Long-term and short-term outcomes after laparoscopic versus open surgery for advanced gastric cancer: An updated meta-analysis.

BACKGROUND: The efficacy of laparoscopy for advanced gastric cancer (AGC) remains controversial.
MATERIALS AND METHODS: We conducted a literature search on the EMBASE, PubMed and Cochrane Library databases to identify relevant available articles published between the time of the databases' inception and July 2020.
RESULTS: A total of 14,689 patients were included in the 41 studies identified. A total of 6976 patients were in an laparoscopic approach group (LG) and 7713 patients were in an open approach group (OG). The meta-analysis showed that in randomized control trials (RCTs), LG were better than OG in terms of estimated blood loss, time to oral intake and time to first flatus while the operation time and proximal resection margin (PRM) were significantly worse in LG than in OG. In the non-RCTs, LG had shorter hospital stays, less blood loss, less intraoperative transfusion, less time to oral intake, time to first flatus, time to ambulation; less overall or serious complications; and better 3-year and 5-year overall or disease-free survival (DFS). Operation times and PRM were significantly worse for LGs.
CONCLUSION: The safety and effectiveness of laparoscopic surgery for AGC is not inferior to that of traditional open surgery, and to a certain extent, can reduce trauma, facilitate recovery, and be validated in RCTs and non-RCTs. In the real-world cohort, laparoscopic surgery for gastric cancer achieved a better survival rate and DFS rate. However, to evaluate the efficacy of these two methods more comprehensively, high-quality randomized controlled trials and longer follow-up times are still needed.

INTRODUCTION

Gastric cancer is a common malignant tumour of the digestive system that has a high incidence rate. Due to the lack of typical symptoms in the early stage, the diagnosis of gastric cancer often occurs in the advanced stage or even the late stage, typically with a poor prognosis. Advanced gastric cancer (AGC) is a subtype of gastric cancer. It mainly refers to the infiltration of cancer cells into the muscular layer and the serous layer of the gastric wall, but without distant metastasis occurring. At this stage, the risk of cancer cell metastasis is high, and can easily develop into a disseminated (or metastatic) cancer. Therefore, patients with AGC need to be actively treated. Radical gastrectomy and local lymph node dissection are the main methods used to treat gastric cancer.[1] In 1994, Kitano et al.[2] reported the first case of early gastric cancer (EGC) undergoing laparoscopic gastrectomy and a Billroth reconstruction. In the following 10 years, a large number of studies reported that laparoscopic radical surgery has obvious advantages of being minimally invasive, and achieved similar short-term and long-term results compared with traditional open radical surgery for EGC. Most of the current guidelines regard laparoscopic gastrectomy as the standard operation for EGC. In the past 10 years, since more and more minimally invasive surgeries for EGC have been performed, and the learning curve for laparoscopy is short, a large number of researchers have tried to use laparoscopy for the treatment of AGC. However, there is still no consensus on whether laparoscopic radical surgery can be performed for AGC. Controversies surrounding this idea focus on whether laparoscopic lymphadenectomy is safe and can meet the requirements of radical surgery. In this article, we systematically reviewed the literature on laparoscopic and open radical surgery in patients with AGC, and discussed the feasibility, safety and long effect of laparoscopic radical surgery for AGC through a cohort study in the real world, and with randomised control trials (RCTs) in the ideal environment.

MATERIALS AND METHODS

This meta-analysis was reported according to the preferred reporting items for systematic reviews and meta-analyses.[3]

Search strategy

We conducted a literature search on the EMBASE, PubMed, and Cochrane Library databases to identify relevant available articles published between the time of the databases’ inception and July 2020. Keywords searched for included laparoscopy, laparoscopy-assisted, open, laparotomy, AGC; the search strategy is ((Advanced gastric cancer) AND (Laparoscop*)) AND (open). We also reviewed the reference lists of the included studies for relevant studies we may have missed. We contacted the original authors to obtain extra information if necessary. If multiple studies were included from the same author or research centre, and the sample size was repeated, only the latest one with the largest sample size and the highest quality was selected. Studies with overlapping cases but no overlap in the reported outcome indicators were still included in the analysis as an independent study. The detailed steps of our literature search are shown in Figure 1.

Figure 1

Preferred reporting items for systematic reviews and meta-analyses 2009 flow diagram

Inclusion criteria

(1) Participants: AGC was diagnosed and a radical operation was performed; (2) The original data were published in the literature, in which there were independent reports on the relative efficacy of laparoscopic approach group (LG) compared to that of open approach group (OG) in the treatment of AGC, including a randomised-controlled, prospective or retrospective cohort study. (3) Study sample size: Unlimited; (4) follow-up time: Unlimited; (5) language of the published literature: Unlimited; research type: Human research.

Exclusion criteria and quality assessment

(1) Incomplete information, no extractable valid data, the author could not be reached, or the author was unresponsive; re-published or unpublished research. (2) Studies reported outcomes from LG or OG alone, without comparisons. (3) AGC treatment without surgery or non-radical surgery. (4) Robot researches, reviews, case reports and animal experiments.

Randomised controlled trials (RCTs), retrospective cohort studies and prospective cohort studies are included in this meta-analysis. The characteristics of these studies are presented in Table 1. In all the included studies, the RCTs conducted a risk assessment according to the ‘risk assessment tool’ recommended by the Cochrane Collaboration Network. The results from these assessments are attached in Figure 2. Quality evaluation of cohort studies are based on the Newcastle-Ottawa Scale (NOS). Details are shown in Table 2.

Table 1

Basic characteristics and quality assessment of enrolled documents

Study	Type	Country	Period	Case		Lymphadenectomy	Type of surgery	Neoadjuvant therapy (%)		Stage		Quality
				LG	OG			LG	OG	LG	OG
Cai J 2011[4]	RCT	China	2008-2009	49	47	D2	PG, DG, TG	NA	NA	□B: 14□:13 □A: 16 □b: 6	□B: 11□:17 □A: 15 □b: 4	--
Chen Q 2012[5]	RCS	China	2008-2012	224	112	D2	DG, TG	NA	NA	□B: 40□:99 □:85	□B: 25□:51 □:36	7
Chen X 2016[6]	RCS	China	2006-2015	69	69	D2, D2+	TG	NA	NA	□:14□:16 □:38 □:1	□:14□:16 □:38 □:1	8
Du X 2009[7]	RCS	China	2004-2008	78	90	D2	DG	NA	NA	□B: 8□:27□:37 □:5	□B: 9□:30□:40 □:11	7
Hamabe 2011[8]	RCS	Japan	2000-2009	66	101	D2	DG, TG	39.4	44.6	□B: 21□:45	□B: 18□:83	8
Hu 2016[9]	RCT	China	2012-2014	519	520	D2	DG	NA	NA	p□151□:77 □:219 □11	p□152□: 138 □:221 □8	--
Huang J 2010[10]	RCS	China	2007-2008	66	69	D2	DG	NA	NA	□A: 5□B13 □:21 □:26 □1	□A: 3□B13 □:21 □:30 □2	6
Huang X 2019[11]	PCS	China	2016-2017	110	238	D2	DGTG	84.4	75.6	□B: 19 □:32 □:59	□B: 43□:70□:125	6
Hur 2008[12]	RCS	Korea	2004-2007	26	25	D2	DG	NA	NA	pT2b 26	pT2b 25	5
Hwang 2008[13]	RCS	Korea	2004-2007	45	83	D1, D1+, D2	DG	93.2	89	□B: 22□:10 □:13	□B: 34□:21 □:28	6
Inokuchi 2018[14]	RCS	Japan	2001-2012	52	52	D2	DG, TG	NA	NA	□B: 15□:25 □:12	□B: 10□:24 □:18	8
Kim K 2012[15]	RCS	Korea	1999-2007	88	88	D2	SG, TG	NA	NA	□B: 32□:35 □A: 11 □B: 8 □C: 2	□B: 28□:33 □A: 8 □B: 11 □C: 8	7
Kim S 2019[16]	PCS	Korea	2006-2016	60	228	D2	DG	63	75.4	□B: 22□:29 □:9	□B: 28□:115□:85	7
Kinoshita 2019[17]	RCS	Japan	2008-2014	305	305	D2	DG, TG	7.2	20.3	□:39□:253:□:374	□:148□:531:□:479	8
Lee 2019[18]	RCT	China	2011-2015	460	458	D2	DG	NA	NA	□:173□:136 □:147 □:4	□:159□:159 □:139 □:1	--
Li Q 2016[19]	RCS	China	2012-2014	101	101	D2	DG, TG	NA	NA	□:58 □A: 24 □B: 19	□:60 □A: 23 □B: 18	7
Li Ziyu 2016[20]	PCS	China	2012-2014	20	24	D2	DG	100	100	□B: 2 □:5 □:13	□B: 0 □:8 □:16	6
Li Ziyu 2019[21]	RCT	China	2015-2017	47	48	D2	DG	100%	100%	□:20 □A: 17 □B: 9;□C: 1	□:32 □A: 8 □B: 5;□C: 3	--
Li ZY 2018[22]	RCS	China	2007-2012	410	410	D2	DG, TG	NA	NA	p□B: 50□:267 □A: 90 B: 82 C: 21	p□B: 46□:163 □A: 79 B: 90 C: 32	8
Liin JX 2016[23]	RCS	China	2005-2011	539	539	D2	DG, TG	NA	NA	p□B: 51□:119 □:369	p□B: 51□:115 □:373	7
Lin JX 2013[24]	RCS	China	2008-2010	83	83	D2	DG, TG	NA	NA	□B: 16□:35 □A: 15 □B: 16	□B: 16□:38 □A: 13 □B: 17	7
Ludwig K 2018[25]	RCS	Germany	2003-2016	45	45	D2	DG, TG	31.1	33.3	□B: 21□:12 □:10 □2	□B: 21□:14 □:8 □2	8
Park 2017[26]	RCT	Korea	2010-2011	105	99	D2	DG			□B: 23□:52 □:25	□B: 22□:46 □:28	--
Sato H 2011[27]	RCS	Japan	2001-2010	158	174	D1, D1+, D2	DG, PG, TG	NA	NA	□A: 121□B: 13□, □:23	□A: 50□B: 20□, □:104	6
Shi 2017/2019[2829]	RCT	China	2010-2012	162	161	D2	DG, TG, PG			p□B: 16□:42 □A: 30 □B: 22 □C: 51	p□B: 10□:43 □A: 26 □B: 21 □C: 56	--
Shinohara 2012[30]	RCS	Japan	1998-2008	186	150	D2	DG, TG, PG	61.30%	58.50%	□:70□:49 □:48 □:19	□:43□:33 □:41 □:6	7
Sica G 2011[31]	RCS	Italy	2000-2004	22	25	D2	DG, TG	NA	NA	□B: 2□:9 □:10 □1	□B: 2□:13 □:7 □:3	5
Son T 2014[32]	RCS	Korea	2003-2009	39	22	D1+, D2	SG, TG	NA	NA	pT4a: 39	pT4a: 22	6
Wang 2018[33]	RCT	China	2014-2017	222	220	D2	DG	NA	NA	□:75□:63 □:80 □:4	□:68□:63 □:82 □:6	--
Wu L 2015[34]	RCS	China	2010-2012	160	195	D2	DG, TG	NA	NA	□B: 35□:84 □:41	□B: 36□:98 □:61	6
Yu J 2019[35]	RCT	China	2012-2017	519	520	D2	DG			□64 □:248 □:207	□88 □:247 □:185	--
Zhang XM 2016[36]	RCS	China	2009-2014	92	92	D2	DG, TG	NA	NA	□B: 16□A: 58 □B: 18	□B: 14□A: 56 □B: 22	8
Zhang Y 2015[37]	RCS	China	2007-2014	86	86	D2	DG	NA	NA	□B: 9□:66 □:11	□B: 10□:67 □:9	7
Zhao X 2013[38]	RCS	China	2008-2010	133	133	D2	DG	NA	NA	□B: 109□:17 □:7 □:0	□B: 109□:14 □:8 □:2	7
Zhao Y 2011[39]	RCS	China	2004-2009	346	313	D1, D2	DG	NA	NA	p□B: 42□:99 □:199 □:6	p□B: 37□:87 □:181 □:8	7
Chan B 2019[40]	RCS	China	2009-2017	54	167	D2	DG, TG	NA	NA	p□:7□:12 □:34 □:1	p□:27□:33 □:92 □:15	7
Shibuya 2019[41]	RCS	Sapporo	2012-2016	87	27	D2	DG	NA	NA	p□:21□:33 □:33 □:0	p□:2□:9 □:16 □:0	5
Wang H 2019[42]	RCS	China	2004-2014	414	355	D1, D1+, D2, D2+	DG	NA	NA	□:132□:101 □:181	□:93□:100 □:162	7
Wang J 2019[43]	RCT	China	2007-2012	60	60	D2	DG	NA	NA	NA	NA	--
	PSM		2012-2014	190	190	D2	DG	NA	NA	□:12□:87 □:91	□:14□:71 □:105	7
Xu y 2019[44]	RCS	China	2005-2012	430	768	D2	DG, TG	NA	NA	□:46□:159 □:225	□:61□:266 □:441	7
Wang N 2020[45]	RCS	China	2007-2016	49	221	D2	DG, TG	100%	100%	□:4 □:45	□:5 □:216	7

LG: Laparoscopic approach group, OG: Open approach group, RCT-Randomized controlled study, RCS: Retrospective cohort study, PCS: Prospective cohort study, PSM: Propensity score matching,

NA: Not available. Quality are based on the NOS

Figure 2

Review authors’ judgements about all cohort studies according to the “risk assessment tool” recommended by the Cochrane Collaboration Network

Table 2

The risk of bias in the included retrospective cohort studies (by the Newcastle-Ottawa quality assessment tool)

Study	Selection				Comparability		Outcome			Total
	1	2	3	4	5	6	7	8	9
Chen Q 2012[5]	☆	☆	☆	☆	☆		☆	☆		7
Chen X 2016[6]	☆	☆	☆	☆	☆	☆	☆	☆		8
Du X 2009[7]	☆	☆	☆	☆	☆		☆			7
Hamabe 2011[8]	☆	☆	☆	☆	☆		☆	☆		8
Huang J 2010[10]	☆	☆	☆	☆	☆		☆			6
Huang X 2019[11]	☆	☆	☆	☆	☆		☆			6
Hur 2008[12]			☆	☆	☆	☆		☆		5
Hwang 2008[13]	☆	☆	☆	☆	☆		☆			6
Inokuchi 2018[14]	☆	☆	☆	☆	☆	☆	☆	☆		8
Kim K 2012[15]	☆	☆	☆	☆	☆		☆	☆		7
Kim S 2019[16]	☆	☆	☆	☆	☆		☆	☆		7
Kinoshita 2019[17]	☆	☆	☆	☆	☆	☆	☆	☆		8
Li Q 2016[19]	☆	☆	☆	☆	☆		☆	☆		7
Li Ziyu 2016[20]	☆	☆	☆	☆	☆		☆			6
Li ZY 2018[22]	☆	☆	☆	☆	☆	☆	☆	☆		8
Lin JX 2016[23]	☆	☆	☆	☆	☆		☆	☆		7
Lin JX 2013[24]	☆	☆	☆	☆	☆	☆	☆			7
Ludwing K 2018[25]	☆	☆	☆	☆	☆	☆	☆	☆		8
Sato H 2011[27]	☆	☆	☆	☆	☆		☆			6
Shinohara 2012[30]	☆	☆	☆	☆	☆		☆	☆		7
Sica G 2011[31]			☆	☆	☆	☆		☆		5
Son T 2014[32]	☆		☆	☆	☆	☆		☆		6
Wu L 2015[34]	☆	☆	☆	☆	☆		☆			6
Zhang XM 2016[36]	☆	☆	☆	☆	☆	☆	☆	☆		8
Zhang Y 2015[37]	☆	☆	☆	☆	☆		☆	☆		7
Zhao X 2013[38]	☆	☆	☆	☆	☆	☆	☆			7
Zhao Y 2011[39]	☆	☆	☆	☆	☆		☆	☆		7
Chan B 2019[40]	☆	☆	☆	☆	☆		☆	☆		7
Shibuya 2019[41]	☆		☆	☆	☆	☆				5
Wang H 2019[42]	☆	☆	☆	☆	☆		☆	☆		7
Wang J 2019[43]	☆	☆	☆	☆	☆	☆	☆			7
Xu Y 2019[44]	☆	☆	☆	☆	☆		☆	☆		7
Wang N 2020[45]	☆	☆	☆	☆	☆		☆	☆		7

Representativeness of exposed cohort; 2. Selection of non-exposed cohort; 3. Ascertainment of exposure; 4. Outcomeof interest was not present at start of study; 5. Study controls for age, sex, and marital status; 6. Study controls for any additional factors; 7. Assessment of outcomes; 8. Follow-up long enough for outcomes to occur; 9. Adequacy of follow-up

Statistical analysis

This meta-analysis used Review Manager 5.3 (The Cochrane Collaboration, Oxford, UK) for statistical analysis. The Haenszel method was used to estimate the effects from the merging binaries (relative risk, [RR]), and the inverse variance method was used to merge the effects from continuous data (weighted mean difference, [WMD]). RRs and WMDs with a 95% confidence interval (CI) were calculated to compare the incidence of postoperative indicators between the LG and OG groups. Heterogeneity among the included studies was qualitatively evaluated using a Chi-squared-based Q test. P < 0.10 showed statistically significant heterogeneity across the studies. The level of heterogeneity between studies was evaluated using I2 statistics. I2 < 30% was considered to have low heterogeneity, and a fixed-effects model was applied; 30%≤I2 ≤50% was considered to have moderate heterogeneity, and I2 >50% represented high heterogeneity. When calculating the combined effect amount of a certain outcome index, only when the heterogeneity test in RCT and cohort study was I2 < 30% was the fixed effect model was used; otherwise, the random effect model was used to combine the amounts of the effects. Funnel charts were used for the qualitative evaluation of the publication bias. Stata software (version SE12.0) (Stata Corp., College Station, TX, USA) was used to calculate Begg’s test and Egger’s test for quantitative evaluation of publication bias of the included studies, with a significant level limited to 0.05.

RESULTS

Search results and study selection

A total of 376 articles were retrieved by searching electronic databases and manually searching through relevant reference lists. We then excluded reviews, case reports, systematic reviews and meta-analyses, as well as studies that were clearly irrelevant based on their title or abstract. And after duplicates were identified and excluded, 51 articles remained. But because some studies come from the same authors or research centers, some of their results are from the same patients. If they are included again, the conclusions may be distorted. Therefore, we eliminated some studies with duplicate cases. Following these exclusions, only 42 articles (41 studies) remained. A total of 41 studies with a total of 14,689 patients were included in the final analysis. In total, 6976 patients (47.5%) received a laparoscopic approach, and 7713 (52.5%) patients received an open approach.

Results from the meta-analysis

We analysed 18 post-operative efficacy indexes of LGs and OGs in the treatment of AGC. The summary is shown in Table 3. The forest plots of recurrence rate, 3-year disease-free survival, 3-year disease-free survival, 5-year disease-free survival, and 5-year overall survival are respectively shown in Figures 3–7.

Table 3

Meta-analysis results of all outcome indicators in the available studies

Measured Outcomes	Subgroup	No. studies	No. Patients	Heterogeneity Test		Model	RR/WMD	95% CI	P
				I2 (%)	P
Operative time (min)	RCT	8	1670 vs 1651	95	<0.00001	Random	43.08	26.11~60.05	<0.00001
	RCS	23	2971 vs. 3545	97	<0.00001	Random	44.55	28.78~60.33	<0.00001
Proximal resection margin	RCT	3	1254 vs 1238	0	0.89	Fixed	-0.35	-0.55~-0.14	0.0008
	RCS	8	1582 vs. 1884	21	0.26	Fixed	-0.17	-0.33~0.00	0.05
Distal resection margin (cm)	RCT	3	1254 vs 1238	0	0.89	Fixed	-0.15	-0.36~0.05	0.14
	RCS	7	1123 vs. 1446	28	0.21	Fixed	0.04	-0.12~0.21	0.6
Hospital stay (d)	RCT	7	1625 vs. 1601	88	<0.00001	Random	-0.91	-1.87~0.06	0.07
	RCS	19	2916 vs. 3350	86	<0.00001	Random	-2.45	-3.13~-1.77	<0.00001
Estimated blood loss (ml)	RCT	6	1525 vs. 1505	93	<0.00001	Random	-41.83	-69.24~-14.41	0.003
	RCS	20	2784 vs. 3375	97	<0.00001	Rondom	-95.99	-124.90~-67.07	<0.00001
Intraoperative transfusion	RCT	3	903 vs 900	0	0.56	Random	0.77	0.56~1.05	0.1
	RCS	7	1186 vs. 990	60	0.02	Random	0.5	0.32~0.78	0.002
Time to oral intake (d)	RCT	6	1106 vs. 1081	83	<0.0001	Random	-0.4	-0.78~-0.01	0.04
	RCS	14	2167 vs. 2276	88	<0.00001	Random	-0.96	-1.27~-0.65	<0.00001
Time to first flatus (d)	RCT	7	1570 vs 1555	82	<0.00001	Random	-0.3	-0.53~-0.07	0.01
	RCS	15	2488 vs. 2842	93	<0.00001	Random	-0.74	-0.95~-0.53	<0.00001
Time to ambulation (d)	RCT	4	952 vs 947	97	<0.00001	Random	-0.43	-1.1~0.24	0.21
	RCS	7	1408 vs. 1307	94	<0.00001	Random	-0.86	-1.21~-0.52	<0.00001
Overall complications	RCT	7	1610 vs 1591	48	0.07	Random	0.78	0.61~1	0.05
	RCS	26	3128 vs. 3808	0	0.51	Random	0.82	0.73~0.92	0.0007
Serious complications	RCT	6	1506 vs 1493	13	0.33	Fixed	0.93	0.69~1.24	0.62
	RCS	11	1867 vs. 2203	7	0.38	Fixed	0.78	0.63~0.97	0.03
Lymph node dissection	RCT	8	2144 vs. 2121	0	0.7	Random	-0.55	-1.17~0.07	0.08
	RCS	21	2556 vs. 2961	66	<0.00001	Random	0.33	-0.70~1.37	0.53
R0 rate	RCT	2	558 vs 548	52	0.15	Random	1.01	0.95~1.08	0.68
	RCS	7	1677 vs. 1956	0	0.6	Random	1	1.00~1.00	0.99
Recurrence rate	RCT	3	740 vs. 736	0	0.95	Random	1.14	0.91~1.44	0.25
	RCS	13	2210 vs. 2582	31	0.13	Random	0.92	0.82~1.03	0.14
3-year DFS	RCS	4	325 vs. 496	26	0.26	Fixed	1.13	1.04~1.23	0.005
3-year OS	RCS	9	1407 vs. 1431	42	0.08	Random	1.11	1.03~1.19	0.004
5-year DFS	RCS	13	2312 vs. 2798	0	0.92	Fixed	1.05	1.00~1.11	0.04
5-year OS	RCS	17	2753 vs. 3242	0	0.57	Fixed	1.05	1.01~1.10	0.02

RCT: Randomized controlled trial, RCS: Retrospective cohort study, PCS: Prospective cohort studies, RR: Relative risk, WMD: Weighted mean difference, CI: Confidence interval, No.: Number of, OS: Overall survival, severe complications: C-D grade 3 and above, DFS: Disease-free survival, NA: Not applicable. P<0.05 indicates a significant difference

Figure 3

Forest plot of recurrence rate

Figure 7

Forest plot of 5-year overall survival

Forest plot of 3-year disease-free survival

Forest plot of 3-year overall survival

Forest plot of 5-year disease-free survival

Sensitivity analysis and publication bias

A sensitivity analysis was conducted by excluding each study in each set’s analysis. The sensitivity analysis of almost all outcome indicators showed that the combined effects between the RCT and cohort studies were stable, and a reversal of the cumulative analysis results did not been found. Funnel plots were used to evaluate publication biases [Figure 8]. The funnel diagram is a symmetrical distribution without an obvious extreme distribution value. No publication bias was detected by Begg’s test and Egger’s test in RCTs and RCSs. As shown in Table 4.

Figure 8

Funnel plot of (a) postoperative complications (b) recurrence (c) 5--year disease--free survival (d) 5--year overall survival

Table 4

Evaluation of publication bias of included studies

Outcomes	Subgroup	No. studies	Begg’s Test		Egger’s test
			Pr>|z|□	Pr > |z|□□	P>|t| □
Operative time (min)	RCT	8	0.458	0.536	0.831
	RCS	23	0.937	0.958	0.735
Proximal resection margin	RCT	3	0.602	1	0.939
	RCS	8	0.621	0.711	0.474
Distal resection margin (cm)	RCT	3	0.602	1	0.791
	RCS	7	0.368	0.453	0.97
Hospital stay (d)	RCT	7	0.453	0.548	0.697
	RCS	19	0.916	0.944	0.107
Estimated blood loss (ml)	RCT	6	0.188	0.26	0.376
	RCS	20	0.27	0.284	0.078
Intraoperative transfusion	RCT	3	0.602	1	0.165
	RCS	7	0.453	0.548	0.201
Time to oral intake (d)	RCT	6	0.851	1	0.782
	RCS	14	0.622	0.661	0.53
Time to first flatus (d)	RCT	7	0.652	0.764	0.477
	RCS	15	0.181	0.198	0.099
Time to ambulation (d)	RCT	4	0.174	0.308	0.545
	RCS	7	0.881	1	0.88
Overall complications	RCT	7	0.881	1	0.616
	RCS	26	0.343	0.355	0.724
Serious complications	RCT	6	0.188	0.26	0.177
	RCS	11	0.436	0.484	0.168
Lymph node dissection	RCT	8	0.536	0.621	0.614
	RCS	21	0.856	0.88	0.777
R0 rate	RCT	2	0.317	1	*
	RCS	7	0.09	0.174	0.056
Recurrence rate	RCT	3	0.602	1	0.275
	RCS	13	0.18	0.2	0.195
3-year DFS	RCS	4	0.174	0.308	0.054
3-year OS	RCS	9	0.297	0.348	0.212
5-year DFS	RCS	13	0.222	0.246	0.166
5-year OS	RCS	17	0.249	0.266	0.334

RCT: Randomized controlled study, RCS: Retrospective cohort study, OS-overall survival, DFS: Disease free survival; *P; **P (continuity corrected). *NA: Not available, Supplementary file 3 Evaluation of publication bias of included studies

DISCUSSION

Laparoscopic treatment of EGC has been confirmed and recommended by the JGCA, CSCO and other clinical guidelines. However, its application in AGC remains controversial. AGC is usually accompanied by infiltration of the surrounding tissue and metastasis into surrounding lymph nodes. Surgical treatment requires not only resection of main cancer but also the implementation of an expanded radical operation in the surrounding tissue and lymph nodes, which is technically more difficult. In 1997, Goh et al.[46] used laparoscopic surgery for the first time to treat four patients with AGC and achieved good results, initially demonstrating the feasibility of laparoscopic surgery for AGC. With the completion of several prospective, multicentre, high-quality, randomised controlled trials in Japan, Korea and China, the safety and effectiveness of laparoscopic surgery for AGC have been further verified. However, the application of laparoscopy in AGC in the real world is quite different in different countries and regions. A non-randomized study can reflect the effect of laparoscopy and laparotomy on locally AGC in a real environment. Therefore, this article systematically reviews the RCT and non-RCT literature, comparing the effects of laparoscopy on locally AGC with those of laparotomy, and systematically evaluates the advantages and disadvantages of laparoscopic treatments for late gastric cancer.

As the included research covers hospitals at all levels, in different regions, in different years; the quality of literature is uneven, and a specific literature quality assessment is shown in Table 1. For each observation outcome, a sensitivity analysis of the participating studies was conducted. The results of the meta-analysis showed that regardless whether the study was an RCT or a cohort study, the patients in the laparoscopic approach group had less estimated blood loss, less time to oral intake (d) (d) and less time to first flatus (d) after their operation. The operative time and PRM for the LGs were significantly worse than in the OGs. The distances of the distal margins, R0 rates, lymph node dissection and recurrence rates between the LG and OG were not statistically different. There was a higher frequency of hospital stays (d), intra-operative blood transfusions, overall/serious complications, 3-year OS, 3-year DFS, 5-year OS, 5-year DFS and in the LG compared to the OG in non-randomised controlled studies, and there were no significant differences in these frequencies in randomised controlled trials (RCTs). In the ideal RCT environment, there was no significant difference between the LG and the OG, but in the real world, the LGs had better outcomes than the OGs.

The number of lymph nodes removed was used to assess tumour adequacy. According to the International Union for Cancer Control, pathological examination of at least 15 lymph nodes is beneficial. In our review, most of the studies were conducted in Eastern countries, while most Asian surgeons preferred D2 dissections. The number of lymph nodes retrieved in the literature is sufficient. The meta-analysis showed that there was no significant difference in RCT between the two types of procedures. Some studies have shown that surgeons need to have 30–50 cases of laparoscopies with D1 removed to overcome the learning curve.[47484950] The anatomy of gastric tissues and organs is complex, the distribution of blood vessels is dense, and there will be variation in the process of operation. AGC requires D2 lymph node dissection, which is difficult and complex to operate on. Therefore, it is difficult for less experienced surgeons. AGC is not recommended in hospitals with fewer patients.

The scope of a laparoscopic radical resection follows the principle of open surgery. The operation scope of local AGC should include the resection of more than two-thirds of the stomach, as well as a D2 lymph node dissection.[1] Most of the existing data are limited to the distal part of the stomach, most of which are performed with a distal resection, and few have undergone total gastrectomy. The distance between the cut edges for gastric cancer and tumours should be >3 cm for local gastric cancer and 5 cm for invasive gastric cancer. The meta-analysis showed that in both RCTs and RCSs, there was no significant difference in the distance between the distal margins and the tumour, while the distance between the proximal margin and the tumour for laparoscopies was significantly smaller than for open approaches. However, there was no significant difference in the rate of R0 between RCTs and retrospective studies. The recurrence rates for different literature follow-up times were different, as were the statistical recurrence time intervals. The recurrence rate of the combination had greater heterogeneity, but the meta-analysis results show that LG and the OG recurrence rates had no significant differences.

The meta-analysis of long-term oncology results showed that in the cohort study, OS and DFS at 3 and 5 years was better in the LG than in the OG. Most patients with AGC underwent adjuvant chemotherapy. However, in terms of evidence-based medicine, this study verified that laparoscopy has the advantages of small trauma and fast functional recovery (short hospitalisation time, less blood loss, less blood loss during the operation; shorter time for getting out of bed for the first time, for drinking water through the mouth for the first time, and shorter time for flatus and defecation to occur after the first operation). This advantage is likely to translate into better compliance with adjuvant chemotherapy in gastric cancer patients, where LGs can obtain earlier chemotherapy and complete more postoperative chemotherapy cycles. LGs are less likely to terminate chemotherapy due to adverse reactions, improving their post-operative survival rate.[1951] This phenomenon also occurs in colorectal cancer.[52]

CONCLUSION

The safety and effectiveness of laparoscopic surgery for AGC are not inferior to that of traditional open surgery, and to a certain extent, reduces trauma, is conducive to recovery and has been verified on RCT. In the real-world cohort, laparoscopic radical gastrectomy can achieve a better survival rate and DFS rate. This may be related to the minimally invasive advantages brought by laparoscopy, which improve patient tolerance and completion of subsequent treatment. However, to evaluate the efficacy of these two methods more comprehensively, high quality, randomised controlled trials, and longer follow-up times are still needed.

Limitations

This study has the following limitations. 1. Due to the inclusion of almost all studies on laparoscopic and open access methods for AGC, there is high heterogeneity in these articles, which limits the interpretation of individual research results. 2. Most of the included studies are retrospective studies, which cannot avoid selection biases.

Financial support and sponsorship

This research is supported by the Sanming Project of Medicine in Shenzhen (No.SZSM 201911008).

Conflicts of interest

Wei Zhang and Zhangkan Huang contributed equally to this work.

There is no conflict of interest among the authors.