUESTION
Diagnosis of gastric cancer.
CPG ID
Ref
Search Recommendation
date
Alarm symptoms
SIGN
[47]
2004
Patients presenting with any of the following alarm symptoms should be referred for early endoscopy:
dysphagia, recurrent vomiting, anorexia, weight loss, gastrointestinal blood loss.
FNCLCC [129]
January
2002
Oesophagogastroscopy
SIGN
[47]
2004
FNCLCC [129]
Barium X-ray
SIGN
[47]
Biopsy
FNCLCC [129]
Study ID
Ref
Alarm symptoms
Bowrey DJ 2006 [49]
January
2002
Le bilan diagnostique repose sur la recherche des signes cliniques d’appel (douleur abdominale,
amaigrissement, dyspepsie), … (standard).
Flexible upper GI endoscopy is recommended as the diagnostic procedure of choice in patients with
suspected gastric cancer.
Routine use of chromoendoscopy during upper GI endoscopy is not recommended, but may be of value
in selected patients at high risk of gastric malignancy.
Le bilan diagnostique repose sur … la gastroscopie … (standard).
Supporting evidence
Level of
evidence
Meineche-Schmidt V 2002
Numans ME 2001
Wallace MB 2001
Kapoor N 2005
Potet 1993
Faivre 1997
Low
Graham DY 1982
Abbas SZ 2004
Mitooka H 1995
Low
No recommendation, only discussion
January
2002
Le bilan diagnostique … doit être confirmé par des biopsies multiples. Ces biopsies (nombre minimum 5 No evidence provided
à 8) doivent être réalisées sur toutes les anomalies du relief muqueux permettant un examen d’anatomie
et cytologie pathologique (standard).
Population
Intervention
Results
NA
Patients referred for
open-access gastroscopy
Application of referral
guidelines using alarm
symptoms
Gastroscopy identified oesophagogastric
carcinoma in 123 (3%) of the 4,018
subjects. Of these 123 patients, 104
(85%) with oesophagogastric cancer had
‘‘alarm’’ symptoms (anemia, mass,
dysphagia, weight loss, vomiting) and
Very low
No evidence provided
2004
Search
date
Very low
Comments
Study type
Level of
evidence
Prospective
study
Low
126
Study ID
Marmo R 2005
Upper GI Cancer
Ref
[233]
Oesophagogastroscopy
Lam EC 2007
[284]
Barium X-ray
No additional studies found
Biopsy
No additional studies found
Search
date
NA
Population
Patients with
uncomplicated dyspepsia
Intervention
Endoscopy
Identification of risk factors
Patients with thickening of Upper endoscopy and EUS by
the gastric wall on CT (n
one endosonographer, blinded
= 71)
to the results of previous
investigations
Results
would have satisfied the referral criteria.
The remaining 15% would not have been
referred
for
initial
endoscopic
assessment because their symptoms
were those of uncomplicated ‘‘benign’’
dyspepsia.
The patients with ‘‘alarm’’ symptoms
had a significantly more advanced tumor
stage (metastatic disease in 47% vs 11%;
p < 0.001), were less likely to undergo
surgical resection (50% vs 95%;
p<0.001), and had a poorer survival
(median, 11 vs 39 months; p = 0.01)
than their counterparts without such
symptoms.
A total of 5,224 patients with
uncomplicated dyspepsia were
considered (training sample). Twentytwo (16 males) had malignancy at
endoscopy. These patients were about
20 yr older than patients with no
malignancy (p < 0.001). The mean age of
females with cancer was almost 10 yr
higher compared to males (p= 0.08).
Such differences in age were confirmed
in a split sample of 3,684 patients (p <
0.001 and p < 0.05, respectively). The
age cut-offs identified were 35 yr for
males and 56 yr for females.
Normal upper endoscopy was strongly
associated with normal EUS. Abnormal
upper endoscopy was associated with
abnormal EUS in 70% of cases.
KCE reports 75
Comments
Study type
Level of
evidence
Prospective
study
Low
Prospective
study
Low
KCE Reports 75
Upper GI Cancer
127
Staging of patients with gastric cancer.
CPG ID
Ref
Search date Recommendation
Supporting
evidence
Level of
evidence
CT scan
SIGN
[47]
2004
Kamel IR 2004
Low
FNCLCC [129]
January 2002
Lee 2001
Delia 2000
Mani 2001
Dux 1999
Davies 1997
Low
Une écho-endoscopie peut être proposée pour affiner le diagnostic en cas d’hypertrophie des plis gastriques
sans histologie, et pour le diagnostic des tumeurs classées T4 et pour mieux apprécier l’envahissement pariétal
et ganglionnaire si un traitement néoadjuvant est envisagé (option).
Kelly 2001
Mancino 2000
Willis 2000
Tseng 2000
Matsumoto 2000
Low
Fujimara T 2002
Low
Clements DM 2004
Molloy RG 1995
Wilkiemeyer MB 2004
Numerous
Low
observational studies
In patients with gastric cancer, CT scan of the chest and abdomen with IV contrast and gastric distention with
oral contrast or water should be performed routinely. The liver should be imaged in the portal venous phase.
Le bilan d’extension doit inclure au minimum un scanner abdominopelvien et une radiographie du thorax
(standard).
Le scanner thoracique peut être proposé pour le bilan d’extension (option).
Endoscopic ultrasonography
FNCLCC [129] January 2002
Laparoscopy
SIGN
[47]
2004
Laparoscopy should be considered in patients with oesophageal tumours with a gastric component, and in
patients with gastric tumours being considered for surgery where full thickness gastric wall involvement is
suspected.
FNCLCC [129]
January 2002
Une laparoscopie peut être proposée pour améliorer l’établissement du stade préthérapeutique dans le cas où
un risque d’extension péritonéale existe, notamment dans les tumeurs suspectées comme T3 et T4 (option).
Magnetic resonance imaging
SIGN
[47]
2004
PET scan
SIGN
[47]
FNCLCC [66]
MRI should be reserved for those patients who cannot undergo CT or used for additional investigation
following CT/EUS.
Sohn KM 2000
Wu LF 2003
Kersjes 1997
Lauenstein TC 2004
Wong R 2000
Low
2004
PET is not routinely indicated in the staging of gastric cancers.
Low
October
2002
L’impact de la TEP-FDG sur la prise en charge thérapeutique des patients atteints d’un cancer de l’estomac
reste à déterminer par des études prospectives (recommendation).
Mochiki E 2004
Yeung HW 1998
McAteer 1999
Hoffmann 1999
Couper 1998
Depotter 2002
Kinkel 2002
128
Upper GI Cancer
KCE reports 75
Study ID
Ref
Searc Population
h date
Intervention
Results
Comments
CT scan
Kwee RM 2007
[130]
August Patients with gastric
2006
carcinoma without
neoadjuvant treatment
MDCT
Pathologic examination after
surgery as standard
English articles only
SR
Also retrospective studies
included
Overall moderate quality
of included studies
Chen CY 2007
[131]
6 studies on MDCT identified
Diagnostic accuracy of overall T staging:
77% - 89%
Sensitivity
for
assessing
serosal
involvement: 83% - 100%
Specificity
for
assessing
serosal
involvement: 80% - 97%
Overall accuracy of T staging: 89% (with
MPR images), or 49/55 correctly staged
Overall accuracy of N staging: 78% (with
MPR images), or 43/55 correctly staged
Tumor detected in only 47% of patients.
Insufficient data to calculate diagnostic
measures.
English articles only
SR
Also retrospective studies
included
Overall moderate quality
of included studies
EUS, three different miniature
probes
23 studies on EUS identified
Diagnostic accuracy of overall T staging:
65% - 92%
Sensitivity
for
assessing
serosal
involvement: 78% - 100%
Specificity
for
assessing
serosal
involvement: 68% - 100%
30-MHz probes most accurate of
invasion depth (92%)
EUS
Standard: histology or clinical
follow-up of at least 2 years
Enlargement of deep layers was only
independent predictive factor for
malignancy.
Kikuchi S 2006
Patients with gastric
cancer (M0) (n = 69)
MDCT
Pathologic examination after
surgery as standard (n = 55)
Patients with gastric
adenocarcinoma (n = 74)
MDCT
Standard: histopathological
diagnosis (n = 70); endoscopic
biopsies and clinical results (n
= 4)
Endoscopic ultrasonography
Kwee RM 2007
[130] August Patients with gastric
2006
carcinoma without
neoadjuvant treatment
Ichikawa T 2007
[285]
Gines A 2006
[286]
Matthes K 2006
[287]
Patients with early gastric
cancer scheduled for
endoscopic submucosal
dissection
Patients with large gastric
folds at endoscopy and
biopsies negative for
malignancy (n = 61)
EUS
Pathologic examination after
surgery as standard
TA-EUS vs. L-EUS
Standard not identical for
all patients
Excluded: only 4 patients
with gastric cancer
Study type
Level of
evidence
Low
Prospective
study
Low
Prospective
study
Very low
Low
Prospective
study
Low
Prospective
study
Low
RCT
KCE Reports 75
Upper GI Cancer
Study ID
Ref
Searc Population
h date
Patients with
histopathologically
confirmed
adenocarcinoma of the
stomach
Chu KM 2004
[288]
Laparoscopy
Mortensen MB 2006
[79]
411 patients with upper
gastrointestinal tract
cancer, of which 134 had
biopsy-proven gastric
cancer
Deogracias ML 2006
[289]
Patients operated on for
Staging laparoscopy
gastric carcinoma (n = 41) Open gastrectomy in 33 cases
Magnetic resonance imaging
Kwee RM 2007
[130] August Patients with gastric
2006
carcinoma without
neoadjuvant treatment
PET scan
No additional studies found
Sentinel lymph node mapping
Lee JH 2006
[136]
Mochiki E 2006
[138]
Patients with cT1N0
gastric adenocarcinoma (T
< 5 cm) (n = 64)
Patients with cN0M0
Intervention
Results
EUS for detection of ascites
Standard: staging laparoscopy
Sensitivity 61%, specificity 99%
Combined endoscopic
ultrasonography (EUS) and
laparoscopic ultrasonography
(LUS)
‘Standard’: treatment actually
undertaken
The combination of EUS and LUS
correctly predicted R0 resection in
90.6%, R1–R2 in 91% and irresectability
in 91.4% of patients. Ten patients (2.4%)
had explorative laparotomy only. There
were no complications associated with
the EUS and LUS procedures.
No port-site metastases or port-site
recurrence
129
Comments
Study type
Prospective
study
To avoid false-positive
findings with regard to
local irresectability
ultrasonographic criteria
were adjusted so that
only a combination of
several ultrasonographic
criteria with a 100 per
cent predictive value for
local
irresectability were used
Standard is not identical
for all patients
Selection bias: study
sample is taken from a
prospective database of
surgically treated patients
Level of
evidence
Low
Prospective
study
Very low
Prospective
study
Very low
MRI
Pathologic examination after
surgery as standard
3 studies on MRI identified
English articles only
SR
Diagnostic accuracy of overall T staging: Also retrospective studies
71% - 83%
included
Sensitivity
for
assessing
serosal Overall moderate quality
involvement: 90% - 93%
of included studies
Specificity
for
assessing
serosal
involvement: 91% - 100%
Low
Dye and isotope double
tracers to improve SLNB
Histology as standard
SLN mapping with Tc-99m
Overall sensitivity 71%; pT1 subset: 88%
Prospective
study
Low
Overall sensitivity 83% and specificity
Prospective
Low
130
Study ID
Upper GI Cancer
Ref
Searc Population
h date
gastric adenocarcinoma (n
= 59)
Patients with stage I-IV
gastric cancer
Gretschel S 2005
[135]
Miwa K 2003
[137]
Patients with early gastric
carcinoma treated with
surgery (n = 211)
Simsa J 2003
[139]
Patients with gastric
cancer treated with
surgery (D2
lymphadenectomy) (n =
22)
Intervention
Results
colloidal rhenium sulphide
Histology as standard
SLN mapping with 99mTccolloid (n = 15) or dye (n =
19)
Maruyama computer model
Histology as standard
Sentinel node biopsy after
mapping with vital dye
100%; pT1 subset 100% sensitivity
Sentinel node biopsy after
mapping with vital dye
Difficult to interpret
The assay was successful in mapping the
lymphatic basins in 203 (96%) of 211
patients. The dye stained one or more
metastatic nodes in 31 patients, but
failed to indicate a metastatic node in
four patients with a large involved node.
Meticulous postoperative examination of
all resected nodes in the standard
paraffin slices revealed no new
metastases.
Sensitivity 89%, specificity 100%.
Success rate of sentinel node detection
with a good relation between metastatic
involvement of the sentinel node and
other nodes was 56% (13 out of 22
patients).
Two false-negatives.
Insufficient data to calculate diagnostic
measures.
KCE reports 75
Comments
Study type
Level of
evidence
study
Only 33 patients included
in calculation of accuracy
Prospective
study
Very low
Prospective
study
Low
Prospective
study
Very low
KCE Reports 75
Upper GI Cancer
131
Diagnosis and treatment of early lesions.
CPG ID
Ref
SIGN
[47]
FNCLCC [129]
Search
date
2004
January
2002
Recommendation
Routine use of chromoendoscopy during upper GI endoscopy is not recommended, but may be of value in
selected patients at high risk of gastric malignancy.
Pathologists should follow the revised Vienna classification for reporting dysplasia.
Where radical intervention is contemplated on the basis of high-grade dysplasia or early adenocarcinoma the
diagnosis should be validated by a second pathologist experienced in this area and further biopsies should be
taken if there is uncertainty.
Patients diagnosed with high-grade dysplasia should have careful assessment (CT, EUS, rigorous biopsy
protocol +/- EMR) to exclude coexisting cancer.
In the absence of invasive cancer, patients with high-grade dysplasia should be offered endoscopic treatment.
The assessment and management of patients with high-grade dysplasia should be centralised to units with the
appropriate endoscopic facilities and expertise.
Early gastric cancer limited to the superficial submucosa should be treated by EMR.
Mucosal ablative techniques, such as PDT, APC, or laser should be reserved for the management of residual
disease after EMR and not for initial management if invasive disease is present in patients fit for surgery.
Supporting
evidence
Mitooka H 1995
Level of
evidence
Very low
Schlemper RJ 2000
Takekoshi T 1994
Very Low
Wang YP 2006
No evidence
provide for gastric
cancer
Low
La mucosectomie n’est pas une attitude standard (standard).
La mucosectomie endoscopique peut être proposée pour les patients à risques opératoires présentant une
lésion usT1N0 limitée à la muqueuse sans envahissement de la muscularis mucosae (option).
Study ID
Ref
Lee SH 2006
[290]
Search
date
Population
Intervention
Results
Patients with early gastric
cancer (n = 72)
EMR with submucosal
No differences in hard outcomes.
injection of normal saline
Shorter mean procedure time in FM
solution (n = 36) vs. fibrinogen group.
mixture solution (n = 36)
Comments
Study type
Randomization with
sealed, opaque envelopes
Not clear if blinded
assessors
RCT
Level of
evidence
Moderate
132
Upper GI Cancer
KCE reports 75
Neoadjuvant treatment.
CPG ID
Ref
Search Recommendation
date
Chemotherapy
SIGN
[47]
2004
CCO
[150]
FNCLCC [129]
Radiotherapy
SIGN
[47]
CCO
[150]
FNCLCC [129]
Ref
Chemotherapy
Wu AN 2007
[147]
Level of
evidence
Janunger KG 2002
Earle CC 2003
Songun I 1999
Fujii M 1999 (abstract)
Kang YK 1999 (abstract)
Songun I 1999
Fujii M 1999 (abstract)
Kang YK 1999 (abstract)
High
Janunger KG 2002
Earle CC 2003
Zang ZX 1998
Skoropad V 1999a
Skoropad V 1999b
Skoropad V 2002
High
There is insufficient evidence from randomized trials to recommend neoadjuvant immunotherapy outside Gouchi A 1997
of a clinical trial.
Peters KM 1990
Terashima M 1998
High
April
2003
The neoadjuvant use of either chemotherapy or radiotherapy for patients with gastric cancer is not
recommended outside clinical trials.
There is insufficient evidence from randomized trials to recommend neoadjuvant chemotherapy outside
of a clinical trial.
January
2002
La chimiothérapie néoadjuvante n’est pas indiquée dans les cancers de l’estomac résécables en dehors
d’essais thérapeutiques.
2004
The neoadjuvant use of either chemotherapy or radiotherapy for patients with gastric cancer is not
recommended outside clinical trials.
There is insufficient evidence from randomized trials to recommend neoadjuvant radiation therapy
outside of a clinical trial.
April
2003
January
2002
Immunotherapy
CCO
[150] April
2003
Study ID
Supporting evidence
High
High
High
No recommendations, only discussion
Search
date
Population
Intervention
Results
June
2005
Patients with resectable
gastric cancer
Neoadjuvant
chemotherapy followed by
surgery vs. surgery alone
Of the four clinical trials enrolled, there were 250
and 332 cases in total, with 106 and 126 deaths at
the end of follow-up in the NAC and control group,
respectively. The OR (odds ratio) was 1.05 (95%CI:
0.73-1.50), which was not statistically significant. Of
the evaluable 129 patients receiving NAC, 28.7%
demonstrated either a complete or a partial
response. Two studies of NAC in resectable gastric
cancer had resection rate data available for analysis
The R0 resection rate in the NAC group was
Comments
Study type
Level of
evidence
SR
High
KCE Reports 75
Study ID
Cunningham D
2006
Ref
[148]
Upper GI Cancer
Search
date
Population
Intervention
Results
comparable to that in the control (OR: 0.96 (95%CI:
0.51-1.83)). The morbidity and mortality of NAC
varied with the regimens used preoperatively. Of
the 129 patients included in the analyzed studies,
some acceptable toxicity was observed.
Patients with histologically
Perioperative
As compared with the surgery group, the
proven adenocarcinoma of
chemotherapy and surgery perioperative-chemotherapy group had a higher
the stomach or lower third of (n = 250) vs. surgery alone likelihood of overall survival (HR for death, 0.75;
the oesophagus that was
(n = 253)
95%CI 0.60 to 0.93; P=0.009; five-year survival rate,
considered to be stage II
36 percent vs. 23 percent) and of progression-free
(through the submucosa) or
survival (HR for progression, 0.66; 95%CI 0.53 to
higher, with no evidence of
0.81; P<0.001).
distant metastases, or locally
No separate data for gastric cancer, but no clear
advanced inoperable disease,
evidence of heterogeneity of treatment effect
as evaluated by computed
according to the site of the primary tumour
tomography, chest
radiography, ultrasonography,
or laparoscopy.
Radiotherapy
No additional studies found
Immunotherapy
Ates E 2004
[291]
Romano F 2004a [292]
Patients with histologically
proven gastric
adenocarcinoma treated with
radical surgery (n = 69)
Preoperative IL-2 (n = 34)
vs. surgery alone (n = 35)
Romano F
2004b
Patients with histologically
proven gastric
adenocarcinoma treated with
radical surgery (n = 39)
Preoperative IL-2 (n = 19)
vs. surgery alone (n = 20)
[151]
IL-2 group showed lower postoperative
complications (2/34 vs. 11/35; P < 0.05). Median
overall and disease-free survivals were longer, even
if not significantly, in the IL-2 group than in the
control arm (P = 0.07 and P = 0.06 respectively).
133
Comments
Study type
Level of
evidence
Randomization
procedure?
No information of
blinding
RCT
Moderate
Excluded: only 11
RCT
patients with gastric
cancer; no separate
analysis of these
patients
No information on RCT
randomization
procedure or
blinding
Excluded: same
patients
RCT
Moderate
134
Upper GI Cancer
KCE reports 75
Restaging after neoadjuvant treatment.
CPG ID
Ref
SIGN
[47]
Searc
h date
2004
Recommendation
Supporting evidence
Patients with locally advanced disease having chemotherapy/chemoradiotherapy should have their
response assessed for an impact on the potential to operate ; following a good response the patient
should be restaged and the role restaged and the role of surgery re-evaluated by the multidisciplinary
team.
Ross P 1996
Wilke H 1995
Level of
evidence
Low
Surgical treatment.
CPG ID
Ref
SIGN
[47]
FNCLCC [129]
Search Recommendation
date
2004
Gastric cancer resectional surgery should be carried out in high volume specialist surgical units by
frequent operators.
Surgery for gastric cancer should be aimed at achieving an R0 resection.
January
2002
Consideration should be given to pouch formation after total gastrectomy.
D2 lymphadenectomy, with a minimum of 25 lymph nodes removed, should be considered for patients
undergoing gastrectomy. Routine resection of additional organs (spleen and pancreas) during
gastrectomy is not recommended.
Une chirurgie d’exérèse à visée curative doit être réalisée (standard).
Pour les tumeurs distales (1/3 inférieur, antre), il est indiqué de pratiquer une gastrectomie des 4/5 et
curage ganglionnaire monobloc avec élargissement monobloc de nécessité aux organes de voisinage
atteints (standard).
Pour les tumeurs proximales (2/3 supérieurs), il est indiqué de pratiquer une gastrectomie totale et
curage ganglionnaire monobloc avec élargissement monobloc de nécessité aux organes de voisinage
atteints (standard).
Pour les cancers superficiels et pour des petites tumeurs limitées, les techniques de chirurgie
laparoscopique sont applicables dans le cadre d’études prospectives (option).
Un curage ganglionnaire de type D1 (ganglions périgastriques, groupes 1 à 6 soit ≥ 15 ganglions) doit
être réalisé selon la topographie de la tumeur (standard).
Un curage de type D2 (D1 + ganglions pédiculaires (groupes 1 à 11 soit ≥ 25 ganglions)) sans
splénectomie ni pancréatectomie peut être envisagé (option).
Supporting evidence
Bachmann MO 2002
Marubini E 2002
Bozzetti F 1997
Lehnert T 2004
Maruyama 1987
Jakl 1995
Allum 1989
Gouzi 1989
Bozzetti 1999
Level of
evidence
Low
High
High?
High
No evidence provided
Observational studies
Low
Dent 1988
Robertson 1994
Cischieri 1996
Bonenkamp 1999
Wu 2004
Dent 1988
Robertson 1994
Cischieri 1996
Bonenkamp 1999
Wu 2004
High
KCE Reports 75
CPG ID
Ref
Upper GI Cancer
Search Recommendation
date
Supporting evidence
Des essais randomisés évaluant le curage D2 sans splénectomie sont recommandés. Une splénectomie
est indiquée en cas d'adénopathies de l'artère splénique ou de cancer de la grosse tubérosité atteignant
la séreuse (recommandation).
Il n’y a pas de modalités standards de reconstruction après gastrectomie distale subtotale (standard).
La reconstruction peut être effectuée par rétablissement de continuité par anastomose gastrojéjunale ou
par établissement de continuité par anastomose gastroduodénale (option).
Il est recommandé de privilégier le rétablissement de continuité par la technique habituelle du chirurgien
(recommandation).
Après gastrectomie totale, le rétablissement de la continuité digestive peut se faire par anse jéjunale
selon la technique en Y de Roux, avec ou sans reconstitution d’un réservoir (J Pouch), ou par
constitution d’un réservoir avec interposition entre oesophage et duodénum d’une anse jéjunale en S ou
du côlon transverse gauche (option).
Study ID
Ref
Search
date
Volume-outcome relation
Enzinger P 2007
[293]
Type of surgery
Hosono S 2006
[164]
August
2006
135
Level of
evidence
Csendes 2002
Csendes 2002
Subanalyses of RCTs
Moderate
Chareton 1996
High
No evidence provided
5 RCTs
4 prospective trials
Low
Population
Intervention
Results
Comments
Study type Level of
evidence
Patients with stage IB
through IV (M0) gastric
and gastroesophageal
junction adenocarcinoma,
previously randomized to
adjuvant chemoradiation
after surgery or surgery
alone (n = 448)
Effect of hospital surgical
volume, as assessed by
Medicare claims data, on
overall survival and gastric
cancer recurrence
Hospital surgical volume was not predictive of
overall survival (P = 0.46) or disease-free survival
(P = 0.43) at a median follow-up of 8.9 years.
However, patients who underwent either a D1
or D2 dissection at a high- or moderate-volume
center experienced an adjusted hazard ratio of
0.80 (95% CI, 0.53-1.20) for overall survival and
0.78 (95% CI, 0.53-1.14) for disease-free survival
compared with those patients resected at a lowvolume hospital; these results were not
statistically significant. When a D0 resection was
performed, hospital procedure volume showed
no impact on survival.
Retrospective selection of
patients from a RCT (n =
556)
Observation Very low
al study
Patients with gastric
cancer
Laparoscopy assisted
distal gastrectomy
(LADG) vs. conventional
open distal gastrectomy
(CODG)
Compared to CODG, LADG was a longer
procedure (weighted mean difference 54.3;
95%CI 38.8 to 69.8; P < 0.001), but
was associated with a lower associated morbidity
(OR 0.54; 95%CI 0.37 to 0.77; P < 0.001); this
was most significant for postoperative ileus (OR
Inclusion of 4 RCTs (only 1 SR
Western study) and 12
retrospective studies
English only
No information on how
quality appraisal was done
Moderate
136
Study ID
Upper GI Cancer
Ref
Search
date
Population
Hayashi H 2005
[163]
Patients with early gastric
cancers in the lower half
of the stomach (n = 28)
Huscher C 2005
[165]
Patients with distal gastric
cancer
Inaba T 2004
[294]
Patients with gastric
cancer undergoing distal
gastrectomy or total
gastrectomy
Lee JH 2005
[166]
Patients with early gastric
cancer
Intervention
Results
0.27; 95%CI 0.09 to 0.84; P = 0.02). There was
no significant difference between the two groups
in anastomotic, pulmonary, and wound
complications and mortality.
Open distal gastrectomy
The LADG group required a significantly shorter
(n = 14) vs. laparoscopy- period of postoperative epidural anesthesia and
assisted distal gastectomy had no major postsurgery complications.
(n = 14)
Pathologic examinations showed that surgery was
equally radical in the two groups.
Laparoscopic-assisted (n
Operative mortality rates were 6.7% (2 patients)
= 30) vs. open radical
in the OG and 3.3% (1 patient) in the LG (P =
subtotal gastrectomy (n = not significant); morbidity rates were 27.6% and
29)
26.7%, respectively (P = not significant). Five-year
overall and disease-free survival rates were 55.7%
and 54.8% and 58.9% and 57.3% in the OG and
the LG, respectively (P = not significant).
Upper midline incision vs. Times for both opening and closing the
transverse incision
abdominal cavity were longer with a transverse
incision, in both the distal gastrectomy group and
total gastrectomy group. In the patients in whom
continuous epidural analgesia was used
postoperatively, the number of additional doses
of analgesics was smaller in the transverseincision group after distal gastrectomy. The
incidence of postoperative pneumonia was lower
in the transverse-incision group after distal
gastrectomy. The number of patients with
postoperative intestinal obstruction was smaller
in the transverse-incision group than in the
midline-incision group after distal gastrectomy. In
contrast to distal gastrectomy, there was no
significant difference in the number of doses of
postoperative analgesics, incidence of
postoperative pneumonia, or incidence of
postoperative intestinal obstruction between the
two study groups after total gastrectomy.
The mean postoperative hospital stay and the
Laparoscopy-assisted
distal gastrectomy
duration of analgesic administration were shorter
(LADG) including
for group L but not significantly. Postoperative
lymphadenectomy vs.
pulmonary complications occurred more
KCE reports 75
Comments
Study type Level of
evidence
Randomization with sealed
envelope
Blinding???
RCT
Moderate
Not clear if randomization
was blinded
Blinded assessment??
RCT
Moderate
No information about
randomization procedure
Blinding???
RCT
Moderate
Blinding??
RCT
Moderate
KCE Reports 75
Study ID
Ref
Upper GI Cancer
Search
date
Population
Intervention
Results
Comments
Study type Level of
evidence
No information on
randomization procedure
RCT
Moderate
No blinding
RCT
Moderate
9 patients excluded from
RCT
analysis
No information on blinding
Moderate
Two randomised and two
SR
non-randomised
comparisons of limited
(D1) versus extended (D2)
node dissection and 11
cohort studies of either D1
or D2 resection were
High
open distal gastrectomy
Lee WJ 2003
[295]
Patients with gastric
cancer treated with
extended lymph node
dissection
(D2) during gastrectomy
Sasako M 2006
[296]
Patients with gastric
cancer of the cardia or
subcardia
Yu W 2006
[297]
Patients with gastric
adenocarcinoma who
underwent total
gastrectomy (n = 216)
Lymphadenectomy
McCulloch 2004 [152]
April
2001
Patients with gastric
cancer
frequently in the O group (p = 0.043). At a
median follow-up of 14 months, there has been
no recurrence of disease in either group.
D2 gastric resection
Ligasure was associated with less intraoperative
performed with the
blood loss (mean (s.d.) 142(73) versus 239(124)
LigasureTM system (n =
ml; P = 0.001) and a shorter operating time
40) vs. resection using
(mean(s.d.) 169(25) versus 222(28) min; P =
conventional haemostatic 0.001) than conventional operation.
methods (n = 40)
Postoperative drainage fluid volumes were
greater in the Ligasure group (mean (s.d.)
1577(940) versus 886(542) ml; P = 0.020). There
were no differences in postoperative
complications or hospital stay.
Left thoracoabdominal
5-year overall survival was 52.3% (95% CI 40.4approach (LTA) (n = 85) 64.1) in the TH group and 37.9% (26.1-49.6) in
vs. abdominal-transhiatal
the LTA group. The hazard ratio of death for
approach (TH) (n = 82)
LTA compared with TH was 1.36 (0.89-2.08,
p=0.92). Three patients died in hospital after LTA
but none after TH. Morbidity was worse after
LTA than after TH.
Total gastrectomy either Gastrectomy combined with splenectomy tended
with (n = 104) or without to be associated with slightly higher morbidity
(n = 103) splenectomy
and mortality rates, a slightly greater incidence of
lymph node metastasis at the splenic hilum and
along the splenic artery, and marginally better
survival, but there were no statistically significant
differences between the groups. Splenectomy had
no impact on survival in patients with metastatic
lymph nodes at the hilum of the spleen or in
those with metastatic lymph nodes along the
splenic artery.
137
Limited vs. extended
lymph node removal
during gastrectomy
Meta-analysis of randomised trials did not reveal
any survival benefit for extended lymph node
dissection (Risk ratio = 0.95 (95%CI 0.83 - 1.09),
but showed increased postoperative mortality
(RR 2.23, 95% CI 1.45 - 3.45). Pre-specified
subgroup analysis suggested a possible benefit in
stage T3+ tumours (RR = 0.68, 95% CI 0.42-
138
Study ID
Degiuli M 2004
Upper GI Cancer
Ref
Search
date
Population
Intervention
[154]
Patients with potentially
curable gastric cancer
D1 (n = 76) and D2
gastrectomy (n = 86)
Hartgrink H 2004 [156]
Patients with gastric
adenocarcinoma treated
with curative intent
Limited (D1) (n = 380)
and extended (D2) lymph
node dissection (n = 331)
Kulig J 2007
[157]
Patients with gastric
adenocarcinoma treated
with curative intent
Standard D2 (n = 141) or
extended D2+ (n = 134)
lymphadenectomy
Sano T 2004
[158]
Patients with potentially
Japanese standard D2 vs.
D2 + para-aortic nodal
curable gastric
dissection
adenocarcinoma (T2subserosa, T3, or T4) (n =
523)
KCE reports 75
Results
Comments
1.10). Non-randomised comparisons showed no
significant survival benefit for extended dissection
(RR 0.92, 95% CI 0.83 -1.02), but decreased
mortality (RR 0.65, 95% CI 0.45-0.93). Subgroup
analysis showed apparent benefit in UICC stage II
and IIIa. Observational studies of D2 resection
reported much better mortality and survival than
those of D1 surgery, but the settings were
strikingly different.
Complications developed in 10.5% of patients
after D1 and in 16.3% of patients after D2
gastrectomy (p<0.29). Reoperation rate was 3.4%
after D2 and 2.6% after D1 resection. Postoperative mortality rate was 1.3% after D1 and
0% after D2 gastrectomy.
Morbidity (25% v 43%; P <.001) and mortality
(4% v 10%; P =.004) were significantly higher in
the D2 dissection group. After 11 years there is
no overall difference in survival (30% v 35%; P
=.53). Of all subgroups analyzed, only patients
with N2 disease may benefit of a D2 dissection.
The relative risk ratio for morbidity and mortality
is significantly higher than one for D2 dissections,
splenectomy, pancreatectomy, and age older than
70 years.
The overall morbidity rates were comparable in
D2 (27.7%; 95% confidence interval [CI], 20.335.1) and D2+ (21.6%; 95% CI, 13.7-29.5) groups
(P = .248). Pre-existing cardiac disease,
splenectomy, and excessive blood loss were
identified as risk factors for overall and
nonsurgical complications. Postoperative
mortality rates were 4.9% (95% CI, 1.4-8.5) and
2.2% (95% CI, 0-4.7), respectively (P = .376).
Although the morbidity for the extended surgery
group (28.1%) was slightly higher than the
standard group (20.9%), there was no difference
in the incidence of four major complications
(anastomotic leak, pancreatic fistula, abdominal
abscess, pneumonia) between the two groups.
analysed.
Study type Level of
evidence
No information on blinding RCT
Moderate
No information on
randomization or blinding
RCT
Moderate
Interim analysis
RCT
Separate randomization for
all participating centres
No information on blinding
Moderate
No information on blinding RCT
Moderate
KCE Reports 75
Study ID
Ref
Upper GI Cancer
Search
date
Population
Intervention
Results
Hospital mortality was reported at 0.80%: one
patient in each group died of operative
complications, while one from each group died of
rapid progressive cancer while inpatient.
Overall 5-year survival was significantly higher in
patients assigned D3 surgery than in those
assigned D1 surgery (59.5% [95% CI 50.3-68.7] vs
53.6% [44.2-63.0]; difference beteween groups
5.9% [-7.3 to 19.1], log-rank p=0.041). 215
patients who had R0 resection (ie, no
microscopic evidence of residual disease) had
recurrence at 5 years of 50.6% [41.1-60.2] for D1
surgery and 40.3% [30.9-49.7] for D3 surgery
(difference between groups 10.3% [-3.2 to 23.7],
log-rank p=0.197).
Five (4%) and two (2%) medical complications
developed in the D2 and D4 groups, respectively.
Surgical complications developed in 28 (22%) and
48 patients (38%) after D2 and D4 gastrectomy.
The most common complications were
anastomotic leakage, pancreatic fistula, and
abdominal abscess. Pancreatic fistula developed in
6 (19%) of 32 patients after D4 plus
pancreatosplenectomy, but the incidence of
pancreatic fistula after D2 gastrectomy plus
pancreatosplenectomy was low (6%, 1/16). Two
patients died within 30 days of operation (0.8%,
2/256), and each patient belonged to the D2 and
D4 group.
Wu C 2004 &
2006
[298]
Patients with gastric
adenocarcinoma treated
with curative intent
D1 (ie, level 1)
lymphadenectomy (n =
110) vs. D3 (ie, levels 1,
2, and 3) dissection (n =
111)
Yonemura Y
2006
[159]
Patients with advanced
gastric adenocarcinoma
D2 (level 1 and 2
lymphadenectomy) (n =
128) vs. D4 (D2 plus
lymphadenectomy of
para-aortic lymph nodes)
dissection (n = 128)
Patients with gastric
cancer (n = 30)
Roux-en-Y
esophagojejunostomy (RY), R-Y with pouch (P-Y),
and jejunal interposition
with pouch (P-I) after
total gastrectomy
No information on hard endpoints.
Reconstruction should be performed with pouch
formation after total gastrectomy with curative
intent.
Patients with gastric
Roux-en-Y
5 of 24 patients with RY reconstruction
Reconstruction
Adachi S 2003
[299]
Ishikawa M 2005
[300]
139
Comments
Study type Level of
evidence
No blinding
RCT
Moderate
No information on
randomization procedure.
No blinded assessment
RCT
Moderate
Randomization with sealed RCT
envelope
In case or recurrence or
impossible follow-up within
2 years after surgery:
replacement by other
patient
Blinding???
Randomization with sealed RCT
Moderate
Moderate
140
Study ID
Upper GI Cancer
Ref
Search
date
Population
Intervention
carcinoma who
underwent distal
gastrectomy (n = 50)
reconstruction vs.
conventional Billroth I
reconstruction
Iwata T 2006
[160]
Patients with gastric
cancer in the upper third
of the stomach who
underwent proximal
gastrectomy (n = 9)
Kono K 2003
[162]
Patients receiving total
gastrectomy for early
gastric cancer (n = 50)
Mochiki E 2004
[301]
Patients with gastric
cancer treated by total
gastrectomy (n = 12)
Shibata C 2004
[302]
Patients with early gastric
cancer (n = 81)
Results
developed gastrojejunal stasis in the early
postoperative period, which led to a longer
postoperative hospital stay as compared with the
B-I group (mean +/- S.D; B-I; 19.0 +/- 6.2, RY;
31.8 +/- 21.7 days) (P < 0.05). Endoscopic
examination revealed that the frequency of bile
reflux (P < 0.01) and degree of inflammation in
the remnant stomach (P < 0.05) were less in the
RY group than in the B-I group. However,
inflammatory findings in the lower esophagus
were observed in 7 (27%) of B-I, and 8 (35%) of
the RY group, suggesting that late phase
esophagitis was not improved in the RY group.
Reconstruction by jejunal The JPI group showed a significant dietary
pouch interposition (JPI
advantage. Three months after surgery, JPI
group) (n = 4) vs.
patients could eat more than 80% of the volume
reconstruction by jejunal of their preoperative meals, whereas JI patients
interposition (JI group) (n ate less than 50%. The percentage of
= 5)
postoperative body weight loss was higher in the
JI group than in the JPI group because the volume
of the remnant stomach was more adequate in
the latter. Moreover, it was easier to enter the
remnant stomach and duodenum for endoscopic
fiberscopy in the JPI group for the treatment of
hepato-biliary pancreatic disease.
Roux-en-Y
Jejunal pouch reconstruction provided the better
reconstruction group
QOL than Roux-en-Y reconstruction without
without pouch (RY
pouch both at short-term and long-term periods.
group) or the jejunal
Pouch reconstruction provided less bile reflux
pouch reconstruction
into the esophagus compared with Roux-en-Y
group (pouch group)
reconstruction.
Jejunal interposition
The interposed jejunum with a pouch shows
without a pouch (n = 12) marked disturbances from the motor pattern of a
vs. jejunal interposition
normal jejunum during the fasting and fed states.
with a pouch (n = 14)
These motor abnormalities may be responsible
for insufficient food intake of the J-P group.
Pylorus-preserving
There were no differences in early results
gastrectomy (PPG) (n =
between PPG and CDG. The incidence of early
36) vs. conventional distal dumping syndrome was lower in PPG (8%) than
gastrectomy (CDG) with in CDG (33%). Other late results including the
KCE reports 75
Comments
Study type Level of
evidence
envelopes
No information on blinding
Very small sample size
No information on
randomization procedure
or blinding
RCT
Moderate
No information on
randomization procedure
or blinding
RCT
Moderate
No information on
randomization procedure
or blinding
RCT
Moderate
Randomization with sealed RCT
envelope
No information on blinding
7 patients excluded from
Moderate
KCE Reports 75
Study ID
Yoo C 2005
Ref
Upper GI Cancer
Search
date
[161]
Population
Patients with upper third
gastric cancer
141
Intervention
Results
Comments
Billroth I anastomosis (n
= 38)
Proximal gastrectomy
with jejunal pouch
interposition (PGJP) (n =
25) vs. Roux-en-Y
esophagojejunostomy
(TGRY) (n = 26)
incidence of gallstones were not different
analysis
between the 2 groups.
No significant differences in operating time,
hospital stay, and postoperative complications.
Blood loss was significantly less in the PGJP group
(P = 0.036). Nineteen patients (73%) in the
TGRY group had one or more postgastrectomy
symptoms, which was significantly more frequent
than in the PGJP group (32%; P = 0.012). There
were also significant differences between the two
groups with regard to food intake, weight
recovery, hemoglobin, and serum vitamin B12
levels in favour of PGJP.
Study type Level of
evidence
RCT
Adjuvant treatment.
CPG ID
Ref
Search Recommendation
date
Chemotherapy
SIGN
[47]
2004
CCO
[150]
FNCLCC [129]
April
2003
January
2002
Radiotherapy
CCO
[150]
April
2003
FNCLCC [129] January
2002
Chemoradiotherapy
SIGN
[47]
2004
CCO
[150]
April
2003
Supporting evidence
Postoperative chemotherapy for patients with gastric cancer is not recommended outside a clinical trial.
Level of
evidence
Janunger 2002
Earle 2003
For patients unable to undergo radiation, adjuvant chemotherapy alone may be of benefit, particularly for Numerous MA and RCTs
patients with lymph node metastases. The optimal regimen remains to be defined.
La chimiothérapie adjuvante n’est pas indiquée dans le traitement des cancers de l’estomac en dehors
Numerous MA and RCTs
d’essais thérapeutiques (standard).
Il est recommandé de poursuivre les essais thérapeutiques, en améliorant les protocoles de
chimiothérapie, comparant la chimiothérapie adjuvante à la chirurgie seule ou à la chirurgie +
radiochimiothérapie postopératoire (recommandation).
High
There is insufficient evidence from randomized trials to recommend adjuvant radiation therapy outside
of a clinical trial.
La radiothérapie externe adjuvante n'est pas une attitude thérapeutique standard dans les cancers de
l'estomac (standard).
Hallissey 1994
Kramling 1996
Hallissey 1994
High
High
Postoperative chemoradiation for patients with gastric cancer is not recommended outside a clinical
trial.
Following surgical resection, patients whose tumours penetrated the muscularis propria or involved
regional lymph nodes should be considered for adjuvant combined chemoradiotherapy. The current
standard protocol consists of one cycle of 5-FU (425 mg/m2/day) and leucovorin (20 mg/m2/day) in a
McDonald JS 2001
Moderate
Dent 1979
Moertel 1984
McDonald 2001
High
High
High
High
142
CPG ID
Upper GI Cancer
Ref
FNCLCC [129]
Search Recommendation
date
daily regimen for five days, followed one month later by 4,500 cGy (180 cGy/day) of radiation given with
5-FU (400 mg/m2/day) and leucovorin (20 mg/m2/day) on days 1 through 4 and the last three days of
radiation. One month after completion of radiation, two cycles of 5-FU (425 mg/m2/day) and leucovorin
(20 mg/m2/day) in a daily regimen for five days are given at monthly intervals.
January Chez tous les patients opérés d’un cancer de l’estomac R0 avec un curage D1 ou D2 et de stade II ou III,
2002
la radiochimiothérapie adjuvante n’est pas considérée comme un traitement standard. En cas de curage <
D1 (moins de 15 ganglions examinés) et chez des patients T3 et/ou N+, la radiochimiothérapie peut être
proposée chez les patients non dénutris selon les modalités de l’essai de Macdonald (standard).
En cas de chirurgie avec curage D1 ou D2 et avec un envahissement ganglionnaire majeur (N2 ou N3),
une radiochimiothérapie adjuvante peut être proposée dans l’attente d’autres résultats, chez des patients
non dénutris (option).
Il est recommandé de réaliser des essais thérapeutiques évaluant la place de la radiochimiothérapie
adjuvante dans le traitement des cancers de l’estomac (accord d’experts). Le choix entre ces différentes
options thérapeutiques doit prendre en compte l'avis ou le souhait des patients (recommandation).
Supporting evidence
Level of
evidence
Bleiberg 1989
Dent 1979
Moertel 1984
McDonald 2001
High
Intraperitoneal chemotherapy and immunotherapy for patients with gastric cancer are not
recommended outside a clinical trial.
Yonemura Y 2001
Moderate
Earle 2003
High
April
2003
Intraperitoneal chemotherapy and immunotherapy for patients with gastric cancer are not
recommended outside a clinical trial.
There is insufficient evidence from randomized trials to recommend adjuvant immunotherapy outside of
a clinical trial.
High
January
2002
L’immunochimiothérapie adjuvante n’est pas un standard dans les cancers de l’estomac en occident
(standard).
Ochiai 1983
Yamamura 1986
Bonfanti 1988
Jakesz 1988
Kim 1992
Popeila 1982
Imaizumi 1990
Kim 1997
Jakesz 1988
IGTSG 1988
Primrose 1998
Tonnesen 1988
Langman 1999
Intraperitoneal
chemotherapy
SIGN
[47]
2004
Immunotherapy
SIGN
[47]
2004
CCO
[150]
FNCLCC [129]
KCE reports 75
Il est recommandé de poursuivre les essais thérapeutiques comparant l’immunochimiothérapie adjuvante
à la chirurgie seule (recommandation).
High
KCE Reports 75
Study ID
Ref
Chemotherapy
Ajani J 2006
[269]
Upper GI Cancer
Search
date
Population
October Patients with gastric
2005
cancer
Berrardi R 2004
[303]
Not
stated
Patients with gastric
cancer
Gastric cancer patients at
high risk for recurrence
including patients with
serosal invasion (stage
pT3 N0) and/or lymph
node metastasis (stage
pT2 or pT3 N1, N2, or
N3)
Cascinu S 2007
[304]
Nishikawa T
2007
Nitti D 2006
[305]
[172]
NA
Patients with
adenocarcinoma of the
stomach or esophagogastric junction treated
with curative resection
Oba K 2006
[168]
March
2005
Patients with gastric
cancer
Intervention
Results
Oral capecitabine
Narrative presentation of results, no
conclusions to be drawn.
143
Comments
Study type
Medline search only
SR
No information on
selection, quality
appraisal, etc
Adjuvant chemotherapy
3 RCTs in favour, 3 RCTs against.
No information on search SR?
Narrative presentation of results.
at all.
PELFw regimen (consisting of 5-year survival rates were 52% in the
No information on
RCT
eight weekly administrations
PELFw arm and 50% in the 5-FU/LV arm. blinding
of cisplatin (40 mg/m2), LV
Compared with the 5-FU/LV regimen,
(250 mg/m2), epidoxorubicin
the PELFw regimen did not reduce the
(35 mg/m2), 5-FU (500
risk of death (HR = 0.95, 95%
mg/m2), and glutathione (1.5
confidence interval [CI] = 0.70 to 1.29)
g/m2) with the support of
or relapse (HR = 0.98, 95% CI = 0.75 to
filgrastim) (n = 201) vs. 51.29). Less than 10% of patients in either
FU/LV regimen (consisting of
arm experienced a grade 3 or 4 toxic
six monthly administrations of episode. Neutropenia (occurring more
a 5-day course of 5-FU (375
often in the PELFw arm) and diarrhea
mg/m2 daily) and LV (20
and mucositis (more prevalent in the 5mg/m2 daily, 5-FU/LV)) (n =
FU/LV arm) were the most common
196)
serious side effects. Nevertheless, only
19 patients (9.4%) completed the
treatment in the PELFw arm and 85
(43%) patients completed the treatment
in the 5-FU/LV arm.
Excluded: re-analysis of
RCT
previous RCT (2001)
FAMTX or FEMTX vs. control In a planned combined analysis of the
Prospective meta-analysis MA
two trials, no significant differences
of 2 RCTs
were found between the treatment and Blinding??
control arms for either DFS (hazards
ratio: 0.98, P=0.87) or OS (hazards
ratio: 0.98, P=0.86). The 5-year OS was
43% in the treatment arm and 44% in
the control arm and the 5-year DFS was
41% and 42%, respectively.
Adjuvant oral fluorinated
For the 4 trials that met the eligibility
Meta-analysis of 4
MA
pyrimidines vs. surgery alone
criteria, the estimated hazard ratio was Japanese centrally
0.73 (95%CI=0.60-0.89) in favour of oral randomized controlled
Level of
evidence
Low
Low
Moderate
Moderate
High
144
Study ID
Upper GI Cancer
Ref
Tentes A 2006
[306]
Ueda Y 2006
Bouche O 2005
[307]
[169]
Tsuburaya A
2005
Chipponi J 2004
[308]
Nashimoto A
2003
Search
date
Population
Intervention
KCE reports 75
Results
Comments
Study type
Level of
evidence
fluorinated pyrimidines.
clinical trials conducted
between 1980 and 2005
No information on
randomization procedure
or blinding
RCT
Moderate
RCT
Moderate
Because of toxicity, 54% of the patients No information on
stopped the protocol before the end of blinding
the nine courses, and 46% of the
patients received the nine courses
including 32% with a decreased dose and
14% with a full dose. The 5-year survival
rate was 39% in the control group and
39% in the chemotherapy group.
RCT
Moderate
There was no significant difference in
relapse-free and overall survival
between the arms (5-year relapse-free
survival 88.8% chemotherapy v 83.7%
RCT
Moderate
Patients with locally
advanced gastric cancer
after potentially curative
gastrectomy
Adjuvant intraarterial
chemotherapy (IARC) vs.
surgery alone
Five-year survival rate for the study and
the control group was 52 and 54%,
respectively (p>0.05). Mean survival for
the study and the control group was
50+/-8 and 62+/-10 months, respectively
(p>0.05). The number of recurrences
and the failure sites were comparable
(p>0.05).
Stage II-III-IVM0 gastric
cancer patients treated
with curative resection (n
= 260)
Postoperative chemotherapy
(n = 127) vs. surgery alone (n
= 133).
5-Fluorouracil (5-FU) 800
mg/m(2) daily (5-day
continuous infusion) was
initiated before day 14 after
resection. One month later,
four 5-day cycles of 5-FU (1
g/m² per day) plus cisplatin
(100 mg/m(2) on day 2) were
administered every 4 weeks.
5- and 7-year overall survival were
41.9% and 34.9% in the control group
versus 46.6% and 44.6% in the
chemotherapy group (P=0.22). Cox
model hazard ratios were 0.74 [95%CI
0.54-1.02; P=0.063] for death and 0.70
(95%CI 0.51-0.97; P=0.032) for
recurrence.
Excluded: protocol
Blinding???
Excluded: protocol
[170]
Patients with gastric
cancer and lymph node or
serosal involvement or
both
[171]
Serosa-negative gastric
cancer patients (excluding
patients who were T1N0)
(n = 252)
Surgery alone (n = 104) vs.
surgery and adjuvant
chemotherapy (daily
administration of 200 mg/m²
of folinic acid, 5-fluorouracil
(375 mg/m² during the first
session increasing 25 mg by
session until reaching 500
mg/m²) and CDDP 15 mg/m²
(n = 101)
Adjuvant chemotherapy
(intravenous mitomycin 1.33
mg/m², fluorouracil (FU) 166.7
mg/m², and cytarabine 13.3
No information on
blinding
KCE Reports 75
Study ID
Ref
Upper GI Cancer
Search
date
Population
Radiotherapy
No additional studies found
Chemoradiotherapy
No additional studies found
Intraperitoneal chemotherapy
Yan TD 2007
[175] Decemb Patients with locally
er 2006 advanced resectable
gastric cancer
Yu W 2006
Xu DZ 2004
[309]
[174]
January
2003
Patients undergoing
curative resection
for gastric cancer
145
Intervention
Results
mg/m² twice weekly for the
first 3 weeks after surgery,
and oral FU 134 mg/m² daily
for the next 18 months for a
total dose of 67 g/m²) vs.
surgery alone
surgery alone; P =.14 and 5-year survival
91.2% chemotherapy v 86.1% surgery
alone; P =.13, respectively). Nine
patients (7.1%) in the chemotherapy arm
and 17 patients (13.8%) in the surgeryalone arm had cancer recurrence.
Adjuvant intraperitoneal
chemotherapy
A significant improvement in survival
13 RCTs of which 10
SR
was associated with hyperthermic
were of good quality
intraoperative intraperitoneal
Very good SR
chemotherapy (HIIC) alone (HR = 0.60;
95% CI = 0.43 to 0.83; p = 0.002) or
combined with early postoperative
intraperitoneal chemotherapy (EPIC)
(HR = 0.45; 95% CI = 0.29 to 0.68; p =
0.0002). Survival improvement was
marginally significant (p = 0.06) with
normothermic intraoperative
intraperitoneal chemotherapy, but not
significant with EPIC alone or delayed
postoperative intraperitoneal
chemotherapy. Intraperitoneal
chemotherapy was also found to be
associated with higher risks for intraabdominal abscess (RR = 2.37; 95% CI =
1.32 to 4.26; p = 0.003) and neutropenia
(RR = 4.33; 95% CI = 1.49 to 12.61; p =
0.007).
Excluded narrative review
Intraperitoneal chemotherapy may
Also identified by Yan et SR
benefit the patients after curative
al.
resection for locally advanced gastric
Chinese and English only
cancer, and the combination of
11 RCTs identified, of
intraperitoneal chemotherapy with
which 2 were not
Adjuvant intraperitoneal
chemotherapy
Comments
Study type
Level of
evidence
High
High
146
Study ID
Upper GI Cancer
Ref
Search
date
Immunotherapy
Chen DW 2005 [310]
Population
Intervention
Patients with gastric
carcinoma who had
undergone major surgery
Immunonutrition (n = 20) vs.
standard nutrition (n = 20)
Patients with curative
resections of gastric
cancers
Immunochemotherapy with
polysaccharide K (PSK)
Farreras N 2005 [311]
Patients with gastric
cancer (n = 66)
Popiela T 2004
Patients with stage III or
IV gastric cancer who had
undergone curative
resection (n = 156)
Early postoperative enteral
immunonutrition (formula
supplemented with arginine,
omega-3 fatty acids and
ribonucleic acid (RNA)) vs. an
isocaloric-isonitrogenous
control
BCG + FAM
(immunochemotherapy) vs.
FAM (chemotherapy) vs.
control (surgery only)
Oba K 2007
[176]
[177]
Not
stated
KCE reports 75
Results
Comments
hyperthermia or activated carbon
particles may provide more benefits to
patients due to the enhanced antitumor
activity of drugs. Sensitivity analysis and
fail-safe number suggested that the
result was comparatively reliable.
However, of 11 trials, only 3 studies
were of high quality.
identified by Yan et al.
(Chen ZX 1996, Tan CQ
2000)
No serious adverse effects were
recorded with the two formulas.
Postoperative procedures were smooth
in both groups.
The overall hazard ratio for eligible
patients was 0.88 (95% confidence
interval, 0.79-0.98; P = 0.018) with no
significant heterogeneity [chi (2)(8) for
heterogeneity = 11.7; P = 0.16]. The
results of this meta-analysis suggest that
adjuvant immunochemotherapy with
PSK improves the survival of patients
after curative gastric cancer resection.
Patients fed with immunonutrition
(n=30) showed significantly lower
episodes of surgical wound healing
complications (0 vs. 8 (26.7%) P=0.005)
when compared to patients fed with the
control formula (n=30).
No full-text
RCT
8 RCTs included
SR
Overall 10-year survival was 47.1% for
the immunochemotherapy group (P <
0.037 vs FAM and P < 0.0006 vs
control), 30% for the chemotherapy
group (vs control, NS), and 15.2% for
the control group. In patients with
pT2/T3 primary tumors, 10-year survival
was 55.3% for BCG + FAM vs 28.2% for
FAM (P < 0.01) and 14.6% for the
control group (P < 0.00018). BCG +
Study type
Level of
evidence
High
No ITT anlysis (6 patients RCT
excluded, 3 in both arms)
Moderate
Randomization with
envelope
No information on
blinding
Moderate
RCT
KCE Reports 75
Study ID
Sato Y 2004
Ref
Upper GI Cancer
Search
date
[312]
Population
Patients who underwent
curative resection of
gastric cancer
Intervention
Results
FAM significantly improved the survival
of patients with intestinal-type but not
diffuse-type cancer.
Immunochemotherapy was well
tolerated.
800 mg/d 5'-DFUR (Furtulon) The 5-year survival rates for groups A
for 2 years from 2 weeks after and B were 62.9% and 63.8%,
the operation (n = 143) vs.
respectively, showing no significant
OK-432 plus 5'-DFUR by the difference (P = 0.7996).
same regimen (n = 144)
147
Comments
Study type
No full-text
RCT
Palliative treatment.
CPG ID
Ref
Search Recommendation
date
Supporting evidence
Level of
evidence
Surgery
SIGN
[47]
2004
Green D 2002
Low
Hanazaki K 1999
Green D 2002
Kunisaki C 2003
Low
Low
Brune IB 1997
Blair S 2001
Low
Low
Ouchi K 1998
Low
Low
FNCLCC
[129]
Chemotherapy
January
2002
Palliative gastrectomy should be avoided in patients with gastric cancer who have disseminated
peritoneal disease.
D2 lymphadenectomy should be avoided in patients with gastric cancer in the palliative setting.
Health professionals should take the following factors into account when considering palliative gastric
resection:
peritoneal disease
tumour diameter
histological type
degree of differentiation
Laparoscopic bypass or gastric outlet stenting are alternatives to palliative gastric bypass.
Palliative gastric bypass should be avoided when malignant ascites or small bowel obstruction are
present.
Exploratory laparotomy alone should be avoided.
La chirurgie palliative est indiquée pour les sténoses symptomatiques, les tumeurs qui saignent et parfois
en urgence pour perforation. Il n’y a pas d’indication à la chirurgie s’il existe une atteinte péritonéale, une
ascite néoplasique ou des métastases hépatiques et si la tumeur est peu symptomatique (standard).
L’exérèse ou la dérivation peuvent être proposes (option).
L’indication de chirurgie palliative dépend de l’intensité des signes fonctionnels, de l’état général et
nutritionnel, de l’âge, des ressources thérapeutiques complémentaires utilisables et surtout de la
résécabilité et d’une espérance de vie supérieure à 6 mois. L’exérèse est préférable à la derivation
(recommendation).
Low
Low
Level of
evidence
148
Upper GI Cancer
CPG ID
Ref
SIGN
[47]
FNCLCC
[129]
Search Recommendation
date
2004
In patients with locally advanced or metastatic cancer of the stomach with good performance status
combination chemotherapy including cisplatin and infusional 5FU (such as ECF or MCF) should be
considered.
January La chimiothérapie doit être proposée aux patients en bon état général dans le but d’améliorer leur
2002
survie (standard).
Modalités (option):
monochimiothérapie par 5FU - acide folinique
polychimiothérapie par des combinaisons à base de 5FU et de cisplatine
Il est recommandé de poursuivre les essais thérapeutiques pour préciser l’intérêt de nouveaux
médicaments en première ligne et en seconde ligne. Le choix de la chimiothérapie doit être fait en
fonction de l’état général et de l’âge. Une polychimiothérapie est recommandée pour les patients en bon
état général. Le choix entre ces différentes options thérapeutiques doit prendre en compte l'avis ou le
souhait des patients (recommendation).
Supportive care
SIGN
[47]
2004
Patients with gastric cancer should have access to a specialist palliative care team.
KCE reports 75
Supporting evidence
Janunger K 2002
Murad 1993
Pyrhonen 1995
Glimelius 1997
Cullinan 1995
Kim 1993
Cullinan 1994
Many other RCTs
No evidence provided
Smeenk FW 1998
Miccinesi G 2003
Costantini M 2003
Costantini M 1993
Level of
evidence
High
High
High
Low
KCE Reports 75
Study ID
Ref
Chemotherapy
Ajani J 2006
[269]
Upper GI Cancer
Search
date
Population
October Patients with gastric
2005
cancer
149
Intervention
Results
Comments
Study type
Level of
evidence
Oral capecitabine
Narrative presentation of results, no
conclusions to be drawn.
Medline search only
No information on
selection, quality
appraisal, etc
Excluded
SR
Low
Trumper M
2006
[274]
Di Cosimo S
2003
[313]
February Patients with advanced
2003
gastric cancer
Docetaxel
Wagner AD
2005 & 2006
[181]
February Patients with advanced
2005
gastric cancer
Chemotherapy
Eight phase II trials focused on docetaxel
as a single agent. Considering
collectively the 262 evaluable patients
enrolled in these studies, the mean
response rate (RR) was 19% (CI 95%
14-24%). Docetaxel was well tolerated
with a dose-limiting myelosuppression
(grade 3-4 neutropenia in 36-95% of
cases). Adding fluorouracil, an RR
ranging from 22% to 86% was
registered, due to differences in
populations studied (young vs elderly)
and modalities of drug administration
(continuous vs. bolus infusion). RRs for
docetaxel-cisplatin combination were
56%, 37% and 36% in three phase II trials
and 35% in a phase III trial. The addition
of both cisplatin and fluorouracil to
docetaxel did not increase toxicity.
Randomized trials comparing docetaxelcisplatin-fluorouracil with ciplatinfluorouoracil or epirubicin-cisplatinfluorouracil, the most commonly used
regimens, are ongoing.
Analysis of chemotherapy versus best
supportive care (HR = 0.39; 95% CI,
0.28 to 0.52) and combination versus
single agent, mainly fluorouracil (FU) based chemotherapy (HR = 0.83; 95%
No information on
selection process or
quality appraisal
27 RCTs included
Retrospective
subanalysis of
3 RCTs
SR
Low
SR
High
150
Study ID
Upper GI Cancer
Ref
Search
date
Population
Intervention
Wohrer SS 2004 [314]
Patients with advanced
gastric cancer
Chemotherapy
Ajani J 2005
Untreated patients with
confirmed advanced
DCF (docetaxel 75 mg/m2,
cisplatin 75 mg/m² on day 1,
[315]
Results
CI = 0.74 to 0.93) showed significant
overall survival benefits in favor of
chemotherapy and combination
chemotherapy, respectively. In addition,
comparisons of FU/cisplatin-containing
regimens with versus without
anthracyclines (HR = 0.77; 95% CI, 0.62
to 0.95) and FU/anthracycline-containing
combinations with versus without
cisplatin (HR = 0.83; 95% CI, 0.76 to
0.91) both demonstrated a significant
survival benefit for the three-drug
combination. Comparing irinotecancontaining versus nonirinotecancontaining combinations (mainly
FU/cisplatin) resulted in a nonsignificant
survival benefit in favor of the
irinotecan-containing regimens (HR =
0.88; 95% CI, 0.73 to 1.06), but they
have never been compared against a
three-drug combination.
Analysis of results shows chemotherapy
to be superior to best supportive care
alone. Combination chemotherapy
compared with monochemotherapy is
associated with significantly higher
overall (complete plus partial) response
rates but nevertheless results in similar
survival. ECF (epirubicin, cisplatin and 5fluorouracil) currently represents one of
the most effective regimens for
advanced gastric cancer, whereas among
the newer combinations, irinotecan- or
taxane-based regimens have also given
promising results. In patients with a
poor performance status, consideration
could be given to leucovorin-modulated
5-fluorouracil alone.
Of 158 randomly assigned patients, 155
(DCF, n = 79; DC, n = 76) received
KCE reports 75
Comments
Study type
Level of
evidence
Medline and English only
No information on
selection process or
quality appraisal
SR
Low
RCT
High
KCE Reports 75
Study ID
Bouche O 2004
Ref
[316]
Cocconi G 2003 [317]
Upper GI Cancer
Search
date
Population
Intervention
gastric or
gastroesophageal
adenocarcinoma
and fluorouracil 750 mg/m²/d
as continuous infusion on days
1 to 5) (n = 79) vs. DC
(docetaxel 85 mg/m² and
cisplatin 75 mg/m² on day 1)
every 3 weeks (n = 76)
Results
treatment. The confirmed ORR was
43% for DCF (n = 79) and 26% for DC
(n = 76). Median time to progression
was 5.9 months for DCF and 5.0 months
for DC. Median overall survival time was
9.6 months for DCF and 10.5 months
for DC. The most frequent grade 3 and
4 events per patient included
neutropenia (DCF = 86%; DC = 87%)
and GI (DCF = 56%; DC = 30%).
Patients with histologically LV 200 mg/m² (2-hour
The overall response rates, which were
proven metastatic gastric infusion) followed by FU 400
confirmed by an independent expert
or cardial adenocarcinoma mg/m² (bolus) and FU 600
panel, were 13% (95%CI, 3.4% to
without linitis
mg/m² (22-hour continuous
23.3%), 27% (95%CI, 14.1% to 40.4%),
infusion) on days 1 and 2
and 40% (95%CI, 25.7% to 54.3%) for
every 14 days (LV5FU2; arm
arms A, B, and C, respectively. Median
A) (n = 45) vs. LV5FU2 plus
progression-free survival and overall
cisplatin 50 mg/m² (1-hour
survival times were 3.2 months (95%CI,
infusion) on day 1 or 2 (arm
1.8 to 4.6 months) and 6.8 months
B) (n = 44), vs. LV5FU2 plus
(95%CI, 2.6 to 11.1 months) with
irinotecan 180 mg/m² (2-hour LV5FU2, respectively; 4.9 months
infusion) on day 1 (arm C) (n
(95%CI, 3.5 to 6.3 months) and 9.5
= 45)
months (95%CI, 6.9 to 12.2 months)
with LV5FU2-cisplatin, respectively; and
6.9 months (95%CI, 5.5 to 8.3 months)
and 11.3 months (95%CI, 9.3 to 13.3
months) with LV5FU2-irinotecan,
respectively.
Patients with untreated
5-Fluorouracil (5-FU),
The complete response (CR) rates to
advanced gastric
doxorubicin and methotrexate PELF and FAMTX were, respectively,
carcinoma
(FAMTX) (n = 97) vs. cisplatin, 13% [95% confidence intervals (CI) 6%
epirubicin, leucovorin and 5to 20%] and 2% (95% CI 0% to 5%; P =
FU (PELF) (n = 98)
0.003), and the objective response rates
[CR plus partial response (PR) rates]
39% (95% CI 29% to 49%) and 22% (95%
CI 13% to 30%; P = 0.009), thus
significantly favouring the PELF
combination. The survival rates after 12
months (30.8% versus 22.4%) and 24
months (15.7% versus 9.5%) were also
151
Comments
Study type
Level of
evidence
No information on exact
randomization procedure
or blinding
Included in Wagner 2006
RCT
Moderate
No information on
blinding
Included in Wagner 2006
RCT
Moderate
152
Study ID
Upper GI Cancer
Ref
Koizumi W
2004
[318]
Lutz M 2007
[319]
Moehler M 2005 [320]
Search
date
Population
Patients with advanced
unresectable gastric
cancer
Patients with advanced
gastric cancer
Patients with untreated
metastatic or locally
advanced gastric cancer
Intervention
Results
KCE reports 75
Comments
higher among patients receiving PELF,
but these differences were not
statistically significant. The toxicities
were qualitatively different but
quantitatively similar. Both regimens
seem to be feasible provided that careful
patient monitoring is assured.
Cisplatin + mitomycin + oral
No significant differences in response
No information on exact
5’-DFUR (n = 32) vs. Cisplatin rate and median survival time.
randomization procedure
+ oral 5’-DFUR (n = 29)
Blinding??
Weekly FU 3000 mg/m²/24
Confirmed responses were observed in No information on exact
hours (HD-FU) (n = 37), FU
6.1% (two of 33) of the eligible patients randomization procedure
2600 mg/m²/24 hours plus dl- treated with HD-FU, in 25% (12 of 48,
FA 500 mg/m² or l-FA 250
including one complete remission [CR])
mg/m² (HD-FU/FA) (n = 53),
with HD-FU/FA, and in 45.7% (21 of 46,
vs. FU 2000 mg/m²/24 hours
including four CRs) with HD-FU/FA/Cis.
plus FA plus biweekly Cis 50
The HD-FU arm was closed after stage
mg/m² (n = 51), each
1 because the required minimum
administered for 6 weeks with number of responses was not met. The
a 1-week rest
median progression-free survival of all
patients in the HD-FU, HD-FU/FA, and
HD-FU/FA/Cis arm was 1.9, 4.0, and 6.1
months, respectively. The median
overall survival was 7.1, 8.9, and 9.7
months, and the survival rate at 1 year
was 24.3%, 30.3%, and 45.3%,
respectively. Grade 4 toxicities were
rare. The most relevant grade 3/4
toxicities were neutropenia in 1.9%,
5.4%, and 19.6%, and diarrhea in 2.7%,
1.9%, and 3.9% of the cycles in the HDFU, HD-FU/FA, and HD-/FU/Cis arms,
respectively.
The objective clinical response rates
No information on exact
Irinotecan plus high-dose 5fluorouracil (5-FU) and
after 14 weeks treatment were 30% for randomization procedure
Blinding???
leucovorin (LV) (ILF) (n = 56) ILF and 17% for ELF (RR 0.57, 95%CI
Included in Wagner 2006
vs. etoposide plus 5-FU/LV
0.29–1.13, P=0.077). Overall response
(ELF) (n = 58)
rates over the entire treatment period
for ILF and ELF were 43 and 24%,
respectively (RR 0.56, 95%CI 0.33–0.97;
Study type
Level of
evidence
RCT
Moderate
RCT
Moderate
RCT
Moderate
KCE Reports 75
Study ID
Ref
Upper GI Cancer
Search
date
Population
Intervention
Ohtsu A 2003
[321]
Patients with advanced
gastric cancer
Fluorouracil (FU) alone vs. FU
plus cisplatin (FP) vs. uracil
and tegafur plus mitomycin
(UFTM)
Park SH 2006
[322]
Pozzo C 2004
[323]
Patients with measurable
metastatic gastric cancer
Patients with advanced
gastric or oesophagealgastric junction
Paclitaxel + 5FU (n = 38) vs.
docetaxel + 5FU (n = 38)
Irinotecan [80 mg/m2² IV], FA
(500 mg/m² IV) and a 22-h
infusion of 5-FU (2000 mg/m²
Results
P=0.047). For ILF and ELF, respectively,
median progression-free survival was 4.5
vs 2.3 months, time to treatment failure
was 3.6 vs 2.2 months (P=0.45), and
overall survival was 10.8 vs 8.3 months
(P=0.28). Both regimens were well
tolerated, the main grade 3/4 toxicities
being diarrhoea (18%, ILF) and
neutropenia (57%, ELF).
At the interim analysis, the UFTM arm
showed a significantly inferior survival
with higher incidences of hematologic
toxic effects than did control arm FU
alone, and the registration to UFTM was
terminated. Both investigational
regimens, FP and UFTM, had a
significantly higher incidence of
hematologic toxic effects than FU alone,
although the effects were manageable.
The overall response rates of the FUalone, FP, and UFTM arms were 11%,
34%, and 9%, respectively. The median
progression-free survival was 1.9
months with FU alone, 3.9 months with
FP, and 2.4 months with UFTM,
respectively. Although FP demonstrated
a higher response rate (P < .001) and
longer progression free survival than did
FU alone (P < .001), no differences in
overall survival were observed between
the arms. The median survival times and
1-year survival rates were 7.1 months
and 28% with FU, 7.3 months and 29%
with FP, and 6.0 months and 16% with
UFTM, respectively.
No significant differences
The overall response rate in the
irinotecan/5-FU/FA arm was 42.4%, with
a complete response rate of 5.1%.
153
Comments
Study type
Level of
evidence
No information on
blinding
Included in Wagner 2006
RCT
Moderate
No information on
randomization procedure
No ITT
RCT
Moderate
RCT
Moderate
154
Study ID
Upper GI Cancer
Ref
Search
date
Population
Intervention
Results
adenocarcinoma
IV), weekly for 6 weeks with
a 1-week rest (n = 59), vs.
irinotecan (200 mg/m² IV) and
cisplatin (60 mg/m² IV), on day
1 for 3 weeks (n = 58)
Corresponding figures for the
irinotecan/cisplatin arm were 32.1% and
1.8%, respectively. The median time to
progression was 6.5 months
(irinotecan/5-FU/FA) and 4.2 months
(irinotecan/
cisplatin) (P < 0.0001), with median
survival times of 10.7 and 6.9 months,
respectively (P = 0.0018). The major
toxicity was grade 3/4 neutropenia,
which was more pronounced with
irinotecan/cisplatin than with
irinotecan/5-FU/FA (65.7% versus 27%).
Diarrhea was the main grade 3/4 nonhematological toxicity with both
irinotecan/5-FU/FA (27.0%) and
irinotecan/cisplatin (18.1%).
Only the TCF group showed statistically
and clinically meaningful improvement in
global QOL (P = 0.001). Surgical and
pathologic response were better with
TCF, but there was no difference in
survival rate between two groups.
First interim analysis was performed
when 80 pts had been randomised.
Doselimiting fluoropyrimidine toxicities
were stomatitis, palmar plantar
erythema (PPE) and diarrhoea; 5.1% of
X-treated pts experienced grade 3/4
toxicity. Protocol planned dose
escalation of X to 625 mg/m² b.i.d. was
instituted and a second interim analysis
has been performed. A total of 204 pts
were randomised at the time of the
protocol planned 2nd interim analysis.
Grade 3/4 fluoropyrimidine-related
toxicity was seen in 13.7% pts receiving
F, 8.4% pts receiving X 500 mg/m² b.i.d.
and 14.7% pts receiving X 625 mg/m²
b.i.d. Combined complete and partial
Sadighi S 2006
[324]
Patients with advanced
gastric cancer
Docetaxel, cisplatin, 5-FU
(TCF) (n = 44) vs. epirubicin,
cisplatin, 5-FU (ECF) (n = 42)
Sumpter K 2005
[270]
Patients with inoperable,
histologically verified
locally advanced or
metastatic
adenocarcinoma,
squamous cell or
undifferentiated
carcinoma of the
oespohagus,
oesophagogastric junction
(OGJ) or stomach
ECF (n = 53)
ECX (n = 48)
EOF (n = 55)
EOX (n = 48)
(E = epirubucin, C = cisplatin,
F = 5FU, O = oxaliplatin, X =
capecitabin)
KCE reports 75
Comments
Study type
Level of
evidence
No information on
randomization procedure
or blinding
RCT
Moderate
Interim analysis
RCT
6 originally randomized
pts not included in results
Noninferiority study
No information on
blinding of randomization
Moderate
KCE Reports 75
Study ID
Ref
Upper GI Cancer
Search
date
Population
Intervention
Results
155
Comments
Study type
Excluded: protocol
RCT
No information on
randomization procedure
Four patients excluded
because of violation of
inclusion criteria
RCT
Excluded: protocol
RCT
Level of
evidence
response rates were ECF 31% (95% CI
18.7–46.3), EOF 39% (95% CI 25.9–
53.1), ECX 35% (95% CI 21.4–50.3),
EOX 48% (95% CI 33.3–62.8). Grade
3/4 fluoropyrimidine toxicity affected
14.7% of pts treated with X 625
mgm 2 b.i.d. 1, which is similar to
that observed with F, confirming this to
be the optimal dose. The replacement of
C by O and F by X does not appear to
impair efficacy. The trial continues to
total accrual of 1000 pts.
Takahashi Y
2004
[325]
Patients with advanced or
recurrent gastric
carcinoma
Patients with metastatic
or locally advanced gastric
adenocarcinoma without
prior chemotherapy (n =
94)
Thuss-Patience P [326]
2005
Tsuburaya A
2005
Berardi R 2004
[308]
Casaretto L
2006
[180]
[303]
Not
stated
Not
stated
Patients with gastric
cancer
Patients diagnosed with
gastric adenocarcinoma
Tailored CPT-11 + S-1 vs S-1
ECF (epirubicin 50 mg/m² day
1, cisplatin 60 mg/m² day 1,
and fluorouracil 200 mg/m²
days 1 through 21, every 3
weeks) (n = 45) or DF
(docetaxel 75 mg/m² day 1,
and fluorouracil 200 mg/m²
days 1 through 21, every 3
weeks) (n = 45)
In the DF arm, two patients (4.4%,
intent to treat) experienced a confirmed
complete tumor remission as best
response, and 15 patients (33.3%)
experienced a confirmed partial
remission (overall response rate [ORR],
37.8%; 95% CI, 25.9% to 51.9%). Two
patients (4.4%) in the ECF arm showed
confirmed complete remission, and 14
(31.1%) showed confirmed partial
remission
(ORR, 35.6%; 95% CI, 24.8% to 48.7%).
For the DF and ECF arms, the median
survival was 9.5 and 9.7 months, and the
median time to tumor progression 5.5
and 5.3 months, respectively.
Chemotherapy versus support The 1-year survival rate was 8% for
cancer treatment
support care and 20% for chemotherapy
(RR = 2.14, 95%CI = 1.00-4.57, P =
0.05); 30% of the patients in the
chemotherapy group and 12% in the
No information on search SR?
at all: excluded
5 RCTs included
SR
Moderate
Low
High
156
Study ID
Upper GI Cancer
Ref
Search
date
Population
Bonnetain F
2005
[327]
Patients with metastatic
gastric adenocarcinoma
Van Cutsem E
2006
[328]
Patients with advanced
gastric cancer
[329]
Septemb Patients with malignant
er 2003 symptomatic
gastroduodenal
obstruction
Stenting
Dormann A
2004
Intervention
Results
support care group attained a 6-month
symptom-free period (RR = 2.33, 95%CI
= 1.41-3.87, P < 0.01). Quality of life
evaluated after 4 months was
significantly better for the chemotherapy
patients (34%; RR = 2.07, 95%CI = 1.313.28, P < 0.01) with tumor mass
reduction (RR = 3.32, 95%CI = 0.7714.24, P = 0.1).
LV5FU2-irinotecan vs. LV5FU2 Patients with a stable or improved global
alone vs. LV5FU2-cisplatin
health ranged from 11% in the LV5FU2cisplatin arm to 18% in the LV5FU2irinotecan arm. The irinotecan-basedtherapy presented 14 to 15 scores with
a better QoL.
Docetaxel 75 mg/m² and
TTP was longer with DCFvs. CF (32%
cisplatin 75 mg/m² (day 1) plus risk reduction; log-rank P < .001).
fluorouracil 750 mg/m²/d (days Overall survival was longer with DCF
1 to 5) every 3 weeks (n =
versus CF
221) vs. cisplatin 100 mg/m²
(23% risk reduction; log-rank P = .02).
(day 1) plus fluorouracil 1,000 Two-year survival rate was 18% with
mg/m²/d (days 1 to 5) every 4 DCF and 9% with CF. Overall response
weeks (n = 224)
rate was higher with DCF (P = .01).
Grade 3 to 4 treatment-related adverse
events occurred in 69% (DCF) v 59%
(CF) of patients. Frequent grade 3 to 4
toxicities for DCF vs. CF were:
neutropenia (82% vs. 57%), stomatitis
(21% vs. 27%), diarrhea (19% vs. 8%),
lethargy (19% vs. 14%). Complicated
neutropenia was more frequent with
DCF than CF (29% vs. 12%).
Self-expanding metal stents
Clinical success was achieved in 526
patients in the group in which technical
success was reported (89 %; 87 % of the
entire group undergoing stenting).
Disease-related factors accounted for
the majority of clinical failures. Oral
KCE reports 75
Comments
Study type
Level of
evidence
No information on
randomization procedure
or blinding
RCT
Moderate
No information on exact
randomization procedure
RCT
Moderate
32 case series included
SR
(only 10 prospective)
No information on quality
appraisal or selection
process (two reviewers?)
Very low
KCE Reports 75
Study ID
Ref
Upper GI Cancer
Search
date
Population
Intervention
Hosono S 2007
[178]
Septemb Patients with malignant
er 2006 gastroduodenal
obstruction
Endoscopic stenting vs.
surgical gastroenterostomy
Jeurnink S 2007
[179]
Decemb Patients with gastric
er 2005 outlet obstruction
Stent vs. gastrojejunostomy
Results
intake became possible in all of the
patients in whom a successful procedure
was carried out, with 87 % taking soft
solids or a full diet, with final resolution
of symptoms occurring after a mean of 4
days. There was no procedure-related
mortality. Severe complications
(bleeding and perforation) were
observed in seven patients (1.2 %). Stent
migration was reported in 31 patients (5
%). Stent obstruction occurred in 104
cases (18 %), mainly due to tumor
infiltration. The mean survival period
was 12.1 weeks.
Endoscopic stenting was found to be
associated with higher clinical success (P
= 0.007), a shorter time from the
procedure to starting oral intake (P <
0.001), less morbidity (P = 0.02), lower
incidence of delayed gastric emptying (P
= 0.002), and a shorter hospital stay
(P < 0.001) than surgical gastroenterostomy. There was no significant
difference between the two groups in
the analysis of 30-day mortality.
No differences between stent placement
and gastrojejunostomy were found in
technical success (96% vs. 100%), early
and late major complications 7% vs. 6%
and 18% vs. 17%, respectively) and
persisting symptoms (8% vs. 9%). Initial
clinical success was higher after stent
placement (89% vs. 72%). Minor
complications were less frequently seen
after stent placement in the patient
series (9% vs. 33%), however the pooled
analysis showed no differences (OR:
0.75, p = 0.8). Recurrent obstructive
symptoms were more common after
stent placement (18% vs. 1%). Hospital
157
Comments
Study type
Level of
evidence
English only
SR
1 RCT and 8 nonrandomized retrospective
studies included
Low
Medline only
No information on study
selection
Inclusion of 44 studies (2
RCTs)
Low
SR
158
Study ID
Upper GI Cancer
Ref
Search
date
Population
Intervention
Results
KCE reports 75
Comments
Study type
Level of
evidence
stay was prolonged after GJJ compared
to stent placement (13 days vs. 7 days).
The mean survival was 105 days after
stent placement and 164 days after GJJ.
Fiori E 2004
Mehta S 2006
Wenger U 2006
[330]
[331]
[271]
Patients with incurable
cancer of the distal
oesophagus or gastric
cardia (n = 41)
Follow up.
No evidence identified.
Antireflux stent (n = 19) vs.
standard stent (n = 22)
Included in Jeurnink S
RCT
Included in Jeurnink S
RCT
Fewer patients with complications were Interim report
RCT
observed in the antireflux stent group (n Central randomization,
= 3) than in the standard group (n = 8), but no information on
but no statistically significant difference
procedure
was shown (p = 0.14). The survival rates Patients were blinded, but
were similar in the two groups (p =
no information on
0.99; hazard ratio, 1.0; 95% confidence
blinding of clinicians
interval, 0.5-2.0). The groups did not
differ significantly in terms of studied
oesophageal or respiratory symptoms
or quality of life. Clinically relevant
improvement in dysphagia occurred in
both groups. Dyspnea decreased after
antireflux stent insertion (mean score
change, -11), and increased after
insertion of standard stent (mean score
change, +21).
Moderate
KCE Reports 75
Upper GI Cancer
159
APPENDIX 6
EVIDENCE TABLES OF GASTRIC LYMPHOMA BY CLINICAL QUESTION
Diagnosis and staging of gastric lymphoma.
Study ID
Ref
Search Population
date
Intervention
Results
Comments
Sensitivity 73%, specificity 46%
Selection of patients??
However, correct interpretation of these
values is impossible
Study type
Level of
evidence
Prospective
study
Very low
Molecular diagnosis
Weston 1998
[332]
Mix of 50 patients of which
15 had gastric lymphoma
PCR monoclonality
Standard: histology
(endoscopy)
[333]
Patients with primary
gastric lymphoma (n = 50)
EUS vs. endoscopy
Endoscopy correctly assessed tumour
Standard: histology (surgery) (n extent in 25% of cases
= 24)
Decision for surgery not
based on EUS
Selection of patients??
Blinding?
Prospective
study
Very low
[203]
Patients with gastric NHL
(n = 44)
EUS (n = 44) vs. CT (n = 24)
vs. US (n = 34)
Standard: histology (surgery)
Sensitivity for diagnosis: 27% (specificity
unknown)
CT not performed in all
patients
Selection of patients??
Blinding?
Prospective
study
Very low
Ferreri 1998
[334]
CT for detection of perigastric
adenopathy
Standard: histology (surgery)
Sensitivity to distinguish II1 from I: 27%
Specificity 100%
Very low
[202]
No information on how
patients were selected
Small study sample
Blinding?
Sensitivity for diagnosis: 57% (specificity Selection of patients??
unknown)
Small study sample
Retrospective
(?) study
Vorbeck 2002
Patients with gastric MALT
lymphoma (n = 20)
Low-grade: n = 11; highgrade: n = 9
Patients with gastric MALT
lymphoma (n = 14)
Prospective
study
Very low
Hoepffner 2003
[203]
Sensitivity for diagnosis: 42% (specificity
unknown)
CT not performed in all
patients
Selection of patients??
Blinding?
Prospective
study
Very low
No information on blinding
during surgery
Standard not applied to all
patients, no information on
follow-up of 142 patients
without gastric malignancy
Prospective
study
Low
Endoscopy
Palazzo 1993
Ultrasonography
Hoepffner 2003
CT scan
Patients with gastric NHL
(n = 44)
EUS vs. CT
Standard: histology
(endoscopy)
EUS (n = 44) vs. CT (n = 24)
vs. US (n = 34)
Standard: histology (surgery)
Endoscopic ultrasonography
Caletti 1993
[199]
Patients with endoscopic
gross appearance
suspicious for gastric
cancer of lymphoma
EUS
42
gastric
cancers,
44
primary
Standard: histology (surgery) (n lymphomas, 142 patients with benign
= 86)
gastric lesions or suspected pancreatic
diseases.
Sensitivity (lymphoma): 89%
Specificity: 97%
PPV: 87%; NPV: 97%
160
Upper GI Cancer
KCE reports 75
Study ID
Ref
Palazzo 1993
[333]
Fischbach 2002
[200]
Patients with primary
gastric B-cell lymphoma
stage I and II (n = 80)
EUS
Standard: histology (surgery)
Sensitivity to distinguish II1 from I: 59%
Specificity 71%
Fusaroli 2002
[335]
Patients with gastric MALT
lymphoma (n = 54; n = 42,
six months after treatment)
Vorbeck 2002
[202]
Patients with gastric MALT
lymphoma (n = 14)
Inter-observer agreement T-stage: kappa
0.38 before and 0.37 after treatment
Inter-observer agreement N-stage: kappa
0.63 before and 0.34 after treatment
Sensitivity for diagnosis: 93% (specificity Selection of patients??
unknown)
Small study sample
Hoepffner 2003
[203]
Patients with gastric NHL
(n = 44)
EUS
Blinded assessment of
photographs by 9 other
endosonographers
EUS vs. CT
Standard: histology
(endoscopy)
EUS (n = 44) vs. CT (n = 24)
vs. US (n = 34)
Standard: histology (surgery)
Sensitivity for diagnosis: 95% (specificity
unknown)
[201]
Mix of 15 patients, of which
8 had primary gastric NHL
and 7 others served as
control
PET vs. CT or MRI
Standard: endoscopic biopsies
Sensitivity 88%
[336]
Patients with NHL of the GI
tract (n = 24, of which 20
had gastric NHL), selected
out of 189 consecutive
patients
Gallium 67 (n = 24) vs. barium
study (n = 24) vs. CT (n = 16)
Sensitivity for diagnosis: 95% (specificity Not only patients with
unknown)
gastric NHL
Blinding?
Search Population
date
Patients with primary
gastric lymphoma (n = 50)
Intervention
Results
EUS vs. endoscopy
Diagnosis of LN metastasis: sensitivity
Standard: histology (surgery) (n 100%, specificity 80%
= 24)
Comments
Study type
Decision for surgery not
based on EUS
Selection of patients??
Blinding?
10 patients excluded from
statistical analysis,
because EUS was
considered inappropriate
for evaluation of nonregional lymph nodes
Prospective
study
Level of
evidence
Very low
Prospective
study
Low
Prospective
study
Very low
Prospective
study
Very low
CT not performed in all
patients
Selection of patients??
Blinding?
Prospective
study
Very low
Patient selection??
Comparator not applied to
all patients
Prospective
study
Very low
Retrospective
study
Very low
PET scan
Rodriguez 1997
Gallium 67 imaging
Kataoka 1990
KCE Reports 75
Upper GI Cancer
161
Treatment of low-grade (Ie and IIE) MALT lymphoma
Study ID
Ref
Search Population
date
Intervention
Results
Eradication treatment
Exclusive H pylori
eradication
Comments
Study type
Level of
evidence
91% achieved disappearance of the
lymphoma
Prospective
study
Low
Complete regression of lymphoma in 56
patients (62%), minimal residual disease
in 17 patients (18%), partial
remission in 11 patients (12%), no
change in four patients (4%), and
progressive disease in two patients
(2%)
Prospective
study
Low
Event-free survival at follow-up (median
follow-up was 7.5 y) :
Surgery : 52 %
Radiotherapy : 52%
Chemotherapy : 87% ( p<0.01)
Overall survival:
Surgery : 80 %
Radiotherapy : 75%
Chemotherapy : 87% ( p= 0.4)
RCT
High
Level of
evidence
Low
Helicobacter eradication
Montalban 2001
[208]
Fischbach 2004
[207]
Patients with stage I lowgrade gastric MALT
lymphoma
Patients with low grade
gastric MALT lymphoma
Chemotherapy
Aviles 2005
[209]
241 patients with low-grade surgery (80 cases),
MALT lymphoma in early
radiotherapy (78 cases), and
stage (IE and IIE)
chemotherapy (83 cases)
(CHOP)
Treatment of high-grade gastric lymphoma IE and IIE
Study ID
Ref
Haim N 1995
[337]
Takaneka T 1997
[338]
25 patients suffering from
primary gastric lymphomas
(stage II)
Kochi M 2007
[339]
Willich NA 2000
[340]
Search Population
date
26 patients , 15 stage I, 7
stage II, 4 stage IV
Intervention
Results
Comments
Study type
Chemotherapy : CHOP : 18
patients, Pro MACE/MOPP: 8
patients
21 patients treated by total
gastrectomy
4 patients treated by partial
gastrectomy
all received chemotherapy
75% endoscopically-confirmed response
follow up : 22 months : no recurrence
Data support non-surgical
approach
Prospective
study
10 patients suffering from
gastric lymphoma
10 patients treated by
preoperative chemotherapy
and extensive surgery
Disease free survival at 86 months
(range 40 to 102 m) : 100 %
190 patients suffering from
gastric lymphoma
58 patients underwent surgery
83 patients underwent
chemotherapy (CHOP)
Overall survival at follow-up (max 68
months (median : 29) :
was 88% (surgery) and 86%
Disease free survival at 10 years : 81.6
and 92% respectively
After chemotherapy,
microscopic evaluation did
not reveal residual
lymphoma cells
Prospective
study
Low
Prospective
study
Low
Prospective
comparative
study
Low
162
Study ID
Upper GI Cancer
Ref
Search Population
date
Intervention
Results
KCE reports 75
Comments
Study type
Level of
evidence
Prospective
study
Low
Prospective
comparative
study
Low
Treatment decision was Prospective
left to each participating study
centre
Low
(chemotherapy) after 5 years for all
stages and histologies.
Chen LT 2001
[341]
patients suffering from
high-grade gastric
lymphomas (DLBCL)
Binn M 2003
[193]
patients suffering from
localized gastric
lymphomas (DLBCL)
Koch P 2005
[342]
[343]
332
patients
underwent
“conservative
treatment”
(radiotherapy +/-chemotherapy)
61 patients received surgery
and conservative treatment.
Chemotherapy (CHOP) and
radiotherapy (40.5Gy)
Overall survival at 42 months :
For surgery was 86% versus
91.0% for patients without surgery
Ishikura S 2005
393 patients with
aggressive localized PGL
were treated between
December 1996 and
December 2003
52 patients with aggressive
localized PGL
were treated between
December 1999 and
December 2003
Complete remission rate: 48 on 52 (CI
82-98%%)
Overall survival at follow-up (median
follow-up was 2y) : 94%
Prospective
study
Low
Aviles A 2006
[344]
101 patients with high
grade lymphoma
were treated between
December 1999 and
December 2003
52 patients underwent surgery
+chemotherapy (CEOP-Bleo)
49 patients underwent
chemotherapy alone
Total : 101
Overall survival at follow-up (median
follow-up was 5 y) :
Surgery + chemotherapy: 78% (CI 7088%)
Chemotherapy: 76% (CI 70-87%)
P=0.8
RCT
High
16 patients received a brief Eradication of H pylori: 15 patients
antibiotic therapy as first-line Rapid gross tumor regression: 10
treatment
patients
Complete remission rate: 62.5% (CI
35.8% - 89.1%)
Median duration of complete response
was 31.2 months (range, 14.4 to 49.1
months)
58 patients underwent
Overall survival at follow-up (59 months
chemotherapy
(range 3–128) :
48 patients underwent surgery Best prognosis : 90.5%(chemotherapy
+chemotherapy
alone) versus 91.1% (surgery
+chemotherapy) (P = 0.303)
Mild Prognosis : 85.9%(chemotherapy
alone) versus 91.6% (surgery
+chemotherapy) (P = 0.187)
a similar 5-year survival
rate
(>90%) is to be expected
with either surgery plus
chemotherapy or
chemotherapy alone
KCE reports 75
Upper GI Cancer
163
APPENDIX 7
TNM CLASSIFICATION
(source: Digestive System Tumours. In: Sobin LH, Witteking Ch, editors. TNM
Classification of Malignant Tumours. 6th ed. New York: Wiley-Liss; 2002. p. 57-96.)
Oesophageal cancer
PRIMARY TUMOUR (T)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour invades lamina propria or submucosa
T2 Tumour invades muscularis propria
T3 Tumour invades adventitia
T4 Tumour invades adjacent structures
REGIONAL LYMPH NODES (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
DISTANT METASTASIS (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Tumours of the lower thoracic oesophagus:
M1a
Metastasis in celiac lymph nodes
M1b
Other distant metastasis
Tumours of the midthoracic oesophagus:
M1a
Not applicable
M1b
Nonregional lymph nodes and/or other distant metastasis
Tumours of the upper thoracic oesophagus:
M1a
Metastasis in cervical nodes
M1b
Other distant metastasis
STAGE GROUPING
Stage 0
Stage I
Stage IIA
Stage IIB
Stage III
Stage IV
Stage IVA
Stage IVB
Tis
T1
T2
T3
T1
T2
T3
T4
Any T
Any T
Any T
N0
N0
N0
N0
N1
N1
N1
Any N
Any N
Any N
Any N
M0
M0
M0
M0
M0
M0
M0
M0
M1
M1a
M1b
164
Upper GI Cancer
KCE reports 75
Gastric cancer
PRIMARY TUMOUR (T)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ : intraepithelial tumour without invasion of the lamina propria
T1 Tumour invades lamina propria or submucosa
T2 Tumour invades muscularis propria or subserosa
T2a Tumour invades muscularis propria
T2b Tumour invades subserosa
T3 Tumour penetrates serosa (visceral peritoneum) without invasion of adjacent
structures
T4 Tumour invades adjacent structures
REGIONAL LYMPH NODES (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in 1 to 6 regional lymph nodes
N2 Metastasis in 7 to 15 regional lymph nodes
N3 Metastasis in more than 15 regional lymph nodes
DISTANT METASTASIS (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
STAGE GROUPING
Stage 0
Stage IA
Stage IB
Stage II
Stage IIIA
Stage IIIB
Stage IV
Tis
T1
T1
T2a/b
T1
T2a/b
T3
T2a/b
T3
T4
T3
T4
T1-3
Any T
N0
N0
N1
N0
N2
N1
N0
N2
N1
N0
N2
N1-3
N3
Any N
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M1
KCE reports 75
Upper GI Cancer
165
APPENDIX 8
USED MESH AND SEARCH TERMS FOR ADDITIONAL EVIDENCE
SEARCH IN MEDLINE (OVID)
1
Oeophageal cancer:
exp esophageal neoplasms/
2
(esophag$ adj5 neoplas$).tw.
3
(oesophag$ adj5 neoplas$).tw.
4
(esophag$ adj5 cancer$).tw.
5
(oesophag$ adj5 cancer$).tw.
6
(esophag$ adj5 carcin$).tw.
7
(oesophag$ adj5 carcin$).tw.
8
(esophag$ adj5 tumo$).tw.
9
(oesophag$ adj5 tumo$).tw.
10
(esophag$ adj5 metasta$).tw.
11
(oesophag$ adj5 metasta$).tw.
12
(esophag$ adj5 malig$).tw.
13
(oesophag$ adj5 malig$).tw.
14
or/1-13
1
Gastric cancer:
exp stomach neoplasms/
2
(stomach adj5 neoplas$).tw.
3
(stomach adj5 cancer$).tw.
4
(stomach adj5 carcin$).tw.
5
(stomach adj5 tumo$).tw.
6
(stomach adj5 metasta$).tw.
7
(stomach adj5 malig$).tw.
8
(gastric adj5 neoplas$).tw.
9
(gastric adj5 cancer$).tw.
10
(gastric adj5 carcin$).tw.
11
(gastric adj5 tumo$).tw.
12
(gastric adj5 metasta$).tw.
13
(gastric adj5 malig$).tw.
14
or/1-13
166
Upper GI Cancer
Systematic reviews / meta-analyses:
1 meta-analysis.pt,ti,ab,sh.
2 1 or (meta anal$ or metaanal$).ti,ab,sh.
3 (methodol$ or systematic$ or quantitativ$).ti,ab,sh.
4
((methodol$ or systematic$ or quantitativ$) adj (review$ or overview$
or survey$)).ti,ab,sh.
5 (medline or embase or index medicus).ti,ab.
6
((pool$ or combined or combining) adj (data or trials or studies or
results)).ti,ab.
7 3 or 4 or 5 or 6
8 7 and review.pt,sh.
9 2 or 8
1
Randomized controlled trials:
Randomized controlled trials/
2
Randomized controlled trial.pt.
3
Random allocation/
4
Double blind method/
5
Single blind method/
6
Clinical trial.pt.
7
exp clinical trials/
8
or/1-7
9
(clinic$ adj trial$1).tw.
10 ((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw.
11 Placebos/
12 Placebo$.tw.
13 Randomly allocated.tw.
14 (allocated adj2 random).tw.
15 or/9-14
16 8 or 15
17 Case report.tw.
18 Letter.pt.
19 Historical article.pt.
20 Review of reported cases.pt.
21 Review, multicase.pt.
22 or/17-21
23 16 not 22
KCE reports 75
KCE reports 75
1
Chemotherapy:
exp drug therapy/
2
exp chemotherapy adjuvant/
3
exp drug therapy combination/
4
exp antineoplastic agents combined/
5
chemothera$.tw.
6
exp chemotherapy/
7
or/1-6
Upper GI Cancer
Endoscopy:
1 endoscopy/ or endoscopy, digestive system/ or endoscopy, gastrointestinal/
2 Gastroscopy/
3 Esophagoscopy/
4 or/1-3
Staging (e.g. gastric cancer):
1 exp stomach neoplasms/
2 (stomach adj5 neoplas$).tw.
3 (stomach adj5 cancer$).tw.
4 (stomach adj5 carcin$).tw.
5 (stomach adj5 tumo$).tw.
6 (stomach adj5 metasta$).tw.
7 (stomach adj5 malig$).tw.
8 (gastric adj5 neoplas$).tw.
9 (gastric adj5 cancer$).tw.
10 (gastric adj5 carcin$).tw.
11 (gastric adj5 tumo$).tw.
12 (gastric adj5 metasta$).tw.
13 (gastric adj5 malig$).tw.
14 or/1-13
tomography scanners, x-ray computed/ or tomography, x-ray computed/
15 or magnetic resonance imaging/ or positron-emission tomography/ or
tomography, spiral computed/ or tomography/
16 Endosonography/
17 Laparoscopy/
18 Bronchoscopy/
19 Thoracoscopy/
20 Ultrasonography/
21 15 or 16 or 17 or 18 or 19 or 20
22 Neoplasm Staging/
23 "Tumor Markers, Biological"/
24 "Immunoenzyme Techniques"/
25 23 or 24
26 Stomach Neoplasms/an, pa, di, ra, ri, us [Analysis, Pathology, Diagnosis,
167
168
Upper GI Cancer
Radiography, Radionuclide Imaging, Ultrasonography]
27 21 or 22 or 25
28 14 and 27
29 26 or 28
30 Prospective Studies/
31 29 and 30
1
Recurrence (e.g. oesophageal cancer):
Salvage Therapy/
2
neoplasm recurrence, local/ or recurrence/
3
exp esophageal neoplasms/
4
(esophag$ adj5 neoplas$).tw.
5
(oesophag$ adj5 neoplas$).tw.
6
(esophag$ adj5 cancer$).tw.
7
(oesophag$ adj5 cancer$).tw.
8
(esophag$ adj5 carcin$).tw.
9
(oesophag$ adj5 carcin$).tw.
10
(esophag$ adj5 tumo$).tw.
11
(oesophag$ adj5 tumo$).tw.
12
(esophag$ adj5 metasta$).tw.
13
(oesophag$ adj5 metasta$).tw.
14
(esophag$ adj5 malig$).tw.
15
(oesophag$ adj5 malig$).tw.
16
or/3-15
17
1 or 2
18
16 and 17
KCE reports 75
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Dépôt légal : D/2008/10.273/17
KCE reports
1.
2.
3.
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6.
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28.
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31.
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34.
Efficacité et rentabilité des thérapies de sevrage tabagique. D/2004/10.273/2.
Etude relative aux coûts potentiels liés à une éventuelle modification des règles du droit de la
responsabilité médicale (Phase 1). D/2004/10.273/4.
Utilisation des antibiotiques en milieu hospitalier dans le cas de la pyélonéphrite aiguë.
D/2004/10.273/6.
Leucoréduction. Une mesure envisageable dans le cadre de la politique nationale de sécurité des
transfusions sanguines. D/2004/10.273/8.
Evaluation des risques préopératoires. D/2004/10.273/10.
Validation du rapport de la Commission d’examen du sous financement des hôpitaux.
D/2004/10.273/12.
Recommandation nationale relative aux soins prénatals: Une base pour un itinéraire clinique de
suivi de grossesses. D/2004/10.273/14.
Systèmes de financement des médicaments hospitaliers: étude descriptive de certains pays
européens et du Canada. D/2004/10.273/16.
Feedback: évaluation de l'impact et des barrières à l'implémentation – Rapport de recherche:
partie 1. D/2005/10.273/02.
Le coût des prothèses dentaires. D/2005/10.273/04.
Dépistage du cancer du sein. D/2005/10.273/06.
Etude d’une méthode de financement alternative pour le sang et les dérivés sanguins labiles dans
les hôpitaux. D/2005/10.273/08.
Traitement endovasculaire de la sténose carotidienne. D/2005/10.273/10.
Variations des pratiques médicales hospitalières en cas d’infarctus aigu du myocarde en Belgique.
D/2005/10.273/12
Evolution des dépenses de santé. D/2005/10.273/14.
Etude relative aux coûts potentiels liés à une éventuelle modification des règles du droit de la
responsabilité médicale. Phase II : développement d'un modèle actuariel et premières estimations.
D/2005/10.273/16.
Evaluation des montants de référence. D/2005/10.273/18.
Utilisation des itinéraires cliniques et guides de bonne pratique afin de déterminer de manière
prospective les honoraires des médecins hospitaliers: plus facile à dire qu'à faire..
D/2005/10.273/20
Evaluation de l'impact d'une contribution personnelle forfaitaire sur le recours au service
d'urgences. D/2005/10.273/22.
HTA Diagnostic Moléculaire en Belgique. D/2005/10.273/24, D/2005/10.273/26.
HTA Matériel de Stomie en Belgique. D/2005/10.273.28.
HTA Tomographie par Emission de Positrons en Belgique. D/2005/10.273/30.
HTA Le traitement électif endovasculaire de l’anévrysme de l’aorte abdominale (AAA).
D/2005/10.273.33.
L'emploi des peptides natriurétiques dans l'approche diagnostique des patients présentant une
suspicion de décompensation cardiaque. D/2005/10.273.35
Endoscopie par capsule. D2006/10.273.02.
Aspects médico-légaux des recommandations de bonne pratique médicale. D2006/10.273/06.
Qualité et organisation des soins du diabète de type 2. D2006/10.273/08.
Recommandations provisoires pour les évaluations pharmacoéconomiques en Belgique.
D2006/10.273/11.
Recommandations nationales Collège d’oncologie : A. cadre général pour un manuel d’oncologie
B. base scientifique pour itinéraires cliniques de diagnostic et traitement, cancer colorectal et
cancer du testicule. D2006/10.273/13.
Inventaire des bases de données de soins de santé. D2006/10.273/15.
Health Technology Assessment : l’antigène prostatique spécifique (PSA) dans le dépistage du
cancer de la prostate. D2006/10.273/18.
Feedback: évaluation de l'impact et des barrières à l'implémentation - Rapport de recherche:
partie II. D2006/10.273/20.
Effets et coûts de la vaccination des enfants Belges au moyen du vaccin conjugué
antipneumococcique. D2006/10.273/22.
Trastuzumab pour les stades précoces du cancer du sein. D2006/10.273/24.
35. Etude relative aux coûts potentiels liés à une éventuelle modification des règles du droit de la
responsabilité médicale – Phase III : affinement des estimations. D2006/10.273/27.
36. Traitement pharmacologique et chirurgical de l'obésité. Prise en charge résidentielle des enfants
sévèrement obèses en Belgique. D/2006/10.273/29.
37. Health Technology Assessment Imagerie par Résonance Magnétique. D/2006/10.273/33.
38. Dépistage du cancer du col de l’utérus et recherche du Papillomavirus humain (HPV).
D/2006/10.273/36
39. Evaluation rapide de technologies émergentes s'appliquant à la colonne vertébrale : remplacement
de disque intervertébral et vertébro/cyphoplastie par ballonnet. D/2006/10.273/39.
40. Etat fonctionnel du patient: un instrument potentiel pour le remboursement de la kinésithérapie
en Belgique? D/2006/10.273/41.
41. Indicateurs de qualité cliniques. D/2006/10.273/44.
42. Etude des disparités de la chirurgie élective en Belgique. D/2006/10.273/46.
43. Mise à jour de recommandations de bonne pratique existantes. D/2006/10.273/49.
44. Procédure d'évaluation des dispositifs médicaux émergeants. D/2006/10.273/51.
45. HTA Dépistage du Cancer Colorectal : état des lieux scientifique et impact budgétaire pour la
Belgique. D/2006/10.273/54.
46. Health Technology Assessment. Polysomnographie et monitoring à domicile des nourrissons en
prévention de la mort subite. D/2006/10.273/60.
47. L'utilisation des médicaments dans les maisons de repos et les maisons de repos et de soins
Belges. D/2006/10.273/62
48. Lombalgie chronique. D/2006/10.273/64.
49. Médicaments antiviraux en cas de grippe saisonnière et pandémique. Revue de littérature et
recommandations de bonne pratique. D/2006/10.273/66.
50. Contributions personnelles en matière de soins de santé en Belgique. L'impact des suppléments.
D/2006/10.273/69.
51. Besoin de soins chroniques des personnes âgées de 18 à 65 ans et atteintes de lésions cérébrales
acquises. D/2007/10.273/02.
52. Rapid Assessment: Prévention cardiovasculaire primaire dans la pratique du médecin généraliste
en Belgique. D/2007/10.273/04.
53. Financement des soins Infirmiers Hospitaliers. D/2007/10 273/06
54. Vaccination des nourrissons contre le rotavirus en Belgique. Analyse coût-efficacité
55. Valeur en termes de données probantes des informations écrites de l’industrie pharmaceutique
destinées aux médecins généralistes. D/2007/10.273/13
56. Matériel orthopédique en Belgique: Health Technology Assessment. D/2007/10.273/15.
57. Organisation et Financement de la Réadaptation Locomotrice et Neurologique en Belgique
D/2007/10.273/19
58. Le Défibrillateur Cardiaque Implantable.: un rapport d’évaluation de technologie de santé
D/2007/10.273/22
59. Analyse de biologie clinique en médecine général. D/2007/10.273/25
60. Tests de la fonction pulmonaire chez l'adulte. D/2007/10.273/28
61. Traitement de plaies par pression négative: une évaluation rapide. D/2007/10.273/31
62. Radiothérapie Conformationelle avec Modulation d’intensité (IMRT). D/2007/10.273/33.
63. Support scientifique du Collège d’Oncologie: un guideline pour la prise en charge du cancer du
sein. D/2007/10.273/36.
64. Vaccination HPV pour la prévention du cancer du col de l’utérus en Belgique: Health Technology
Assessment. D/2007/10.273/42.
65. Organisation et financement du diagnostic génétique en Belgique. D/2007/10.273/45.
66. Drug Eluting Stents en Belgique: Health Technology Assessment. D/2007/10.273/48.
67. Hadronthérapie. D/2007/10.273/51.
68. Indemnisation des dommages résultant de soins de santé - Phase IV : Clé de répartition entre le
Fonds et les assureurs. D/2007/10.273/53.
69. Assurance de Qualité pour le cancer du rectum – Phase 1: Recommandation de bonne pratique
pour la prise en charge du cancer rectal D/2007/10.273/55
70. Etude comparative des programmes d’accréditation hospitalière en Europe. D/2008/10.273/02
71. Recommandation de bonne pratique clinique pour cinq tests ophtalmiques. D/2008/10.273/05
72. L’offre de médecins en Belgique. Situation actuelle et défis. D/2008/10.273/08
73. Financement du programme de soins pour le patient gériatrique dans l’hôpital
classique : Définition et évaluation du patient gériatrique, fonction de liaison et évaluation d’un
instrument pour un financement approprié. D/2008/10.273/12
74. Oxygénothérapie Hyperbare: Rapid Assessment. D/2008/10.273/14.
75. Guideline pour la prise en charge du cancer oesophagien et gastrique : éléments scientifiques à
destination du Collège d’Oncologie D/2008/10.273/17