Articles

Short-term outcomes of complete mesocolic excision versus

D2 dissection in patients undergoing laparoscopic colectomy
for right colon cancer (RELARC): a randomised, controlled,
phase 3, superiority trial
Lai Xu*, Xiangqian Su*, Zirui He*, Chenghai Zhang, Junyang Lu, Guannan Zhang, Yueming Sun, Xiaohui Du, Pan Chi, Ziqiang Wang, Ming Zhong,
Aiwen Wu, Anlong Zhu, Fei Li, Jianmin Xu, Liang Kang, Jian Suo, Haijun Deng, Yingjiang Ye, Kefeng Ding, Tao Xu, Zhongtao Zhang†,
Minhua Zheng†, Yi Xiao†, on behalf of the RELARC Study Group‡

Summary
Background Whether extended lymphadenectomy for right colon cancer leads to increased perioperative complications Lancet Oncol 2021; 22: 391–401
or improves survival is still controversial. This trial aimed to compare the efficacy and safety of complete mesocolic Published Online
excision (CME) versus D2 dissection in laparoscopic right hemicolectomy for patients with right colon cancer. February 12, 2021
https://doi.org/10.1016/
This article reports the early safety results from the trial.
S1470-2045(20)30685-9
See Comment page 293
Methods This randomised, controlled, phase 3, superiority, trial was done at 17 hospitals in nine provinces of China.
*Joint first authors
Eligible patients were aged 18–75 years with histologically confirmed primary adenocarcinoma located between the
†Senior authors who contributed
caecum and the right third of the transverse colon, without evidence of distant metastases. Central randomisation equally
was done by means of the Clinical Information Management-Central Randomisation System via block randomisation
‡RELARC study group members
(block size of four). Patients were randomly assigned (1:1) to CME or D2 dissection during laparoscopic right are listed in the appendix
colectomy. Central lymph nodes were dissected in the CME but not in the D2 procedure. Neither investigators nor (pp 1–2)
patients were masked to their group assignment but the quality control committee were masked to group Division of Colorectal Surgery,
assignment. The primary endpoint was 3-year disease-free survival, but the data for this endpoint are not yet Department of General
Surgery, Peking Union Medical
mature; thus, only the secondary outcomes—intraoperative surgical complications and postoperative complications
College Hospital (L Xu MD,
within 30 days of surgery, graded according to the Clavien-Dindo classification, mortality (death from any cause J Lu MD, G Zhang MD,
within 30 days of surgery), and central lymph node metastasis rate in the CME group only—are reported in this Prof Y Xiao MD) and
Article. This early analysis of safety was preplanned. The outcomes were analysed according to a modified intention- Department of Epidemiology
and Statistics, Institute of
to-treat principle (excluding patients who no longer met inclusion criteria after surgery or who did not have
Basic Medical Sciences
surgery). This study is registered with ClinicalTrials.gov, NCT02619942. Study recruitment is complete, and (T Xu MD), Chinese Academy of
follow-up is ongoing. Medical Sciences and
Peking Union Medical College
Beijing, China; School of Basic
Findings Between Jan 11, 2016, and Dec 26, 2019, 1072 patients were enrolled and randomly assigned. After
Medicine, Peking Union
exclusion of 77 patients, 995 patients were included in the modified intention-to-treat population (495 in the CME Medical College, Beijing, China
group and 500 in the D2 dissection group). The postoperative surgical complication rate was 20% (97 of (T Xu); Key Laboratory of
495 patients) in the CME group versus 22% (109 of 500 patients) in the D2 group (difference, −2·2% [95% CI −7·2 Carcinogenesis and
Translational Research
to 2·8]; p=0·39); the frequency of Clavien-Dindo grade I–II complications were similar between groups (91 [18%] (Ministry of Education),
vs 92 [18%], difference, −0·0% [95% CI −4·8 to 4·8]; p=1·0) but Clavien-Dindo grade III−IV complications were Department of Gastrointestinal
significantly less frequent in the CME group than in the D2 group (six [1%] vs 17 [3%], −2·2% [−4·1 to −0·3]; Surgery IV (Prof X Su MD,
p=0·022); no deaths occurred in either group. Of the intraoperative complications, vascular injury was significantly C Zhang MD) and Department
of Unit III & Ostomy Service,
more common in the CME group than in the D2 group (15 [3%] vs six [1%], difference, 1·8 [95% CI 0·04 to 3·6]; Gastrointestinal Cancer Centre
p=0·045). Metastases in the central lymph nodes were detected in 13 (3%) of 394 patients who underwent central (Prof A Wu MD), Peking
lymph node biopsy in the CME group; no patient had isolated metastases to central lymph nodes. University Cancer Hospital and
Institute, Beijing, China;
Department of General
Interpretation Although the CME procedure might increase the risk of intraoperative vascular injury, it generally Surgery, Ruijin Hospital, School
seems to be safe and feasible for experienced surgeons. of Medicine, Shanghai Jiao
Tong University, Shanghai,
Funding The Capital Characteristic Clinical Project of Beijing and the Chinese Academy of Medical Sciences. China (Z He MD,
Prof M Zheng MD); Department
of Colorectal Surgery, The First
Copyrigh © 2021 Elsevier Ltd. All rights reserved. Affiliated Hospital of Nanjing
Medical University, Nanjing,
Introduction remains controversial, with the extent of lymphadenectomy China (Prof Y Sun MD);
Department of General
For decades, surgery has been considered the best option being one of the most hotly debated topics. Surgery, Chinese General
for treatment of advanced colon cancer without distant Since the 1980s, Japanese guidelines have advocated Hospital of People’s Liberation
metastasis. However, the optimal surgical intervention removal of the central lymph nodes (D3 dissection) Army, Beijing, China

www.thelancet.com/oncology Vol 22 March 2021 391

 Articles
(Prof X Du MD); Department of
Colorectal Surgery, Fujian
Medical University Union
Hospital, Fujian, China
(Prof P Chi MD); Department of
Gastrointestinal Surgery, West
China Hospital, Sichuan
University, Chengdu, China
(Prof Z Wang MD); Department
of Gastrointestinal Surgery,
Renji Hospital, School of
Medicine, Shanghai Jiao Tong
University, Shanghai, China
(Prof M Zhong MD);
Department of Colorectal
Surgery, The First Affiliated
Hospital of Harbin Medical
University, Harbin, China
(Prof A Zhu MD); Department of
General Surgery, Xuanwu
Hospital, Capital Medical
University, Beijing, China
(Prof F Li MD); Department of
General Surgery, Zhongshan
Hospital, Fudan University,
Shanghai, China (Prof J Xu MD);
Department of Colorectal
Surgery, The Sixth Affiliated
Hospital, Sun Yat-sen
University, Guangzhou, China
(L Kang MD); Department of
Gastrointestinal Surgery,
The First Hospital of Jilin
University, Changchun, China
(Prof J Suo MD); Department of
General Surgery, Nanfang
Hospital, Southern Medical
University, Guangzhou, China
(H Deng MD); Department of
Gastroenterological Surgery,
Peking University People’s
Hospital, Beijing, China
(Prof Y Ye MD); Department of
Colorectal Surgery and
Oncology, Key Laboratory of
Cancer Prevention and
Intervention (Ministry of
Education), The Second
Affiliated Hospital, School of
Medicine, Zhejiang University,
Hangzhou, China
(Prof K Ding MD); Department
of General Surgery, Beijing
Friendship Hospital, Capital
Medical University and
National Clinical Research
Centre for Digestive Diseases,
Beijing, China (Prof Z Zhang MD)
Correspondence to:
Prof Y Xiao, Division of Colorectal
Surgery, Department of General
Surgery, Peking Union Medical
College Hospital, Chinese
Academy of Medical Sciences
and Peking Union Medical
College, Beijing 100730, China
xiaoy@pumch.cn
See Online for appendix
392
Research in context
Evidence before this study
In order to clarify the short-term and long-term effects of
complete mesocolic excision (CME) in colon cancer, we searched
PubMed with the keyword “complete mesocolic excision” to
search the literature published from May 1, 2009, up to
Aug 20, 2020.We did not use any language restrictions in our
search. A total of 368 articles were retrieved, but we did not find
any completed randomised, controlled trial on the topic. There is
only one ongoing randomised, controlled trial that studies the
extent of surgery for colon cancer. Most of the studies published
so far are small, single-centre, retrospective studies, except the
large-scale, single-centre, historical control study reported by
Hohenberger and colleagues in 2009 and the multicentre,
retrospective cohort study reported by Bertelsen and colleagues.
D3 dissection, in which the aim is removal of the central lymph
nodes, has been implemented in colon cancer resection for
more than 30 years. In addition to central node
lymphadenectomy, CME introduced the concept of
embryological plane surgery, as well as extended resection of the
colon and its mesentery. CME has been shown to improve
overall survival from colon cancer in several retrospective cohort
series. However, in these retrospective studies, the quality of the
specimens used as the control group were not similar to those in
the CME group, and some studies did not have a control group.
Therefore, we cannot justifiably say whether the improvement
in survival was a result of central lymphadenectomy, specimen
quality, or extended resection of mesentery. Therefore, whether
CME surgery for colon cancer risks perioperative complications
during colectomy for colon cancer greater than T2 stage.1
In 2009, Hohenberger and colleagues2 introduced the
concept of complete mesocolic excision (CME), which
involved central node removal similar to D3 dissection,
but emphasised that surgical dissection be strictly along
the embryological planes, so that the diseased colon and
its mesentery could be removed as a complete package
and leakage of cancer cells prevented. Later, other
surgeons continued to refine the CME technique and
more clearly defined the scope of lymph node dissection
and the embryological planes of dissection in D2 surgical
resection.3,4
Traditional D2 dissection might not always be done
along the embryological planes, and so the integrity of
the mesocolon—currently considered an important para­
meter of surgical specimen quality—is not guaranteed.
Although no clearly defined standards have yet been
developed for dissecting planes or the extent of
lymphadenectomy in D2 or non-CME procedures, there
is broadly agreed consensus on the extent of
lymphadenectomy in D3 and CME. In this situation,
comparison of D2 or non-CME procedures with D3 and
CME procedures is difficult.
Some retrospective studies have showed that CME
improves survival in patients with colon cancer,
or has oncological benefits versus the standard D2 dissection is
still not clear. A higher level of evidence is needed to answer this
question.
Added value of this study
Owing to the complexity of right hemicolectomy and the
precise advantages of laparoscopic technology in colon cancer,
this study used a randomised, controlled trial design to
compare the short-term efficacy and long-term survival of CME
and D2 dissection in laparoscopic right hemicolectomy. In order
to ensure high quality of the research, this study used strict
screening conditions for the research participants, and blindly
judges the actual surgical group (CME or D2) and the quality of
the specimens by the quality control committee. This trial was
expected to provide a high level evidence for the extent of
lymphadenectomy in right colectomy for colon cancer.
Implications of all the available evidence
For experienced colorectal surgeons, compared with standard
D2 dissection, CME during laparoscopic right hemicolectomy
does not increase the risk of intraoperative and postoperative
complications. However, CME does increase the risk of vascular
injuries to vessels such as the superior mesenteric vein and
Henle trunk and their tributaries. Owing to the difficulty of
laparoscopic CME surgery for right colon cancer, systematic
training is required to shorten the learning curve. Whether CME
should be used as the gold standard for right colon cancer still
needs to be proven by the final oncological outcomes from this
trial, which are expected to be available in December, 2022.
probably owing to the en-bloc excision of mesentery
tissue and the acquisition of more lymph nodes.2,5,6
However, these studies included patients treated over a
long period of time (>20 years) and surgeons with
varying experience in doing CME; thus, the survival
outcomes would inevitably have been affected by
differences in the anticancer drugs used over time and
the surgeons’ skills. Two meta-analyses have not been
able to show a clear survival benefit with CME versus
D2 dissection.7,8 Randomised, controlled trials are
therefore needed to settle this debate.
The laparoscopic technique in colon cancer surgery
has been shown to be non-inferior to open surgery in
terms of safety and oncological outcomes.9,10 Although
laparoscopic surgery for colon cancer has become
popular, there is concern regarding the possibility of
serious vascular injury during laparoscopic CME on the
anatomically complex right colon, with its wide variations
in vasculature between patients.
In the present study, the aim was to establish whether
3-year disease-free survival was superior in patients
receiving CME than in those undergoing D2 dissection
during laparoscopic right colon cancer resection. In this
Article, we report the secondary (short-term) outcomes;
this analysis of the safety was preplanned.
www.thelancet.com/oncology Vol 22 March 2021

Methods
Study design and participants
The RELARC trial is a phase 3, randomised, controlled,
superiority trial that is being done at 17 centres in nine
provinces of China (appendix p 3).
Patients with right colon cancer (located between the
caecum and the right third of the transverse colon, without
evidence of distant metastases) were eligible for this trial
if they were 18–75 years old, American Society of
Anesthesiologists (ASA) class I, II, or III, had histologically
confirmed primary adenocarcinoma staged as cT2–4a
N0–2M0 or cTanyN+M0, on enhanced CT for preoperative
clinical staging, and were willing to sign informed
consent. Patients in whom preoperative CT scan or
surgical exploration revealed central lympha­ denopathy,
mandating CME lymphadenectomy, and those who
needed emergency surgery, were excluded. All patients
provided written informed consent. We did not exclude
patients who received preoperative chemotherapy. Co-
morbidities were allowed.
The study protocol and all amendments were approved
by the Ethics Committee of Peking Union Medical
College Hospital. Approval of the local ethics committee
at each centre was also obtained before starting the study.
The trial protocol11 is available online.
Randomisation and masking
Patients were enrolled by the treating investigator at each
centre and were randomly assigned (1:1) by the Clinical
Information Management-Central Randomisation
System (CIMS-CRS) data management centre (Chengdu,
China) to undergo either CME or D2 dissection. Central
ran­domisation was done with the CIMS-CRS, which
used block randomisation (with a block size of four),
without any stratification factors. Investigators and
patients were not masked to treatment assignment;
however, the quality control committee was masked to
the randomisation details during assessment of the
primary and secondary outcomes. The assessment of
perioperative complications was not masked, because the
research team members were involved in all aspects of
patient care. All case record forms were gathered and
stored at Brightech Clinical Information Management
System (Chengdu, China).
Procedures
The surgical procedures for D2 dissection and CME
have been described in detail in the study protocol.11 The
main difference between the D2 and the CME procedures
was that lymphadenectomy was done around the
superior mesenteric artery and vein in the latter group.3,4,11
Further details about the two procedures are in the
appendix (p 8).
The anastomosis method was not uniform in all study
patients because each centre was permitted to follow its
usual protocol. All patients had abdominal drainage
tubes. Patients with intraoperatively discovered distant
www.thelancet.com/oncology Vol 22 March 2021
Articles
metastases or central lymph node enlargement, or
postoperative histology that did not show colon adeno­
carcinoma, or patients who did not undergo surgery, or
patients with random allocation errors, were removed
from the study when the baseline data was cleaned and
rendered for surgical safety analysis by the data
monitoring committee.
All participating surgeons were required to have
experience of doing at least 100 laparoscopic procedures
for colorectal cancer per year, and no less than 20 CME
and 20 D2 lymph node dissection procedures for right
colonic cancer. The quality control committee (YX, ZW,
and XD) reviewed unedited videos of surgical procedures
(two CME procedures and two D2 procedures for
laparoscopic right colectomy) done by the surgeons to
check that the surgical steps fulfilled protocol require­
ments; each surgeon was only registered for the trial
after approval by the committee.
Videos of the surgeries on all study patients were
retained for random inspection by the quality control
committee. Additionally, after the specimen had been
harvested, photographs of the surgical field and of the
anterior and posterior aspects of the specimens were
uploaded to the electronic data capture system for
assessment of the extent of lymph node dissection and For the RELARC study protocol
quality of mesocolon by the quality control committee. The see http://www.trialsjournal.
com/content/17/1/582
final resection boundary of the operation was evaluated by
the quality control committee on the basis of intraoperative
photographs obtained after removal of the colon specimen,
and whether or not the superior mesenteric vascular area
had undergone skeletonisation (central vascular ligation)
in the intraoperative photos was used as an evaluation
criterion to judge whether CME or D2 surgery had been
done.
The resected specimens were initially classified by the
quality control committee into three groups according to
the plane of dissection: mesocolic plane, intramesocolic
plane, and muscularis propria plane; the method has been
described previously.5 In this study, we applied West’s
classification system to photographs of the anterior and
posterior aspects of fresh specimens instead of formalin-
fixed specimens.11 At the end of patient enrolment, the
quality control committee evaluated the quality of the
specimens. Benz and colleagues applied a similar method
to evaluate the quality of mesocolon after resection: the
categories a–c describe the same phenomena as in the
original West classification of grades I–III.12 Finally, on
the basis of the anterior and posterior photographs, the
specimens were classified into three groups: grade I,
intact mesocolon; grade II laceration in the mesocolon;
and grade III laceration in the mesocolon reaching the
bowel. In this study, en-bloc resection was used, and the
lymph nodes were removed along with colon and
mesocolon as one package in both groups; the central
group of lymph nodes in the CME group was examined
separately in vitro after the specimens had been removed.
Pathological staging was done according to the American
393
 Articles
Joint Committee on Cancer 7th edition TNM staging
system. The total number of lymph node dissections, the
number of metastatic lymph nodes, and the distribution
of T and N stage in the two groups were recorded. We
measured and recorded the area of the mesangial colon
and the length of the intestine at the proximal and distal
ends of the tumour. The area of mesocolon and intestine
length were measured by means of Camera Measure
software (version 2.1.4.253) developed by E2ESOFT
(Shanghai, China).
The follow-up period was 30 days after surgery, and it
was done on an outpatient basis. Laboratory and
radiographic assessments within 30 days after surgery
were done by the treating physician, with the frequency
and nature of these assessments dependent on the
patient’s condition, with no uniform regulations specified
in the trial protocol. A minimum follow-up of 5 years was
required for each patient after surgery. Follow-up care
included physical examination and blood tests with
carcinoembryonic antigen and cancer antigen 19-9 every
4 months for the first 2 years, and every 6 months
thereafter; chest x-ray and abdominal ultrasound every
4 months for the first 2 years, and every 6 months
thereafter; and chest and abdominopelvic enhanced CT
and colon endoscopy annually for 5 years.
Outcomes
The primary endpoint was disease-free survival at 3 years
after surgery. The primary endpoint data are expected to
mature in December, 2022, and will therefore be reported
at a later date. The primary endpoint will be centrally
reviewed by the quality control committee.
The secondary endpoints, reported here, were morbidity
and mortality occurring within 30 days of surgery, and
central lymph node metastasis rate in the CME group.
This analysis of the safety of the trial was prespecified. An
additional secondary endpoint was 3-year overall survival,
which also will not be available until December, 2022.
Mortality was defined as death from any cause within
30 days after surgery. Morbidity was defined as intra­
operative or postoperative surgical complications, which
were diagnosed by evaluation of imaging or clinical
symptoms and signs. Intraoperative complications were
defined as unexpected surgical adverse events occurring
during surgery (eg, iatrogenic injury of the bowel, blood
vessels, or other organs; severe bleeding). Vascular injury
was defined as laceration or break of blood vessels
supplying the right colon (eg, Henle trunk, right colic
vein, superior mesenteric vein, or superior mesenteric
artery). Intra­operative haemorrhage was defined as blood
loss of more than 200 mL in the absence of vascular
injury. Intraperitoneal haemorrhage was defined as
bloody drainage of more than 100 mL in 1 h, or total
drainage of 300 mL in the first 24 h after surgery. The
surgical time starts from the incision of the skin and
continues to the suture of the skin. In addition, the
intraoperative blood loss was recorded in both groups.
394
Postoperative complications, including anastomotic leak,
anastomotic site haemor­rhage, impaired wound healing,
ileus, intraperitoneal haemorrhage, chyle leak, diarrhoea,
pulmonary infection, deep surgical site infection,
acute cardiac events, thromboembolic events, and other
adverse events occurring within 30 days of surgery were
recorded. Complications were graded according to the
Clavien-Dindo classification; grade I–II events are
classified as minor complications, grade III–IV events are
classified as serious complications.13
Statistical analysis
We calculated that a total of 894 patients would be
required to show an 8% improvement in 3-year disease-
free survival with CME relative to D2 dissection (from
72% to 80%) with an α error of 5% (in a two-sided test)
and power of 80%. Assuming a dropout rate of 20%, we
planned to enrol a total of 1072 patients for this trial.
We calculated post hoc that sample sizes of 495 patients
in the intervention group and 500 in the control group
would achieve 14% power to detect a difference of
surgical complications between the group proportions
of 0·022. The proportion in the treatment group is
assumed to be 0·20 under the null hypothesis and
0·22 under the alternative hypothesis. The significance
level of the test was set to be two-sided with p<0·05.
Continuous variables were summarised as mean (SD)
or as median (IQR), and analysed by the t test or
Wilcoxon rank-sum test; categorical variables were
summarised as numbers and percentages and analysed
by the χ2 test or Fisher’s exact test. Blood loss was assessed
as mean (SD), and analysed by the t test. The Newcombe
method was used to calculate the 95% CIs for between-
group differences in intraoperative and postoperative
complication rates. Two-sided p<0·05 indicated signifi­
cance. SAS version 9.2 was used for statistical analyses.
A modified intention-to-treat approach was used for
all analyses. Patients were excluded from the analysis
after randomisation if intraoperative distant metastases
or central lymph node enlargements were discovered,
postoperative histology did not show colon adeno­
carcinoma, surgery was not done, or random allocation
errors occurred.
A comparison of the short-term results of the CME and
the D2 groups in the per-protocol population was used as
a sensitivity analysis. Patients were excluded from the
modified intention-to-treat analysis if they did not receive
randomly assigned surgery or had a history of malignant
tumour. A data monitoring committee was used. We also
did post-hoc analyses of the length of hospitalisation, the
size of the mesocolon area, and specimen quality. This
trial is registered at ClinicalTrials.gov, NCT02619942.
Role of the funding source
The funder of the study had no role in study design, data
collection, data analysis, data interpretation, or writing of
the report. All authors had access to the raw data.
www.thelancet.com/oncology Vol 22 March 2021
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Results
Between Jan 11, 2016, and Dec 26, 2019, 1072 patients 1072 patients enrolled and randomly assigned

were enrolled and randomly assigned to the two groups

(n=536 per group). After randomisation, 77 patients were
excluded from the modified intention-to-treat population 536 assigned to D2 dissection 536 assigned to complete mesocolic excision
(figure). Thus, 995 patients were included in the final
modified intention-to-treat final analysis: 495 in the
CME group and 500 in the D2 group (figure). The short- 36 excluded 41 excluded
8 distant metastases 12 distant metastases
term outcomes were followed up within 30 days after 7 postoperative pathology was not 11 postoperative pathology was not
surgery, and all the patients were included in the follow- colon adenocarcinoma colon adenocarcinoma
14 enlargement of the central lymph 11 enlargement of the central lymph
up within 30 days after surgery. nodes discovered during surgery nodes discovered during surgery
35 patients did not receive their randomly assigned 5 no surgery after random assignment 5 no surgery after random assignment
treatment (figure); these patients remained in their 2 random allocation error 2 random allocation error

allocated group for the modified intention-to-treat

analyses, although not for the per-protocol analysis. 500 included in mITT analysis 495 included in mITT analysis
These 35 patients included 21 in the D2 group who
received CME lymph node dissection, and 14 patients
in the CME group who were described by the surgeon 21 underwent complete mesocolic excision 14 underwent D2 dissection
5 history of other malignant tumour* 2 history of other malignant tumour*
as having had CME but who were subsequently
judged to have had D2 dissection by the quality control
committee. 474 included in per-protocol analysis 479 included in per-protocol analysis
Table 1 summarises the baseline clinical characteristics
of the patients, which were well balanced across the Figure: Trial profile
two groups. No patients in the modified intention-to- mITT=modified intention-to-treat.*These patients underwent surgery assigned by the random allocation.
treat population had received preoperative neoadjuvant
chemotherapy.
CME group D2 group
The median follow-up was 30 days (IQR 30–30). The (n=495) (n=500)
surgical time was significantly longer in the CME group
Sex
than in the D2 group (163·0 min [IQR 135·0–195·0] vs
Male 279 (56%) 306 (61%)
150·5 min [125·0–180·0], p=0·0002). Intraoperative blood
Female 216 (44%) 194 (39%)
loss was similar in the two groups (60·1 mL [SD 65·0] vs
Age, years 60 (52–66) 62 (54–67)
54·7 mL [63·8]; p=0·19). Perioperative blood transfusion
was necessary in 28 (6%) of 495 patients in the CME group Body-mass index, kg/m² 23·6 (3·3) 23·5 (3·1)

versus 21 (4%) of 500 patients in the D2 group (table 2). American Society of Anesthesiologists class
A total of 24 patients in the two groups underwent I 138 (28%) 129 (26%)
combined organ resection. 11 patients underwent con­ II 313 (63%) 334 (67%)
current multi­organ resections owing to tumour adhesion, III 44 (9%) 37 (7%)
three of whom were in the CME group (one case each of Tumour location
right partial hepatectomy, partial small bowel resection, Caecum 108 (22%) 102 (20%)
and partial resection duodenal wall resection), and eight Ascending colon 231 (47%) 262 (52%)
in the D2 group (four cases of right partial hepatectomy, Hepatic flexure 122 (25%) 113 (23%)
three cases of cholecystectomy, and one case of gastric Transverse colon (right third) 34 (7%) 23 (5%)
greater curvature resection). Postoperatively, nine cases Clinical T category
were confirmed to be stage T4b, whereas the other cT2 45 (9%) 41 (8%)
two cases with only inflammatory adhesions were cT3 299 (60%) 327 (65%)
classified as stage T3. All analysed patients underwent cT4a 151 (31%) 132 (26%)
radical right hemicolectomy. Conversion to open surgery Clinical N category
was necessary for a similar proportion of patients in each cN0 289 (58%) 282 (56%)
group (table 2). cN+ 206 (42%) 218 (44%)
The prevalence of intraoperative complications was Data are n (%), median (IQR), or mean (SD). CME=complete mesocolic excision.
similar in the two groups, occurring in 24 (5%) patients
in the CME group and in 20 (4%) patients in the D2 group Table 1: Baseline clinical characteristics
(difference 0·8 [95% CI −1·7 to 3·4]; p=0·52).
The sites of vascular injuries in the CME group were the D2 group were Henle trunk (n=4), middle colic
the Henle trunk (n=6), superior mesenteric vein (n=4), vein (n=1), and right gastroepiploic vein (n=1).
right colic or accessory right colic vein (n=2), middle colic In the D2 group, six out of the seven patients with
vein (n=2), and superior mesenteric artery (n=1), and in anastomotic leak underwent ostomy. In the CME group,

www.thelancet.com/oncology Vol 22 March 2021 395

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CME group (n=495) D2 group (n=500) Difference (95% CI) p value

Duration of operation, min* 163·0 (135·0 to 195·0) 150·5 (125·0 to 180·0) 11·6 (5·7 to 17·5) 0·0002
Blood loss, mL 60·1 (65·0) 54·7 (63·8) 5·4 (−2·6 to 13·4) 0·19
Anastomotic technique ·· ·· ·· 1·0
Stapled 493 (100%) 497 (99%) ·· ··
Hand-sewn 2 (<1%) 3 (1%) ·· ··
Anastomosis approach ·· ·· ·· 0·13
Extracoporeal 443 (90%) 432 (86%) ·· ··
Intracorporeal 52 (11%) 68 (14%) ·· ··
Blood transfusion 28 (6%) 21 (4%) 1·5 (−1·0 to 4·0) 0·29
Severe anaemia 22 (4%) 16 (3%) 1·2 (−1·1 to 3·6) 0·31
Vascular injury 5 (1%) 3 (1%) 0·4 (−0·7 to 1·5) 0·50
Postoperative bleeding 1 (0·2%) 1 (0·2%) 0·0 (−0·6 to 0·6) 1·0
Thrombocytopenia 0 1 (<1%) −0·2 (−0·6 to 0·2) 1·0
Intraoperative complications 24 (5%) 20 (4%) 0·8 (−1·7 to 3·4) 0·52
Haemorrhage 7 (1%) 12 (2%) −1·0 (−2·7 to 0·7) 0·26
Vascular injury 15 (3%) 6 (1%) 1·8 (0·04 to 3·6) 0·045
Intestinal injury 0 2 (<1%) 0·4 (−0·2 to 1·0) 0·50
Ureter injury 1 (<1%) 0 0·2 (−0·2 to 0·6) 0·50
Subcutaneous emphysema 1 (<1%) 0 0·2 (−0·2 to 0·6) 0·50
Conversion to open surgery† 13 (3%) 7 (1%) 1·2 (−0·5 to 3·0) 0·17
Concurrent multiorgan resections‡ 8 (2%) 16 (3%) −1·6 (−3·5 to 0·3) 0·10
Data are median (IQR), mean (SD), or n (%). CME=complete mesocolic excision. *Time from first incision to closure of the surgical incision. †The reasons for conversion in the
CME group were duodenal invasion (n=1), large tumour size (n=6), severe intraperitoneal adhesion (n=5), and vascular injury (n=1). The reasons for conversion in the
D2 group were tumour invasion of the gallbladder (n=1), severe intraperitoneal adhesion (n=2), intestinal bloating caused by colonoscopy (n=1), large tumour size (n=2),
and vascular injury (n=1). ‡Other organs resected included the gallbladder (three in the CME group and seven in the D2 group), ovaries (one in the CME group and two in the
D2 group), liver (one in the CME group and three in the D2 group), the bladder and abdominal wall (three in the CME group and six in the D2 group), small bowel (one in the
CME group and two in the D2 group), and other (one in the CME group and two in the D2 group).

Table 2: Surgical outcomes

only one out the four patients who developed anastomotic

CME group D2 group Difference (95% CI) p value
(n=495) (n=500) leak received ostomy; the other three had mild symptoms
and were managed by local drainage only.
Morbidity* 97 (20%) 109 (22%) −2·2 (−7·2 to 2·8) 0·39
No deaths occurred in either group in the first 30 days
Anastomotic leak 4 (1%) 7 (1%) −0·6 (−1·9 to 0·7) 0·37
after surgery. Postoperative morbidity (ie, at least
Anastomotic bleeding 3 (1%) 3 (1%) −0·1 (−1·2 to 0·9) 1·0
one postoperative complication) was reported in 97 (20%)
Wound infection 26 (5%) 27 (5%) −0·2 (−2·9 to 2·6) 0·92
of 495 patients in the CME group versus 109 (22%) of
Ileus 13 (3%) 15 (3%) −0·4 (−2·4 to 1·7) 0·72
500 patients in the D2 group (difference, −2·2% [95% CI
Abdominal bleeding 1 (<1%) 5 (1%) −0·8 (−1·8 to 0·2) 0·22
−7·2 to 2·8]; p=0·39; table 3). The majority of compli­
Chyle leak 24 (5%) 14 (3%) −2·1 (−4·4 to 0·3) 0·09 cations were Clavien-Dindo grades I–II; they occurred
Cardiac or pulmonary embolism 3 (1%) 7 (1%) −0·8 (−2·0 to 0·4) 0·34 in 91 (18%) patients in the CME group versus
Diarrhoea 9 (2%) 11 (2%) −0·4 (−2·0 to 1·4) 0·67 92 (18%) patients in the D2 group and required only
Respiratory 15 (3%) 13 (3%) 0·4 (−1·6 to 2·5) 0·68 conservative treatment. Grade III–IV complications
Abscess 8 (2%) 18 (4%) −2·0 (−4·0 to −0·0) 0·05 occurred significantly less frequently in the CME group
Others 21 (4%) 24 (5%) −0·6 (−3·1 to 2·0) 0·67 than in the D2 group. No cases of superior mesenteric
Clavien-Dindo grade vein or portal vein thrombosis occurred in any patients
I–II 91 (18%) 92 (18%) −0·0 (−4·8 to 4·8) 1·0 during the study.
III–IV 6 (1%) 17 (3%) −2·2 (−4·1 to −0·3) 0·022 Table 4 shows the surgical specimen properties in the
Duration of hospital stay, days 7 (6 to 8) 7 (6 to 9) −0·0 (−0·7 to 0·4) 0·80 two groups, including the distribution of T and N stage.
Mortality within 30 days 0 0 ·· ·· In the CME group, 87 patients did not have a separate
Data are n (%) or median (IQR). CME=complete mesocolic excision. *More than one complication could have occurred biopsy done of the central lymph nodes (45 men and
per patient. The differences calculated are absolute differences. 42 women) across 15 centres owing to an error in
procedure. Among these patients, 44 had negative
Table 3: Comparison of 30-day postoperative morbidity and mortality and duration of hospitalisation
lymph nodes, the other 33 patients had positive lymph
nodes. Of the 87 patients, nine had stage T1–2 tumours,

396 www.thelancet.com/oncology Vol 22 March 2021

 Articles

CME group (n=495) D2 group (n=500) Difference (95% CI) p value

Area of mesocolon removed, cm² 116·4 (89·4 to 144·8) 107·8 (84·9 to 132·7) 8·4 (3·3 to 13·5) 0·0010
Missing data 3 (1%) 2 (<1%) ·· ··
Proximal clearance, mm 150·0 (120·0 to 202·3) 149·3 (109·0 to 197·0) 1·9 (–6·6 to 10·4) 0·46
Distal clearance, mm 132·0 (103·0 to 180·0) 137·0 (102·0 to 180·0) –0·8 (–8·4 to 6·8) 0·65
Quality of specimens ·· ·· ·· 0·0020
Grade I 453 (92%) 481 (97%) ·· ··
Grade II 38 (8%) 17 (3%) ·· ··
Grade III 1 (<1%) 0 ·· ··
Missing data 3 (1%) 2 (<1%) ·· ··
Tumour differentiation ·· ·· ·· 0·75
Well 17 (3%) 23 (5%) ·· ··
Moderate 376 (76%) 362 (72%) ·· ··
Poor 94 (19%) 104 (21%) ·· ··
Other 8 (2%) 11 (2%) ·· ··
Pathological T category ·· ·· ·· 0·23
pT1 18 (4%) 15 (3%) ·· ··
pT2 37 (7%) 37 (7%) ·· ··
pT3 339 (68%) 330 (67%) ·· ··
pT4a 99 (20%) 111 (22%) ·· ··
pT4b 2 (<1%) 7 (1%) ·· ··
Pathological N category ·· ·· ·· 0·95
pN0 315 (64%) 320 (64%) ·· ··
pN1a 59 (12%) 65 (13%) ·· ··
pN1b 60 (12%) 46 (9%) ·· ··
pN1c 9 (2%) 10 (2%) ·· ··
pN2a 42 (9%) 33 (7%) ·· ··
pN2b 10 (2%) 26 (5%) ·· ··
Total pN+ 180 (36%) 180 (36%) ·· 0·86
Number of harvested lymph nodes 26·0 (19·0 to 35·0) 23·0 (17·5 to 29·0) 3·4 (2·0 to 4·9) <0·0001
Metastases in central lymph nodes*
Yes 13/394 (3%) NA ·· ··
No 381/394 (97%) NA ·· ··
D2 dissection 14/495 (3%) NA ·· ··
Missing data 87/495 (18%) NA ·· ··
Pathology stage† ·· ·· ·· 0·65
I 48 (10%) 47 (9%) ·· ··
II A 218 (44%) 226 (45%) ·· ··
II B 47 (10%) 43 (9%) ·· ··
II C 2 (0·4%) 3 (1%) ·· ··
III A 7 (1%) 4 (1%) ·· ··
III B 153 (31%) 132 (26%) ·· ··
III C 20 (4%) 45 (9%) ·· ··
Data are n (%) or median (IQR). CME=complete mesocolic excision. NA=not applicable. pN+=pathological node positive.*The central lymph nodes were not biopsied in
87 patients and the extent of excision was not large enough for harvesting of the central lymph nodes in 14 patients. †Pathological staging was by the American Joint
Committee on Cancer 7th edition TNM staging system.

Table 4: Specimen properties from operated patients

60 stage T3, and 18 stage T4a. In a further 14 patients in
the CME group, the extent of excision was not large
enough for harvesting of the central lymph nodes;
these patients were classed as having D2 dissection.
394 patients in the CME group underwent central
lymph node biopsy, of whom 39 had stage T1–2
tumours, 275 stage T3, and 80 stage T4. Metastases in
the central lymph nodes were detected in 13 (3%) of
394 patients in the CME group; these included
ten patients with stage T3 and three with stage T4a
disease. No patient had isolated metastases to central
lymph nodes.

www.thelancet.com/oncology Vol 22 March 2021 397

 Articles
In our post-hoc analyses, median duration of
hospitalisation was similar between the CME and
D2 groups (table 3). The area of excised mesocolon was
significantly larger in the CME group than in the
D2 group (median 116·4 cm² [IQR 89·4–144·8] vs
107·8 cm² [84·9–132·7]; p=0·0010). In the prespecified
measure­ment of distal clearance, distances between the
tumour and the proximal and distal surgical margins did
not differ significantly between the two groups (table 4).
Quality assessment data are in table 4; quality assessment
of the mesocolon could not be done for three patients in
the CME group and two patients in the D2 group because
data were not available (photographs were not taken
during surgery). Results from the per-protocol analysis
were consistent with the modified intention-to-treat
analysis (appendix pp 4–7).
Discussion
The results of this trial indicate that the incidence of
perioperative complications was not significantly higher
with CME than with D2 dissection during laparoscopic
right hemicolectomy for colon cancer.
Since the CME procedure involves harvesting of lymph
nodes and adipose tissue around mesenteric blood
vessels, the duration of surgery was longer with CME
than with D2, although the volume of blood loss was
similar for both procedures; however, the CME procedure
harvested a larger area of mesentery and more lymph
nodes. The median duration of hospital stay in both
groups was 7 days, which is relatively normal for this
surgical procedure in China.
Several studies comparing CME and traditional
procedures have reported that specimens obtained by the
CME procedure are of higher quality than those obtained
by traditional procedures, which is partly the reason why
CME is highly recommended worldwide.14–16 The findings
of previous studies might be questioned because
comparisons were made between surgeries done in
different eras or in different hospitals; moreover, the
studies did not have clear definitions for the traditional
or non-CME procedures. In our study, we ensured that
we used clear definitions of the CME and D2 techniques
and also compared the preservation of anatomical planes
and the quality of the specimens obtained with the
two surgical approaches.
In the present study, surgeons were required to do
retrocolic dissection according to CME principles in both
the D2 and the CME groups, and the quality of the
procedures was then assessed by evaluation of the
photographs of the surgical field and the anterior and
posterior views of the fresh specimens.12 Nevertheless, in
the early stages of the study, some surgeons inadvertently
did not do the surgery according to the plan, and some
patients assigned to the D2 group received CME surgery
instead. Specimen quality was found to be better in the
D2 group than in the CME group. One grade III specimen
from the CME group was judged to be of poor quality. In
398
both groups, sharp dissection of the mesocolon was done
strictly along the retrocolic space of the colon, so the
integrity of the mesocolon was good in both groups.
However, since the medial resection margin of the
mesocolon in the CME group was located on the surface
of the mesenteric blood vessels, and the edge of
mesocolon was sometimes serrated because of poor
dissecting skill, such specimens were classified as
grade II. A smooth margin is more easily achieved in
D2 dissection than in CME because it only requires
severing of the blood vessels at the right side of the
superior mesenteric vein. This might be why mesocolon
quality was worse in the CME group than in the D2 group.
Previous retrospective studies have concluded that
the improved prognosis after CME procedures versus
D2 dissection was due to the resection of a larger area
of mesentery and the harvesting of more lymph
nodes.6,14,17 In one of these studies comparing CME and
D2 resection, the distance between the tumour and the
distal resection margin was 10 cm more in the
CME group, and the vascular pedicle between the
tumour and the ligation site was 4 cm longer, resulting
in an area of mesentery that was 78·3 cm2 larger and a
greater number of lymph nodes harvested (30 vs 18);14
the authors attributed this to the resection of a longer
segment of colon. In the present study, the site of
resection was determined by the location of the tumour.
Because the same dissection principles were applied in
patients in both the CME and D2 groups, the only
difference between the two groups was the complete
excision of tissue surrounding the superior mesenteric
vein and the resection of central lymph nodes in the
CME group.11
In our trial, no differences were found in the distance
between the tumour and the proximal or distal resection
margins; however, the additional resection of the central
lymph nodes in the CME group made the area of resected
mesentery 8·4 cm² larger in the CME group than in the
D2 group; the number of lymph nodes harvested was
also significantly higher in the CME group than in the
D2 group. However, the absolute differences in the area
of resected mesentery and the number of lymph nodes
harvested between the CME and D2 groups in our study
were less than in previous retrospective studies.5,14,16
Whether or not the larger number of lymph nodes
obtained in the CME group translates into survival
benefits, or improvement in the quality of surgical
specimens means that extensive lymph node dissection
is no longer needed will be known only when the 3-year
disease-free survival outcomes of our trial are available.
Central lymph node metastasis is reported to be
significantly associated with the T stage of the tumour.18–20
Central lymph node metastasis is seen in up to 3·7% of
stage T4 colon cancers, but is rarely found in cancers of
stage T2 and lower.18–20 In our study, metastases were
found in 13 of the 394 patients who underwent central
lymph node biopsy: ten patients with stage T3 and
www.thelancet.com/oncology Vol 22 March 2021

three with stage T4a disease. This prevalence is similar to
that reported in previous studies.18,19,21 However, in this
study, 87 patients did not additionally have a separate
biopsy of the central lymph nodes, which might affect
the true detection of central lymph node metastases in
our trial. According to previous studies and our
research,18–20 we found that almost all central lymph node
metastases occurred in patients at stage T3–4. Patients
with stage pT3–4 accounted for 440 (89%) of 495 patients
in the CME group, and 355 (90%) of 394 who underwent
central lymph node biopsy. Similarly, 78 (90%) of the
87 patients who did not have a separate biopsy of the
central lymph nodes had stage T3–4 stage tumours.
Thus, the similar incidence of T3–4 stage tumours
between evaluable and non-evaluable patients would
probably have little effect on the results for central lymph
node metastasis rate Additionally, we excluded patients
in whom preoperative assessment or intraoperative
exploration revealed central lymphadeno­ pathy, which
might have artificially lowered the prevalence of central
lymph node involvement.
There has been much debate about whether or not
CME increases the risk for postoperative complications.
In the retrospective study in which the CME procedure
was first introduced, the overall incidence of compli­
cations was 19·7%, with anastomotic leak reported in
2·6% patients and postoperative mortality in 3·1%.2
Subsequent studies have reported inconsistent results
regarding the safety of CME. Some studies reported
similar safety profiles for the CME procedure and the
traditional D2 procedure,17,22,23 whereas others found a
higher incidence of vascular injury and increased need
for vasoactive medications in patients undergoing CME.24
In our study, the incidence of complications in the first
30 days after surgery was similar in the two groups.
Anastomotic leak occurred in four (1%) patients in the
CME group and seven (1%) patients in the D2 group.
Interestingly, eight of these 11 patients had undergone
intracorporeal anastomosis; whether the risk for anasto­
motic leak is higher with intracorporeal anastomosis
than with extracorporeal anastomosis remains to be
established. Most complications in both groups were
Clavien-Dindo grade I–II, with incidence rates similar
between the groups; however, grade III–IV complications
were more common in the D2 group than in the
CME group. Of the patients who had anastomotic leak,
more patients in the D2 group than in the CME group
required ostomy. This could be accounted for by the
differences in the severity of intraperitoneal infection
after the development of anastomotic leak and the
subsequent management. However, on the basis of the
current data, we are inclined to believe that there is no
causal relationship between this result and the surgical
procedure. The worse anastomotic leak in the D2 group
might be explained by chance.
Mortality and incidence of postoperative anastomotic
leak were much lower in our study than in some of the
www.thelancet.com/oncology Vol 22 March 2021
Articles
previous registry studies done in Europe;25–27 this
difference was probably because the national databases
in Europe include data from all grades of hospital, and so
reflect the reality of postoperative complications
following colectomy for right colon cancer. Other reasons
for the high mortality in the registry studies could be the
presence of a higher percentage of elderly patients in
the database, more patients with ASA score of 3–4
(around 40%), or a low proportion (<50%) of surgeries
done by specialists in colorectal surgery. The median age
of the patients in our study was 60 years, only 8% had
ASA score 3, and the mean body-mass index was
23·5 kg/m²; thus, our patients were in relatively good
condition. The low body-mass index and young age of
our study patients might have been partly responsible for
the low incidence of complications. Moreover, all
participating centres in our study were tertiary care
hospitals, and all surgeries were done by specialists who
operated on a large number of patients every year, which
might also have decreased the incidence of complications
in our patients.28 Finally, both groups in our study
received laparoscopic surgery, with conversion to open
surgery necessary in only 2%; this too is likely to have
contributed to the lower incidence of complications.15
The incidence of complications in our study was similar
to that reported in the JCOG 0404 study from Japan on
radical laparoscopic dissection for colon cancer.29
Very few studies have assessed the intraoperative
complications of CME. In a Danish cohort, the CME
procedure was associated with an increased risk of
intraoperative injuries to the spleen, superior mesenteric
vein, and other structures.17,24 In our study, the incidence
of intraoperative complications was similar in the CME
and D2 groups of patients. The major intraoperative
complications were haemorrhage and vascular injury;
organ injury was relatively rare, probably because all
procedures were done by experienced colorectal
specialists. Although the overall incidence of compli­
cations was similar in the two groups, vascular injury
was significantly more common in patients in the
CME group than in the D2 group. Bertelsen and
colleagues reported injury to the superior mesenteric
vein during CME in nine (3%) of 272 of their patients
who underwent right colectomy,24 which is similar to our
results. Injury was usually to the veins (as it was in our
study), which is probably because CME requires complete
exposure of the mesenteric vein and Henle trunk and
their tributaries; the frequent anatomical variations also
increase the risk for vascular tears and injuries. In this
study, only two of the 21 patients with vascular injuries
needed conversion to open surgery; the others could be
managed by laparoscopic haemostasis or cauterisation.
Eight patients required blood transfusion for intra­
operative vascular injury or haemorrhage.
To our knowledge, this study is the first randomised,
controlled trial to directly verify the safety of
CME procedure in laparoscopic right hemicolectomy.
399
 Articles
With the significantly better short-term and long-term
outcomes widely reported with the use of laparoscopic
technology than with open surgery, laparoscopic surgery
will inevitably become the first choice colectomy
approach; thus, the results of this study are of great
significance. However, this study has several limitations.
First, all the surgeons in this study are highly specialised
experts, whereas in real-world situations colectomies are
usually done by general surgeons with much smaller
annual volumes of colectomy, which limits the
generalisability of our findings. If the final results of this
study prove that the CME can improve the survival of
patients with right colon cancer in the future, it will be
worth considering how an effective learning system
could be established to facilitate optimal training for this
surgical technique. Second, all participating centres in
this study were in China, and because the characteristics
of Asian populations, especially with regard to body-
mass index, differ to those in other countries or races,
the results might not be applicable to patients globally.
Third, although central lymph node metastasis rate was a
secondary outcome measure in this study, the exclusion
of some patients from the analysis of this endpoint
means that the study findings might not reflect the true
central lymph node metastasis rate in colon cancer.
One ongoing international, prospective, observational
cohort study is investigating optimal bowel resection
extent and central radicality for colon cancer (the
T-REX Study; NCT02938481); we look forward to the
results of that study.
In conclusion, compared with D2 dissection, CME
does not seem to increase the intraoperative and
postoperative complications of laparoscopic right
hemicolectomy when done by experienced surgeons.
However, the risk of vascular injury during CME is
significantly increased. Whether CME can benefit
patients’ survival needs to be confirmed by future
disease-free survival results.
Contributors
ZZ, MZhe, and YX contributed equally to this trial. LX, JL, XD, TX, ZZ,
ZW, and YX were responsible for the conception and design of the study.
LX, XS, ZH, CZ, JL, GZ, YS, XD, PC, ZW, MZho, AW, AZ, FL, JX, LK, JS,
HD, YY, KD, ZZ, MZhe, and YX contributed to the collection of data.
TX directed the statistical analysis. LX, JL, TX, and YX accessed and
verified the data. All authors were responsible for the interpretation of data
and writing the manuscript, as well as reviewing and approving the
manuscript for submission. The corresponding author had full access to
all data and had final responsibility for the decision to submit the paper for
publication.
Declaration of interests
We declare no competing interests.
Data sharing
The original data of the published results can be shared, if needed by
other researchers; it can be obtained through the email address of the
corresponding author (xiaoy@pumch.cn).
Acknowledgments
Funding for the study was provided by the Capital Characteristic Clinical
Project of Beijing Municipal Science & Technology Commission
(Z161100000516014) and the Non-profit Central Research Institute Fund
of the Chinese Academy of Medical Sciences (2019XK320003). We thank
400
Yuelun Zhang for statistical method consulting and Wei Ge for
modifying the language and grammar of the manuscript.
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