Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach,gastroesophageal junction, and lower esophagus (Review)

7/27/2019 Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach,gastroe

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Perioperative chemo(radio)therapy versus primary surgery

for resectable adenocarcinoma of the stomach,

gastroesophageal junction, and lower esophagus (Review)

Ronellenfitsch U, Schwarzbach M, Hofheinz R, Kienle P, Kieser M, Slanger TE, Jensen K, GE

Adenocarcinoma Meta-analysis Group

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2013, Issue 5

http://www.thecochranelibrary.com

Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach, gastroesophageal junction,

and lower esophagus (Review)

Copyright 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/


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T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 5BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Figure 7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Figure 8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Figure 9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24Figure 10. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

Figure 11. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Figure 12. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Figure 13. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

28ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .

31DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

34REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

55DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Overall survival, Outcome 1 Hazard ratio plot for overall survival. . . . . . . . . 58

Analysis 1.2. Comparison 1 Overall survival, Outcome 2 Hazard ratio plot for overall survival by type of data. . . . 59Analysis 1.3. Comparison 1 Overall survival, Outcome 3 Hazard ratio plot for overall survival by tumor site. . . . 60

Analysis 1.4. Comparison 1 Overall survival, Outcome 4 Interaction treatment-tumor site (only IPD). . . . . . 61

Analysis 1.5. Comparison 1 Overall survival, Outcome 5 Hazard ratio plot for overall survival by chemo-/radiotherapy. 62

Analysis 1.6. Comparison 1 Overall survival, Outcome 6 Hazard ratio plot for overall survival by timing of regimen. 63

Analysis 1.7. Comparison 1 Overall survival, Outcome 7 Hazard ratio plot for overall survival by chemotherapeutic

agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Analysis 1.8. Comparison 1 Overall survival, Outcome 8 Hazard ratio plot for overall survival by performance status (only

IPD). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Analysis 1.9. Comparison 1 Overall survival, Outcome 9 Interaction treatment-performance status (only IPD). . . 66

Analysis 1.10. Comparison 1 Overall survival, Outcome 10 Hazard ratio plot for overall survival by age (only IPD). . 67

Analysis 1.11. Comparison 1 Overall survival, Outcome 11 Interaction treatment-age (only IPD). . . . . . . . 68

Analysis 1.12. Comparison 1 Overall survival, Outcome 12 Hazard ratio plot for overall survival by sex (only IPD). . 69

Analysis 1.13. Comparison 1 Overall survival, Outcome 13 Interaction treatment-sex (only IPD). . . . . . . . 70Analysis 1.14. Comparison 1 Overall survival, Outcome 14 Hazard ratio plot for overall survival by pretreatment T class

(only IPD). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Analysis 1.15. Comparison 1 Overall survival, Outcome 15 Interaction treatment-T class (only IPD). . . . . . 71

Analysis 1.16. Comparison 1 Overall survival, Outcome 16 Hazard ratio plot for overall survival by pretreatment N class

(only IPD). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Analysis 1.17. Comparison 1 Overall survival, Outcome 17 Interaction treatment-N class (only IPD). . . . . . 73

Analysis 2.1. Comparison 2 Disease-free survival (landmark time 6 months), Outcome 1 Hazard ratio plot for disease-free

survival (landmark time 6 months). . . . . . . . . . . . . . . . . . . . . . . . . . . 74

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Analysis 3.1. Comparison 3 Presence of tumor-free resection margin, Outcome 1 Odds ratio plot for tumor-free resection

margin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Analysis 4.1. Comparison 4 Tumor stage at resection, Outcome 1 Odds ratio plot for tumor stage T0/T1/T2. . . . 76

Analysis 4.2. Comparison 4 Tumor stage at resection, Outcome 2 Odds ratio plot for nodal status N0. . . . . . 77

Analysis 6.1. Comparison 6 Postoperative morbidity, Outcome 1 Risk difference plot for postoperative morbidity. . 79

Analysis 7.1. Comparison 7 Postoperative mortality, Outcome 1 Risk difference plot for postoperative mortality. . . 8080ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

82APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

84CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

84DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

84SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

85DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

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[Intervention Review]

Perioperative chemo(radio)therapy versus primary surgeryfor resectable adenocarcinoma of the stomach,

gastroesophageal junction, and lower esophagus

Ulrich Ronellenfitsch1, Matthias Schwarzbach2, Ralf Hofheinz3, Peter Kienle1, Meinhard Kieser4, Tracy E Slanger5, Katrin Jensen4,

GE Adenocarcinoma Meta-analysis Group6

1Department of Surgery, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany. 2Department

of Surgery, Klinikum Frankfurt Hoechst, Frankfurt am Main, Germany. 3Day Treatment Center, Interdisciplinary Tumor Center

Mannheim and III Medical Clinic, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany. 4Institute

of Medical Biometry and Informatics, University Hospital Heidelberg, Heidelberg, Germany. 5Institute for Quality and Efficiency in

Health Care (IQWiG), Cologne, Germany. 6See Contributions of Authors, Germany

Contact address: Ulrich Ronellenfitsch, Department of Surgery, University Medical Centre Mannheim, University of Heidelberg,

Theodor-Kutzer-Ufer 1-3, Mannheim, 68167 Mannheim, Germany. [email protected].

Editorial group: Cochrane Upper Gastrointestinal and Pancreatic Diseases Group.

Publication status and date: New, published in Issue 5, 2013.

Review content assessed as up-to-date: 29 November 2011.

Citation: Ronellenfitsch U, Schwarzbach M, Hofheinz R, Kienle P, Kieser M, Slanger TE, Jensen K, GE Adenocarcinoma Meta-

analysis Group. Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach, gastroe-

sophageal junction, and lower esophagus. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD008107. DOI:

10.1002/14651858.CD008107.pub2.


A B S T R A C T

Background

The outcome of patients with locally advanced gastroesophageal adenocarcinoma (adenocarcinoma of the esophagus, gastroesophageal

(GE) junction, and stomach) is poor. There is conflicting evidence regarding the effects of perioperative chemotherapy on survival and

other outcomes.

Objectives

To assess the effect of perioperative chemotherapy for gastroesophageal adenocarcinoma on survival and other clinically relevant

outcomes in the overall population of participants in randomized controlled trials (RCTs) and in prespecified subgroups.

Search methods

We performed computerized searches in the Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts ofReview of Effectiveness (DARE), the Cochrane Database of Systematic Reviews (CDSR) from The Cochrane Library, MEDLINE

(1966 to May 2011), EMBASE (1980 to May 2011), and LILACS (Literatura Latinoamericana y del Caribe en Ciencias de la Salud),

combining the Cochrane highly sensitive search strategy with specific search terms. Moreover, we handsearched several online databases,

conference proceedings, and reference lists of retrieved papers.

Selection criteria

We included RCTs which randomized patients with gastroesophageal adenocarcinoma, in the absence of distant metastases, to receive

either chemotherapy with or without radiotherapy followed by surgery, or surgery alone.

1Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach, gastroesophageal junction,


mailto:[email protected]:[email protected]


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Data collection and analysis

Two independent review authors identifiedeligible trials. We solicited individual patient data(IPD) fromall selected trials. We performed

meta-analyses based on intention-to-treat populations using the two-stage method to combine IPD with aggregate data from RCTs for

which IPD were unavailable. We combined data from all trials providing IPD in a Cox proportional hazards model to assess the effect

of several covariables on overall survival.

Main results

Weidentified 14 RCTs with 2422 eligible patients. For eight RCTs with 1049 patients (43.3%), we were able to obtain IPD. Perioperative

chemotherapy was associated with significantly longer overall survival (hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.73

to 0.89). This corresponds to a relative survival increase of 19% or an absolute survival increase of 9% at five years. This survival

advantage was consistent across most subgroups. There was a trend towards a more pronounced treatment effect for tumors of the GE

junction compared to other sites, and for combined chemoradiotherapy as compared to chemotherapy in tumors of the esophagus

and GE junction. Resection with negative margins was a strong predictor of survival. Multivariable analysis showed that tumor site,

performance status, and age have an independent significant effect on survival. Moreover, there was a significant interaction of the

effect of perioperative chemotherapy with age (larger treatment effect in younger patients). Perioperative chemotherapy also showed a

significant effect on several secondary outcomes. It was associated with longer disease-free survival, higher rates of R0 resection, and

more favorable tumor stage upon resection, while there was no association with perioperative morbidity and mortality.

Authors conclusionsPerioperative chemotherapy for resectable gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should

thus be offered to all eligible patients. There is a trend to a larger survival advantage for tumors of the GE junction as compared to

other sites and for chemoradiotherapy as compared to chemotherapy in esophageal and GE junction tumors. Likewise, there is an

interaction between age and treatment effect, with younger patients having a larger survival advantage, and no survival advantage for

elderly patients.

P L A I N L A N G U A G E S U M M A R Y

Chemotherapy before surgery in patients with adenocarcinoma of the esophagus, the gastroesophageal junction, and the

stomach

This systematic review uses the data of individual patients from eight and published data from another six randomized controlledtrials. We found that the administration of chemotherapy before surgery leads to longer survival in patients with adenocarcinoma of

the esophagus, the junction between esophagus and stomach, and the stomach. The findings suggest that patients whose tumor is in

the junction between esophagus and stomach and younger patients benefit most from the chemotherapy. Moreover, the addition of

radiation to the chemotherapy seems to yield an additional advantage to patients, at least in tumors of the esophagus and the junction

between esophagus and stomach. Chemotherapy before surgery does not increase the risk of suffering a complication during or after

surgery.





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SU

M

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A

RY

OF

FIN

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IN

G

S

FO

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PA

RISO

N

[Explanation]

Perioperativechemothera

pycomparedtoprimarysurgeryforresec

tableadenocarcinomaofthestomach,gastroesophagealjunction,andloweresophagus

Patientorpopulation:rese

ctableadenocarcinomaofthestomach,

gastroesophagealjunction,

andloweresophag

us

Settings:

Intervention:perioperative

chemotherapy

Comparison:primarysurgery

Outcomes

Illustrativecomparativerisks*(95%

CI)

Relativeeffect

(95%

CI)

Noof

participants

(studies)

Qualityoftheevidenc

e

(GRADE)

Comments

Assumedrisk

Correspondingrisk

Primarysurgery

Perioperative

chemo-

therapy

Overallsurvivalamong

allpatients

Moderate

HR0.8

1

(0.7

3to0.8

9)

2422

(14studies)

high

Disease-free

survival(landmarktime

6months)

Moderate

HR0.8

4

(0.6

9to1.0

1)

931

(7stu

dies)

high

Overallsurvivalbytype

ofdata-Individualpa-

tientdata

Moderate

HR0.8

0

(0.6

6to0.9

7)

1049

(8stu

dies)

high

Overallsurvivalbytype

of

data

-

Aggregated

data

Moderate

HR0.8

1

(0.7

2to0.9

2)

1373

(6stu

dies)

moderate1

Overallsurvivalby

tu-

morsite-Esophagus

Moderate

HR0.8

7

(0.7

3to1.0

5)

473

(5stu

dies)

high

Overallsurvivalby

tu-

morsite-GEjunction

Moderate

HR0.6

9

(0.5

4to0.8

7)

470

(6stu

dies)

high



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Overallsurvivalby

tu-

morsite-Stomach

Moderate

HR0.9

4

(0.8

2to1.0

6)

828

(7stu

dies)

high

*Thebasisfortheassumedrisk(e.g.

themediancontrolgrouprisk

acrossstudies)isprovidedinfootnotes.T

hecorrespondingrisk(andits95%

confid

enceinterval)isbasedonthe

assumedriskinthecompa

risongroupandtherelativeeffectoftheintervention(andits95%CI).

CI:confidenceinterval;GE:gastroesophageal;HR:hazardratio

GRADEWorkingGroupgra

desofevidence

Highquality:Furtherresea

rchisveryunlikelytochangeourconfidenc

eintheestimateofeffect.

Moderatequality:Furtherresearchislikelytohaveanimportantimpactonourconfidenceintheestimateofeffec

tandmaychangetheestimate.

Lowquality:Furtherresearchisverylikelytohaveanimportantimpac

tonourconfidenceintheestimateofeffect

andislikelytochangetheestimate.

Verylowquality:Wearev

eryuncertainabouttheestimate.

1Fouroutofthesixstudiesincludedinthisanalysishaveahighoverall

riskofbias.





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B A C K G R O U N D

Description of the condition

The epidemiology of adenocarcinoma of the stomach, gastroe-

sophageal (GE) junction, and esophagus (gastroesophageal ade-nocarcinoma) has changed in recent years. Incidence and mor-

tality figures for cancers of the distal stomach have decreased in

most countries whereas corresponding figures for adenocarcinoma

of the esophagus and gastroesophageal junction have risen (Ferlay

2010; Vial 2010). Combined, gastroesophageal adenocarcinoma

ranks among the most common cancers worldwide with an esti-

mated toll of approximately1,000,000 deathsper year (DeMeester

2006; Ferlay 2010; Forman 2006; Gallo 2006).

Although differences in risk factors, gene expression, and tumor

biology exist between adenocarcinoma of the stomach, gastroe-

sophageal junction, and esophagus (Marsman 2005; Shah 2011),

they are often regarded as oneentity and conveniently treated alike

in metastatic or non-resectable stages. In fact, an analysis on a largenumber of patients showed that the degree of efficacy of chemo-

therapy does not differ for tumors of different origin in this set-

ting (Chau 2009). Radical surgery is the only curative treatment

modalityfor gastroesophageal adenocarcinoma.Depending on the

exact tumor localization, distal or total gastrectomy, or esophagec-

tomy with radical lymph node dissection, needs to be performed

(Marsman 2005). Despite the fact that surgical techniques and

perioperative management have substantially improved over the

last decades (DeMeester 2006; Gallo 2006), five-year survival af-

ter curatively intended resection is only 20% to 30% for patients

with locally advanced disease (Hagen 2001; Siewert 1998).

Description of the intervention

Until recently, the standard treatment for gastroesophageal adeno-

carcinoma has been primary surgery; i.e. resection without prior

tumor-specific therapy. In lightof poorsurvival rates(Hagen 2001;

Siewert 1998), there has been a strong rationale to design new

treatment modalities in order to achieve better outcomes for pa-

tients with non-metastatic tumors, especially for those with lo-

cally advanced disease at diagnosis. Perioperative chemotherapy,

defined as chemotherapy before and, optionally, after surgery, is

oneapproach aiming to increaseoverall and disease-freesurvival of

patients. Based on promising results from phase II studies (Ajani

1995; Kelsen 1996; Ott 2003) it has been tested in several ran-domized controlled trials.

How the intervention might work

There are several proposed mechanisms forhow perioperative che-

motherapy might improve outcomes. A higher likelihood of tu-

mor-free resection margins due to preoperative down-staging of

the tumor, the elimination of micrometastases before and directly

after surgery, and the rapid preoperative improvement of tumor-

related symptoms which leads to better tolerability of the upcom-

ing large surgical intervention might all contribute to higher over-

all and disease-free survival (Eguchi 2008; MAGIC 2006). One

concern when administering perioperative chemotherapy is thepotentially higherlevel of treatment-related morbidity and mortal-

ity due to cytotoxic effects, which might be particularly hazardous

during and directly after surgical procedures. Most phase II tri-

als have shown that the applied chemotherapeutic regimens have

acceptable morbidity and mortality (Ajani 1995; Kelsen 1996),

but there have been reports of substantial adverse effects of certain

regimens of cytotoxic drugs (Ajani 1993).

Why it is important to do this review

The evidence regarding the effect of perioperative chemother-

apy on survival of patients with gastroesophageal adenocarci-

noma is conflicting, with inconclusive results reported from tri-als (ACCORD 07 2011; CALGB 9781 2008; EORTC 40954

2010; FAMTX 2004; Feng 2008; Kobayashi2000; MAGIC 2006;

OE02 2009; RTOG 8911 2007; TROG-AGITG 2005; Urba

2001; Walsh 2002; Wang 2000; Zhao 2006). Several recent sys-

tematic reviews aimed to summarize the available evidence.

A prior Cochrane Review, published in 2007, assessed perioper-

ative chemotherapy for gastric adenocarcinoma by performing a

meta-analysis (Wu 2007). The authors did not find significant

differences in survival between patients treated with perioperative

chemotherapy and those directly operated. However, the review

excluded studies in which patients had received additional postop-

erative chemotherapyand studies comprising patients with adeno-

carcinoma of the esophagus. Thus, the number of included trialswas limited to only four. Furthermore, after the authors carried out

their literature search in mid-2005, the results of three large ran-

domized controlled trials (RCTs) (ACCORD 07 2011; EORTC

40954 2010; MAGIC 2006), of which two showed significant

survival benefits for perioperative chemotherapy, have been pub-

lished. The review has meanwhile been withdrawn for method-

ological reasons.

A meta-analysis published in 2004 included trials and previous

meta-analyses on patients with thoracic esophageal carcinoma of

both histologies. It compared various neoadjuvant and adjuvant

modalities, amongst which were perioperative chemotherapy and

chemoradiotherapy, and found no survival advantage for perioper-

ative chemotherapy alone and for perioperative chemoradiother-

apyat oneand two years postoperatively. A modest survival benefit

for perioperative chemoradiotherapy was foundat three yearspost-

operatively. However, no subgroup analyses for the different his-

tologies were conducted (Malthaner 2004). A Cochrane Review,

which was updated in 2006, included 11 RCTs comparing periop-

erative chemotherapywith surgery alone for esophageal carcinoma

of any histology. The authors concluded that the results suggested





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that perioperative chemotherapymay prolong survival, but judged

the evidence to be inconclusive. Like the previous review, no sub-

group analyses according to histological subtype were conducted

(Vogt 2006). Another systematic review with meta-analysis, rely-

ing on individual patient data (IPD) from trials including patients

with carcinoma of the esophagus and gastroesophageal junction,was published as an abstract only (Thirion 2007). The authors re-

ported a modest but significant benefit in terms of overall survival

for perioperative chemotherapy. A subgroup analysis showed that

this benefit was independent of histological subtype, and signifi-

cant also in the subgroup of patients with adenocarcinoma, which

comprised 46% of all included patients. The same group con-

ducted an IPD meta-analysis comparing perioperative chemora-

diotherapy with surgery alone for esophageal carcinoma. Results

were published as an abstract only (Thirion 2008). A survival ben-

efit for chemoradiotherapy was found independently of histolog-

ical subtype, but patients with adenocarcinoma constituted only

33% of the trial populations.

Lastly, a recently published update of a systematic review withmeta-analysis included RCTs comparing both perioperative che-

motherapy and chemoradiotherapy with primary surgery in pa-

tients with esophageal cancer of both histologies (Sjoquist 2011).

The analysis did not include patients with gastric adenocarci-

noma. It showed a significant survival benefit for both periopera-

tive modalities and in both histological subtypes with the excep-

tion of perioperative chemotherapy for squamous cell carcinoma,

where the effect did not reach statistical significance.

None of the cited analyses included data for allthree tumor sites of

gastroesophageal adenocarcinoma(esophagus, GE junction,stom-

ach). Moreover, none of the analyses, mostly due to non-availabil-

ity of IPD, were able to sufficiently assess in subgroup and mul-

tivariable analyses the extent to which certain covariables such aspatient and tumor characteristics might alter the treatment effect

of perioperative chemotherapy.

Therefore, we performed a new systematic comparison of peri-

operative chemotherapy with surgery alone for patients with lo-

coregionally advanced resectable adenocarcinoma of the stomach,

GE junction, and esophagus, including all three tumor sites and

relying on IPD.

O B J E C T I V E S

The primary objective of this systematic review was to assess if pe-

rioperative chemotherapy leads to a longer overall survival as com-

pared to surgery without prior tumor-specific therapy in patients

with locoregionally advanced resectable adenocarcinoma of the

stomach, GE junction, and esophagus. Secondary objectives are

to compare disease-free survival, resectability, tumor stage upon

resection, perioperative morbidity, and mortality, and to assess the

safety and toxicity of perioperative chemotherapyas well as reasons

for possible non-administration of the postoperatively planned cy-

cles of chemotherapy where foreseen in the study protocol.

M E T H O D S

Criteria for considering studies for this review

Types of studies

The review included only RCTs. Due to the specific intervention

under study, blinding and placebo treatment are technically and/

or ethically difficult because the unavoidable delay of surgery in a

studyarm wheresubjects receive a neoadjuvant placebo treatment

would indubitably lead to a significant worsening of their survival.

Therefore, we did not consider blinding and placebo treatment ascriteria for inclusion or exclusion.

Types of participants

To be included in the review, trials needed to be conducted on

patients fulfilling the following criteria:

histologically confirmed adenocarcinoma of the stomach,

GE junction, or esophagus; for studies which include patients

with both adenocarcinoma and other histological entities like

squamous cell carcinoma, we sought to obtain IPD or aggregate

measures (see below) relating to patients with adenocarcinoma

only;

previously untreated; locoregionally advanced (UICC stage Ib and higher for

adenocarcinoma of the stomach, UICC stage II for

adenocarcinoma of the esophagus (Sobin 2002));

resectable based on staging exams;

absence of distant or peritoneal metastases.

Types of interventions

The experimental intervention in the context of this systematic re-

view was definedas surgerywith curative intentioncombined with

perioperative chemotherapy, defined as a treatment regimen with

any kind of cytotoxic/antineoplastic drug or a combination of sev-

eral of these drugs. To be regarded as perioperative, chemotherapy

needed to be administered in a neoadjuvant (preoperative) setting

and, optionally, in an additional adjuvant (postoperative) manner.

We also included studies if patients received pre- or postoperative

radiotherapy in addition to perioperative chemotherapy. We de-

fined the control intervention as surgery with curative intention

without any prior tumor-specific therapy, and included patients

undergoing any surgery with curative intention.





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Types of outcome measures

Primary outcomes

The primary outcome was time to death measured in days from

the date of randomization, based on an intention-to-treat analysis.If censored time-to-event data or adequate summary measures of

time-to-event data were not available from the single trials, we

used the vital status (alive or deceased) at the end of follow-up.

Secondary outcomes

Secondary outcomes were:

disease-free survival time, defined as the time from a

landmark six months after randomization until recurrence

(local or distant) or death of any cause (the landmark method

accounts for the difference in the timing of surgery between the

two treatment groups, for details see Data synthesis);

presence of a tumor-free resection margin, as assessed fromthe surgical specimen by a pathologist (dichotomous outcome

yes/no);

tumor stage at resection, as assessed from the surgical

specimen according to the version of the UICCs TNM (T0-4,

N0-3, M0-1) classification (Sobin 2002) provided in the

respective trials IPD or aggregate data;

safety of the perioperative chemotherapy regimen measured

by toxicity according to the version of the National Cancer

Institute Common Terminology Criteria for Adverse Events

(CTCAE) provided in the respective trials IPD or aggregate data;

perioperative morbidity (measured by assessing how many

of the following events occurred: anastomotic leakage,

postoperative pneumonia, postoperative wound infection), andmortality (measured by assessing if a patient died during surgery

or the consecutive hospital stay);

the frequency and reason(s) for possible non-administration

of the postoperatively planned cycles of chemotherapy where

foreseen in the study protocol (for the perioperative

chemotherapy arms).

Search methods for identification of studies

Electronic searches

In September 2008,we performed a computerized literature search

in:

the Cochrane Central Register of Controlled Trials

(CENTRAL), Database of Abstracts of Review of Effectiveness

(DARE), the Cochrane Database of Systematic Reviews (CDSR)

from The Cochrane Library(3rd Quarter 2008); MEDLINE (1950 to 2008 Sept week 2) (Appendix 1);

EMBASE (1980 to week 38, 2008); and

LILACS (Literatura Latinoamericana y del Caribe en

Ciencias de la Salud) (up to September 2008).

We limited our search to studies in humans. There were no lan-

guage restrictions for either searching or trial inclusion. We com-

bined the Cochrane highly sensitive search strategy for identifying

randomized trials in MEDLINE, sensitivity-maximizing version,Ovid format (Higgins 2011) with specific search terms to identify

randomized controlled trials in MEDLINE (see Appendix 1).

We adapted the MEDLINE search strategy for use in the other

databases searched. Moreover, we searched the following online

databases of ongoing trials:

www.clinicaltrials.gov;

www.centerwatch.com;

www.cancer.gov/clinicaltrials;

www.trialscentral.org;

www.calgb.org;

www.controlled-trials.com;

www.eortc.be;

www.swog.org/Visitors/ClinicalTrials.asp; www.ctg.queensu.ca.

We extended our search using EMBASE, Ovid MEDLINE, and

EBM Reviews - Cochrane Central Register of ControlledTrials for

studies publisheduntil31 May2011, which wasthe date when our

database was closed for analysis (see Dealing with missing data).

Searching other resources

We handsearched the abstracts from 1995 to 2008 of the Amer-

ican Digestive Disease Week (DDW) published in Gastroenterol-

ogy, the United European Gastroenterology Week (UEGW) pub-

lished in Gutand the Annual Meetings of the American Society

of Clinical Oncology (ASCO) published in the Journal of Clin-ical Oncology. We scanned reference lists of retrieved articles to

identify further relevant trials. We contacted experts in the field

about any unpublished or ongoing studies. We asked the authors

of trial reports published only as abstracts or of ongoing studies to

contribute IPD or completed papers.

Data collection and analysis

Selection of studies

Two independent review authors (UR, TS) extracted the data.

They assessed title, keywords, and abstracts of all studies retrieved

with the search strategy described above. If, based on this infor-

mation, the authors believed studies met the defined inclusion cri-

teria, they retrieved and further assessed the full text and made a

final decision on whether to include a trial. Arbitration of a third

author, which was foreseen in cases where one author believed a

specific trial met the inclusion criteria for the review whereas the

other author did not, was not required.



http://www.clinicaltrials.gov/http://www.centerwatch.com/http://www.cancer.gov/clinicaltrials/http://www.trialscentral.org/http://www.calgb.org/http://www.controlled-trials.com/http://www.eortc.be/http://www.swog.org/Visitors/ClinicalTrials.asphttp://www.ctg.queensu.ca/http://www.ctg.queensu.ca/http://www.swog.org/Visitors/ClinicalTrials.asphttp://www.swog.org/Visitors/ClinicalTrials.asphttp://www.swog.org/Visitors/ClinicalTrials.asphttp://www.eortc.be/http://www.controlled-trials.com/http://www.controlled-trials.com/http://www.calgb.org/http://www.trialscentral.org/http://www.cancer.gov/clinicaltrials/http://www.cancer.gov/clinicaltrials/http://www.centerwatch.com/http://www.clinicaltrials.gov/


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Data extraction and management

The review authors used a standardized data extraction form to

compile and document relevant facts on general trial characteris-

tics, trial quality, patients characteristics, interventions, and out-

comes as specified above. This data extraction was performed in-

dependently. The data extraction form compiled the followingitems.

General information on the trial: title, authors, contact

address, funding sources, language, publication status, year of

publication, place(s), and year(s) of trial conduction.

Trial design issues: inclusion and exclusion criteria,

randomization/quasi-randomization, concealment of treatment

allocation (adequate/unclear/inadequate/not used), length of

trial/follow-up period.

Baseline characteristics of participants: size of intervention

and comparison group and for each group the distribution of

age, sex, comorbidity (measured, if given as World Health

Organization (WHO) performance status or American Society

of Anesthesiologists (ASA) classification), tumor location(esophagus, gastroesophageal junction, stomach), and tumor

stage (TNM and UICC stage).

Characteristics of the intervention: used chemotherapeutic/

antineoplastic drugs, regimens (frequency of chemotherapy,

timing in relation to the date of surgery, application mode,

cumulative dose of chemotherapy planned and administered

both pre- and postoperatively).

Frequency of different types of surgery (approach, extent)

performed in the intervention and control groups.

Loss to follow-up in each group.

Outcomes in each group: hazard ratios (HRs) and

confidence intervals (CIs) both for overall and, if available,

disease-free survival; number of events (death, disease recurrence)if HRs are not given; number of resections with tumor-free

margins; tumor stage at resection (TNM and UICC stage);

toxicity according to CTCAE (number of grade 3/4 adverse

events); hospital mortality; morbidity as the number of the

following events combined: anastomotic leakage, postoperative

pneumonia, postoperative wound infection.

We pilot tested the data extraction form on five retrieved studies

and slightly revised it. Two authors (UR, TS) performed data ex-

traction independently. Consultation of a third author for arbi-

tration, which was foreseen for cases where no consensus could be

reached, was not required.

Individual patient data (IPD)

Data requests

For each trial, we requested IPD from the respective trialists. The

solicited variables were as follows:

age at randomization

sex

histological type

allocated treatment arm (intervention/control)

date of randomization

comorbidity (WHO/ECOG performance status)

site of tumor (esophagus/GE junction/stomach) pretreatment tumor stage (TNM T stage)

pretreatment nodal stage (TNM N stage)

chemotherapy regimen received (protocol, alternative,

none)

date of surgery

surgical approach

extent of resection

reasons no surgery undertaken

postoperative death

non-fatal postoperative complications (type)

toxicity of preoperative treatment (type, grade)

tumor stage at resection (TNM yT stage)

nodal status at resection (TNM yN stage) date of death or last visit

vital status

cause of death

date of first recurrence

date of progression

nature of first failure (recurrence)

lost to follow up (yes/no)

We requested data for all randomized patients in the trial (inten-

tion-to-treat population). We solicited trialists to provide the most

complete and updated follow-up data which were available, even

if the follow-up was longer than that used for the pertinent pub-

lication. We entered data in a dedicated database.

Quality control

We assessed the quality of the submitted IPD from the single trials

in several ways.

We compared the number of individual patient data sets

with the intention-to-treat population reported in publications.

We screened data sets for obvious duplicates or omissions (e.g. by

checking patient IDs).

We checked plausibility of the values supplied for each

variable by looking for extreme outliers.

We compared summary measures calculated from the data

set with data reported in publications.

We derived overall survival and disease-free-survival of the

different treatment groups in each trial using the Kaplan-Meier

method and standard Cox regression analysis and compared with

published survival estimates.

We checked completeness and equality of follow-up in the

two trial arms by plotting a reverse Kaplan-Meier curve

considering censored patients as patients who incurred the





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outcome (Stewart 1995). In addition, for the reverse Kaplan-

Meier curves we evaluated the median follow-up time.

We attempted to clarify and solve any detected inconsistencies

with the respective trialists.

Assessment of risk of bias in included studies

Both independent review authors assessed trial quality with regard

to bias in the domains: selection bias, performance bias, detection

bias, attrition bias, reporting bias, and other bias. The assessing

author stated the level of bias (low/high/unclear) that was as-

sumed for each item. Based on this assessment, the author assigned

an overall level of risk of existing bias to each trial (low if low

bias was assumed for all items, moderate if high or unclear bias

was assumed for one or two items, high if high or unclear bias

was assumed for at least three items). We used this bias level as

a measurement of the quality of each trial in sensitivity and sub-

group analyses (see below). In cases where the two review authors

came to different conclusions regarding the risk of bias in the sin-gle domains, a third author acted as an arbiter and a consensus was

reached. Statements, e.g. quotations from publications, support-

ing the judgment of the authors were to be given and presented

in a Risk of bias table for each trial.

Measures of treatment effect

We measured the effect of the intervention on overall and disease-

free survival with hazard ratios (HR). If possible the HR was based

onIPD. If IPDwerenot availablewe calculated theHR (i)fromthe

publishedreports,using methods describedin Parmar et al (Parmar

1998) and Tierney et al (Tierney 2007), (ii) from binary mortality

data. For thelattermethod a relative risk based on vital status (aliveordeceased)at theend of follow-upandsample sizes was calculated

and imputed in the corresponding section in RevMan. Where it

was feasible, we used various methods to indirectly estimate the

trial HR, to check its reliability.

For each trial we estimated log HRs and the standard errors of

log HR using the following methods (based on those reported by

Parmar, Tierney, and Williamson; Parmar 1998; Tierney 2007;

Williamson 2002), listed in order of preference:

1. HR and confidence interval calculated directly from IPD.

2. O-E and variance of the log hazard ratio: log hazard ratio

and its standard error estimated directly.

3. HR reported with confidence interval or log-rank P value:

standard error estimated from confidence interval or P value

(confidence interval used if both available). This is the preferred

indirect method since the HR is directly extracted and the

standard error is estimated very accurately.

4. Adjusted HR reported with confidence interval or Cox

proportional hazards P value: standard error estimated from

confidence interval or P value (confidence interval used if both

available). This will generally give an estimate close to the

unadjusted HR, but different studies adjust for different factors,

and the choice of adjustment factors could be data-driven,

leading to bias.

5. Numbers of events reported with log-rank P value: HR

estimated from numbers of events, standard error estimated from

this estimated HR and P value. This gives a indirect estimate ofthe HR since all events are considered, but may not be close to

the actual HR, particularly if the hazards are not proportional.

6. Kaplan-Meier survival curve.

7. Actuarial rates at fixed follow-up and log-rank P value. This

gives an estimate of the HR similar to that of method (3), but

only events up to the fixed follow-up time are considered.

For the effect of the intervention on disease-free survival we cal-

culated the HRs using these methods in their listed order of pref-

erence but for a landmark time of six months after date of ran-

domization (for details see Data synthesis). This landmark analysis

accounts for the difference in the timing of surgery between the

two treatment groups.

We measured the interventions effect on the presence of tumor-free resection margins, a binary outcome, with an odds ratio

(OR). We treated tumor stage upon resection as binary data by

dichotomizing T stage (1/2 versus 3/4) and N stage (0 versus 1/

2), and calculating ORs. We measured the interventions toxicity

by the total number of CTCAE grade 3/4 adverse events as well

as of the single events. We compared postoperative mortality as

well as postoperative morbidity, measured as the number of events

specified above, by calculating risk differences.

Dealing with missing data

We performed analyses with the results of the intention-to-treat

analysis if provided in the single studies. For missing data, we tried

to contact the authors of the single studies and asked them for thespecific values.

Ourdatabasewas closedon 31 May 2011. Anydatanot availableat

that date, either because it was not provided by the trialists as IPD

or because results of the respective trial had not been published as

full manuscripts, were not included in our analyses.

Assessment of heterogeneity

We assessed heterogeneity clinically (by the judgment of the two

independent review authors), as well as through the calculation of

anI statisticwhichis a measure forthe percentage of thevariability

in effect estimates attributedto heterogeneity rather than sampling

error. If heterogeneity between the effects found in single trialswas shown to be too large, i.e. relevant clinical differences or an I

of above 0.5, we did not do a pooled analysis including all trials.

Assessment of reporting biases

To assess possible publication bias, if the number of included stud-

ies was sufficient, we created a funnel plot using the different out-

comes and evaluated funnel asymmetry with Beggs and Eggers





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tests (Begg 1994; Egger 1997) with respect to continuous data or

Peters test (Peters 2006) with respect to binary data.

Data synthesis

For all outcomes, we combined IPD and aggregate data, according

to availability from the single studies, using the two-stage method(Riley 2007). This implies that from those studies for which IPD

were available, we calculated the outcome measure, as defined

above, from the provided data. For studies where IPD were not

available, we used the aggregateoutcome measure derived from the

pertinent publication. If for a given outcome a summary measure

was not available from either IPD or publications, the respective

trial was not included in the analysis of that endpoint.

We performed data synthesis with results based on intention-to-

treat analysis if available for the single studies. The estimated log

HRs were combined using the generic inverse-variance method,

the result of which is presented as pooled HR with 95% confi-

dence intervals on a logarithmic scale. The pooled HR represents

the overall risk of an event for perioperative chemotherapy ver-sus surgery alone. We calculated absolute effects on survival from

the proportion of event-free patients in the control group and the

estimated HR (exp[ln(proportion event free)xHR]). We used a

random-effects model for all meta-analyses. The usage of a ran-

dom-effects model was preferred to that of a fixed-effect model

because we assumed the existence of non-explainable heterogene-

ity between the true effects of the different treatment regimens

implied in the studies. However, we re-calculated all analyses with

a fixed-effect model in order to detect potential differences due to

the methodological approach. In all tests of significance we calcu-

lated a two-sided P value.

For the secondary outcome disease-free survival, we only pooled

the HRs of those trials which provided disease-free survival calcu-lated from a landmark time of six months from randomization,

either obtained by IPD or by aggregated data. In this analysis, re-

currence (localand distant) anddeath occurringwithin sixmonths

of randomization were regarded as events at this landmark time,

thus defining the respective patients disease-free survival as zero.

Likewise, analyzing IPD, patients discovered to be never disease-

free during the first six months after randomization (including

patients with R2 resection, patients who were operated on with-

out any resection performed, and patients who were not operated)

were also regarded as events at this landmark time.

In theanalysesof the secondary outcomes postoperative morbidity

and mortality, the denominator included only patients who un-

derwent surgery. In the analyses of the secondary outcome tumor

stage at resection (pT stage and pN stage), the denominator was

formed by the ITT population of the respective trials in order to

treat patients who were not resected as treatment failures, as they

were analyzed in the group of the more unfavorable pT and pN

stage).

We performed analyses using Review Manager (RevMan 2011).

We used the statistical software packages R and SAS (R 2010; SAS

2011) for additional analyses that could not be done with RevMan

2011.

Subgroup analysis and investigation of heterogeneity

For the primary outcome, we conducted subgroup analyses strat-

ified for:

tumor site (esophagus, GE junction, stomach); for

stratifying patients according to tumor site, we used the

definition from the single trial; either as variable in IPD databases

or from a subgroup analysis in the respective publication;

sequence of planned perioperative therapy in the

intervention arm (preoperative only versus preoperative and

postoperative combined);

chemotherapeutic agents used in preoperative

chemotherapy (platinum-based non-anthracycline regimens

versus anthracycline-based non-platinum regimens versus

regimens containing both platinum and anthracycline versus

other regimens); regimens including radiotherapy versus chemotherapy-only

schemes

performance status (PS 0 versus 1 versus 2 or higher);

age upon randomization (< 65 years, 65 to 75 years, > 75

years);

sex (male versus female).

Other subgroup analyses were defined based on exploratory anal-

yses of the available data.

For trial-specific subgroup analyses, such as those stratified accord-

ing to sequence of perioperative therapy, chemotherapeutic agents

and regimen, we calculated pooled HRs for every prespecified trial

group. For patient-specific subgroup analyses such as those strati-

fied according to performance status, age, and sex, we undertook

Cox regressions including the relevant treatment by subgroup in-

teraction term within each trial and pooled the interaction coeffi-

cients across trials. For this PWT (pooling of within-trial covari-

ate interactions) approach we followed Fisher 2011 by assessing

heterogeneity with I statistics and reporting if the fixed-effect and

random-effects results are consistent.

All patients were included in the analyses as originally randomized

in the respective trial (i.e. according to the intention-to-treat prin-

ciple), regardless of whether they were analyzed in the trial pub-

lication. In cases where specific data were missing, the respective

patients were excluded from the analysis.

Investigation of important covariates

In a second step, we combined data from all trials providing IPD

for the primary outcome overall survival in a Cox proportional

hazards model for clustered data. We used a shared frailty model

for incorporating the trial, which represents a cluster, as random-

effects. By this, we examined how the association of treatment

with survival was altered when covariates were accounted for. The





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covariates accounted for were treated as fixed-effect, the trial as

random-effects. The following covariates were considered:

treatment (chemotherapy only, chemoradiotherapy, surgery

alone);

tumor site (esophagus, GE junction, stomach);

T stage (0/1/2 versus 3/4); N stage (0 versus 1/2/3);

performance status (PS 0/1 versus 2 or higher);

age upon randomization (as continuous variable);

sex.

Sensitivity analysis

For all outcomes, we conducted sensitivity analyses based on the

risk of bias assigned to studies as described in Assessment of risk of

bias in included studies (low, moderate, high). Furthermore, we

compared results from aggregate data for the primary endpoint

and the secondary endpoint disease-free survival with results from

pooled IPD (Pignon 2001).

R E S U L T S

Description of studies

Results of the search

After excluding duplicates, the prespecified electronic search of lit-

erature databases yielded 5848 results. An additional two trials, for

which final efficacy results were already available, were identified

by manual searches in conference proceedings and reference lists.

Full papers of these trials (ACCORD 07 2011; EORTC 40954

2010) were published after our electronic search was conducted,but before our database was closed for analysis.

The extension of the search until the closure date of our database,

31May 2011 (see Electronic searches), yielded 1251 results after

exclusion of duplicates. None of these were included in our analy-

sis. One trial included only one patient with adenocarcinoma and

was published only as conference abstract. One abstract was a du-

plicate of a fully published study included in our analysis (Walsh

2002). We assessed the full-text paper of one trial. It showed that

this trial formally met our inclusion criteria. However, since pa-

tients received chemotherapy for a very short period immediately

prior to surgery(starting 72 and 68 hours and finishing 8 and 19.5

hours before surgery, respectively), we decided not to include this

trial in our analysis as such an unconventional scheme is highlydoubtful to influence our primary outcome, overall survival. Two

other trials were not included because the full-text publications

were either unavailable or available only in Chinese for which a

possibility of translation was not available at the time of the liter-

ature search, and because from the abstracts it remained unclear

if the trials included any patients with adenocarcinoma. One trial

was not included in our analysis as it was only available as a con-

ference abstract and because it included only seven patients with

adenocarcinoma (see Characteristics of excluded studies).

A summary of all searched, included, and excluded studies

(PRISMA diagram) is given in Figure 1.





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Figure 1. Study flow diagram.





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Included studies

From the search results, we identified 14 RCTs (total numberof patients in ITT populations analyzed for overall survival: n

= 3034) meeting our inclusion criteria (ACCORD 07 2011;

CALGB 9781 2008; EORTC 40954 2010; FAMTX 2004; Feng

2008; Kobayashi 2000; MAGIC 2006; OE02 2009; RTOG 8911

2007; TROG-AGITG 2005; Urba 2001; Walsh 2002; Wang

2000; Zhao 2006). Five of the trials (total n = 1657) included

both patients with adenocarcinoma and squamous cell carcinoma

of the esophagus (CALGB 9781 2008; OE02 2009; RTOG 8911

2007; TROG-AGITG 2005; Urba 2001). These trials comprised

n = 612 patients with squamous cell carcinoma and n = 1045 pa-

tients with adenocarcinoma. Thus, the total number of patients

with adenocarcinoma in all included trials was n = 2422. One

trial was a three-armed RCT comparing two different preopera-tive chemotherapy regimens with one control group not receiving

chemotherapy (Zhao 2006). For this trial (total n = 54) we com-

bined the chemotherapy treatment arms into one (n = 34) and

compared this combined treatment arm to the control group (n =

20). Consequently, our final analysis was based on data from n =

2422 patients. The 14 included RCTs were carried out between

1989 (first patient randomized) and 2004 (last patient random-

ized). The number of included patients per trial ranges from 42

(CALGB 9781 2008) to 533 (OE02 2009). Across all included

trials, 2477 patients with adenocarcinoma had originally been ran-

domized, out of which 25 (and an unknown number from OE02

2009) could not be included in our meta-analysis either because

they were not included in the trial analysis presented in the re-

spective publication or because they were not contained in the

provided IPD data sets (for details see Characteristics of included

studies).

For all trials, data on the primary outcome, overall survival, were

available either as HRs calculated from individual patient data

(IPD) provided by the investigators (eight trials, n = 1049 pa-

tients), as HRs indirectly estimated from aggregate data presented

in the original publications(three trials, n = 1207patients), as HRs

estimated from Kaplan-Meier survival curves (one trial, n = 54 pa-

tients), or as HRs estimated from binary mortality data (two trials,

n = 112 patients) (compare Methods). For four trials including

patients with both adenocarcinoma and squamous cell carcinoma

(CALGB 9781 2008; RTOG 8911 2007; TROG-AGITG 2005;

Urba 2001), HRs for the primary outcome were calculated for

patients with adenocarcinoma based on IPD. For some secondary

outcomes, data were not available from all included studies. Thus,

respective analyses are based on a smaller number of studies (seeEffects of interventions).

Excluded studies

Mariette 2010 and van Hagen 2012 were published after closure

of our database and were not included.

Risk of bias in included studies

Quality of single studies

Risk of bias was low in three studies, moderate in seven studies,

and high in four studies (see Figure 2 and Figure 3).





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Figure 2. Risk of bias summary: review authors judgments about each risk of bias item for each included

study.





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Figure 3. Risk of bias graph: review authors judgments about each risk of bias item presented as

percentages across all included studies.

IPD quality

Number of patients in IPD data sets compared with the

intention-to-treat population reported in publications.

The number of patients contained in IPD data sets were in all but

one trial identical with the intention-to-treat population reported

in the corresponding publications. Only in the data set belonging

to Urba 2001 was there one additional patient in the surgery alone

treatment group. The first author ofUrba 2001 clarified this as a

coding error in the data set the publication was based on.

Extreme outliers?

We could not identify any extreme and implausible outliers in the

IPD provided.

Any deviations in summary measures calculated from IPD

compared with data reported in publications.

We compared the number of patients in the different strata of tu-

mor site, resection margin, T stage, N stage, performance status,

median or mean age, age range, and sex between IPD and pub-

lished data for the single studies:

Urba 2001: In the publication, data were only presented for the

whole trial population (patients with both squamous cell carci-

noma and adenocarcinoma); no separate data were available for

patients with adenocarcinoma.

Walsh 2002: In the IPD 23 patients in the perioperative chemo

and 44 patients in the surgery alone group had nodal metastasis;

in the publication 23 patients in the perioperative chemo and 45

patients in the surgery alone group had nodal metastasis.

FAMTX 2004: In the IPD 16 patients in the perioperative chemo

and 19 patients in the surgery alone group had R0 resection; in

the publication 18 patients in the perioperative chemo and 19

patients in the surgery alone group had R0 resection.

TROG-AGITG 2005: In the publication, data were only pre-

sented for the whole trial population (patients with both squa-

mous cell carcinoma and adenocarcinoma); no separate data were

available for patients with adenocarcinoma.

RTOG 8911 2007: In the publication, data were only presented

for the whole trial population (patients with both squamous cell





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carcinoma and adenocarcinoma); no separate data were available

for patients with adenocarcinoma.

CALGB 9781 2008: In the publication, data were only presented

for the whole trial population (patients with both squamous cell

carcinoma and adenocarcinoma); no separate data were available

for patients with adenocarcinoma.EORTC 40954 2010: No differences between IPD and published

data.

ACCORD 07 2011: No difference between IPD and published

data with respect to tumor site, resection margin, performance

status, mean age, age range, and sex. The aggregated data of T

stage and N stage upon resection could not be directly compared

between IPD and aggregate data, as the figures given in the pub-

lication were based on a different denominator.

Deviations in overall survival and disease-free-survival of the

different treatment groups in each trial (derived from IPD using

Kaplan-Meier method and standard Cox regression analysis) as

compared with published survival estimates.

In FAMTX 2004, an estimate of the hazard ratio and its stan-dard error resulted in 1.52 (95% confidence interval 0.84 to 2.74)

in favor of surgery alone using method 5 described in Measures

of treatment effect. The hazard ratio estimate based on the cor-

responding database was 1.40 (95% confidence interval 0.78 to

2.53). This discrepancy in the hazard ratios resulted from a longer

follow-up of the patients in the IPD data set compared to the data

set used for analysis in the pertinent publication.

The legend in TROG-AGITG 2005, Figure 4 B and D, was not

correct. The label of the patients at risk would need to be swapped

(confirmed by the authors).

In ACCORD 07 2011 the estimated HRs and their 95% con-

fidence intervals for the three tumor sites, esophagus, gastroe-

sophageal junction, and stomach, based on the IPD differed from

those given in Figure A1 in the corresponding publication. In a

discussion with the authors it has been figured out that the dis-

crepancies are due to the fact that the IPD has a longer follow-up

than the data the publication was based on.

Completeness and equality of follow-up in the two trial armswere checked by plotting a reverse Kaplan-Meier curve considering

censored patients as patients who incurred the outcome (Stewart

1995). In addition, for the reverse Kaplan-Meier curves the median

follow-up time was evaluated.

For each trial with IPD the cumulative accrual rate was compared

between the two treatment arms.No relevant differences occurred.

By checking the completenessand equality of follow-up in the two

treatment arms by plotting the reverse Kaplan-Meier curves (not

shown here), again no relevant differences became obvious. Table

1 summarizes the median potential follow-up time for each trialwith IPD.

Effects of interventions

See: Summary of findings for the main comparison

Perioperative chemotherapy compared to primary surgery for

resectable adenocarcinoma of the stomach, gastroesophageal

junction, and lower esophagus; Summary of findings 2

Perioperative chemotherapy compared to primary surgery for

resectable adenocarcinoma of the stomach, gastroesophageal

junction, and lower esophagus

Primary outcome (overall survival)Overallsurvival was reported by all 14 included studies. The meta-

analysis (Analysis 1.1) yielded a pooled hazard ratio (HR) of 0.81

(95% confidence interval (CI) 0.73 to 0.89, P < 0.0001) for pa-

tients who received preoperative chemotherapy or chemoradio-

therapy as compared to those who underwent surgery alone. This

corresponds to a relative increase in survival of 19%. The sim-

ple (non-stratified) overall survival curves of perioperative che-

motherapy plus surgery versus surgery alone showed an absolute

improvement in survival of 9% at five years, increasing survival

from 23% for patients undergoing primary surgery to 32% for

patients receiving perioperative chemotherapy. The results of the

single studies showed differences in the magnitude of the treat-

ment effect, but the I was 10% and the test for heterogeneity was

not significant. HRs ranged from 0.45 for CALGB 9781 2008

to 1.40 for FAMTX 2004. The latter, together with Kobayashi

2000, were the only studies showing a trend towards longer overall

survival in the surgery alone arm. The corresponding funnel plot

(Figure 4) suggests possible reporting bias, as there are two small

positive studies, but no small negative studies published. Never-

theless, Beggs and Eggers test revealed no evidence for funnel plot

asymmetry (Beggs test P = 0.96, Eggers test P = 0.68, trim and

fill method HR 0.82 with 95% CI 0.73 to 0.91).





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Figure 4. Funnel plot of comparison: 1 Overall survival, outcome: 1.1 Hazard ratio plot for overall survival.

The pooled HR of 0.81 is mirrored in the cumulative survival

curve, which shows a sustained survival advantage for patients in

the preoperative chemotherapy arms, starting at about 18 months

after treatment onset, and lasting as long as 10 years (Figure 5).





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Figure 5. Simple (non-stratified) overall survival curves of perioperative chemotherapy plus surgery versus

surgery alone (perioperative chemo: 372 events, 525 total; surgery alone: 405 events, 524 total; hazard ratio

0.80, 95% CI 0.69 to 0.93).

Subgroup analyses

Tumor site

Definitions of tumor sites differed between trials, but they were

usually stratified into esophagus, cardia/gastroesophageal (GE)

junction, and stomach. One trial (TROG-AGITG 2005) in-

cluded only patients with esophageal tumors. Five trials (CALGB

9781 2008; OE02 2009; RTOG 8911 2007; Urba 2001; Walsh

2002) included patients with esophageal and GE junction tu-

mors. One trial (Wang 2000) included only patients with gas-troesophageal junction tumors. Four studies (FAMTX 2004; Feng

2008; Kobayashi 2000; Wang 2000; Zhao 2006) included only

patients with gastric tumors. One trial (EORTC 40954 2010) in-

cluded patients with gastric and GE junction tumors. Two studies

(ACCORD 07 2011; MAGIC2006) included patients with alltu-

mor sites. For OE02 2009, site-specific results were not presented

in the publication, and IPD was not provided. For CALGB 9781

2008 and Urba 2001, site-specific results were available neither

from publications nor from provided IPD, and thus these studies

could not be included in the subgroup analyses for tumor site,

which could be performed for the three tumor sites: esophagus,

GE junction, and stomach, based on data from five, six, and seven

studies, respectively (Analysis 1.3). Theresults showeda more pro-

nounced survival advantage for perioperative chemotherapy in pa-

tients with tumors of the GE junction (pooled HR 0.69, 95% CI

0.54 to 0.87) compared to the esophagus (pooled HR 0.87, 95%

CI 0.73 to 1.05), and stomach (pooled HR 0.94, 95% CI 0.82 to

1.06), but the interaction test did not reach statistical significance(P = 0.08).

In this subgroup analysis the effect of trial characteristics and pa-

tient characteristics are mixed as some trials include only certain

tumor sites. Therefore, we investigated the interaction between

treatment and tumor site in those trials where this was possible,

i.e. IPD trials (Analysis 1.4). The heterogeneity coefficient of I =





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4% was not significant.

Sequence of planned perioperative therapy in the

intervention arm

There were no relevant differences in theeffectof preoperative che-

motherapy on overall survival between the nine trials where only

preoperative chemotherapy was stipulated and the five trials where

both pre- and postoperative chemotherapy were foreseen (Analysis

1.6). However, it must be noted that even in the trials where post-

operative chemotherapy was planned (ACCORD 07 2011; Feng

2008; Kobayashi 2000; MAGIC 2006; RTOG 8911 2007), only

between 22% (ACCORD 07 2011) and 42% (MAGIC 2006) of

patients received the full number of planned postoperative cycles

(see below).

Chemotherapeutic agents used in preoperative

chemotherapy

Ten of the 14 included trials relied on a platinum-based non-an-

thracycline regimen. Therefore, this preplanned subgroup analysis

was of limited value, as the other subgroups (anthracycline-based

non-platinum regimens, regimens containing both platinum and

anthracycline, andother regimens), consisted of one, one, andtwo

trials. Forplatinum-based non-anthracycline regimens, the pooled

HR was 0.80 (95% CI 0.72 to 0.89) and thus almost identical to

the pooled HR of all included trials (Analysis 1.7).

Regimens including radiotherapy versus chemotherapy only

schemes

In 10 trials (ACCORD 07 2011; EORTC 40954 2010; FAMTX

2004; Feng 2008; Kobayashi 2000; MAGIC 2006; OE02 2009;

RTOG 8911 2007;Wang 2000; Zhao2006), the intervention arm

stipulated a regimen which included chemotherapy only. In four

trials (CALGB 9781 2008; TROG-AGITG 2005; Urba 2001;

Walsh 2002), the intervention was chemoradiotherapy (Analysis

1.5). Allof the lattercomprised exclusively patients with tumors of

the esophagus or GE junction. Pooled subgroup analyses showed a

significant benefit in terms of overall survival for both modalities.

The magnitude of the effect was stronger for chemoradiotherapy,

but the confidence interval of the pooled HR was wider due to

the lower absolute number of participants in this subgroup. The

interaction test was not significant. Of note, there was consider-

ably higher heterogeneity among results of trials using chemora-

diotherapy with the corresponding I value just at the border of

what we considered meaningful for a pooled analysis.

Performance status

No publication provided sufficient information regarding over-

all survival stratified by performance status upon randomiza-

tion. Two IPD data sets (Urba 2001; Walsh 2002) did not con-

tain information on performance status. Five (ACCORD 07

2011; CALGB 9781 2008; EORTC 40954 2010; FAMTX 2004;

TROG-AGITG 2005) out ofthe six remaining IPD datasetsmea-

sured performance status according to ECOG/WHO, whereas

RTOG 8911 2007 used the Karnofsky score. This was converted

to the ECOG/WHO classification according to Verger 1992.In alltrials with data on performance status, only five patients with

a performance status of 2 or higher were included. Thus, this small

group was not included in the subgroup analysis. The treatment

by performance status interaction effect estimates from each trial

were consistent (I = 0%, P = 0.90, = 0; pooledinteraction effect

under REM and FEM 0.34 with 95% CI -0.03 to 0.71; Analysis

1.9). The within-trial HRs for overall survival in each subgroup

are presented in Analysis 1.8 .

Age

No publication provided sufficient information regarding overall

survival stratified by age upon randomization. This information

was however available in all IPD data sets. Only 16 patients with an

age of more than 75 years were randomized in any of the included

trials, which precluded analysis in that subgroup. There was no

evidence of subgroup differences with respect to the treatment by

age interaction effect estimates. The latter were consistent over all

trials(I= 9%, P = 0.36, = 0.02; pooled interaction effect under

REM -0.07 with 95% CI -0.40 to 0.26; pooled interaction effect

under FEM -0.06 with 95% CI -0.37 to 0.24; Analysis 1.11).

The within-trial HRs for overall survival are presented in Analysis

1.10.

Sex

No publication provided sufficient information regarding overall

survival stratified by sex. This information was however available

in all IPD data sets. About 83% of participants in the trials were

male. Pooling of within-trial covariate interactions revealed no

subgroup difference between males andfemales (I= 0%,P = 0.45,

= 0; pooled interaction effect under REM and FEM -0.18 with

95% CI -0.59 to 0.23; Analysis 1.13). The within-trial HRs for

overall survival are presented in Analysis 1.12.

Pretreatment tumor stage

Post hoc subgroup analyses accordingto pretreatmentT stage (T0/

1/2 versus T3/4) and pretreatment N stage (N0 versus N1/2/3)

were done for all IPD data sets with available information (Analysis

1.14; Analysis 1.16). Three (CALGB 9781 2008; EORTC 40954

2010; RTOG 8911 2007) out of eight trials with IPD provided

information on pretreatment T stage but only one (RTOG 8911

2007) had included enough patients with pretreatment stage T3/

4 to investigate an interaction between treatment and T stage

(Analysis 1.15). Four trials provided information on pretreatment

N stage (CALGB 9781 2008; EORTC 40954 2010; RTOG 8911





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2007; TROG-AGITG 2005). Pooling of within-trial covariate in-

teractions revealed no subgroup difference between N0 and N1/

2/3 (I = 0%, P = 0.58, = 0; pooled interaction effect under

REM and FEM -0.02 with 95% CI -0.63 to 0.59; Analysis 1.17).

Resection status

In order to assess the influence of resection status (R0/1/2) on

survival, we conducted a pooled survival analysis with patients

from both arms of all five trials for which respective data were

available (ACCORD 07 2011; EORTC 40954 2010; FAMTX

2004; RTOG 8911 2007; TROG-AGITG 2005). A subgroup

analysis according to resection status comparing overall survival

for patients who received perioperative chemotherapy and those

who underwent primary surgery was not appropriate, as the dis-

tribution of resection status was significantly different between

treatment arms, probably because it was directly influenced by the

treatment a patient received. For the same reason, the variable re-

section status was not included in the Cox model (see below). The

Kaplan-Meier curves show that resection status is a strong pre-dictor for overall survival, with patients with R1 or R2 resection

having a substantially poorer prognosis than patients with R0 re-

section (Figure 6). Five-year survival probabilities were 37% (95%

CI 33% to 42%) in the R0 group, 7% (95% CI 0% to 15%) in

the R1 group, and 0% in the R2 group. The corresponding HRs

were 0.31 (95% CI 0.22 to 0.44) for R0 versus R1 and 0.18 (95%

CI 0.25 to 0.13) for R0 versus R2.

Figure 6. Overall survival curves by type of resection: 719 patients with R0, R1 or R2, 99 patients not

resected or missing (R0: 390 events, 611 total; R1: 43 events, 46 total; R2: 60 events, 62 total).

Sensitivity analysesA sensitivity analysis which compared trials from which only ag-

gregate data were available with those from which IPD were avail-





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able revealed no differences, with both pooled HRs being almost

identical (Analysis 1.2). A meta-analysis excluding trials with high

risk of bias yielded a HR of 0.82 (95% CI 0.72 to 0.93), which is

virtually identical to the result of the meta-analysis of all trials. A

meta-analysis including only the three trials with low risk of bias

(424 patients) yielded a HR of 0.88 (95% CI 0.60 to 1.28). Ameta-analysis excluding the two trials from which only data on

vital status at end of follow-up and no time-to-event data were

available yielded a HR of 0.81 (95% CI 0.72 to 0.92).

Investigation of important covariates

A Cox proportional hazards model without any covariates but the

treatment arm chemo(radio)therapy versus surgery alone as fixed-

effect and trial as random-effects applied to all eight IPD data sets

summarized in a single database (with 1049 patients) resulted in

a HR of 0.80 (95% CI 0.69 to 0.93; see also Figure 5).

Two (CALGB 9781 2008; Urba 2001) out of eight trials with

available IPD provided no information on exact tumor site (gas-troesophageal junction or esophagus). For five (ACCORD 07

2011; FAMTX 2004; TROG-AGITG 2005; Urba 2001; Walsh

2002) out of eight trials with available IPD no information on

pretreatment T stage was available, for four (ACCORD 07 2011;

FAMTX 2004; Urba 2001; Walsh 2002) trials no information on

pretreatment N stage was available. For two trials (Urba 2001;

Walsh 2002) information on performance status was missing. As

the imputation of a covariate for a who

Documents

Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach,gastroesophageal junction, and lower esophagus (Review)