A Randomized, Single Center, Controlled Phase II Study to Compare Laparoscopic Versus Open Distal Gastrectomy in Locally Advanced Gastric Cancer After Neoadjuvant Chemotherapy
Phase: PHASE2
Conditions: Gastric Cancer
Sponsor: Peking University

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Li Z, et al. BMJ Open 2018;8:e021633. doi:10.1136/bmjopen-2018-021633
Open access
Laparoscopic or open distal gastrectomy 
after neoadjuvant chemotherapy for 
advanced gastric cancer: study protocol 
for a randomised phase II trial
Ziyu Li, Fei Shan, Xiangji Ying, Lianhai Zhang, Hui Ren, Shuangxi Li, Yongning Jia, 
Rulin Miao, Kan Xue, Zhemin Li, Yinkui Wang, Chao Yan, Yan Zhang, Fei Pang, 
Jiafu Ji
To cite: Li Z, Shan F, Ying X, 
et al.  Laparoscopic or open 
distal gastrectomy after 
neoadjuvant chemotherapy 
for advanced gastric cancer: 
study protocol for a randomised 
phase II trial. BMJ Open 
2018;8:e021633. doi:10.1136/
bmjopen-2018-021633
►
►Prepublication history for 
this paper is available online. 
To view these files, please visit 
the journal online (http://​dx.​doi.​
org/​10.​1136/​bmjopen-​2018-​
021633).
Received 12 January 2018
Revised 20 June 2018
Accepted 13 July 2018
Gastrointestinal Cancer 
Center, Key Laboratory 
of Carcinogenesis and 
Translational Research (Ministry 
of Education), Peking University 
Cancer Hospital and Institute, 
Beijing, China
Correspondence to
Professor Jiafu Ji;  
​jijiafu@​hsc.​pku.​edu.​cn
Protocol
© Author(s) (or their 
employer(s)) 2018. Re-use 
permitted under CC BY-NC. No 
commercial re-use. See rights 
and permissions. Published by 
BMJ.
Abstract
Introduction  Current guidelines recommend open 
gastrectomy with D2 lymph node dissection and adjuvant 
chemotherapy as the standard treatment for advanced 
gastric cancer. However, the prognosis is not satisfactory. 
Perioperative chemotherapy has been proposed to 
improve survival. Although still in debate, the efficacy of 
laparoscopic distal gastrectomy (LDG) in patients with 
advanced gastric cancer has been demonstrated in a few 
trials. Therefore, LDG after neoadjuvant chemotherapy can 
be a candidate for future standard treatment on advanced 
distal gastric cancer. We propose a randomised phase II 
trial to compare LDG and open distal gastrectomy (ODG) 
after neoadjuvant chemotherapy for advanced gastric 
cancer.
Methods and analysis  To test the efficacy and safety, a 
randomised, open-label, single-centre, phase II trial was 
designed to evaluate the non-inferiority of LDG compared 
with ODG after neoadjuvant chemotherapy, with 3-year 
recurrence-free survival as the primary endpoint. The 
chosen critical value of a non-inferiority margin was an 
increase of <8%. The study started in 2015 and enrolled 
96 patients according to a prior sample size calculation. 
Intention-to-treat and per-protocol approach will be 
used for efficacy analysis, and as-treated analysis will 
be applied for safety analysis. The survival curves will 
be constructed as time-to-event plots using the Kaplan-
Meier method and compared using log-rank tests and 
Cox proportional hazards model. All statistical analyses 
will be conducted in standard statistical software with a 
significance level of 0.05.
Ethics and dissemination  This study was approved by 
the Peking University Cancer Hospital Ethics Committee. 
The results will be submitted for publication in peer-
reviewed journals.
Trial registration number  NCT02404753; Pre-results.
Introduction 
Gastric cancer is one of the most common 
malignant tumours and the second leading 
cause of cancer death worldwide. Due to the 
difficulty of screening and early diagnosis, 
approximately 80% of patients with gastric 
cancer in China are already at advanced stage 
(ie, tumour, node, metastases (TNM) stages II 
and III) at first hospital visit. The established 
treatment for advanced gastric cancer is open 
gastrectomy with D2 lymph node dissection, 
and postoperative adjuvant chemotherapy 
of S-1 for 1 year or combination therapy with 
capecitabine and oxaliplatin for 6 months.1 
Although such a treatment regimen is effec-
tive, the prognosis of patients is not satis-
factory, which calls for a more intensive 
chemotherapy. From theoretical perspectives, 
an intensified chemotherapy can be better 
tolerated and complied by patients if being 
administered before the surgery. By far, two 
large European phase III trials, the Medical 
Research Council Adjuvant Gastric Infu-
sional Chemotherapy (MAGIC) trial, and the 
Fédération Nationale des Centres de Lutte 
contre le Cancer (FNCLCC) and the Fédéra-
tion Francophone de Cancérologie Digestive 
(FFCD) 9703 study, have provided supportive 
evidence that preoperative (neoadjuvant) 
chemotherapy results in high compliance, as 
Strengths and limitations of this study
►
►The proposed study is one of the few randomised 
trials to compare laparoscopic distal gastrectomy 
with open distal gastrectomy after neoadjuvant che-
motherapy for distal advanced gastric cancer.
►
►This trial aims to evaluate the efficacy and safety 
using short-term and long-term endpoints.
►
►We designed this study to be sufficiently powered 
to identify non-inferiority in terms of 3-year recur-
rence-free survival, although it may be underpow-
ered to detect non-difference on other outcomes.
►
►This is a phase II trial performed at a single medical 
centre; thus, if the non-inferiority of laparoscopic 
surgery is proven, a subsequent larger multicentre 
phase III verification clinical trial may be needed.

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well as other favourable factors such as high rate of R0 
resection and tumour regression, which lead to a better 
prognosis.2 3 
Laparoscopic gastrectomy has been used as a supe-
rior alternative to open gastrectomy to treat early gastric 
cancer.4 Although still in debate, the application of lapa-
roscopic surgery in advanced gastric cancer has drawn 
increasing attention over the years. The most recent 
meta-analysis published in 2016 concluded that laparo-
scopic gastrectomy for advanced gastric cancer appeared 
to be comparable with open gastrectomy in the number 
of lymph nodes achieved, overall survival and disease-
free survival, but had advantages over open gastrectomy 
in terms of faster postoperative recovery.5 However, 25 
out of the 26 studies included in this analysis are retro-
spective, and randomised trials on laparoscopic versus 
open gastrectomy for advanced gastric cancer are scarce.6 
Thus, more research providing higher level of evidence 
is needed.
It is therefore worthwhile to compare the safety and 
efficacy of laparoscopic and open gastrectomy when 
combining with neoadjuvant chemotherapy. There have 
been a few randomised trials comparing laparoscopic 
with open gastrectomy,7–9 and multiple on comparing 
gastrectomy 
with 
gastrectomy+neoadjuvant chemo-
therapy for advanced gastric cancer,10 but very few on 
the comparison between laparoscopic gastrectomy+neo-
adjuvant chemotherapy and open gastrectomy+neoad-
juvant chemotherapy. To our best knowledge, only one 
similar trial was proposed to be carried out from 2011 
to 2014 in Japan, but results have yet to be published.11 
A retrospective study recently conducted by our team 
suggested that laparoscopic gastrectomy after neoadju-
vant chemotherapy had comparable safety and efficacy 
as open gastrectomy in perioperative period.12 In partic-
ular, laparoscopic distal gastrectomy after neoadjuvant 
chemotherapy did not increase operation time, blood 
loss, postoperative complications and length of stay in the 
hospital compared with open gastrectomy. Additionally, 
patients in laparoscopy group can benefit from the short-
ened length of incision and faster recovery of gastroin-
testinal functioning. However, no significant difference 
was found between the two groups in proximal and distal 
margin, and the number of resected lymph nodes.
The present study therefore aims to evaluate the safety 
and efficacy of laparoscopic gastrectomy after neoad-
juvant chemotherapy for distal advanced gastric cancer 
using a randomised phase II clinical trial design, and to 
provide theoretical basis for conducting a multicentre 
phase III verification clinical trial.
Methods and analysis
Trial design
The current study is a prospective, randomised, open-
label, single-centre, non-inferiority phase II clinical trial 
using a parallel-arm design. The study is designed on 
the hypothesis of non-inferiority on the basis of prior 
study comparing laparoscopic and open gastrectomy 
for advanced gastric cancer.7 The study takes place in 
the Gastrointestinal Cancer Center of Peking University 
Cancer Hospital and Institute. Patient enrolment started 
on 23 April 2015, and the trial is expected to end in 2020. 
Figure 1 summarises the design of the trial, and each of 
the trial’s aspects is described in detail below.
Eligibility criteria
The inclusion criteria are ambulatory men or women 
aged 18–80; Karnofsky score ≥70%; histologically proven 
gastric adenocarcinoma on biopsy (including Lauren 
classification); proven clinical stage of cT2n+M0 or 
cT3-4a/n+M0 
by 
baseline 
ultrasound 
endoscope, 
enhanced CT/MRI examination or diagnostic laparos-
copy using Habermann standards; no past chemotherapy 
or radiotherapy before diagnosis; tumour located in 
the middle and lower third of the stomach; achievable 
naked-eye complete resection (R0/1) via distal subtotal 
gastrectomy plus D2 lymphadenectomy; haematology 
and biochemistry index meet the following: haemo-
globin ≥80 g/L, absolute neutrophil count ≥1.5×109/L, 
platelet ≥100×109/L, Alanine transaminase (ALT)  and 
Aspartate transaminase (AST)  ≤2.5 times the upper limit 
of normal value, Alkaline phosphatase (ALP) ≤2.5 times 
the upper limit of normal value, serum total bilirubin 
<1.5 times the upper limit of normal value, serum creat-
inine <1 times the upper limit of normal value, and 
serum albumin ≥30 g/L; no severe concomitant disease 
that leads to survival <5 years; willing and able to comply 
with the study protocol; and written consent agreement 
before enrolment and fully aware of the right to quit the 
study at any time with no loss.
Patients are excluded from the study if they meet one 
of the following: pregnant or breastfeeding; uncon-
trolled seizure, central nervous system diseases or mental 
disorders; history of upper abdominal surgery (except 
for laparoscopic cholecystectomy); history of gastric 
surgery (including diagnosis procedure such as endo-
scopic submucosal dissection and endoscopic mucosal 
resection); other malignant diseases in 5 years (except 
for cured skin carcinoma and cervical carcinoma in situ); 
clinically severe or active heart diseases, such as symp-
tomatic coronary heart disease, the New York Heart 
Association (NYHA) grade II or above congestive heart 
failure, severe arrhythmia, or myocardial infarction 
in 6 months; cerebral haemorrhage or infarction in 6 
months; organ transplant recipient under immunosup-
pressive therapy; severe uncontrolled repeated infec-
tion or other severe uncontrolled concomitant diseases; 
medium or severe renal damage (creatinine clearance 
rate ≤50 mL/min or serum creatinine greater than the 
upper limit of normal value); other diseases requiring 
synchronous surgery; requiring emergent surgery due 
to oncological emergency (eg, bleeding, perforation, 
obstruction); forced expiratory volume in 1 s <50% of 
expected value; and participated in other studies 4 weeks 
before the randomisation.

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Randomisation and blinding
Patients are enrolled by the oncologists on the team. 
Eligible patients treated with advanced gastric cancer at 
the Gastrointestinal Cancer Center of Peking University 
Cancer Hospital and Institute first receive neoadjuvant 
chemotherapy with three cycles (3 weeks for one cycle) 
of intravenous oxaliplatin (130 mg/m2 on day 1 of each 
cycle) plus oral capecitabine (1000 mg/m2 twice daily on 
days 1–14 of each cycle). Three weeks after the comple-
tion of neoadjuvant chemotherapy, assessment on the 
resectability of the tumour is conducted on the basis of 
vital sign examination, physical examination, laboratory 
Figure 1  Flow chart. 

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tests, electrocardiograph, lung function examination and 
tumour evaluation. Patients who passed the resectability 
confirmation are then randomised to receive either lapa-
roscopic distal gastrectomy with D2 lymph node dissec-
tion (group A) or open distal gastrectomy with D2 lymph 
node dissection (group B) on a 1:1 ratio. Randomisa-
tion is achieved using random number table by the data 
manager and allocation is not concealed. While blinding 
surgeons or participants is not feasible, pathologists are 
blinded on the types of surgical approach.
Treatments
A standard laparoscopic or open distal gastrectomy 
with D2 lymphadenectomy (including lymph nodes 
of numbers 1, 3, 4sb, 4d, 5, 6, 7, 8a, 9, 11p and 12a) is 
performed by two experienced surgeons, according to 
the Japanese Gastric Cancer Treatment Guidelines 2014 
(V.4)1 and the Japanese Classification of Gastric Carci-
noma (3rd English edition).13
In the open group, an approximately 20–25 cm incision is 
made from the falciform process to the periumbilical area. 
In the laparoscopic group, one 10 mm trocar for the camera 
is inserted below the umbilicus. Another three 10 mm ports 
are inserted in the left upper quadrants 2 cm below the left 
lower rib margins, the right and left flank areas, respectively. 
One 5 mm trocar is lastly placed on the right upper quad-
rants 2 cm below the right lower rib margins. Anastomosis is 
performed using the instrumental method. The specimen 
was pulled out through a small median incision under the 
xiphoid (about 6–8 cm).12
For those who underwent laparoscopic gastrectomy, the 
case is required to be converted to open surgery if one of 
the following happens: confluent lymph nodes with long 
axis >3 cm, severe or life-threatening intraoperative compli-
cations such as intra-abdominal massive haemorrhage, 
severe organ damage, or other technical or instrumental 
factors that require conversion to open surgery.
All patients are managed by a standardised clinical 
pathway after the surgery. Discharge is recommended 
when the patients have tolerated more than 2 days of soft 
diet without abdominal pain or fever. All patients start to 
accept five cycles of oxaliplatin and capecitabine regimens 
for postoperative adjuvant chemotherapy within 6 weeks 
postsurgery. Dose reductions or interruptions are allowed 
to manage potentially serious or life-threatening adverse 
events (AEs). In cases of oxaliplatin-related neurological 
AEs, capecitabine can be continued as monotherapy. Oxal-
iplatin monotherapy is not allowed. Palliative and supportive 
care are offered as needed for disease-related symptoms.
Outcomes
The primary endpoint is 3-year recurrence-free survival 
(RFS) rate. Recurrence includes any recurrence (local or 
regional, or distant) and death due to any cause (both 
gastric cancer and non-gastric cancer causes of death).14 
The secondary endpoints are overall survival, radicalness 
of surgery, 30-day postoperative surgical morbidity and 
mortality, 2-week postoperative recovery index, cycles of 
postoperative chemotherapy, and up to 1-year postoper-
ative quality of life. The radicalness of surgery includes 
assessments on the number of lymph nodes retrieved and 
the length of resection margin. Postoperative compli-
cations are defined as complications occurring within 
30 days after surgery, and will be classified according 
to the Clavien-Dindo classification system.15 16 Hospital 
mortality is defined as death occurring within 30 days 
after initial surgery, regardless of the cause. Postoperative 
recovery index considers blood loss, first aerofluxus time, 
first defaecating time, first time on a liquid diet, time of 
pulling gastric tube and drainage, and length of hospital 
stay. Postoperative pain intensity is measured by using a 
Visual Analogue Scale up to 72 hours after surgery.17 18 
The time of applying intravenous patient-controlled anal-
gesia and rescue morphine consumption is recorded. 
One-year postoperative quality of life is assessed using the 
European Organisation for Research and Treatment of 
Cancer (EORTC) Quality of Life questionnaires (QLQ-
C30 and EORTC-QLQ-STO22).19 20
Adverse events
AEs are any unfavourable or unintended events that affect 
the patients of the study, regardless of the relevance to 
the treatment. Any AEs are recorded in detail on the case 
report form (CRF) and include time of occurrence, dura-
tion, relevance to the treatment, stopping or continuing 
of the treatment, and others. Events are defined as serious 
adverse events (SAEs) if they lead to death, prolongation 
of hospitalisation, permanent or severe disability, terato-
genesis or carcinogenesis, and significant clinical sequela. 
The occurrence of SAEs will be reported to Peking Univer-
sity Cancer Hospital EthicsCommittee within 24 hours of 
the initial discovery.
Sample size
Due to the lack of results from previous similar research, 
a double-criteria approach described in the paper of 
Neuenschwander et al21 was used to calculate the required 
sample size in order to identify non-inferiority of laparo-
scopic versus open gastrectomy in terms of RFS. The first 
criterion was that the HR estimate was smaller than a crit-
ical threshold of 1.12, which corresponded to a difference 
of 8% in the 3-year RFS between two arms. As suggested 
by the paper, this number was chosen on the basis of clin-
ical considerations. The second criterion required that 
the upper estimated one-sided 95% confidence bound of 
the non-inferiority margin was smaller than 1.59, which 
was calculated based on prior clinical research on lapa-
roscopic gastrectomy after neoadjuvant chemotherapy, 
as well as on open gastrectomy after neoadjuvant chemo-
therapy.22 23
On the basis of this approach, a sample size of 80 (40 
per arm) is planned, with a type I error of 0.05 (two-sided) 
and a statistical power of 80%. The total sample size is 96 
(48 per am) after taking account of a 20% dropout rate 
in each group. The planned recruitment period is 2 years 
and the follow-up duration is 3 years.

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Data collection and analysis
Trained oncologists collect data via datasheets on paper 
daily until the patient’s discharge. Initial staging and ther-
apeutic efficiency assessment include endoscopy, endo-
scopic ultrasound, non-contrast-enhanced CT scan of the 
thorax, and contrast-enhanced CT scan of the abdomen 
and pelvis. MRI examination will be used as an alternative 
to CT scan if the patient is allergic to radiocontrast agent 
or has other contraindications on CT examination. Lapa-
roscopy and peritoneal washings for malignant cells are 
conducted before and after neoadjuvant chemotherapy. 
Tumour response evaluation after neoadjuvant chemo-
therapy includes both imageological and pathological 
examinations. The former is conducted according to the 
Response Evaluation Criteria in Solid Tumours (V.1.1).24 
The latter is performed in accordance with the Tumour 
Regression Grade Standards of the National Compre-
hensive Cancer Network clinical practice guidelines in 
oncology for gastric cancer (V.3.2015).25 Gastrectomy 
specimens are open along the greater curvature, and 
macroscopic examination is conducted before representa-
tive blocks are taken from the tumour and its surrounding 
areas, and paraffin-embedded. All removed lymph nodes 
are embedded separately. Microscopic features are 
reported according to the seventh edition of the Interna-
tional Union Against Cancer TNM classification.26
Information on prognostic status is collected via 
follow-up up to 3 years after the last treatment. Follow-up 
is conducted on a 3-month basis in the first 2 years and 
every half year in the third year. To promote participant 
retention and complete follow-up, three attempts are 
made to contact and remind the participants to come to 
the hospital for follow-up, and their transportation fees are 
covered by the research project. Every follow-up, partici-
pants receive physical examinations (ie, height, weight, 
Karnofsky score and others), laboratory tests (including 
blood cell test, blood biochemical test and serum tumour 
marker test) and imageological examinations (including 
ultrasonography, enhanced CT/MRI, endoscopy and 
chest radiograph). Tumour assessment will be conducted 
if recurrence is suspected, and further treatments such as 
surgery or chemotherapy will be performed when needed 
and will be recorded on the CRF. Data entry in EpiData 
is completed by two independent staff, with a third staff 
monitoring the quality.
Intention-to-treat and per-protocol approach will 
be used for efficacy analysis. As-treated analysis will be 
applied for safety analysis. For variables with a signifi-
cant amount of missingness, multiple imputations will be 
conducted for the purpose of sensitivity analysis. In terms 
of descriptive analysis, categorical data will be presented 
as number and percentage. Continuous variable will be 
presented as mean and SD if normally distributed, or as 
median and range otherwise. The primary analysis in this 
study aims to compare the 3-year RFS rate between lapa-
roscopic and open gastrectomy after neoadjuvant chemo-
therapy. The date of recurrence is defined as the date 
of all-cause death or when a clinician judges recurrence 
considering all information including serum tumour 
and the results of imageological examination. The RFS 
curves will be constructed as time-to-event plots using the 
Kaplan-Meier method. Log-rank tests will be used to make 
a simple comparison of the survival curves. Cox propor-
tional hazards model will be performed to compare RFS 
after taking into account potential confounders. The 
overall survival will also be analysed in the same manner. 
Subgroup analyses will be conducted by age group, 
tumour location, body mass index category and TNM 
stage. All statistical analyses will be conducted in standard 
statistical software with a significance level of 0.05.
Data monitoring, auditing and interim analysis
Data monitoring and auditing are conducted by the 
funding agency annually. An interim analysis will be 
performed by an independent statistician when half of 
the patients have been randomised. The trial will be 
stopped if one treatment is found to be statistically more 
beneficial or harmful than the other.
Patient and public involvement
The development of current research question and 
outcome measures was informed by patients’ priorities, 
experience and preferences in a way that minimally inva-
sive surgery may be a safe and effective option for patients 
with advanced gastric cancer. Patients were not involved 
during the phase of study design; however, patients’ 
concerns and questions were addressed during patient 
recruitment and study implementation. The summarised 
results of the current study will be published in peer-re-
viewed journals, but participating patients will not be 
particularly notified with these results. Indicators of inter-
vention burden will be partially patient self-reported, 
such as first aerofluxus time, first defaecating time and 
first time on a liquid diet, while the other endpoints will 
be assessed by the research investigators.
Ethics and dissemination
On the completion of the study, at least two manuscripts 
with the results of the primary study will be published in 
a peer-reviewed journal. The deidentified data sets gener-
ated from the current study will be publicly available via 
an appropriate data archive 6 months after the comple-
tion of the trial.
Contributors  JJ was the principal investigator of the study. JJ and ZiL developed 
the research idea and directed the study. FS designed the study in detail, wrote the 
grant except for the statistical analyses part, and monitored the implementation 
of the study. XY was responsible for the statistical analyses part of the protocol 
and preparing this manuscript. LZ, HR, SL, YJ, RM, KX, ZhL, YW, CY, YZ and FP 
participated in participant enrollment and data collection as this randomised trial is 
ongoing. All authors edited and approved the final version of this manuscript. 
Funding  This work is funded by the Beijing Municipal Science and Technology 
Commission (Z151100004015070). 
Competing interests  None declared.
Patient consent  Obtained.

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Li Z, et al. BMJ Open 2018;8:e021633. doi:10.1136/bmjopen-2018-021633
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Ethics approval  This study was approved by Peking University Cancer Hospital 
Ethics Committee in accordance with the Chinese legislation and the Declaration 
of Helsinki. The committee judged the study design, ethics, feasibility, level of 
non-inferiority and safety rules.
Provenance and peer review  Not commissioned; externally peer reviewed.
Open access This is an open access article distributed in accordance with the 
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which 
permits others to distribute, remix, adapt, build upon this work non-commercially, 
and license their derivative works on different terms, provided the original work is 
properly cited, appropriate credit is given, any changes made indicated, and the use 
is non-commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/.
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