META ANALYSES

Meta-Analysis of D1 Versus D2 Gastrectomy

for Gastric Adenocarcinoma
Muhammed Ashraf Memon, MBBS, MA Clin Ed, DCH, FRCSI, FRCSEd, FRCSEng, FRACS,∗ †‡§
Manjunath S. Subramanya, MBBS, MRCS, Shahjahan Khan, PhD,¶ Md Belal Hossain, MSc,¶
Emma Osland, BHSc, M Phil,∗ ¶ and Breda Memon, RGN, LLB, PGCEd∗

Objectives: To conduct a meta-analysis of randomized controlled trials eval-

uating the efficacy and drawbacks of limited (D1) versus extended lym-
G astric adenocarcinoma is a locoregional disease with a high
propensity for nodal metastasis. Therefore, nodal status remains
1 of the most critical independent predictors of patient’s survival af-
phadenectomy (D2) for proven gastric adenocarcinoma.
ter gastrectomy for this disease.1,2 Studies have shown that lymph
Methods: A search of Cochrane, Medline, PubMed, Embase, Science Cita-
node involvement occurs in 3% to 5% of cases when gastric cancer
tion Index and Current Contents electronic databases identified randomized
is limited to the mucosa; 11% to 25% of cases for those limited to
controlled trials published in the English language between 1980 and 2008
the submucosa; 50% for T2 cancers and 83% for T3 cancers.3,4 D1
comparing the outcomes of D1 versus D2 gastrectomy for gastric adenocar-
gastrectomy entails removing lymph nodes adjacent to the stomach
cinoma. The meta-analysis was prepared in accordance with the Preferred
(stations 1 to 6, N1 level), D2 dissection extends this resection to
Reporting Items for Systematic reviews and Meta-analyses statement. The
include the nodes around the branches of the celiac axis (stations 7
6 outcome variables analyzed included length of hospital stay; overall com-
to 11, N2 level) whereas D3 dissection removes lymph nodes from
plication rate; anastomotic leak rate; reoperation rate; 30-day mortality rate
station 12 to 20 (N3 level) as per second edition of Japanese Clas-
and 5-year survival rate. Random effects meta-analyses were performed using
sification of Gastric Carcinoma.5 Metastases are expected be found
odds ratios (OR) and weighted mean differences (WMD).
in 8 to 31%, and 40% of N2 lymph nodes in T2 and T3 tumors
Results: Six trials totaling 1876 patients (D1 = 946, D2 = 930) were analyzed.
respectively. Therefore for T2 and T3 tumors, D1 dissection may
In 5 of the 6 outcomes the summary point estimates favored D1 over D2 group
inadequately stage a substantial portion of patients and leads to non-
with a statistically significant reduction of (i) 6.37 days reduction in hospital
curative intervention leading to poor patient outcome. In spite of
stay (WMD –6.37, confidence interval [CI] –10.66, –2.08, P = 0.0036);
these facts, the relative merits of gastrectomy with limited (D1) ver-
(ii) 58% reduction in relative odds of developing postoperative complications
sus extended lymphadenectomy (D2) as an oncological treatment of
(OR 0.42, CI 0.27, 0.66, P = 0.0002); (iii) 60% reduction in anastomotic
gastric adenocarcinoma remains contentious and unpopular except
breakdown (OR 0.40, CI 0.25, 0.63, P = 0.0001); (iv) 67% reduction in
in Asian countries.6 This is because D2 resection is technically de-
reoperation rate (OR 0.33, CI 0.15, 0.72, P = 0.006); and (v) 41% reduction
manding, has a steep learning curve and its benefits remain doubtful
in 30-day mortality rate (OR 0.59, CI 0.40, 0.85, P = 0.0054). Lastly there
based on a number of randomized controlled trials (RCTs) published
was no significant difference in the 5-year survival (OR 0.97, CI 0.78, 1.20,
to date.7–13 The majority of Western surgeons therefore continue to
P = 0.7662) between D1 and D2 gastrectomy patients.
practice D1 resection achieving a 5-year survival rate of 10% to 30%.9
Conclusions: On the basis of this meta-analysis we conclude that D1 gas-
On the other hand surgeons in Asian surgical centers (most notably
trectomy is associated with significant fewer anastomotic leaks, postoperative
Japan) routinely perform D2 gastrectomy achieving an impressive 5-
complication rate, reoperation rate, decreased length of hospital stay and 30-
year survival of 50% to 60% with a low morbidity and mortality.14,15
day mortality rate. Finally, the 5-year survival in D1 gastrectomy patients was
However, the greatest criticism of these reports from Japan (and the
similar to the D2 cohort.
East) demonstrating such an impressive benefit and modest morbid-
(Ann Surg 2011;253:900–911) ity and mortality from D2 resection has been the retrospective nature
of the data. Nonetheless the continuing debate on D1 versus D2 has
lead some researchers to address this issue objectively in the form
From the ∗ Department of Surgery, Ipswich Hospital, Ipswich, Queensland, Aus- of well-designed RCTs,7–13 however this has further polarized the lit-
tralia; †Mayne Medical School, School of Medicine, University of Queensland, erature on this subject due to conflicting results obtained. Therefore
Brisbane, Queensland, Australia; ‡Faculty of Health Sciences and Medicine, this meta-analysis which was prepared in accordance with the “Pre-
Bond University, Gold Coast, Queensland, Australia; §Faculty of Health and ferred Reporting Items for Systematic reviews and Meta-analyses”
Social Science, Bolton University, Bolton, Lancashire, UK; and ¶Department
of Mathematics and Computing, Australian Centre for Sustainable Catchments, statement16 has been undertaken to develop a better understanding of
University of Southern Queensland, Toowoomba, Queensland, Australia. these 2 approaches for the treatment of gastric cancer by pooling data
Reprints: Professor Muhammed Ashraf Memon, FRCS, FRACS, Ipswich Hospi- from all of the available RCTs published to date.
tal, Chelmsford Avenue, Ipswich, Queensland, Australia. E-mail: mmemon@
yahoo.com.
The authors did not receive any financial support or commercial sponsorship. MATERIAL AND METHODS
Conception and design: Muhammed Ashraf Memon. Furthermore, he takes full re-
sponsibility for the integrity of the work as a whole, from inception to published Literature Search and Study Selection
article; Acquisition, compilation, and interpretation of the data: Manjunath S. RCTs of any size that compared outcomes of D1 with D2 gas-
Subramanya, Breda Memon, Muhammed Ashraf Memon; Shahjahan Khan trectomy for the treatment of gastric adenocarcinoma between Jan-
and Md Belal Hossain were responsible for statistical analysis of this article
including writing R codes, interpretation of the results and computer output of
uary 1980 and December 2008 in full peer-reviewed journals were
the data. All authors were involved in drafting the manuscript and revising it considered for inclusion (Fig. 1). Only those studies which have re-
critically for important intellectual content and have given final approval of the ported on at least 1 clinically relevant outcome were included. Unpub-
version to be published. Furthermore, all authors have participated sufficiently lished RCTs, nonrandomized prospective and retrospective compar-
in the work to take public responsibility for its content.
Copyright  C 2011 by Lippincott Williams & Wilkins
ative trials were excluded. Furthermore abstracts of RCTs presented
ISSN: 0003-4932/11/25305-0900 at national and international meetings were also excluded to prevent
DOI: 10.1097/SLA.0b013e318212bff6 the duplication of data. Studies not published in English were also

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Annals of Surgery r Volume 253, Number 5, May 2011 Meta-Analysis of D1 Versus D2 Gastrectomy for Gastric Adenocarcinoma
FIGURE 1. Flow chart providing information through the different phases of systematic review.
excluded. Finally, studies which reported on gastric cancers other
than adenocarcinoma such as lymphomas were excluded because of
different biological behavior and treatment options for these tumors.
Type of Participants
Adult patients requiring surgical intervention for histologically
proven gastric adenocarcinoma were the target population for this
meta-analysis.
Types of Intervention
Surgical interventions assessed the differences in outcomes
between D1 gastrectomy (limited lymphadenectomy) and D2 gas-
trectomy (extended lymphadenectomy) as curative management for
gastric adenocarcinoma.
Types of Outcome Measures Analyzed
The 6 outcome variables analyzed included (a) length of hos-
pital stay; (b) overall complication rate; (c) anastomotic leak rate;
(d) reoperation rate; (e) 30-day mortality rate; and (f) 5-year survival
rate. These outcomes were thought to be important because they ex-
ert influence over practical aspects of surgical practice and policy
decisions within institutions.
Data Collection
Trials were identified by conducting a comprehensive search
of Medline, Embase, Science Citation Index, Current Contents and
PubMed databases, using medical subject headings “D1 gastrectomy,”
“D2 gastrectomy,” “gastric cancer,” “comparative study,” “prospective

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Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
studies,” “randomized controlled trials,” “random allocation,” and
“clinical trial”. Manual search of the bibliographies of relevant articles
was also carried out to identify trials for possible inclusion (Fig. 1).
Data extraction and critical appraisal were carried out by 3 authors
(MSS, BM, and MAM) for compliance with inclusion criteria and
methodological quality. Standardized data extraction forms17 were
used by authors to independently and blindly summarize all the data
available in the RCTs meeting the inclusion criteria. The authors
were not blinded to the source of the document or authorship for the
purpose of data extraction. The data were compared and discrepancies
were addressed with discussion until consensus was achieved.
Methodological Quality
Evaluation of methodological quality of identified studies was
conducted using the Jadad scoring system18 in which each study was
assigned a score of between zero (lowest quality) and 5 (highest qual-
ity) based on reporting of randomization, blinding, and withdrawals
reported within the study period.
STATISTICAL ANALYSIS
Meta-analyses were performed using odds ratios (ORs) for
binary outcomes and weighted mean differences (WMDs) for con-
tinuous outcome measures. A slightly amended estimator of OR was
used to avoid the computation of reciprocal of zeros among observed
counts/values in the calculation of the original OR.19 Random ef-
fects models using the inverse variance weighted method approach
were used to combine the data.20 Heterogeneity among studies was
assessed using the Q statistic proposed by Cochran20–22 and I2 index
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Memon et al
introduced by Higgins and Thompson.23,24 For the computations of
the confidence intervals (CI) estimates of mean and standard devia-
tion are required. However, some of the published clinical trials did
not report the mean and standard deviation, but rather reported the
size of the trial, the median and range. From these available statis-
tics, estimates of the mean and standard deviation were obtained
using formulas proposed by Hozo et al.25 Funnel plots were obtained
to determine the presence of publication bias in the meta-analysis.
Both total sample size and precision (reciprocal of the standard error)
were plotted against the treatment effects (log OR for the dichoto-
mous variables and WMD for the continuous variables).20,26,27 All
estimates were obtained using computer programs written in R.28 All
plots were obtained using the “rmeta” package.29 In the case of tests
of hypotheses, the article reports the value of the test statistics and as-
sociated P-values for different study variables. Effect measures have
been considered to be statistically significant if the P-value is less
than or equal to 5%. Ninety-five percent CI are presented for each
effect measure.
RESULTS
There was almost a perfect agreement (κ = 0.99) between the
3 authors (MSS, BM, MAM) regarding the inclusion and exclusion
of various RCTs. On the basis of this agreement, a total of 6 RCTs
(Europe = 3, Asia = 2, Africa = 1)7–12 that included 1876 gas-
trectomies (D1 = 946 and D2 = 930) were considered suitable for
meta-analysis (Table 1).
Description of Various RCTs Including Inclusion and
Exclusion Criterias
The study size in half of these RCTs was less than 100 patients
in each arm except for the United Kingdom10 (200 each arm), Dutch9
(>300 each arm), and Taiwanese12 (>100) trials (Table 1). All the
patients had histologically proven gastric adenocarcinoma by endo-
scopic biopsies before being enrolled in the trial. They also had a
preoperative cancer staging predominantly via computerized tomog-
raphy, and less frequently with ultrasound scan. The patients were
also excluded from the study if distant metastases involving liver or
lungs were found during preoperative staging; if they had inoperable
gastric cancer at laparotomy; were >80 or <20 years of age; had
severe co-morbidities (ASA ≥ 4), and if they had a history of pre-
vious gastric surgery. The inclusion criteria were (a) tumor stage (S)
0 to 2; (b) absence of macroscopic involvement of liver, peritoneum
or adjacent organs (T < 4); (c) absence of N2 nodal involvement;
(d) absence of malignant cells in peritoneal washing during surgery;
(e) absence of macroscopic residual tumor (R0); and (f) absence of
oesophageal or duodenal involvement. A surgical resection margin
of at least 5 cm, both proximally and distally was considered mini-
mum in all the RCTs except for the UK study10 where the minimum
margins of 2.5 cm were considered adequate.
The dissection was carried out in accordance with the guide-
lines of Japanese Research Society for Gastric Cancer (JRSGC)5
and the extended procedure was performed according to Maruyama
technique.30 A minimum of 25 retrieved nodes were considered es-
sential for the definition of proper D2 dissection in the Italian trial.11
Pancreatic and splenic resection was carried out according to
JRSGC criteria5 except in the Italian trail11 where distal pancrea-
tectomy and/or splenectomy were performed if these organs were
involved by the cancer (Table 1).
Description of Quality Control for Performing
D2 Gastrectomy
The surgeons involved in various RCTs had diverse experience
in performing gastrectomies before the start of the trial. Surgeons
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Annals of Surgery r Volume 253, Number 5, May 2011
from Italy and Taiwan were trained by Japanese gastric surgeons
and achieved the required competency of at least 25 independent D2
gastrectomies before the start of the trial.11,12 Surgeons from Hong
Kong8 and the Netherlands9 were trained in D2 gastrectomy dur-
ing the trial by Japanese surgeons whereas South African7 and the
United Kingdom10 surgeons had no dedicated training in performing
D2 gastrectomy. Lymph node dissection, which has been proven to
be crucial in Japanese practice, was carried out in accordance with
JRSGC guidelines5 in most of the studies. However there were signif-
icant breaches and contamination of this protocol in the Dutch trial31
and it is highly likely that the UK trial may have suffered the similar
fate. Therefore the role of learning curve in radical gastric resection
and its impact on the overall results remains a major issue of concern.
Publication Bias
Funnel plots (precision vs. WMD or log OR) demonstrate
asymmetry for length of hospital stay and postoperative complica-
tions suggesting the presence of publication bias for these outcomes
(Fig. 2).23,24 No points fall outside of the 95% confidence interval
limits for anastomotic leak, reoperation, mortality or 5-year sur-
vival, suggesting the absence of publication bias for these outcomes
(Fig. 2).
Methodological Quality
In general, the quality of the studies was poor on critical ap-
praisal (mean Jadad score of 2 of 5; Table 2). All RCTs reported an
appropriate method of randomization. None of the studies reported
on blinding. The inability to blind participants and investigators to
surgical interventions is a common limitation to the application of
traditional methodological quality assessments in surgical research:
this has been observed in other reviews and meta-analyses of surgical
trials.32–34 A description of withdrawals and drop-outs was not always
evident in the included studies; however there should be no obstacle
to the reporting of this information.
Outcomes Assessed
Six trials totaling 1876 patients (D1 = 946, D2 = 930) were
analyzed. In 5 of the 6 outcomes the summary point estimates favored
D1 over D2 group with a statistically significant reduction of (i) 6.37
days reduction in hospital stay (WMD –6.37, CI –10.66, –2.08, P
= 0.0036; Fig. 3); (ii) 58% reduction in relative odds of developing
postoperative complications (OR 0.42, CI 0.27, 0.66, P = 0.0002;
Fig. 4); (iii) 60% reduction in anastomotic breakdown (OR 0.40, CI
0.25, 0.63, P = 0.0001; Fig. 5); (iv) 67% reduction in reoperation rate
(OR 0.33, CI 0.15, 0.72, P = 0.006; Fig. 6); and (v) 41% reduction
in 30-day mortality rate (OR 0.59, CI 0.40, 0.85, P = 0.0054; Fig.
7). Finally, there was no significant difference in the 5-year survival
(OR 0.97, CI 0.78, 1.20, P = 0.7662; Fig. 8) between D1 and D2
gastrectomy patients. Table 3 summarizes the pooled data for D1 and
D2 gastrectomy.
Significant heterogeneity, as evidenced by the values of the
Q statistic and I2 index, was found to be present in both length of
hospital stay and complication rate outcome measures (Q = 36.34,
P = 0.0001, I2 = 86.2%; and Q = 11.85, P = 0.037, I2 = 57.8%,
respectively). No heterogeneity was detected for any other outcome
assessed (Table 3).
DISCUSSION
Gastric adenocarcinoma survival is proportional to the level
of lymph node metastases in nodal echelons N1 to N4 based on
the nodal classification by the JRSGC.5 Surgeons in Asian surgi-
cal centers have routinely practiced D2 gastrectomies involving ex-
tended lymphadenectomy which provides both diagnostic and thera-
peutic advantage.14,15 However surgeons in the West have struggled

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Meta-Analysis of D1 Versus D2 Gastrectomy for Gastric Adenocarcinoma

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TABLE 1. Salient Features of 6 RCTs
Authors Dent et al7 Robertson et al8 Bonenkamp et al9 Cuschieri et al10 Degiuli et al11 Wu et al12
Year 1988 1994 1995 1999 2004 2006
Country South Africa Hong Kong Netherlands UK Italy Taiwan
Pts (M,F) D1 M = 12, F = 10 M = 20, F = 5 M = 216, F = 164 M = 132, F = 68 M = 39, F = 37 M = 84, F = 26
D2 M = 15, F = 6 M = 22, F = 7 M = 188, F = 143 M = 138, F = 62 M = 48, F = 38 M = 86, F = 25
Age (yr) D1 45.1∗ 60 64.9 67 64 68
D2 55.8∗ 58 63.1 67 61.4 67
Pathological Tumor T0 D1 = 0, D2 = 0 D1 = 0, D2 = 0 D1 = 2, D2 = 3 D1 = 0, D2 = 0 D1 = 0, D2 = 0 D1 = 0, D2 = 0
T1 D1 = 6, D2 = 7 D1 = 10, D2 = 9 D1 = 98, D2 = 85 D1 = 48, D2 = 40 D1 = 27, D2 = 27 D1 = 23, D2 = 20
Stage T2 D1 = 5, D2 = 5 D1 = 7, D2 = 8 D1 = 181, D2 = 152 D1 = 63, D2 = 69 D1 = 23, D2 = 28 D1 = 26, D2 = 20
T3 D1 = 11, D2 = 14 D1 = 8, D2 = 10 D1 = 94, D2 = 82 D1 = 84, D2 = 86 D1 = 26, D2 = 31 D1 = 56, D2 = 59
T4 D1 = 0, D2 = 0 D1 = 0, D2 = 2 D1 = 3, D2 = 9 D1 = 0, D2 = 0 D1 = 0, D2 = 0 D1 = 5, D2 = 3
Tx D1 = 0, D2 = 0 D1 = 0, D2 = 0 D1 = 2, D2 = 0 D1 = 5, D2 = 5 D1 = 0, D2 = 0 D1 = 0, D2 = 0
Pancreatectomy D1 0 0 10 8 1 1
D2 0 29 98 113 3 13
Splenectomy D1 0 0 41 62 4 4
Annals of Surgery r Volume 253, Number 5, May 2011

D2 0 29 124 131 12 14
Type of Gastrectomy Subtotal D1 = 18, D2 = 19 D1 = 25, D2 = 0 D1 = 264, D2 = 203 NA D1 = 57, D2 = 64 D1 = 80, D2 = 88
Total D1 = 4, D2 = 2 D1 = 0, D2 = 29 D1 = 115, D2 = 126 NA D1 = 19, D2 = 22 D1 = 30, D2 = 23
Blood Transfusion D1 4 (total units) 0 (median no of units) 113 (no of pts) NA NA Less (exact no NA)
D2 25 (total units) 2 (median no of units) 170 (no of pts) NA NA More (exact no NA)
Primary outcome Morbidity & mortality Morbidity and mortality Morbidity and mortality Morbidity and mortality Morbidity and mortality Morbidity and mortality
Secondary outcome None Long-term survival Long-term survival Long-term survival Long-term survival Long-term survival

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No 5 or 10 year data available 10 and 15 yr data available 5 year data available 5 year data available 5 year data available
∗
Mean (rest are median).
F, female; M, male; n, number; NA, not available.


Memon et al Annals of Surgery r Volume 253, Number 5, May 2011

FIGURE 2. Funnel plots demonstrate asymmetry for postoperative complications and length of hospital stay suggesting the
presence of publication bias No points fall outside of the 95% CI limits for any other variables suggesting the absence of
publication bias.

of gastric cancer and therefore scant opportunities even in large ter-

TABLE 2. Jadad’s Score
tiary referral centers to perform more radical forms of gastrectomy;41
Jadad’s (b) lack of training in performing D2 resection compared with their
Authors Score Randomization Blinding Withdrawal Japanese counterpart; (c) technical demands of performing D2 gas-
trectomies with unproven benefits based on a number of RCTs7–12
Dent et al7 2 2 0 0
published to date; and (d) fear of increased risk of complications and
Robertson et al8 2 2 0 0
even deaths.7–12 Wu et al42 have found that surgical morbidity and
Bonenkamp et al9 2 2 0 0 mortality rates decrease only after 200 radical gastric resections. In
Cuschieri et al10 2 2 0 0 the West achieving this type of number in radical gastrectomy would
Degiuli et al11 2 2 0 0 be a daunting task even in a tertiary referral center due to the low inci-
Chew-Wun Wu et al112 2 2 0 0 dence of gastric cancer and consequent indication for these surgeries.
The incidence of gastric cancer has steadily decreased in the last 4
decades in most Western countries, Japan and USA,43–46 which ham-
to achieve similar outcomes with D2 gastrectomies compared with pers gaining surgical experience in gastric surgery. However, Japan
their eastern counterparts except on occasion.35–40 There could be a still has the highest age-standardized rates of gastric cancer compared
number of reasons for this disparity. Surgeons from the West have con- with other countries.43–46 This fact when combined with early cancer
ventionally preferred the D1 approach because of (a) lower incidence detection using nationwide endoscopic screening program has led to

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Annals of Surgery r Volume 253, Number 5, May 2011 Meta-Analysis of D1 Versus D2 Gastrectomy for Gastric Adenocarcinoma

FIGURE 3. Forest plot for length of hospital stay favoring D1. The text and values, on the left, are study identification, mean
(standard deviation), weighted mean difference (WMD) and the lower (LL) and upper limits (UL) of 95% confidence interval (CI).
In the graph, squares indicate point estimates of treatment effect (WMD, ie, mean for D1 and D2 patients) with the size of the
squares representing the weight attributed to each study. The horizontal lines represent 95% CI for mean differences. The pooled
estimate of hospital stay (days) is the WMD, obtained by combining all mean differences using the inverse variance weighted
method and is represented by the diamond. The (horizontal) length of the diamond depicts the 95% CI. Values to the left of the
vertical line favor D1.

FIGURE 4. Forest plot for postoperative complications favoring D1. The text and values, on the left, are study identification,
number of cases (n), sample sizes (N), odds ratio (OR), and lower (LL) and upper limits (UL) of 95% confidence interval (CI).
In the graph, squares indicate point estimates of treatment effect (odds ratio for D1 over D2 groups) with the size of the
squares representing the weight attributed to each study. The horizontal lines represent 95% CI for OR. The pooled estimate for
postoperative complications is the pooled OR obtained by combining all ORs of the 5 studies using the inverse variance weighted
method, and is represented by the diamond. The horizontal length of the diamond depicts the 95% CI. Values to the left of the
vertical line favor D1.

extensive and continuing experience with surgical resection of the
stomach for the treatment of gastric cancer. Furthermore, early gas-
tric cancer is encountered more often in Japan which when treated
with extended lymphadenectomy (ie, D2 gastrectomy) has the 5-year
survival rate of >95%.47–49 Additionally Japanese patients tend to be
younger and have fewer co-morbidities as compared with their West-
ern counterparts and therefore radical gastrectomy in Asian practice
is the norm rather than the exception. Because of the above reasons
and the fact that Japanese surgeons have been practicing D2 resection
for a longer period of time has lead to an extensive surgical expe-
rience in the more radical forms of gastrectomy. This implies that
the superior surgical results reported in the Asian literature for D2
gastrectomy are achieved as a result of a greater degree of technical
experience through increased exposure over a prolonged period of
time.
A number of RCTs7–12 have been undertaken to investigate
the issues of efficacy and drawbacks of limited versus extended lym-
phadenectomy. Two of these largest RCTs have been published from
the European centers9,10 where the experience of participating sur-
geons in radical gastric surgery has been minimal. The landmark
trial from the Netherlands conducted an evaluation of their first 389
patients to identify factors leading to protocol deviations, ie, non-
compliance (ie, performance of less dissection than specified) and
contamination (ie, performance of more extensive dissection than
specified).50 These violations have an impact on the feasibility of
the trial and the reliability of TNM staging in general. The propor-
tion of patients operated on with curative intent was 66% (ie, 255
patients). Noncompliance occurred in 84% of D1 and D2 cases. In
D1 gastrectomy, noncompliance was only minor (1 to 2 stations) in
75% of the cases (vs. 51% in D2), whereas in D2 gastrectomy, major


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Memon et al
FIGURE 5. Forest plot for anastomotic leak favoring D1.
FIGURE 6. Forest plot for reoperation favoring D1.
FIGURE 7. Forest plot for mortality favoring D1.
noncompliance (≥3 stations) occurred in 33% of the cases (vs. 9% in
D1). Contamination occurred in 48% of the D1 and 52% of D2 cases
and the magnitude of contamination was modest and distributed over
D1 and D2 gastrectomy. In D1 and D2 cases, contamination was re-
stricted to 1 or 2 stations in 45% of the cases. Contamination occurred
at 3 stations in only 3% of the D1 cases. The results showed substantial
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Annals of Surgery r Volume 253, Number 5, May 2011
protocol violations by the surgical-pathologic teams due to extend-
ing or limiting lymphadenectomy, leading either to undertreatment
or overtreatment in both the D1 and D2 groups impacting both short
and long-term results (ie, locoregional recurrences and overall sur-
vival). Finally, the protocol deviations also have an impact on accurate
TNM staging (stage migration).51 Therefore, one can summarize that

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Annals of Surgery r Volume 253, Number 5, May 2011 Meta-Analysis of D1 Versus D2 Gastrectomy for Gastric Adenocarcinoma

FIGURE 8. Forest plot for 5-year survival indicating no advantage for either group.

TABLE 3. Summary Statistics of Pooled Data Comparing D1 versus D2 Gastrectomy

Test for Overall Effect Test for Heterogeneity
Pooled OR or WMD
Outcome Variables (95% CI) Z P value Q P value I2 Index (CI)
Length of hospital stay −6.37 (−10.66, −2.08) −2.9097 0.0036 36.34 0.0001 86.2% (72.2%; 93.2%)
Complication rate 0.42 (0.27, 0.66) −3.7635 0.0002 11.85 0.0369 57.8% (0%; 82.9%)
Anastomotic leak rate 0.40 (0.25, 0.63) −3.9633 0.0001 1.72 0.8868 0% (0%; 26.1%)
Reoperation rate 0.33 (0.15, 0.72) −2.7485 0.006 3.52 0.3179 14.8% (0%; 87%)
30-day mortality rate 0.59 (0.40, 0.85) −2.7795 0.0054 1.86 0.8684 0% (0%; 31.7%)
5-year survival rate 0.97 (0.78; 1.20) −0.2973 0.7662 1.67 0.797 0% (0%; 50.1%)

surgical inexperience and the learning curve occurring throughout
the trial may have impacted the overall results in both arms of these
studies. Other confounding factors include patient population and
their selection, operative techniques and outcome descriptors have
fuelled the ongoing debate on the risks and benefits of D1 versus D2
gastrectomy despite reasonable attempts being made by the authors
to provide trials of high quality. The authors of this article have un-
dertaken a meta-analytical review based on the available RCTs data
in an attempt to provide some clarification. To date D2 gastrectomy
has shown better results than D1 gastrectomy in mainly retrospective
studies.39,40,52 However, this has not been seen in 2 of the largest
RCTs published from Europe.9,10 In the Dutch trial,53 where the me-
dian duration of follow-up was 15 years, survival rates were 21% for
D1 and 29% for D2 groups (which were not statistically significant).
The risk of local and regional recurrence were 22% and 19% for D1
and 12% and 13% for D2 which were not significantly different as
well. These results when viewed in the context of noncompliance or
contamination in the extent of lymphadenectomy performed in Dutch
RCT31,50,54 needs to be interpreted with extreme caution.
All 6 studies7–12 have reported on the length of hospital stay.
Of these, 5 had a significantly longer hospital stay for D2 group
compared with D1 group (Fig. 3). The reasons for the longer stay
in D2 cohort could be multiple and include (a) prolonged and more
complex surgical procedures; (b) more perioperative complications;
(c) the higher rate for reoperation; and (d) greater amount of blood
transfusions.7–9,12 Four of 6 RCTs7–9,12 have consistently shown a
statistically significant higher requirement for transfusion in D2 pa-
tients. Perioperative blood transfusion has a negative impact on the
length of hospital stay and increases morbidity and mortality. This
is because it exposes the patients to acute or delayed adverse effects
such as acute lung injury, volume overload, hypothermia, graft ver-
sus host disease, and immunomodulatory effects. The greater length
of stay has a negative impact on cost and efficiency in the surgical
units, exposing patients to further hospital acquired complications
and imparts a higher overall cost to the procedure. On the other
hand, early-discharge is associated with lower direct medical, direct
nonmedical, and indirect costs leading to significant cost savings.
Furthermore, early discharge reduces the pressure on hospital bed
occupancy. This in turn increases the efficiency and turnover of elec-
tive surgical procedures with positive impact on health care finances.
These issues (ie, of cost and efficiency) have not been addressed in
any of the RCTs.
All 6 trials7–12 have reported significantly higher complication
rates for D2 group (Fig. 4). The pooled data is also in line with these
RCTs (Table 3). Complications ranged from simple wound infection,
intraabdominal abscess formation to anastomotic leak. Different stud-
ies have enumerated complications on different bases, which made
summation of the results difficult. Most of the studies have reported
complication under 2 major headings, surgical and nonsurgical (Table
4). Among the surgical complications, intraabdominal or subphrenic
abscess formation was not only commonly seen but also required
reoperation in the majority of cases. The high incidence of sub-
phrenic abscess in the D2 cohort may be related to pancreatic injury
(duct leakage, direct pancreatic injury or ischaemia).7–12 The intraab-
dominal sepsis was also responsible for other complications such
as secondary haemorrhages and death.11 These complications were
seen exclusively in D2 group. Similarly in various nonrandomized
comparative studies, D2 patients seem to have a higher incidence


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Memon et al Annals of Surgery r Volume 253, Number 5, May 2011

TABLE 4. Surgical and Nonsurgical Complications of RCTs

Authors Surgical Complications Nonsurgical Complications
Type D1 D2 Type D1 D2
Dent et al7 Wound Infection 0 0 Pulmonary 3 3
Retrocolic intestinal hernia 0 1
Subphrenic abscess 0 1
Gastrojejunal leak 0 1
Colonic infarction 0 1
Robertson et al8 Subphrenic abscess 0 14 DVT 0 0
Haemorrhage 0 3 PE 0 0
Oesophagojejunal leak 0 3
Bonenkamp et al9 Haemorrhage 8 15 Pulmonary 23 49
Wound infection/dehiscence 15 30 Cardiac 14 17
Anastomotic leaks 16 30 UTI 6 5
Intraabdominal infection 30 55 Thromboembolic 2 7
Pancreatic leak 3 10
Cuschieri et al10 Haemorrhage 6 4 Pulmonary 5 8
Anastomotic leak 11 26 Cardiac 2 8
PE 1 1
Degiuli et al11 Duodenal stump leak 0 1 Pulmonary 2 7
Pancreatic leak 1 1 Cardiac 2 0
Colonic perforation 1 0
Acute pancreatitis 0 2
Haemorrhage 2 1
Abdominal abscess 0 2
Wu et al12 Abdominal abscess 0 9 Cardiac 0 1
Anastomotic leaks 0 5 Post-op psychosis 1 0
Duodenal stump leak 0 1 Renal failure 1 0
Pnacreatic fistula 0 1 Thermal injury 1 0
Chylous leak 0 1
Bleeding 0 1
Cholecystitis 1 0
Wound infection 2 5
Splenic injury 6 19

of intraabdominal sepsis and other complications.55,56 Among the
nonsurgical complications, pulmonary and cardiac were the 2 most
common ones seen in both groups.
All 6 trials7–12 have reported on anastomotic leak rate (Fig.
5) which was higher in the D2 group. The overall pooled data also
confirmed this finding. The United Kingdom10 and the Dutch9 trials,
however have not provided any information on the site(s) of these
leaks or following which procedures (such as distal or total gastrec-
tomy) these leaks occurred. In the Hong Kong study8 3 anastomotic
leaks were recorded, all in D2 group at oesophagojejunal junction (ie,
after a total gastrectomy) which were treated conservatively with total
parenteral nutrition with favorable outcome. In the Taiwanese trial,12
5 leaks were recorded all in D2 group. Three were at gastrojejunal
site, whereas 2 at oesophagojejunal site. All of these were minor
according to the authors and were managed conservatively with
nutritional support.
Disappointingly not all the RCTs (especially the 2 larger
ones9,10 ) have documented their operating time for the D1 and D2
groups. Dent et al,7 Robertson et al,8 and Wu et al12 have shown
statistically significant longer operating time for D2 gastrectomy. A
protracted operating time exposes the patient to a longer duration of
anesthesia, and a greater risk of thermic, thromboembolic, cardiac,
and respiratory complications. In addition, it negatively impacts on
the efficiency of the operating staff and the operating complex as a
whole, and imparts a higher overall cost to the procedure.
Four of the 6 trials7–9,11 have documented reoperation rate
(Fig. 6). The pooled data revealed a statistically significant higher
reoperation rate for D2 group. The most common cause reported for
reoperation was a subphrenic abscess. Other causes include intraperi-
toneal haemorrhage, anastomotic leaks, duodenal stump leak, colonic
perforation, colonic infarction, retro-colic hernia, intraabdominal ab-
scesses, and acute pancreatitis. The reasons for reoperation in the
Dutch study9 are not given and the UK study10 failed to provide any
information on this variable all together. The commonest cause for
reoperation in the Hong Kong study8 was subphrenic abscess, all in
D2 group. Two of 4 studies7,8 had no incidence of reoperation in the
D1 group.
All 6 trials7–12 have reported on 30-day mortality rates (Fig. 7).
Pooled data showed a statistically significant higher mortality rate for
D2 cohort compared with their D1 counterpart. The inadequacy of
pretrial training in D2 gastrectomy may have had a significant impact
on the mortality and morbidity as explained by minimal surgical com-
plications from Italian and Tiawanese trials11,12 when compared with
their UK, Dutch, Hong Kong, and South African counterparts7–10

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Annals of Surgery r Volume 253, Number 5, May 2011 Meta-Analysis of D1 Versus D2 Gastrectomy for Gastric Adenocarcinoma
(Table 4). It is entirely possible that surgical experience may have
been an independent risk factor for predicting mortality in various tri-
als. Other factors which may have had an impact on the mortality and
morbidity was pancreatic or splenic resection, which was inconsistent
throughout the trials. Pancreatosplenectomy recommended as part of
the D2 gastrectomy in the second edition of Japanese classification5,57
was not routinely performed in all the RCTs.7,10,12–14 Although sur-
geons in Hong Kong and Taiwanese trials8,12 performed pancreatic
and splenic resection routinely, the rest of the surgeons performed
these resections only when the upper two-thirds of the stomach
was involved7,9,10 or if the cancer had extended into these organs.11
Cuschieri et al10 felt that higher morbidity rate in D2 cohort were
secondary to pancreatosplenic resection which was similarly seen in
the Tawianese trial.12 However Bonenkamp et al9 found no such as-
sociation. Immunological abnormalities especially after splenectomy
such as higher rate of septic complications, higher rate of blood trans-
fusion or pancreatic leakage may all contribute to higher morbidity
seen after pancreatosplenectomy.
A number of authors have suggested that spleen and pancre-
atic preservation during gastric cancer resection produces not only
better short-term outcome but have no impact on 5-year survival.
Csendes et al58 have produced the only RCT in the Western countries
addressing specifically the risk and benefits of splenectomy in D2 pa-
tients. In several Japanese studies59–63 it has been demonstrated that
micrometastasis in station 10 lymph nodes varies between 12% and
20% and therefore avoiding routine splenectomy may compromise tu-
mor free and overall survival in patients with gastric cancer. Csendes
et al58 detected micrometastasis in 9% of their patients. However, the
5-year survival was not significantly different in their patients with
or without splenectomy. On the other hand, they found postoperative
septic complications to be significantly higher in patients with the
splenectomy. In yet another RCT from Korea64 comparing 104 with
and 103 patients without splenectomy, the authors have shown similar
results to the Csendes et al58 study. A number of other studies61,63,64–68
evaluating the role of routine splenectomy during gastrectomy have
shown similar results in the past, although none were of random-
ized nature. Two large retrospective studies67,68 involving almost 500
patients with or without splenectomy after total gastrectomy found
that splenectomy failed to improve the long-term survival but in-
stead increased the postoperative complications. In a retrospective
Finnish study56 comparing D1 versus D2–3 gastrectomy, of the 22
patients who underwent pancreas resection, 40.9% had at least 1
surgical complication postoperatively compared with 22.8% without
pancreas resection. Two of the RCTs9,10 although not designed to
specifically answer the impact of pancreatic or splenic resection in
D2 gastrectomy, have shown unfavorable results with caudal pan-
createctomy and concomitant splenectomy in a subset analysis. The
overall consensus is that routine splenectomy and distal pancreate-
ctomy during D2 dissection has no long-term survival benefit and
may even be counter productive. However it may be performed for
selected patients with T3 tumors or direct invasion or metastasis at
the splenopancreatic hilum.
The most important outcomes after any cancer treatment is
the actual 5-year survival rate. Interestingly this meta-analysis does
not show any difference in the 5-year survival rate between the 2
groups (Fig. 8) which questions the very rationale for performing
aggressive D2 gastrectomy for gastric cancer with its higher incidence
of morbidity and mortality.
There are some limitations associated with this meta-analysis.
First, publication bias was detected on funnel plot analysis for the
outcomes of length of stay and postoperative complications. This
is of concern as the selective publication of studies may result in
pooled effect sizes obtained from studies exclusively located from
the published scientific literature demonstrating a more significant

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Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
result in terms of the magnitude of harm or benefit of an intervention
than in actuality.69,70 However, it should be noted there are number of
limitations to the assessment of publication bias in this meta-analysis.
First, the numbers of studies included are inadequate to sensitively
detect such a bias.22,24 Second, a random effects model of meta-
analysis was utilized for this analysis, and this model is known to
exaggerate the presence of publication bias due to attributing heavier
weighting to smaller studies than occurs in the fixed effects model
of meta-analysis. Finally, funnel plots are not an ideal method for
assessing71,72 publication bias due to their inability to differentiate
between forms of bias present, however they remain the accepted
method for assessment of publication bias.73
A second possible limitation within this meta-analysis is the
presence of heterogeneity detected within several outcomes, specifi-
cally length of stay and postoperative complications. Although some
degree of heterogeneity is inevitable in a medical meta-analysis due to
the realities of clinical practice,69,74 the degree of between-study het-
erogeneity present may undermine the quality and legitimacy of the
results obtained.75 A visual assessment of the forest plots for the 2 out-
comes with significant degrees of heterogeneity clearly demonstrate
that the Robertson et al study8 reports results considerably stronger
in favor of the D1 procedure than any other included study. A review
of the included articles failed to demonstrate significant differences
in the practices reported that may indicate the Robertson et al article8
was inappropriate for inclusion with this meta-analysis: true hetero-
geneity may therefore account for the differences observed. In view
of this it is also interesting to consider that it was in these outcomes
that publication bias was detected, as funnel plots are also sensitive
to the presence of true heterogeneity.27,72
The exclusion of studies published in languages other than
English is another potential limitation to this work, particularly in
view of the fact that the main advocates for the D2 procedure are
from Japan and largely published in Japanese. The latter can have
little bearing on the outcomes of this meta-analysis as the Japanese
studies supporting the use of D2 procedures would not have met
the RCT inclusion criteria for this meta-analysis. The impact of the
inclusion of English only studies was also challenged by rerunning
the search terms without this limit applied–no eligible studies in
languages other than English were located.
Finally, the small number of studies included in this meta-
analysis remains a largely unavoidable limitation of this and many
other meta-analyses conducted in surgical fields. Producing a large
number of good quality clinical trials is expensive, logistically dif-
ficult and time consuming,76 and as such only a limited number
with comparable interventions and methods are generally conducted
on any given topic. This makes the production of a reliable meta-
analysis difficult as limited study numbers have implications for sta-
tistical power for all statistical tests conducted, including those for
determining point estimates, confidence interval, heterogeneity test,
and publication bias.24,69,72,77
CONCLUSIONS
On the basis of this meta-analysis and its limitations, we con-
clude that D1 is associated with significantly fewer anastomotic leaks,
postoperative complications, reoperations, decreased length of hos-
pital stay and 30-day mortality rate compared with D2 gastrectomy.
Furthermore, the 5-year survival rate in D1 gastrectomy patients was
similar to the D2 cohort. Therefore, at present best clinical evidence
comparing D1 and D2 surgery does not favor the D2 resection, We
therefore need to consider whether further well-designed RCTs with
more rigorous quality control in performing D2 gastrectomy are nec-
essary or the addition of other modalities such as chemotherapy may
provide a better patient outcome as opposed to more extensive sur-
gical operation. Other important issues that need urgent attention
www.annalsofsurgery.com | 909
Memon et al
include (a) surgical experience in performing D2 resections to prevent
breaches and contaminations; (b) number of gastrectomies needed to
be performed yearly to participate in such trials; (c) standardization of
D2 dissection (eg, with or without pancreatosplenectomy); (d) train-
ing requirement and standards; (e) higher versus lower volume centers
(ie, volume–quality or outcome relationship) participating in the tri-
als; (f) accurate pathological staging; and (g) cost-benefit analysis.
Finally, with the developing appreciation of the biomolecular basis
for these cancers obtained with the genetic decoding technology, the
future of this debate and surgical procedures may be rendered void
as biomolecular agents become the first line of treatment for these
cancers.
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