Research

JAMA Surgery | Original Investigation

Laparoscopic vs Open Distal Gastrectomy for Locally Advanced

Gastric Cancer
Five-Year Outcomes From the CLASS-01 Randomized Clinical Trial
Changming Huang, MD; Hao Liu, MD; Yanfeng Hu, MD; Yihong Sun, MD; Xiangqian Su, MD; Hui Cao, MD;
Jiankun Hu, MD; Kuan Wang, MD; Jian Suo, MD; Kaixiong Tao, MD; Xianli He, MD; Hongbo Wei, MD;
Mingang Ying, MD; Weiguo Hu, MD; Xiaohui Du, MD; Jiang Yu, MD; Chaohui Zheng, MD; Fenglin Liu, MD;
Ziyu Li, MD; Gang Zhao, MD; Jiachen Zhang, MPH; Pingyan Chen, PhD; Guoxin Li, MD, PhD; for the Chinese
Laparoscopic Gastrointestinal Surgery Study (CLASS) Group

Visual Abstract
IMPORTANCE It is not clear whether laparoscopic and open distal gastrectomy produce Supplemental content
similar outcomes among patients with locally advanced gastric cancer. Data from a
multicenter, randomized clinical trial (Chinese Laparoscopic Gastrointestinal Surgical Study CME Quiz at
jamacmelookup.com
[CLASS]–01) showed that laparoscopic distal gastrectomy did not result in inferior
disease-free survival at 3 years compared with open distal gastrectomy.

OBJECTIVE To report 5-year overall survival data from the CLASS-01 trial of laparoscopic
vs open distal gastrectomy among patients with locally advanced gastric cancer.

DESIGN, SETTING, AND PATIENTS This was a noninferiority, open-label, randomized clinical trial
conducted at 14 centers in China. A total of 1056 eligible patients with clinical stage T2, T3,
or T4a gastric cancer without bulky nodes or distant metastases were enrolled from
September 12, 2012, to December 3, 2014. Final follow-up was on December 31, 2019.

INTERVENTIONS Participants were randomized in a 1:1 ratio after stratification by site, age,
cancer stage, and histologic features to undergo either laparoscopic distal gastrectomy
(n = 528) or open distal gastrectomy (n = 528) with D2 lymphadenectomy.

MAIN OUTCOMES AND MEASURES The 5-year overall survival rates were updated to compare
laparoscopic distal gastrectomy with open distal gastrectomy. All analyses were performed
on an intention-to-treat basis. In addition, per-protocol and as-treated analyses were
performed for overall survival.

RESULTS Data from 1039 patients (726 men [69.9%]; mean [SD] age, 56.2 [10.7] years) who
received curative therapy were analyzed. At 5 years, the overall survival rates were 72.6% in
the laparoscopic distal gastrectomy group and 76.3% in the open distal gastrectomy group
(log-rank P = .19; hazard ratio, 1.17; 95% CI, 0.93-1.48; P = .19). After comparison for
competing risk events, gastric cancer–related deaths (hazard ratio, 1.14; 95% CI, 0.87-1.49;
P = .34) and deaths from other causes (hazard ratio, 1.23; 95% CI, 0.74-2.05; P = .42)
did not differ significantly between groups. Overall rates of survival did not differ significantly
between groups with each tumor stage.

CONCLUSIONS AND RELEVANCE This study found that laparoscopic distal gastrectomy
with D2 lymphadenectomy performed by experienced surgeons in high-volume specialized
institutions resulted in similar 5-year overall survival compared with open distal gastrectomy Author Affiliations: Author
affiliations are listed at the end of this
among patients with locally advanced gastric cancer.
article.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01609309 Group Information: The Chinese
Laparoscopic Gastrointestinal
Surgery Study (CLASS) Group
collaborators are listed in
Supplement 3.
Corresponding Author: Guoxin Li,
MD, PhD, Department of General
Surgery, Guangdong Provincial Key
Laboratory of Precision and Minimally
Invasive Medicine for GI Cancers,
Nanfang Hospital, Southern Medical
University, 1838 N Guangzhou Ave,
JAMA Surg. 2022;157(1):9-17. doi:10.1001/jamasurg.2021.5104 Guangzhou 510-515, China
Published online October 20, 2021. (gzliguoxin@163.com).

(Reprinted) 9
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 Research Original Investigation
G
astric cancer is the fifth most common malignant neo-
plasm and the third leading cause of cancer-related
death, causing an estimated 783 000 deaths world-
wide in 2018, based on GLOBOCAN 2018 data.1 Patients with-
out metastases are treated with surgery. There are 2 surgical
options for patients with potentially curable gastric cancer.
Kitano et al2 first reported treatment of early-stage distal gastric
cancer with laparoscopic-assisted gastrectomy in 1991. After
this report, the procedure rapidly achieved popularity in
Eastern countries3,4 especially for treatment of early gastric
cancer (T1, any N, and M0).
The Japanese Clinical Oncology Study Group provides a
platform to launch randomized trials to evaluate treatment ap-
proaches, including surgery and laparoscopy, among pa-
tients with gastric cancer. The Korean Laparoscopic Gastroin-
testinal Surgical Study Group (KLASS) was founded in 2004
for the sharing of technical information and the effects of lapa-
roscopic surgery on patients with gastric cancer. After an ini-
tial trial to investigate the effect of laparoscopic surgery on early
gastric cancer (KLASS-01 trial), researchers initiated the
KLASS-02 trial of patients with locally advanced gastric can-
cer (LAGC).5 Laparoscopic surgery is an option for treatment
of patients in general practice with stage I cancer indicated for
distal gastrectomy. In the 2014 version of the guidelines from
the Japan Society for Endoscopic Surgery,6 distal gastrec-
tomy via laparoscopy was recommended for patients with stage
I cancer (rated recommendation B). This recommendation was
made because the safety of the laparoscopic approach was
proven in a prospective phase 2 study (JCOG0703)7 that in-
volved only certified surgeons with sufficient experience.
Data regarding the long-term outcome of pivotal phase 3 stud-
ies conducted in Japan (JCOG0912)8 and Korea (KLASS-01)9
were recently published, providing evidence for the efficacy
of laparoscopic surgery in treatment of early gastric cancer.
For patients with more advanced cancer, there is cur-
rently insufficient evidence to recommend a laparoscopic ap-
proach, but randomized trials of its safety and long-term out-
comes are underway. In China, more than 80% of all patients
with gastric cancer have received a diagnosis of advanced-
stage disease.10 The Chinese Laparoscopic Gastrointestinal
Surgical Study (CLASS) Group was founded in 2009; it launched
its first trial for patients with LAGC (the CLASS-01 trial) in 2012
and published primary end points from the study in May 2019.11
The CLASS-01 trial was the first completed multicenter, ran-
domized clinical trial to compare long-term outcomes of
laparoscopic distal gastrectomy (LDG) with open distal gas-
trectomy (ODG) for LAGC. The study found no significant dif-
ference in disease-free survival at 3 years among patients un-
dergoing LDG (76.5%) vs those undergoing ODG (77.8%).
A randomized clinical trial of patients in Korea with LAGC
also recently reported that LDG was not inferior to ODG in
disease-free survival at 3 years.12
However, overall survival is the standard end point for can-
cer trials. Although the CLASS-01 trial was designed with
disease-free survival as its primary end point, it was also pow-
ered to determine effects on overall survival. At the time of
the primary analysis of disease-free survival, overall survival
data were immature; the outcomes of the CLASS-01 trial were
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Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer
Key Points
Question Does laparoscopic distal gastrectomy yield similar
5-year overall survival to open distal gastrectomy for patients
with locally advanced gastric cancer?
Findings In this randomized clinical trial of 1056 patients with
clinically staged, locally advanced gastric cancer, laparoscopic
distal gastrectomy resulted in a 5-year overall survival rate of 73%
vs 76% for open distal gastrectomy, with no statistically significant
difference between the 2 groups.
Meaning The finding provides further evidence for the safety
and efficacy of laparoscopic gastrectomy for patients assessed
preoperatively as having locally advanced cancer.
updated, after a minimum 5 years of follow-up, at the end of
2019. We report the 5-year overall survival data from the
CLASS-01 trial, along with data on the effects of LDG, among
patients with tumors of different stages, especially in stage III
tumors, and causes of death in the per-protocol, as-treated
population.
Methods
Study Design
The CLASS-01 trial is an open-label, multicenter, random-
ized clinical noninferiority trial conducted at 14 centers in
China. Patients were enrolled from September 12, 2012,
through December 3, 2014. The final follow-up was on
December 31, 2019. Participants were randomly assigned in a
1:1 ratio, after matching for study site, patient age, tumor
stage, and histologic features, to groups that underwent LDG
(n = 528) or ODG (n = 528) with D2 lymphadenectomy. The
primary end point was 3-year disease-free survival. A
detailed description of the study protocol and the main
results have been published with clinical and demographic
baseline characteristics (trial protocol and statistical analysis
plan in Supplement 1).11,13 Each participating center (Nan-
fang Hospital, Southern Medical University, Guangzhou,
China; Fujian Medical University Union Hospital, Fuzhou,
China; Zhongshan Hospital, Fudan University, Shanghai,
China; Peking University Cancer Hospital and Institute,
Beijing, China; Renji Hospital, Shanghai Jiao Tong University
School of Medicine, Shanghai, China; West China Hospital,
Sichuan University, Chengdu, China; the Cancer Hospital of
Harbin Medical University, Harbin, China; the First Hospital
of Jilin University, Changchun, China; Union Hospital, Tongji
Medical College, Huazhong University of Science and Tech-
nology, Wuhan, China; Tangdu Hospital, Fourth Military
Medical University, Xi’an, China; the Third Affiliated Hospi-
tal of Sun Yat-Sen University, Guangzhou, China; Fujian Pro-
vincial Cancer Hospital, Fuzhou, China; Ruijin Hospital,
Shanghai Jiao Tong University School of Medicine, Shanghai,
China; and General Hospital of PLA, Beijing, China) obtained
institutional review board approval, according to local regu-
lations. Patients provided written informed consent.
jamasurgery.com
 Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer Original Investigation Research

Study Population Figure 1. CONSORT Flow Diagram of Patient Enrollment

The CLASS-01 trial enrolled patients with LAGC (cT1-4aN1- and Randomization
3M0) planned for elective surgery; the inclusion and exclu-
sion criteria were published.11 Patients were included if they
1056 Randomizeda
were aged 18 to 75 years; had an Eastern Cooperative Oncol-
ogy Group (ECOG) performance status of 0 (asymptomatic) or
1 (symptomatic but completely ambulatory); had histologi-
528 Randomized to undergo LDG 528 Randomized to undergo ODG
cally confirmed gastric adenocarcinoma, detected at a locally 519 Underwent gastrectomy 520 Underwent gastrectomy
advanced stage, according to the Japanese Classification11 1 Withdrew consent 1 Withdrew consent
8 Had unresectable tumor 7 Had unresectable tumor
(and to T2-4aN0-3M0, corresponding to stages IB-IIIC exclud- intraoperatively intraoperatively
ing T1 or T4b tumors); had tumors located in the lower or
middle third of the stomach by preoperative evaluation; or were 519 Included in modified 520 Included in modified
intention-to-treat analysisb intention-to-treat analysisc
expected to undergo distal gastrectomy with D2 lymphad-
enectomy for curative intent. Patients were excluded if they
481 Included in per-protocol analysis 477 Included in per-protocol analysis
had enlarged or bulky regional lymph nodes larger than 3-cm 38 Excluded from analysis 43 Excluded from analysis
maximum diameter, determined during preoperative imaging. 4 Underwent laparoscopic 13 Underwent open total
total gastrectomy gastrectomy
1 Underwent laparoscopic 30 Declined randomization to
End Points inadequate D2 ODG and received
lymphadenectomy laparoscopic gastrectomy
Patients were followed up for a minimum of 60 months after 33 Converted to open 29 Underwent LDG
surgery. Overall survival was calculated from the day of ran- gastrectomy intraoperatively 1 Underwent laparoscopic
25 Underwent ODG inadequate D2
domization until the day of death (event) or the day of the last 7 Underwent open total lymphadenectomy
follow-up examination (censored). Data were censored for pa- gastrectomy
1 Underwent open inadequate
tients with no evidence of disease at the last follow-up exami- D2 lymphadenectomy
nation or for patients who died of diseases other than gastric
cancer without evidence of a recurrence. 510 Included in as-treated analysis 502 Included in as-treated analysis
481 Received LDG as randomized 477 Received ODG as randomized
29 Received LDG (crossover) 25 Received ODG (crossover)
Statistical Analysis
We used the Kaplan-Meier method to estimate the difference
CONSORT indicates Consolidated Standards of Reporting Trials;
in overall survival between the groups at 5 years after the pro- LDG, laparoscopic distal gastrectomy; and ODG, open distal gastrectomy.
cedures. Cox proportional hazards regression analysis was used a
Data for number screened for eligibility and reasons for exclusion were not
to determine the effect of covariates on time of death. In- available.
stead of median survival time, we used the area under the b
Includes 18 patients who were lost to follow-up and 2 patients who died within
Kaplan-Meier curve within a specific time window as a rea- 30 days after the surgery (1 died of respiratory failure as a result of pneumonia
and the other died of a cerebrovascular accident).
sonable summary to quantify the survival time, which is called
c
Includes 15 patients who were lost to follow-up.
restricted mean survival time (RMST). Laparoscopic distal
gastrectomy was considered to be noninferior to ODG if the
1-sided 95% CI for the difference in overall survival excluded detected intraoperatively. The primary analysis set com-
an absolute difference of 10 percentage points or more. We also prised 1039 patients (519 in the LDG group and 520 in the ODG
conducted competing risk regression to eliminate the influ- group). The per-protocol population comprised 958 patients,
ence of different causes of death, and used the Gray test to with 481 in the LDG group (519 patients in the primary analy-
assess differences between the LDG and ODG groups. All analy- sis set minus 38 patients who did not adhere to their treat-
ses were performed on an intention-to-treat basis. In addi- ment plans) and 477 in the ODG group (520 patients in the pri-
tion, we performed per-protocol and as-treated analyses for mary analysis set minus 43 patients who did not adhere to their
overall survival. All analyses were performed using SPSS, ver- treatment plans). The as-treated population comprised 510 pa-
sion 25 (IBM Corp), SAS, version 9.4 (SAS Institute Inc), and tients in the laparoscopic group (481 per-protocol patients plus
R, version 3.6.2 (R Group for Statistical Computing). P < .05 29 patients with protocol crossovers) and 502 patients in the
was considered significant. ODG group (477 per-protocol patients plus 25 patients with pro-
tocol crossovers). The median follow-up period was 71 months
(IQR, 43-77 months), with a total of 33 patients (3.2%) lost to
follow-up (18 in the LDG group and 15 in the ODG group). A de-
Results tailed description of the study protocol and the main results
Study Population have been published previously with clinical and demo-
From September 12, 2012, through December 3, 2014, 528 pa- graphic baseline characteristics.11,13 Most patients in both
tients were randomly assigned to the LDG group and 528 to groups were men (380 [73.2%] in the LDG group and 346
the ODG group (Figure 1). In the LDG group, 1 patient with- [66.5%] in the ODG group); the mean (SD) age was 56.5 (10.4)
drew informed consent and 8 had unresectable gastric can- years in the LDG group and 55.8 (11.1) years in the ODG group
cer detected intraoperatively. In the ODG group, 1 patient with- (Table 1). Although all patients had a diagnosis of T2 stage or
drew informed consent and 7 had unresectable gastric cancer, higher, 248 patients (23.9%) were found to have T1 tumors (116

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 Research Original Investigation Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer

therapy was 192 (37.0%) in the LDG group, and 217 (41.7%)
Table 1. Demographic and Clinical Characteristics of the Patients
at Baseline in the ODG group, with no significant difference between the
2 groups.
Patients, No. (%)
Laparoscopic Open surgery
Characteristic surgery (n = 519) (n = 520) Overall Survival
Sex At the last follow-up, 286 patients (27.5%) had died (152 in the
Female 139 (26.8) 174 (33.5) LDG group and 134 in the ODG group). The rates of 5-year over-
Male 380 (73.2) 346 (66.5) all survival were 72.6% in the LDG group and 76.3% in the
Age, mean (SD), y 56.5 (10.4) 55.8 (11.1) ODG group (log-rank P = .19; hazard ratio [HR], 1.17;
BMI, mean (SD) 22.7 (3.2) 22.7 (3.2) 95% CI, 0.93-1.48; P = .19) (Figure 2). The rates of 5-year over-
Eastern Cooperative Oncology Group all survival were 90.0% in the LDG group vs 88.5% in the ODG
performance status group for patients with stage I tumors, 79.1% in the LDG
0 375 (72.3) 391 (75.2) group vs 84.5% in the ODG group for patients with stage II tu-
1 142 (27.4) 127 (24.4) mors, and 58.6% in the LDG group vs 59.5% in the ODG group
Comorbidities for patients with stage III tumors. The HR for ODG vs LDG
None 359 (69.2) 378 (72.7) was 1.14 (95% CI, 0.89-1.46; P = .25) after we adjusted for age,
≥1 159 (30.6) 139 (26.7) sex, body mass index, ECOG performance status, comorbid-
Tumor size, mean (SD), cm 4.0 (2.0) 4.0 (2.1) ity, tumor size, histologic features, TNM stage, and chemo-
Histologic features therapy. For RMST, we set truncation at 60 months (5 years).
Signet ring cell 79 (15.2) 99 (19.0) The RMST in the LDG group was 51.5 months (95% CI, 50.2-
Others 440 (84.8) 421 (81.0) 52.8 months). Corresponding restricted mean times lost were
Retrieved lymph node, mean (SD), No. 36.1 (16.7) 36.9 (16.1) 8.5 years (95% CI, 7.2-9.8 years) in the LDG group and 8.5 years
Metastatic lymph node, mean (SD), 4.9 (8.0) 4.5 (6.9) in the ODG group (95% CI, 7.2-9.8 years). The RMST in the ODG
No.
group was 52.5 months (95% CI, 51.3-53.8 months) and the re-
Received chemotherapy
stricted mean time lost in the ODG group was 7.5 months
Yes 192 (37.0) 217 (41.7)
(95% CI, 6.2-8.7 months). The RMST ratio for LDG to ODG was
No 327 (63.0) 303 (58.3)
0.98 (95% CI, 0.94-1.01), indicating that the LDG group had a
Pathological T stage
median survival time that was 2% less than that of the ODG
<T2 116 (22.4) 132 (25.4) group (P = .27).
T2-T4a 394 (76.1) 383 (73.7) In the LDG vs ODG groups, the rates of 5-year overall sur-
T4b 8 (1.5) 4 (0.8) vival were 90.0% vs 88.5% for patients with stage I tumors (log-
Pathological N stage rank P = .70); 79.1% vs 84.5% for patients with stage II tu-
N0 214 (41.2) 216 (41.5) mors (log-rank P = .14); and 58.6% vs 59.5% for patients with
N1 87 (16.8) 79 (15.2) stage III tumors (log-rank P = .95). Crude HRs for 5-year
N2 88 (17.0) 98 (18.8) overall survival with LDG vs ODG were 0.81 (95% CI, 0.29-
N3 129 (24.9) 126 (24.2) 2.25) for patients with stage I tumors, 1.34 (95% CI, 0.91-1.97)
Nx 1 (0.2) 1 (0.2) for patients with stage II tumors, and 1.01 (95% CI, 0.74-1.37)
Pathological M stage for patients with stage III tumors. After we adjusted for age,
M0 510 (98.3) 511 (98.3) sex, body mass index, ECOG performance status, comorbid-
M1 8 (1.5) 8 (1.5) ity, tumor size, histologic features, and chemotherapy, the
Missing data 1 (0.2) 1 (0.2) adjusted HRs for 5-year overall survival with LDG vs ODG were
Pathological TNM stage 0.59 (95% CI, 0.16-2.13) for patients with stage I tumors, 1.40
IA 87 (16.8) 99 (19.0) (95% CI, 0.93-2.10) for patients with stage II tumors, and 1.03
IB 64 (12.3) 53 (10.2) (95% CI, 0.75-1.42) for patients with stage III tumors (Figure 2).
IIA 66 (12.7) 59 (11.3) Univariate analysis of overall survival at 5 years found no
IIB 71 (13.7) 79 (15.2) differences in outcomes of ODG vs LDG in terms of age, sex,
IIIA 69 (13.3) 77 (14.8) or tumor stage (Table 2).
IIIB 73 (14.1) 78 (15.0) The cause of death was analyzed for all patients; the dis-
IIIC 77 (14.8) 66 (12.7) tribution for LDG and ODG group is presented in the eTable in
IV 11 (2.1) 8 (1.5) Supplement 2. After we controlled for all other competing risk
Missing data 1 (0.2) 1 (0.2) events, gastric cancer–related death (HR, 1.14; 95% CI, 0.87-
Adjuvant chemotherapy 192 (37.0) 217 (41.7)
1.49; P = .34) and death from other causes (HR, 1.23; 95% CI,
0.74-2.05; P = .42) did not differ significantly different be-
Abbreviation: BMI, body mass index (calculated as weight in kilograms divided
tween the LDG and ODG groups (Figure 3). In the post hoc sen-
by height in meters squared).
sitivity analysis, exclusion of the 248 patients with patho-
logic T1N0 to 3M0 tumors resulted in an HR for death of 1.13
[22.4%] in the LDG group and 132 [25.4%] in the ODG group). for LDG vs ODG (95% CI, 0.89-1.44; P = .29) (eFigure 1 in
The number of patients who received adjuvant chemo- Supplement 2).

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 Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer Original Investigation Research

Figure 2. Overall Survival for Laparoscopic Distal Gastrectomy (LDG) vs Open Distal Gastrectomy (ODG)
at 5 Years After Surgery

A All stages B TNM stage I

1.00 1.00
Survival probability

Survival probability
0.75 0.75

0.50 0.50

LDG
0.25 ODG 0.25

Log-rank P = .19 Log-rank P = .70

0 0
0 12 24 36 48 60 72 0 12 24 36 48 60 72
Time after surgery, mo Time after surgery, mo
No. at risk No. at risk
LDG 520 511 473 423 391 379 LDG 64 63 62 60 56 54
ODG 519 508 461 407 374 359 ODG 88 88 86 79 74 73

C TNM stage II D TNM stage III

1.00 1.00
Survival probability

Survival probability

0.75 0.75

0.50 0.50

0.25 0.25

Log-rank P = .14 Log-rank P = .95

0 0
0 12 24 36 48 60 72 0 12 24 36 48 60 72
Time after surgery, mo Time after surgery, mo
No. at risk No. at risk
LDG 248 241 227 208 196 189 LDG 207 204 172 139 122 116
ODG 247 245 230 215 202 197 ODG 185 178 157 129 115 109

E RMST in LDG group = 51.5 mo F RMST in ODG group = 52.5 mo

1.0 1.0

0.9 0.9
Survival probability

Survival probability

0.8 0.8

0.7 0.7
A, Patients with all stages of cancer.
0.6 0.6 B, Patients with TNM stage I cancer.
C, Patients with TNM stage II
0.5 0.5 cancer. D, Patients with TNM stage III
0 12 24 36 48 60 72 0 12 24 36 48 60 72 cancer. E, Restricted mean survival
Time after surgery, mo Time after surgery, mo time (RMST) in the LDG group.
F, RMST in the ODG group.

Per-Protocol and As-Treated Populations

In the per-protocol analysis, 134 of 481 patients in the LDG Discussion
group died within 5 years (72% survival rate), compared with
119 of 481 patients in the ODG group (74% survival rate); the In this multicenter randomized clinical trial to compare out-
HR for ODG vs LDG was 1.14 (95% CI, 0.89-1.45; P = .29). In the comes of LDG vs ODG among patients with LAGC (the CLASS-01
as-treated analysis, 143 of 506 patients in the LDG group died trial), we found 5-year overall survival not to differ signifi-
within 5 years (72% survival rate), compared with 127 of 506 cantly between patients who underwent LDG with D2 lymph-
of patients (75% survival rate) in the ODG group; the HR for adenectomy vs ODG performed by experienced surgeons at
ODG vs LDG was 1.10 (95% CI, 0.87-1.40; P = .40) (eFigure 2 high-volume, specialized centers, regardless of tumor stage.
in Supplement 2). This is the first multicenter, randomized study to our knowl-

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 Research Original Investigation Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer

Table 2. Univariate Analysis of Overall Survival at 5 Years’ Follow-up

LDG group, 5-y OS ODG group, 5-y OS
Variable Patients, No. (95% CI), % Patients, No. (95% CI), % Hazard ratioa Log-rank P value
Total 519 73 (69-77) 520 76 (73-80) 1.17 (0.93-1.48) .19
Sex
Male 380 72 (68-77) 346 76 (72-81) 1.12 (0.90-1.57) .22
Female 139 73 (66-81) 174 76 (69-82) 1.12 (0.73-1.72) .60
Age, y
≤65 419 75 (71-79) 418 77.4 (73.5-81.6) 1.13 (0.86-1.48) .39
>65 99 63 (55-74) 102 69 (61-79) 1.30 (0.83-2.06) .25
N stage
N0 214 90.5 (86.6-94.5) 216 90.5 (86.7-94.6) 0.92 (0.51-1.64) .77
N1 87 85 (78-93) 79 83 (75-92) 0.98 (0.47-2.03) .96
N2 88 66 (57-77) 98 73 (65-83) 1.31 (0.79-2.12) .30
N3 129 37(29-46) 126 48 (40-58) 1.37 (0.99-1.90) .05
TNM stage
IA 87 94 (89-99) 99 94 (89-99) 1.31 (0.44-3.89) .63
IB 64 95 (90-100) 53 94 (88-100) 0.51 (0.12-2.13) .34
IIA 66 91 (84-98) 59 90 (82-98) 0.87 (0.28-2.71) .81
IIB 71 81 (72-91) 79 82 (73-92) 0.99 (0.47-2.07) .97
IIIA 69 73 (63-85) 77 71 (61-82) 1.02 (0.56-1.86) .94
IIIB 73 47 (37-61) 78 60 (50-72) 1.31 (0.83-2.07) .24
IIIC 77 28 (19-41) 66 41 (33-55) 1.35 (0.90-2.05) .14
IV 11 27 (10-72) 8 38 (15-92) 1.20 (0.39-3.70) .77

Abbreviations: LDG, laparoscopic distal gastrectomy; ODG, open distal gastrectomy; OS, overall survival.
a
Reference, ODG group.

edge that compared effects of LDG vs ODG on long-term
(5-year) survival. This finding provides further evidence for
the safety and efficacy of LDG for treatment of gastric cancer.
The efficacy of LDG for early gastric cancer has been evalu-
ated in a multicenter trial of 1416 patients in Korea with stage
I gastric cancer.9 Rates of 5-year overall survival were 94.2%
in the LDG group and 93.3% in the ODG group, indicating the
noninferiority of LDG. However, this study did not have suf-
ficient data on long-term oncologic outcomes of patients with
advanced gastric cancer.
With accumulating surgical experience, indications for
laparoscopic surgery have been gradually extended to LAGC,
especially in Eastern countries.14,15 Because the complete-
ness of lymphadenectomy becomes more important with in-
creasing tumor stage, it is important to determine whether a
minimally invasive approach is equivalent to ODG among pa-
tients with advanced gastric cancer. A recent meta-analysis of
data from 6 randomized trials found that LDG with D2 lymph-
adenectomy does not differ significantly from ODG in short-
term morbidity and mortality of patients with LAGC.16 Our
safety analysis of data from the CLASS-01 trial found rates of
postoperative morbidity to be 15.2% in the LDG group and
12.9% in the ODG group (not a significant difference).13 How-
ever, a multicenter randomized trial from Korea (the KLASS-02
trial) of 1050 patients reported that a significantly lower pro-
portion of patients experienced morbidities in the early pe-
riod after LDG (16.6%) compared with ODG (24.1%).17
The JLSSG0901 trial is underway in Japan to evaluate the
efficacy of LDG in the treatment of LAGC.18 In the CLASS-01
trial, rates of 3-year disease-free survival (the primary end
point) were 76.6% in the LDG group vs 77.8% in the ODG group;
recurrence did not differ significantly between groups.11 The
KLASS-02 trial reported the noninferiority of LDG to ODG in
3-year relapse-free survival (80.3% vs 81.3% in the ODG
group).12 Although those trials set different noninferiority mar-
gins, their findings indicated that LDG is a safe and effective
alternative treatment for LAGC.
Overall survival is the standard end point for cancer trials,
although disease-free survival is another end point that might
be used.19 Retrospective studies reported similar survival times
between patients who underwent LDG vs ODG for LAGC,20,21
but there was insufficient evidence for effects on long-term
survival from a large-scale, well-designed, randomized trial.
In our trial, the 5-year overall survival for patients with any
stage of gastric cancer was 72.6% in the LDG group vs 76.3%
in the ODG group (90.0% vs 88.5% for patients with stage I tu-
mors, 79.1% vs 84.5% for patients with stage II tumors, and
58.6% vs 59.5% for patients with stage III tumors). These find-
ings support LDG with D2 lymphadenectomy as a treatment
for LAGC.
In a large-scale, retrospective, multicenter study in Ko-
rea, rates of 5-year overall survival for patients with stage IA
tumors were 94.0% in in the ODG group vs 95.6% in the LDG
group; for patients with stage IB tumors these rates were
96.9% and 92.7%; for patients with stage IIA tumors these rates
were 88.4% and 85.5%; for patients with stage IIB tumors these
rates were 80.3% and 80.0%; for patients with stage IIIA tu-
mors these rates were 70.0% and 61.9%; for patients with stage

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 Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer Original Investigation Research

Figure 3. Cumulative Risk of Death Due to Gastric Cancer or Other Causes

A Gastric tumors B Nongastric tumors

0.4 0.4

LDG
Cumulative incidence

Cumulative incidence
0.3 ODG 0.3

0.2 0.2

0.1 0.1

P = .34 P = .42
0 0 A, Gastric tumors. B, Nongastric
0 12 24 36 48 60 72 0 12 24 36 48 60 72 tumors. LDG indicates laparoscopic
Time after surgery, mo Time after surgery, mo distal gastrectomy; and ODG, open
distal gastrectomy.

IIIB tumors these rates were 68.8% and 47.8%; and for patients especially in serosa-positive gastric cancer that has a risk of can-
with stage IIIC tumors these rates were 40.0% and 33.3%.22 cer cell dissemination resulting from laparoscopic tumor han-
There were no significant differences between the ODG and dling. In our previous 3-year results, the Kaplan-Meier curves
LDG groups among patients with any stage gastric cancer. of disease-free survival between LDG and ODG (58.0% vs
In a multicenter cohort study of 610 patients with stage II 63.8%; P = .23) for patients with stage III disease seem to di-
or III gastric cancer in Japan (the LOC-A study), rates of 5-year verge, suggesting the need for long-term follow-up.11 In pre-
overall survival were 54.2% in the ODG group vs 53.0% in the sent 5-year outcomes, the 5-year OS was 58.6% in the LDG
LDG group, demonstrating noninferiority of LDG.23 A study of group and 59.5% in the ODG group among patients with stage
17 449 patients in the National Cancer Database found that III tumors, and the Kaplan-Meier curve between the 2 groups
minimally invasive surgery for gastric cancer was associated was crossed, indicating that LDG could be a potential stan-
with increased 5-year survival compared with open surgery dard treatment option for more advanced gastric cancer.
(51.9% vs 47.7%), and found no difference between laparo-
scopic and robotic approaches.24 We analyzed data using the Limitations
RMST method, which is increasingly recognized as a robust and Our study has several limitations. First, 29 patients crossed over
clinically interpretable summary measure that is an alterna- from the ODG to the LDG group and 25 patients crossed over
tive to HRs and median survival time, because it directly quan- from the LDG to the ODG group before the procedure. How-
tifies information of the entire observed survival curve.25-28 ever, analyses of the per-protocol population after we ex-
We found that RMSTs did not differ significantly between the cluded these crossover patients produced the same long-
LDG and ODG groups, indicating that mean survival time was term results. Furthermore, the study was performed in China,
2% lower in the LDG group vs the ODG group. so it is not clear whether the findings will be the same in West-
Laparoscopic gastrectomy is underused in Western coun- ern countries, where total or proximal gastrectomy is more
tries, with fewer trials, compared with Eastern countries. Analy- common. The CLASS-02 trial was launched to compare lapa-
sis of data from the US National Cancer Databases showed that roscopic total gastrectomy with open surgery for patients with
73.4%, 23.1%, and 3.5% of all gastrectomies in patients with advanced cancer in the upper body of the stomach.33 Also, none
gastric cancer were performed using open, laparoscopic, and of the patients received neoadjuvant therapy, which is typi-
robotic procedures, respectively, from 2010 to 2012.29 It is not cally recommended in Western countries and could affect sur-
clear whether results from Eastern countries can be extrapo- gical outcomes. The CLASS-03 trial is therefore being planned
lated to Western countries. Therefore, a prospective random- to evaluate the safety of laparoscopic gastrectomy after neo-
ized multicenter trial (LOGICA trial) of LDG vs ODG for pa- adjuvant therapy. Finally, it will be difficult to generalize our
tients with surgically resectable gastric adenocarcinoma was findings to surgeons with less-intensive training.
launched in the Netherlands in 2014; final results are not ex-
pected until 2022.30 There is also evidence that patients in
Eastern countries have better outcomes than patients in West-
ern countries in stage by stage comparisons.31,32 However,
Conclusions
there is no evidence yet to associate outcomes with technical We found no significant difference in 5-year overall survival
procedures. of patients with LAGC treated with LDG with D2 lymphad-
Laparoscopic gastrectomy with extended lymph node enectomy vs ODG performed by experienced surgeons at high-
dissection has been used for more advanced gastric cancer, volume, specialized institutions.

ARTICLE INFORMATION Published Online: October 20, 2021. Author Affiliations: Department of Gastric Surgery,
Accepted for Publication: August 1, 2021. doi:10.1001/jamasurg.2021.5104 Fujian Medical University Union Hospital, Fuzhou,
China (Huang, Zheng); Department of General

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 Research Original Investigation
Surgery, Guangdong Provincial Key Laboratory of
Precision and Minimally Invasive Medicine for GI
Cancers, Nanfang Hospital, Southern Medical
University, Guangzhou, China (H. Liu, Y. Hu, Yu,
G. Li); Department of General Surgery, Zhongshan
Hospital, Fudan University, Shanghai, China (Sun,
F. Liu); Key Laboratory of Carcinogenesis and
Translational Research (Ministry of Education/
Beijing), Gastrointestinal Cancer Center Unit 4,
Peking University Cancer Hospital, Beijing, China
(Su); Department of Gastrointestinal Surgery, Renji
Hospital, Shanghai Jiao Tong University School of
Medicine, Shanghai, China (Cao, Zhao); Department
of Gastrointestinal Surgery and Laboratory of
Gastric Cancer, State Key Laboratory of Biotherapy,
West China Hospital, Sichuan University, Chengdu,
China (J. Hu); Department of Gastrointestinal
Surgery, the Cancer Hospital of Harbin Medical
University, Harbin, China (Wang); Department of
Gastrointestinal Surgery, the First Hospital, Jilin
University, Changchun, China (Suo); Department of
Gastrointestinal Surgery, Union Hospital, Tongji
Medical College, Huazhong University of Science
and Technology, Wuhan, China (Tao); Department
of General Surgery, Tangdu Hospital, Fourth Military
Medical University, Xi’an, China (He); Department
of Gastrointestinal Surgery, the Third Affiliated
Hospital of Sun Yat-Sen University, Guangzhou,
China (Wei); Department of Gastrointestinal
Oncological Surgery, Fujian Provincial Cancer
Hospital, Fujian Medical University Teaching
Hospital, Fuzhou, China (Ying); Department of
Surgery, Ruijin Hospital, Shanghai Jiao Tong
University School of Medicine, Shanghai, China
(W. Hu); Department of General Surgery, General
Hospital of PLA, Beijing, China (Du); Key Laboratory
of Carcinogenesis and Translational Research
(Ministry of Education/Beijing), Ward I of the
Gastrointestinal Cancer Center, Peking University
Cancer Hospital and Institute, Beijing, China (Z. Li);
Clinical Research Center, Nanfang Hospital,
Southern Medical University, Guangzhou, China
(Zhang); Department of Biostatistics, School of
Public Health, Southern Medical University,
Guangzhou, China (Chen).
Author Contributions: Dr G. Li had full access to all
of the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis. Drs Huang, H. Liu, Y. Hu, Sun, Su, Cao,
and J. Hu contributed equally to this work and
should be considered co–first authors.
Concept and design: Huang, H. Liu, Y. Hu, Sun, Su,
Cao, J. Hu, Suo, Tao, He, Wei, Ying, W. Hu, Du, F. Liu,
Z. Li, Zhao, Chen, G. Li.
Acquisition, analysis, or interpretation of data:
Huang, H. Liu, Sun, Su, Cao, J. Hu, Wang, Yu, Zheng,
Zhao, Zhang, Chen, G. Li.
Drafting of the manuscript: Huang, H. Liu, Wei,
W. Hu, Du, Yu, F. Liu, Z. Li, Zhao, G. Li.
Critical revision of the manuscript for important
intellectual content: Huang, Y. Hu, Sun, Su, Cao,
J. Hu, Wang, Suo, Tao, He, Ying, Zheng, Zhao,
Zhang, Chen, G. Li.
Statistical analysis: Huang, H. Liu, J. Hu, Wang, Wei,
Yu, Zhang, Chen.
Obtained funding: G. Li.
Administrative, technical, or material support:
H. Liu, Y. Hu, Sun, Su, Cao, J. Hu, Wang, Suo, Tao,
He, Wei, Ying, W. Hu, Du, Zheng, F. Liu, Z. Li, G. Li.
Supervision: Huang, Y. Hu, Sun, Su, Cao, Wang, G. Li.
Conflict of Interest Disclosures: None reported.
16 JAMA Surgery January 2022 Volume 157, Number 1 (Reprinted)
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Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer
Funding/Support: Funding was provided by
Guangdong Provincial Key Laboratory of Precision
Medicine for Gastrointestinal Cancer (grant
2020B121201004), Guangdong Provincial Major
Talents Project (grant 2019JC05Y361), National
Natural Science Foundation of China (grant
81872013), the National Project of Improvement of
Complex Diseases Diagnosis and Treatment from
National Development and Reform Commission,
the Key Clinical Specialty Discipline Construction
Program from the National Health and Family
Planning Commission of China, and the Program of
Global Medical Affairs Department of Johnson &
Johnson Medical Ltd (grant IIS2012-100236).
Role of the Funder/Sponsor: The funding sources
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Group Information: The Chinese Laparoscopic
Gastrointestinal Surgery Study (CLASS) Group
collaborators are listed in Supplement 3.
Data Sharing Statement: See Supplement 4.
REFERENCES
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL,
Torre LA, Jemal A. Global cancer statistics 2018:
GLOBOCAN estimates of incidence and mortality
worldwide for 36 cancers in 185 countries. CA
Cancer J Clin. 2018;68(6):394-424. doi:10.3322/
caac.21492
2. Kitano S, Iso Y, Moriyama M, Sugimachi K.
Laparoscopy-assisted Billroth I gastrectomy. Surg
Laparosc Endosc. 1994;4(2):146-148.
3. Honda M, Hiki N, Kinoshita T, et al. Long-term
outcomes of laparoscopic versus open surgery for
clinical stage I gastric cancer: the LOC-1 Study. Ann
Surg. 2016;264(2):214-222. doi:10.1097/SLA.
0000000000001654
4. Kim W, Kim HH, Han SU, et al; Korean
Laparo-endoscopic Gastrointestinal Surgery Study
(KLASS) Group. Decreased morbidity of
laparoscopic distal gastrectomy compared with
open distal gastrectomy for stage I gastric cancer:
short-term outcomes from a multicenter
randomized controlled trial (KLASS-01). Ann Surg.
2016;263(1):28-35. doi:10.1097/SLA.
0000000000001346
5. Hur H, Lee HY, Lee HJ, et al. Efficacy of
laparoscopic subtotal gastrectomy with D2
lymphadenectomy for locally advanced gastric
cancer: the protocol of the KLASS-02 multicenter
randomized controlled clinical trial. BMC Cancer.
2015;15:355. doi:10.1186/s12885-015-1365-z
6. Japanese Gastric Cancer Association. Japanese
gastric cancer treatment guidelines 2014 (ver. 4).
Gastric Cancer. 2017;20(1):1-19. doi:10.1007/s10120-
016-0622-4
7. Katai H, Sasako M, Fukuda H, et al; JCOG Gastric
Cancer Surgical Study Group. Safety and feasibility
of laparoscopy-assisted distal gastrectomy with
suprapancreatic nodal dissection for clinical stage I
gastric cancer: a multicenter phase II trial (JCOG
0703). Gastric Cancer. 2010;13(4):238-244. doi:10.
1007/s10120-010-0565-0
8. Katai H, Mizusawa J, Katayama H, et al. Survival
outcomes after laparoscopy-assisted distal
gastrectomy versus open distal gastrectomy with
nodal dissection for clinical stage IA or IB gastric
cancer (JCOG0912): a multicentre, non-inferiority,
phase 3 randomised controlled trial. Lancet
Gastroenterol Hepatol. 2020;5(2):142-151. doi:10.
1016/S2468-1253(19)30332-2
9. Kim HH, Han SU, Kim MC, et al; Korean
Laparoendoscopic Gastrointestinal Surgery Study
(KLASS) Group. Effect of laparoscopic distal
gastrectomy vs open distal gastrectomy on
long-term survival among patients with stage I
gastric cancer: the KLASS-01 randomized clinical
trial. JAMA Oncol. 2019;5(4):506-513. doi:10.1001/
jamaoncol.2018.6727
10. Li G, Hu Y, Liu H. Current status of randomized
controlled trials for laparoscopic gastric surgery for
gastric cancer in China. Asian J Endosc Surg. 2015;
8(3):263-267. doi:10.1111/ases.12198
11. Yu J, Huang C, Sun Y, et al; Chinese Laparoscopic
Gastrointestinal Surgery Study (CLASS) Group.
Effect of laparoscopic vs open distal gastrectomy
on 3-year disease-free survival in patients with
locally advanced gastric cancer: the CLASS-01
randomized clinical trial. JAMA. 2019;321(20):
1983-1992. doi:10.1001/jama.2019.5359
12. Hyung WJ, Yang HK, Park YK, et al; Korean
Laparoendoscopic Gastrointestinal Surgery Study
Group. Long-term outcomes of laparoscopic distal
gastrectomy for locally advanced gastric cancer: the
KLASS-02-RCT randomized clinical trial. J Clin Oncol.
2020;38(28):3304-3313. doi:10.1200/JCO.20.01210
13. Hu Y, Huang C, Sun Y, et al. Morbidity and
mortality of laparoscopic versus open D2 distal
gastrectomy for advanced gastric cancer:
a randomized controlled trial. J Clin Oncol. 2016;34
(12):1350-1357. doi:10.1200/JCO.2015.63.7215
14. Hu Y, Ying M, Huang C, et al; Chinese
Laparoscopic Gastrointestinal Surgery Study
(CLASS) Group. Oncologic outcomes of
laparoscopy-assisted gastrectomy for advanced
gastric cancer: a large-scale multicenter
retrospective cohort study from China. Surg Endosc.
2014;28(7):2048-2056. doi:10.1007/s00464-014-
3426-9
15. Yu J, Hu J, Huang C, et al; Chinese Laparoscopic
Gastrointestinal Surgery Study (CLASS) Group.
The impact of age and comorbidity on
postoperative complications in patients with
advanced gastric cancer after laparoscopic D2
gastrectomy: results from the Chinese
Laparoscopic Gastrointestinal Surgery Study
(CLASS) group. Eur J Surg Oncol. 2013;39(10):
1144-1149. doi:10.1016/j.ejso.2013.06.021
16. Beyer K, Baukloh AK, Kamphues C, et al.
Laparoscopic versus open gastrectomy for locally
advanced gastric cancer: a systematic review and
meta-analysis of randomized controlled studies.
World J Surg Oncol. 2019;17(1):68. doi:10.1186/
s12957-019-1600-1
17. Lee HJ, Hyung WJ, Yang HK, et al; Korean
Laparo-endoscopic Gastrointestinal Surgery Study
(KLASS) Group. Short-term outcomes of a
multicenter randomized controlled trial comparing
laparoscopic distal gastrectomy with D2
lymphadenectomy to open distal gastrectomy for
locally advanced gastric cancer (KLASS-02-RCT).
Ann Surg. 2019;270(6):983-991. doi:10.1097/SLA.
0000000000003217
18. Inaki N, Etoh T, Ohyama T, et al.
A multi-institutional, prospective, phase II feasibility
study of laparoscopy-assisted distal gastrectomy
with D2 lymph node dissection for locally advanced
jamasurgery.com
 Laparoscopic vs Open Distal Gastrectomy for Locally Advanced Gastric Cancer
gastric cancer (JLSSG0901). World J Surg. 2015;39
(11):2734-2741. doi:10.1007/s00268-015-3160-z
19. Oba K, Paoletti X, Alberts S, et al; GASTRIC
group. Disease-free survival as a surrogate for
overall survival in adjuvant trials of gastric cancer:
a meta-analysis. J Natl Cancer Inst. 2013;105(21):
1600-1607. doi:10.1093/jnci/djt270
20. Shinohara T, Satoh S, Kanaya S, et al.
Laparoscopic versus open D2 gastrectomy for
advanced gastric cancer: a retrospective cohort
study. Surg Endosc. 2013;27(1):286-294. doi:10.
1007/s00464-012-2442-x
21. Park DJ, Han SU, Hyung WJ, et al; Korean
Laparoscopic Gastrointestinal Surgery Study
(KLASS) Group. Long-term outcomes after
laparoscopy-assisted gastrectomy for advanced
gastric cancer: a large-scale multicenter
retrospective study. Surg Endosc. 2012;26(6):
1548-1553. doi:10.1007/s00464-011-2065-7
22. Kim HH, Han SU, Kim MC, et al. Long-term
results of laparoscopic gastrectomy for gastric
cancer: a large-scale case-control and
case-matched Korean multicenter study. J Clin Oncol.
2014;32(7):627-633. doi:10.1200/JCO.2013.48.8551
23. Kinoshita T, Uyama I, Terashima M, et al; LOC-A
Study Group. Long-term outcomes of laparoscopic
versus open surgery for clinical stage II/III gastric
jamasurgery.com
© 2021 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ Mexico | Access Provided by JAMA by Alondra Escobedo on 06/28/2023
cancer: a multicenter cohort study in Japan (LOC-A
study). Ann Surg. 2019;269(5):887-894. doi:10.
1097/SLA.0000000000002768
24. Hendriksen BS, Brooks AJ, Hollenbeak CS,
Taylor MD, Reed MF, Soybel DI. The impact of
minimally invasive gastrectomy on survival in the
USA. J Gastrointest Surg. 2020;24(5):1000-1009.
doi:10.1007/s11605-019-04263-4
25. Huang B, Kuan PF. Comparison of the restricted
mean survival time with the hazard ratio in
superiority trials with a time-to-event end point.
Pharm Stat. 2018;17(3):202-213. doi:10.1002/pst.1846
26. Royston P, Parmar MK. Restricted mean
survival time: an alternative to the hazard ratio for
the design and analysis of randomized trials with a
time-to-event outcome. BMC Med Res Methodol.
2013;13:152. doi:10.1186/1471-2288-13-152
27. Pak K, Uno H, Kim DH, et al. Interpretability of
cancer clinical trial results using restricted mean
survival time as an alternative to the hazard ratio.
JAMA Oncol. 2017;3(12):1692-1696. doi:10.1001/
jamaoncol.2017.2797
28. Weir IR, Marshall GD, Schneider JI, et al.
Interpretation of time-to-event outcomes in
randomized trials: an online randomized
experiment. Ann Oncol. 2019;30(1):96-102. doi:10.
1093/annonc/mdy462
(Reprinted) JAMA Surgery January 2022 Volume 157, Number 1
Original Investigation Research
29. Greenleaf EK, Sun SX, Hollenbeak CS, Wong J.
Minimally invasive surgery for gastric cancer: the
American experience. Gastric Cancer. 2017;20(2):
368-378. doi:10.1007/s10120-016-0605-5
30. Haverkamp L, Brenkman HJ, Seesing MF, et al;
LOGICA study group. Laparoscopic versus open
gastrectomy for gastric cancer, a multicenter
prospectively randomized controlled trial
(LOGICA-trial). BMC Cancer. 2015;15:556. doi:10.
1186/s12885-015-1551-z
31. Strong VE, Song KY, Park CH, et al. Comparison
of gastric cancer survival following R0 resection in
the United States and Korea using an internationally
validated nomogram. Ann Surg. 2010;251(4):
640-646. doi:10.1097/SLA.0b013e3181d3d29b
32. Strong VE, Song KY, Park CH, et al. Comparison
of disease-specific survival in the United States and
Korea after resection for early-stage node-negative
gastric carcinoma. J Surg Oncol. 2013;107(6):
634-640. doi:10.1002/jso.23288
33. Liu F, Huang C, Xu Z, et al; Chinese
Laparoscopic Gastrointestinal Surgery Study
(CLASS) Group. Morbidity and mortality of
laparoscopic vs open total gastrectomy for clinical
stage I gastric cancer: the CLASS02 multicenter
randomized clinical trial. JAMA Oncol. 2020;6(10):
1590-1597. doi:10.1001/jamaoncol.2020.3152
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