Survival After Neoadjuvant Chemo or CRT for Re Sec Table CA an Updated Meta Analysis

8/3/2019 Survival After Neoadjuvant Chemo or CRT for Re Sec Table CA an Updated Meta Analysis

1/12www.thelancet.com/oncology Vol 12 July 2011 681

Articles

Lancet Oncol 2011; 12: 68192

Published Online

June 17, 2011

DOI:10.1016/S1470-

2045(11)70142-5

See Comment page 615

National Health and Medical

Research Council Clinical Trials

Centre, University of Sydney,

Sydney, NSW, Australia

(K M Sjoquist FRACP,

Prof R J Simes MD,

Prof V Gebski MStat); Division of

Cancer Services, University of

Queensland, Princess

Alexandra Hospital, Brisbane,

QLD, Australia

(Prof B H Burmeister MD);

Department of Surgery,

University of Queensland,

Brisbane, QLD, Australia

(Prof B M Smithers FRACS,

A Barbour FRACS); UpperGastrointestinal and Soft

Tissue Unit, Princess Alexandra

Hospital, Brisbane, QLD,

Australia (B M Smithers,

A Barbour); and Peter

MacCallum Cancer Centre, and

Department of Medicine,

University of Melbourne,

Melbourne, VIC, Australia

(Prof J R Zalcberg FRACP)

Correspondence to:

Prof Val Gebski, National Health

and Medical Research Council

Clinical Trials Centre, Locked

Bag 77, Camperdown 1450 NSW,

Australia

[email protected]

Survival after neoadjuvant chemotherapy or

chemoradiotherapy for resectable oesophageal carcinoma:an updated meta-analysis

Katrin M Sjoquist, Bryan H Burmeister, B Mark Smithers, John R Zalcberg, R John Simes, Andrew Barbour, Val Gebski, for the Australasian

Gastro-Intestinal Trials Group

SummaryBackground In a previous meta-analysis, we identified a survival benefit from neoadjuvant chemotherapy orchemoradiotherapy before surgery in patients with resectable oesophageal carcinoma. We updated this meta-analysiswith results from new or updated randomised trials presented in the past 3 years. We also compared the benefits ofpreoperative neoadjuvant chemotherapy compared with neoadjuvant chemoradiotherapy.

Methods To identify additional studies and published abstracts from major scientific meetings, we searched Medline,Embase, and Central (Cochrane clinical trials database) for studies published since January, 2006, and also manuallysearched for abstracts from major conferences from the same period. Only randomised studies analysed by intentionto treat were included, and searches were restricted to those databases citing articles in English. We used publishedhazard ratios (HRs) if available or estimates from other survival data. We also investigated treatment effects by tumourhistology and relations between risk (survival after surgery alone) and effect size.

Findings We included all 17 trials from the previous meta-analysis and seven further studies . 12 were randomisedcomparisons of neoadjuvant chemoradiotherapy versus surgery alone (n=1854), nine were randomised comparisons ofneoadjuvant chemotherapy versus surgery alone (n=1981),and two compared neoadjuvant chemoradiotherapy withneoadjuvant chemotherapy (n=194) in patients with resectable oesophageal carcinoma; one factorial trial included twocomparisons and was included in analyses of both neoadjuvant chemoradiotherapy (n=78) and neoadjuvant chemotherapy(n=81). The updated analysis contained 4188 patients whereas the previous publication included 2933 patients. This

updated meta-analysis contains about 3500 events compared with about 2230 in the previous meta-analysis (estimated57% increase). The HR for all-cause mortality for neoadjuvant chemoradiotherapy was 078 (95% CI 070088;p


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We aimed to assess whether the results of recently

published or updated trials have changed the outcomesof our previous meta-analysis.6 We also sought to comparethe benefits of neoadjuvant chemotherapy and neo-adjuvant chemoradiotherapy before surgery for resectableoesophageal carcinoma, and to assess whether anyincrease in survival benefits was offset by an increase inperioperative mortality.

MethodsFor the first section of the meta-analysis, we sought toassess the survival benefits of neoadjuvant treatmentwith either neoadjuvant chemotherapy or neoadjuvantchemoradiotherapy of any regimen. All randomisedcontrolled trials that compared survival after

neoadjuvant chemoradiotherapy or neoadjuvantchemotherapy followed by surgery with surgery alonein the initial management of resectable oesophageal oroesophagogastric junction carcinoma (squamous-cellcarcinoma, adenocarcinoma, or mixed tumours) wereeligible for inclusion, provided they were analysed byintention-to-treat.

We included all trials from our previous meta-analysis.6

We searched Medline, Embase, and Central (Cochraneclinical trials database) for studies published sinceJanuary, 2006. We used the following search terms:esophageal neoplasms, gastro-esophageal junctionneoplasms, antineoplastic agents, chemotherapy,radiotherapy, surgery, and esophagectomy orgastrectomy. We also manually searched for abstractsfrom major conferences over the same period. Articlesfor which neither the abstract nor full text was availablein English were excluded after review. We also includedstudies in an analysis of histological subtypes if subgroupdata could be identified separately, with the same criteriafor inclusion as described in the previous meta-analysis.6

The primary outcome of interest for the first section of

the meta-analysis was all-cause mortality. The secondaryendpoint was the effect on all-cause mortality of treatmentfor each histological subtype (squamous-cell carcinomaor adenocarcinoma).

For the second section of the meta-analysis, we soughtto assess the survival benefits of neoadjuvant chemo-therapy compared with neoadjuvant chemoradiotherapy.All randomised trials of this comparison that includedadult patients with squamous-cell carcinoma, adeno-carcinoma, or mixed tumours were eligible. We did notidentify any previous systematic reviews or meta-analysesof suffi cient quality,and so we searched Medline, Embase,and Central with the same terms as for the first section.All trials published between January, 1980 andNovember, 2010, were included if the abstract or fullarticle was available in English.

For both sections of the meta-analysis, we wrote toauthors of studies that had previously only appeared asabstracts and were not in the databases to clarify whetherupdated data had been published, including the authorsof four studies that were excluded from the previousmeta-analysis.2528 Trials that focused on primary gastriccancers were excluded if the results for oesophagogastricjunction tumours were not available separately.

Statistical analysesFor the first section of the meta-analysis, we used the

same statistical methods as previously reported.6 We usedthe hazard ratio (HR) for the comparison in each trial toassess the treatment effects. Where possible, the HR andassociated variance were obtained directly from each trialpublication or from individual patient data. HRs notreported were calculated by the methods of Parmar andcolleagues.29 Statistical tests were two-sided. Pooledestimates with 95% CIs were calculated by the weightedvariance technique and we used the test to assessheterogeneity, with the level of significance set at 5%. Weassessed publication bias by the methods described byGleser and Olkin,30 and we used Fishers failsafe N31 toidentify the number of studies with a p value of 05 (ie,an HR of 10) that would need to be added to those in themeta-analysis to produce a non-significant result.

Figure 1: Flow diagram showing inclusion and exclusion of studies

*Includes 17 studies that were included in this meta-analysis and five studies that could not be included. Includes

abstracts that reported earlier results where full papers were subsequently published and multiple abstracts thatreported the results of the same study. See webappendix p 1 for reference.

22 studies identified from

previous meta-analysis*

388 studies identified from

database searches

76 additional records identified

from other sources

302 studies after duplicates removedTitle and abstracts screened for eligibility

35 abstracts reviewed 3 excluded1 (An, 2003): abstract not available in English and no

further details provided by author2 (Peng, 2008,33 and Wang, 200125): full text not in

English, insufficient detail in abstract, and no furtherdetails provided by author

32 full-text articles assessed for eligibility

8 excluded2 (Cunningham, 2006,34 and Schuhmacher, 201035):

results for gastro-oesophageal junction andoesophageal tumours not available separately; mostpatients received gastrectomy

2 (Bokhyan, 200936 [abstract] and Stidil, 2006

[abstract]; both abstracts describe the same study):insufficient information available from abstract andno response from authors

1 (Boige, 2007 [abstract]): abstract not used;insufficient data on subgroups; final publication(Ychou7) used because additional informationavailable to meet inclusion criteria

1 (Kok, 199728 [abstract]): abstract not used becauseupdated results available (Boonstra37) after contactingauthors

2 (Kelsen, 1998, and Medical Research Council,200238): updated results available (Kelsen, 2007,8and Allum, 2009,1 respectively)24 included in meta-analysis

See Online for webappendix


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We calculated the overall 2-year survival estimate in

the control group from a mean of individual 2-yearsurvival rates weighted by the sample size of the controlgroup. The estimate of the 2-year survival rate in theintervention was obtained by applying the HR to the

estimated control rate. We then used these data to

calculate the absolute risk reduction and numberneeded to treat.Because the individual trials could be deemed

independent of each other, we used indirect comparisons

Year

started

Radiotherapy schedule Chemotherapy schedule Concurrent

or sequential

Tumour type Sample

size

Median

follow-up

(months)*

Chemoradiotherapy vs surgery alone

Nygaard9 1983 35 Gy, 175 Gy per fraction

over 4 weeks

Two cycles: cisplatin 20 mg/m days 15; bleomycin 5 mg/m

days 15

Sequential SCC 78 18

Apinop39 1986 40 Gy, 2 Gy per fraction

over 4 weeks

Two cycles: cisplatin 100 mg/m day 1; fluorouracil 1000 mg/m

days 14

Concurrent SCC 69 12

Le Prise10 1988 20 Gy in 10 fractions over

12 days


days 25 and 2225

Sequential SCC 86 12

Urba40 1989 45 Gy, 15 Gy per fractionover 3 weeks

Two cycles: cisplatin 20 mg/m days 15; fluorouracil 300 mg/mdays 121; vinblastine 1 mg/m days 14

Concurrent SCC andadenocarcinoma

100 98

Bosset12 1989 37 Gy, 37 Gy per fractionover 2 weeks

Two cycles: cisplatin 80 mg/m days 02 Sequential SCC 293 55

Walsh13 1990 40 Gy in 15 fractions over3 weeks

Two cycles: cisplatin 75 mg/m day 7; fluorouracil 15 mg/kgdays 15


Walsh14 1990 40 Gy in 15 fractions over3 weeks

Two cycles: cisplatin 75 mg/m day 7; fluorouracil 15 mg/kgdays 15

Concurrent Adenocarcinoma 113 24

Burmeister22 1994 35 Gy in 15 fractions over3 weeks

One cycle: cisplatin 80 mg/m day 1; fluorouracil 800 mg/mdays 25


256 65

Tepper43 1997 504 Gy, 18 Gy per fraction

over 56 weeks


days 35

Concurrent SCC and

adenocarcinoma

56 72

Lv41|| 1997 40 Gy, 2 Gy per fraction

over 4 weeks

Two cycles: cisplatin 20 mg/m per day days 13 and 2225;

paclitaxel 135 mg/m starting on day 1 and day 22 of radiotherapy


Lee17

1999 456 Gy, 12 Gy per fractionover 28 days

Two cycles: cisplatin 60 mg/m day 1; fluorouracil 1000 mg/mdays 35


Mariette11|| 2000 45 Gy in 25 fractions over5 weeks

Two cycles: cisplatin 75 mg/mday 1 or 2; fluorouracil 800 mg/m

days 14Concurrent SCC and

adenocarcinoma195 68

van der Gaast42|| 2004 414 Gy, 18 Gy per fractionover 46 weeks

5 weeks concurrent chemotherapy: carboplatin area undercurve=2 and paclitaxel 50 mg/m on day 1 weekly


364 32

Chemotherapy vs surgery alone

Roth23 1982 Two cycles: cisplatin 120 mg/m day 1; vindesine 3 mg/m days 1,8; bleomycin 10 U/m days 36

SCC 39 20

Nygaard9 1983 Two cycles: cisplatin 20 mg/m days 15; bleomycin 5 mg/mdays 15

SCC 81 18

Schlag19 1988** Three cycles: cisplatin 20 mg/m days 15; fluorouracil1000 mg/m days 15

SCC 46 75

Maipang24 1988 Two cycles: cisplatin 100 mg/m day 1; bleomycin 10 mg/m

days 38; vinblastine 3 mg/m days 1 and 8

SCC 46 17

Law20

1989 Two cycles: cisplatin 100 mg/m day 1; fluorouracil 1000 mg/mdays 15

SCC 147 17

Boonstra37|| 1989 Two cycles: cisplatin 80 mg/m day 1; etoposide 200 mg/m

days 15

SCC 169 145

Kelsen8 1990 Three cycles: cisplatin 100 mg/m day 1; fluorouracil 1000 mg/mdays 15

SCC andadenocarcinoma

467 106

Ancona21 1992 Two cycles: cisplatin 100 mg/m day 1; fluorouracil 1000 mg/mdays 15

SCC 96 24

Allum1 1992 Two cycles: cisplatin 80 mg/m day 1; fluorouracil 1000 mg/mdays 14

SCC andadenocarcinoma

802 72

Ychou7|| 1995 Planned six perioperatively: (two or three cycles before surgeryplus four or three cycles after surgery) of intravenous cisplatin(100 mg/m) on day 1, and a continuous intravenous infusion of

fluorouracil (800 mg/m per day) for 5 consecutive days (days15) every 28 days

Adenocarcinoma 169 684

(Continues on next page)


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to obtain estimates of the benefit of neoadjuvant chemo-radiotherapy compared with neoadjuvant chemotherapy.Potential biases might occur in such comparisons, thusthe amount to which the results of the indirectcomparisons corroborate those of the randomised studiesis also of interest. We assessed this by comparingdifferences between the effects obtained from the directand indirect comparisons. Consistency between effectsfor indirect and direct comparisons provides confidenceabout the additional information in the indirectcomparisons. These approaches were described by Songand colleagues,32as was the comparison of the amount ofdiscrepancy between the indirect comparisons and thoseof the randomised trials; a p value of greater than 005would suggest that the results for the indirect and directcomparisons are statistically consistent. Data wereanalysed with software provided by the Cochrane Library(Rev Man 4.3, and 5.0 downloaded April, 2010).Differences between outcomes in the control arms of thedifferent trials were measured against the logarithm of

the HR to give an estimate of the relation between riskand benefit of neoadjuvant chemotherapy or neoadjuvantchemoradiotherapy. The number of events (deaths) usedwas estimated from the sample size and median follow-up time reported for each trial and an assumption thatabout 50% of events had occurred within 18 months.

We also did prespecified subgroup analyses toexamine the effects of neoadjuvant chemotherapy orneoadjuvant chemoradiotherapy according to tumourhistology (squamous-cell carcinoma or adenocarcinoma)where this information was available.

Differences between treatment arms for 30-daypostoperative or in-hospital mortality were calculatedfrom the absolute difference in the proportion of deaths,with 95% CIs.

Role of the funding sourceThe sponsor of the study had no role in study design,data collection, data analysis, data interpretation,writing of this report, or the decision to publish theresults. KS and VG had full access to all of the data inthe study and had the final responsibility, with theagreement of all authors, for the decision to submit forpublication.

ResultsWe included 24 studies in total (figure 1),1,715,1724,37,3943which consisted of all 17 trials from the previousmeta-analysis810,1214,16,17,1924,38,39,40 and seven furtherstudies.7,11,15,18,37,41,42 12 were randomised comparisons ofneoadjuvant chemoradiotherapy versus surgery alone(n=1854),1014,17,22,3943 nine were randomised comparisons ofneoadjuvant chemotherapy versus surgery alone(n=1981),1,7,8,1921,23,24,37 two compared neoadjuvant chemo-radiotherapy with neoadjuvant chemotherapy (n=194),15,18and one study included two comparisons and was

included in analyses of both neoadjuvant chemo-radiotherapy (n=78) and neoadjuvant chemotherapy(n=81).9 This study was a 2 2 factorial study thatsimultaneously compared the effect of neoadjuvantchemotherapy, neoadjuvant chemoradiotherapy, andneoadjuvant radiotherapy on survival, and the controlgroup was used for both the neoadjuvant chemotherapyand neoadjuvant chemoradiotherapy comparisons.Accordingly, half the sample size for the control groupwas reported in each of the comparisons. The HR for thecomparison of neoadjuvant chemotherapy with surgeryalone in this study was used as calculated for the previousmeta-analysis.6

The updated analysis contained 4188patients whereasthe previous publication included 2933 patients. The

Year

started

Radiotherapy schedule Chemotherapy schedule Concurrent

or sequential

Tumour type Sample

size

Median

follow-up(months)*

(Continued from previous page)

Chemoradiotherapy vs chemotherapy

Stahl(chemoradiotherapy)18||

2000 30 Gy, 2 Gy per fractionover 3 weeks,commencing

2 weeks after last day ofinduction chemotherapy

12 weeks (induction): fluorouracil 2000 mg/m over 24 h day 1;folinic acid 500 mg/m day 1; and cisplatin 80 mg/m biweekly.Followed by cisplatin 50 mg/m on day 1 and day 8 and etoposide

80 mg/m on days 35, concurrent with radiotherapy

Induction andconcurrent


Burmeister

(chemoradiotherapy)15||

200 0 35 Gy in 15 fract ions

commencing day 22

1 cycle induction: cisplatin 80 mg/m day 1 and fluorouracil

1000 mg/m infusion over 96 h day 1. Followed by cisplatin80 mg/m day 1 and fluorouracil 800 mg/m infusion over 96 h

on day 1; concurrent with radiotherapy

Induction and

concurrent


Stahl (chemotherapy)18|| 2000 15 weeks: fluorouracil 2000 mg/m over 24 h day 1, folinic acid500 mg/m day 1; cisplatin 80 mg/m biweekly


Burmeister

(chemotherapy)

15

||

2000 Two cycles: cisplatin 80 mg/m day 1, fluorouracil 1000 mg/m

infusion over 96 h day 1


SCC=squamous-cell carcinoma. AC=adenocarcinoma. NR=not reported. *As published. Estimated as the median survival. Unpublished thesis. Updated since previous meta-analysis. Does not include the

78 patients in this study who received postoperative chemoradiotherapy. ||Not included in previous meta-analysis. **Year of activation not reported, but imputed. Imputed, rather than published.

Previously published as abstract only. Does not includes the 55 patients in this study who had primary gastric cancer. An additional seven patients were randomised but deemed ineligible. Survival

analysis includes 119 patients in total.

Table 1: Chemoradiotherapy and chemotherapy regimens in randomised trials included in the meta-analysis


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Figure 2: All-cause mortality for chemoradiotherapy compared with surgery alone

Effects of chemoradiotherapy compared with surgery alone on survival in patients with oesophageal cancer (A) and in subgroups of patients with oesophageal

carcinoma (squamous-cell carcinoma, adenocarcinoma or pooled histology type subgroups; B). SCC=squamous-cell carcinoma. *Includes all randomised patients. Includes four patients whose histology was unknown or who had mixed tumours. Includes three patients whose histology was unknown or who had mixed tumours.

Nygaard9

Apinop39

Le Prise10

Urba40

Bosset12

Walsh (SCC)13

Walsh (adenocarcinoma)14

Burmeister22

Tepper43

Lv41

Lee17

Mariette11

van der Gaast42

Total

Heterogeneity: 2=1804, df=12 (p=011); I2=33%

Test for overall effect:Z=428 (p


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updated work includes information on 3994patients forneoadjuvant treatments compared with surgery aloneand 194 patients for comparisons of neoadjuvantchemoradiotherapy with neoadjuvant chemotherapy.This updated meta-analysis contains about 3500 eventscompared with 2230 in the previous meta-analysis(estimated 57% increase).

22 randomised trials were suitable for inclusion inthe quantitative analysis of the survival benefits of

neoadjuvant treatment with either neoadjuvant chemo-therapy or neoadjuvant chemoradiotherapy,1,7,814,17,1924,37,3943and two were suitable for inclusion in the quantitativeanalysis of neoadjuvant chemotherapy with neoadjuvantchemoradiotherapy.15,18 17 of these were included in theprevious publication (webappendix p 1),9,10,1214,16,17,1924,3840three of which have been updated,1,8,43 and five neweligible studies were identified.7,11,37,41,42 Four studies wereexcluded from the previous meta-analysis because of

Figure 3: All-cause mortality for chemotherapy compared with surgery alone

Effects of chemotherapy compared with surgery alone on survival in patients with oesophageal cancer (A) and in subgroups of patients with oesophageal carcinoma

(squamous-cell carcinoma or adenocarcinoma histology; B). *Includes ten patients whose histology was unknown or who had mixed tumours. Includes 12 patients

whose histology was unknown or who had mixed tumours.

Roth23

Nygaard9

Schlag19

Maipang24

Law20

Boonstra37

Kelsen8

Ancona21

Allum1

Ychou7

Total


Test for overall effect:Z=283 (p=0005)

19

56

22

24

74

85

233*

48

400

85

1046

20

25

24

22

73

84

234

48

402*

84

1016

071 (036143)

122 (082181)

097 (060157)

161 (079327)

073 (053100)

071 (051098)

105 (086128)

085 (050144)

084 (072098)

063 (045089)

087 (079096)

02 05 1 2 5Favours surgery aloneFavours chemotherapy

Chemotherapy(total)

Surgery alone(total)

Hazard ratio(95% CI)

A

Squamous-cell carcinoma

Roth23

Nygaard9

Schlag19

Maipang24

Law20

Boonstra37

Kelsen8

Ancona21

Allum1

Total



Adenocarcinoma

Kelsen8

Allum1

Ychou7

Subtotal



Total



Test for subgroup differences: 2

=114, df=1 (p=029); I2

=124%

19

56

22

24

74

85

103

48

123

554

120

265

85

470

1024

20

25

24

22

73

84

110

48

124

530

124

268

84

476

1006

071 (036143)

122 (082181)

097 (060157)

161 (079327)

073 (053100)

071 (051098)

125 (094167)

085 (050144)

081 (061107)

092 (081104)

090 (069118)

086 (071105)

063 (045089)

083 (071095)

088 (080096)

02 05 1 2 5

Favours surgery aloneFavours chemotherapy

Chemotherapy(total)

Surgery alone(total)

Hazard ratio(95% CI)

B


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unclear or unavailable information. We wrote to all theseauthors again but were unable to obtain suffi cientinformation for three of the four studies to allow inclusionin this analysis. Reasons for exclusion were: unclearrandomisation method,26 analysis not by intention totreat,44 and full text not in English and insuffi cientinformation available in English abstract.25 The remainingstudy was excluded from the previous quantitativeanalysis because it had only been published in abstractform28 at the time of the previous publication. The long-term results have recently been published and are nowincluded.37 All patients had stages T03, N01 diseaseaccording to the 2002 AJCC staging.45 There were nomajor differences in the age of participants betweenstudies or groups, although no formal statisticalcomparison was done. Three trials included only patientswith early (stage III) disease, all of which comparedneoadjuvant chemoradiotherapy with surgery alone.10,11,46Table 1 summarises details of all trials included in themeta-analysis.

13 studies were included in the comparison of

neoadjuvant chemoradiotherapy with surgery alone inpatients with resectable oesophageal carcinoma(n=1932): 12 were randomised comparisons ofneoadjuvant chemoradiotherapy followed by surgerywith surgery alone1014,16,17,22,3942 and one study includedthis comparison within a 2 2 factorial study.9 Ten hadbeen included in the previous meta-analysis;6 of these,one (Tepper16) had been published only in abstract form,and the data included in this version is the updatedfinal publication.43 Two additional trials (Mariette11 andvan der Gaast42) were presented at the American Societyof Clinical Oncology meeting in June, 2010, and onestudy was published since the previous meta-analysis.41One further publication from China with an Englishabstract was identified;33 however, it was not included

because the information from the abstract wasinsuffi cient to calculate an HR and we were unable toobtain further details from the author. A test forpotential publication bias suggested ten potentiallyunpublished studies for neoadjuvant chemoradiotherapy,but 23 more studies with a HR of 10 would need to beadded to these 13 to produce an overall non-significantresult, suggesting that the meta-analysis is robust topublication bias.

Figure 2 shows pooled estimates for all-cause mortalityfor the trials that compared neoadjuvant chemoradiot-herapy followed by surgery with surgery alone. The pooledHR was 078 (95% CI 070088; p


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169 patients (85 neoadjuvant chemotherapy and84 surgery alone) with tumours arising in theoesophagogastric junction and oesophagus were used.The HRs for oesophageal and oesophagogastric junctiontumours from this study were pooled to give an HR

of 063 (95% CI 045089; figure 3). We identified twostudies that included oesophagogastric junction tumoursand primary gastric adenocarcinomas, the UK MAGICtrial34 and the European Organisation for Research andtreatment of Cancer (EORTC) 40954 study.35 The numbersof patients with lower oesophageal and oesophagogastriccancers were small (n=73 and n=58, respectively inMAGIC34 and n=76 for oesophagogastric in EORTC35),and most patients received a gastrectomy. Also, thesestudies did not publish outcomes by tumour site and sowere excluded from the quantitative meta-analysis. Inthe UK MAGIC trial,34 there was a significant survivaladvantage for patients who received perioperativechemotherapy. However, the EORTC study,35 whichexamined preoperative treatment, was closed because of

poor accrual and did not show a survival advantage for

this strategy. Using the HR for the primary oesophagealcancer subgroups from the MAGIC study (HR 075,95% CI 042133; p=033), as provided by theinvestigators (personal communication) we did asensitivity analysis. This analysis did not affect the overallestimate of benefit from neoadjuvant chemotherapy(HR 087, 95% CI 087095; p=0001).

One additional study had final results published inabstract form as part of conference proceedings.36 Theauthors reported a disease-free survival advantage for thechemotherapy arm; however, information about censoredobservations was not reported. Attempts to obtain furtherinformation from the authors were unsuccessful andhence the study was not included in the main analysis.

We did a sensitivity analysis with an HR calculated byestimating the relative risk from the overall survival ratesreported at years 3 and 5 in each treatment arm, by amethod described by Parmar.29 The inclusion of this studydid not substantially change the pooled HR forneoadjuvant chemotherapy compared with surgery alone(HR 086, 95% CI 079094; p=0001). A test forpotential publication bias suggested that there are zeropotentially unpublished studies on neoadjuvant chemo-therapy compared with surgery alone, and 15 furtherstudies with an HR of 10 would need to be added to theseten studies to produce an overall non-significant result.

Figure 3 shows the pooled estimate for all-causemortality for trials that compared neoadjuvantchemotherapy followed by surgery with surgery alone.The pooled HR was 087 (079096; p=0005). Thiscorresponds to an absolute survival difference at 2 yearsof 51%, which is equivalent to a number needed to treatof 19. A subgroup analysis by histological type for thosestudies where histology data were available gave an HRfor squamous-cell carcinoma of 092 (95% CI 081104;p=018) and for adenocarcinoma of 083 (071095;p=001). There was no evidence of significantheterogeneity overall or between subgroups bytumour histology.

For the second component of the meta-analysis,assessing the survival benefits of neoadjuvant chemo-

therapy compared with neoadjuvant chemoradiotherapy,we identified two studies, one published before18 and onepublished after15 the database search (n=194). TheGerman study18 included only patients withoesophagogastric junction adenocarcinoma and used15 weeks of chemotherapy in each arm and 18% had agastrectomy only. The subsequent Australian trialcompared these modalities, but used two cycles ofcisplatin and fluorouracil and radiotherapy of 35 Gy in15 fractions starting on day 22.15 The outcomes in thechemoradiotherapy arm were similar to those of theGerman study, but the preoperative chemotherapy grouphad higher median and 3-year survivals. 15 Neither trialshowed an advantage for neoadjuvant chemoradiotherapyover neoadjuvant chemotherapy, although both trials

Intervention Control

Neoadjuvant chemoradiotherapy versus surgery alone

Nygaard9 8/53 (15%) 5/50 (10%)

Apinop39 3/35 (9%) 5/34 (15%)

Le Prise10 4/45 (9%) 3/41 (7%)

Urba40 1/50 (2%) 2/50 (4%)

Bossett12 17/148 (11%) 5/145 (3%)

Walsh13 (SCC) 5/29 (17%) 6/32 (19%)

Walsh14 (adenocarcinoma) 4/58 (7%) 1/55 (2%)

Burmeister22 5/128 (4%) 6/128 (5%)

Tepper16 0/30 (0%) 1/26 (4%)

Lv41* 3/80 (4%) 0/80 (0%)

Lee17 1/51 (2%) 1/50 (2%)

Mariette11 7/97 (7%) 1/98 (1%)

van der Gaast42 7/176 (4%) 7/188 (4%)

Neoadjuvant chemotherapy versus surgery alone

Roth23 2/19 (11%) 0/20 (0%)

Nygaard9 6/56 (11%) 5/50 (10%)

Schlag19 5/34 (15%) 4/41 (10%)

Maipang24 NR/24 NR/22

Law20 5/74 (7%) 6/73 (8%)

Boonstra37 4/85 (5%) 3/84 (4%)

Kelsen8 10/233 (4%) 13/234 (6%)

Ancona21 1/48 (2%) 2/48 (4%)

Allum1 36/400 (9%) 40/402 (10%)

Ychou7 5/113 (4%) 5/111 (5%)

Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy

Stahl18 6/60 (10%) 2/59 (3%)Burmeister15 0/39 (0%) 0/36 (0%)

Data are n/N (%). NR=not reported. SCC=squamous-cell carcinoma.

*Treatment-related death. Intervention=chemoradiotherapy,

control=chemotherapy. In-hospital mortality.

Table 2: Perioperative mortality (absolute 30-day or in-hospital

mortality) after chemotherapy or chemoradiotherapy


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closed prematurely and were consequently underpowered

to detect a significant survival advantage. We combinedthese two studies with the pooled results of theneoadjuvant chemoradiotherapy and neoadjuvantchemotherapy arms from the other analysed studies tocompare the survival benefits of neoadjuvant chemo-radiotherapy and neoadjuvant chemotherapy (n=2220).Figure 4 shows the estimates for all-cause mortality forthe two individual studies and the pooled indirectcomparison. The HR from the randomised comparisonswas 077 (95% CI 053112; p=017), in favour ofneoadjuvant chemoradiotherapy. From the indirectcomparison, the HR was 090 (077104; p=015).Combining the indirect and direct comparisons yieldedan overall HR of 088 (076101; p=007). Compared

with the direct comparison, the discrepancy of theindirect comparison (ie, ratio of the indirect and directHRs) was 17% larger (HR 117, 078175; p=045).

We also examined whether the potential benefit of theneoadjuvant treatment regimens was offset by a highermortality rate by comparing the benefit (HR) with theabsolute 30-day or in-hospital mortality difference (as apercentage) between the control and intervention arms(table 2 and figure 5). There was little association betweenrisk of postoperative mortality (in-hospital or 30-daypostoperative death) and the neoadjuvant interventions.

We examined the relation between the benefits achievedby the addition of neoadjuvant treatment and the outcomein the surgery alone group by plotting the logarithm ofthe HR against the absolute 2-year survival in the controlgroup for each trial. The webappendix p 2 shows thisfinding for chemotherapy and chemoradiotherapy. Asthe 2-year survival in the control group increased (a betterprognosis for patients in the trial), there seemed to be asmaller benefit from the intervention, but this was notstatistically significant (neoadjuvant chemoradiotherapyp=084; neoadjuvant chemotherapy p=082).

DiscussionSurvival benefits of neoadjuvant chemoradiotherapy andneoadjuvant chemotherapy were shown in the previousmeta-analysis by our group.6 This updated analysis

included updated data on previously published studiesand additional studies, with 43% more patients and about57% more events compared with the previous meta-analysis. The additional information has strengthened theevidence of a survival advantage of neoadjuvant therapycompared with surgery alone. In the present meta-analysis, there is evidence in favour of both neoadjuvantchemoradiotherapy and neoadjuvant chemotherapy beforesurgery. The evidence supporting the use of chemo-radiotherapy is not only stronger than previously reportedbut is also clear for both squamous-cell carcinoma andadenocarcinoma histologies. Neoadjuvant chemotherapyalso seemed to be associated with improvements in eachhistological subtype compared with surgery alone,although the treatment effects were not as large as for

chemoradiotherapy. Both treatment strategies causetoxicities that are well known and that potentially increasethe risk of surgical morbidity.

There is evidence that neoadjuvant chemoradiotherapyincreases the rate of complete resection,15,47 particularlyfor patients with locally advanced disease, although thisincrease has not always translated into a survival benefitin individual studies. The two most recent trials thatassessed neoadjuvant chemoradiotherapy have beenreported as abstracts only.11,42 In the larger Dutch trial,42there was a survival benefit for patients who hadneoadjuvant chemoradiotherapy with paclitaxel andcarboplatin weekly for 5 weeks with 414 Gy radiotherapycompared with those who had surgery alone. In theFrench trial,11 in which patients received the typical

Figure 5: Effect of chemoradiotherapy or chemotherapy on 30-day or in-hospital absolute mortality

Effect of chemoradiotherapy (A) and chemotherapy (B) compared with surgery alone in patients with

oesophageal carcinoma.

20

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rtalitydifference(%)

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Walsh adenocarcinoma14

Lv41

Tepper43Urba40

van der Gaast42

Walsh SCC13 Apinop39

Burmeister22

Mariette11

Bossett12Le Prise10

Nygaard9

Lee17

Roth23

Ancona21

Schlag19

Nygaard9

Kelsen8

Law20

Allum1Ychou7

Boonstra37


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combination of 45 Gy concurrent with two cycles of

cisplatin and fluorouracil for early-stage disease (stage 1or 2a, 68%), there was weak evidence of higherperioperative mortality with no difference in survivalcompared with patients who had surgery alone. Thedifferences in outcomes between these two studies mightbe because of the tumour stage, choice of chemotherapy,or both. In another study of neoadjuvant chemo-radiotherapy, taxanes were used.41 Compared with theDutch trial, a higher dose of radiotherapy (40 Gy in 2 Gyfractions over 4 weeks) and different schedule of paclitaxel(135 mg/m every 3 weeks for two cycles) was used. Thistrial also reported a survival benefit compared withsurgery aloneand supports the further development oftaxane-based chemoradiotherapy schedules.

The previous meta-analysis showed a proportionatelylarger benefit for chemoradiotherapy prior to surgerythan for chemotherapy prior to surgery, although bothwere associated with a survival benefit compared withsurgery alone. Many centres use the favourable results oflarge trials of neoadjuvant or perioperative chemotherapycompared with surgery alone (UK MAGIC,34MRC OEO2,1and FFCD 97037) to justify the exclusion of preoperativeradiotherapy in patients with adenocarcinoma of thelower oesophagus and oesophagogastric junction. Inupdating this meta-analysis, we sought to assess bothpotential benefits from the addition of radiotherapy tochemotherapy prior to surgery, and potential increases inmortality from the combined approach.

Only two studies that met the inclusion criteria for ourmeta-analysis have directly compared neoadjuvantchemoradiotherapy with neoadjuvant chemotherapy. Wewanted to quantify the relative survival benefits whenthese two treatment modalities were compared directly tobetter inform decisions on future trial design andtreatment decisions for individual patients. Therefore, toquantify any difference in outcome from adding radiationto preoperative chemotherapy, we compared the treatmentarms of the trials we have analysed. The indirectcomparison of neoadjuvant chemoradiotherapy withneoadjuvant chemotherapy showed weak evidence infavour of neoadjuvant chemoradiotherapy, but this

comparison might also have been prone to selection bias.Previous meta-analyses of chemoradiotherapy have

been criticised because of small sample sizes; heterogeneityof the tumour types, radiation doses, and chemotherapyregimens; methods of preoperative staging and treatmentdelivery; and adequacy of surgical resection.48 Assessmentof the early neoadjuvant chemotherapy trials might attractthe same criticisms. The benefit of adding radiotherapymight be at least in part due to improved locoregionalcontrol when suboptimal surgical resection has occurred.Evidence from multicentre data shows that lymph noderetrieval at resection affects outcome.49,50 Future trialsshould include modern staging methods to facilitateappropriate stratification of patients and measures forassessing the quality of surgery.

We took into account the possibility that any survival

gains from the addition of either neoadjuvantchemoradiotherapy or neoadjuvant chemotherapy beforesurgery might be offset by surgical mortality. The viewthat the overall survival advantage gained fromneoadjuvant treatment is offset by higher 30-daypostoperative or in-hospital mortality was not supported(table 2, figure 5, and webappendix p 2). Surgical morbiditywas inconsistently reported across trials and directcomparisons were not possible.

In trying to assess the relevant published work, anotherissue is the overlap between primary gastric,oesophagogastric junction, and lower oesophageal cancers.Assessment of the effects of neoadjuvant treatments onsurvival by tumour site was not possible in this analysis

(oesophagogastric junction vs lower oesophageal) forpatients with adenocarcinoma because most of theincluded studies did not provide this information. The roleof preoperative radiotherapy for oesophageal andoesophagogastric junction cancer is further confused bythe meta-analysis from Germany, reported in abstractform.51 This meta-analysis included all studies that assessedpatients with gastric, oesophageal, and oesophagogastricjunction adenocarcinoma who received preoperativechemotherapy with or without radiotherapy. Postoperativetherapy was not assessed. The authors concluded thatneoadjuvant chemotherapy is beneficial, but the subgroupanalysis that assessed the role of preoperative radiotherapywas underpowered because this modality was not used inthe patients with adenocarcinoma confined to the stomach.These patients reported the highest benefit foroesophagogastric junction cancers, but the statisticalpower of this subgroup analysis was low. This findinghighlights the need to differentiate and analyse separatelythe sites of adenocarcinomas in future trials.

Building on the results of the previous publication,6 thismeta-analysis has several strengths. Only minor publicationbias was noted, and sensitivity analyses suggested thatunpublished results would not alter conclusions forprimary resectable oesophageal cancers. This study alsocompared results of two neoadjuvant treatment strategies(neoadjuvant chemoradiotherapy and neoadjuvant

chemotherapy), although most of the weighted result camefrom the indirect comparison of pooled outcomes. In theindirect comparison, the surgery alone arms of all the trialswere assumed to be homogeneous, and although therewas nostatistical inconsistency between the results fromthe direct and indirect comparisons, this comparisonmight have been affected by selection bias and must beinterpreted with caution.

Investigation of the effects of heterogeneity of tumourstage was not possible; the benefits of neoadjuvantchemoradiotherapy (and even neoadjuvant radiotherapy)might exist only for locally advanced tumours(T2+ and N1+) where downstaging is likely to be greatest,with minimum or no benefit in early cancers (T1). Threetrials restricted enrolment to early-stage tumours,10,11,46 all


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of which examined neoadjuvant chemoradiotherapy

compared with surgery alone. Two of these trials onlyincluded squamous-cell carcinomas and used earlierstaging systems,10,46 and the other, more recent trial11included both adenocarcinoma and squamous-cellcarcinoma. None of these trials reported survival benefitsfor the intervention, and the study by Mariette andcolleagues11 reported a significant survival benefit infavour of the control arm. These trials used differentradiation doses, chemotherapy schedules, and stagingsystems. None used endoscopic ultrasound or PETroutinely; therefore firm conclusions as to whether theabsence of benefit in these trials is a result of diseasestage or the treatment given are diffi cult. An individualpatient data meta-analysis that examined the role of

neoadjuvant therapy over surgery alone in more detailaccording to histology and tumour site would be of valuein investigating these questions. Other potentiallimitations have been discussed previously.6

The optimum neoadjuvant treatment regimen has notbeen established, because included trials used differentdrugs, doses, and schedules of chemotherapy andradiotherapy. The inclusion of chemoradiotherapy armsin future trials of neoadjuvant treatments is supported bythe results of this meta-analysis. Treatment decisions forindividual patients should take into account the risk ofmorbidity from neoadjuvant therapy, and the effects ofeach treatment on quality of life should be considered,which was not done in these analyses. The focus of futuretrials should be on identification of the optimum regimenof neoadjuvant therapy and should aim to minimisetreatment toxicities and effect on quality of life, as well asattempt to identify and select those patients most likely tobenefit from specific treatment options.

Based on present eveidence, neoadjuvant chemo-radiotherapy improves survival compared with surgeryalone for patients with operable oesophageal cancer.Neoadjuvant chemotherapy is also associated withimprovements in survival compared with surgery aloneand can be deemed a standard treatment. Although thebenefit for neoadjuvant chemotherapy was not as greatas for neoadjuvant chemoradiotherapy, a clear advantage

has not been established and further randomised trialscomparing these two strategies directly are warranted.

Contributors

KMS, BHB, BMS, JRZ, RJS, and VG designed the study. KMS and VGdid the literature search, created the figures, and extracted data. KMS,BHB, BMS, AB, and VG collected and contributed data. All authorsinterpreted and analysed the data and wrote the manuscript.

Conflicts of interest

JRZ is a board member of Australasian Gastro-Intestinal Trials Group(AGITG) who pay for his travel to meetings. JRZ and RJS receive grantfunding from Cancer Australia and Cancer Institute (NSW) to theNational Health and Medical Research Council Clinical Trials Centre andAGITG as program grants or infrastructure funding. All other authorsdeclare that they have no conflicts of interest.

Acknowledgments

This meta-analysis was funded by grants from Cancer Australia and theNSW Cancer Institute to the National Health and Medical Research

Council Clinical Trials Centre and the Australasian Gastro-Intestinal TrialsGroup. We thank Rhana Pike, who is funded by the Australian National

Health and Medical Research Council Clinical Trials Centre, for hervaluable assistance with the report; Kathryn Winter for providing resultson behalf of the RTOG from their study RTOG 8911; Jurjien Boonstra forproviding results from his updated manuscript; Sally Stenning andDavid Cunningham for providing information on the oesophageal cancersubgroup from the MAGIC trial on behalf of the Medical ResearchCouncil; and Stephen Thompson for advice on the concept.

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