Short- and long-term outcomes of laparoscopic surgery for locally advanced gastric cancer after neoadjuvant chemotherapy: A propensity score matching analysis

doi:10.21203/rs.3.rs-2569155/v1

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Short- and long-term outcomes of laparoscopic surgery for locally advanced gastric cancer after neoadjuvant chemotherapy: A propensity score matching analysis

https://doi.org/10.21203/rs.3.rs-2569155/v1

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Background: The long-term outcomes of laparoscopic surgery for locally advanced gastric cancer after neoadjuvant chemotherapy are ambiguous because of limited evidence.

Methods:The clinicopathological data of locally advanced gastric cancer patients with clinical stage of cT2-4a/N1-3/M0 who underwent gastrectomy after neoadjuvant chemotherapy were retrospectively examined. The short- and long-term effects of the laparoscopic gastrectomy group and open gastrectomy group were compared after propensity score matching.

Results:This study enrolled 148 cases, of which 110 cases were included after propensity score matching. The laparoscopic gastrectomy group had shorter postoperative first flatus time and shorter postoperative first liquid diet time than the open gastrectomy group. There were no significant differences in 3-year relapse-free survival (P = 0.888) and overall survival (P = 0.432) between the two groups. Multivariate Cox regression analysis revealed that the absence of postoperative adjuvant chemotherapy (P = 0.009) was an independent risk factor for relapse-free survival. Tumor size ≥4 cm after neoadjuvant chemotherapy (P = 0.014) and absence of postoperative adjuvant chemotherapy (P = 0.002) were independent risk factors for overall survival.

Conclusions:Laparoscopic gastrectomy can serve as an alternative surgical method for locally advanced gastric cancer after neoadjuvant chemotherapy in consideration of its better postoperative gastrointestinal recovery and comparable long-term outcomes.

Gastric cancer

Laparoscopic surgery

Open surgery

Surgical oncology

Neoadjuvant chemotherapy.

Gastric cancer is the fifth most common cancer and the fourth leading cause of cancer-related mortality worldwide [1]. In China, approximately 70% of gastric cancer patients are already at an advanced stage of cancer when their diagnoses are confirmed. The primary treatment methods for locally advanced gastric cancer (LAGC) are complete surgical resection and D2 lymph node dissection. Laparoscopic surgery has been widely performed for gastric cancer since the first reported case of laparoscopic distal gastrectomy [2]. The results of the CLASS-01 [3-5] and KLASS-02 trial [6, 7] showed that laparoscopic surgery for distal gastric cancer was safe and feasible; therefore, the 2021 National Comprehensive Cancer Network guidelines recommend laparoscopic surgery for LAGC.

The MAGIC trial indicated that perioperative chemotherapy with epirubicin, cisplatin, and infused fluorouracil for operable adenocarcinomas of stomach or lower esophageal could decrease tumor stage and significantly improve the 5-year progression-free survival and 5-year overall survival (OS) [8]. The EORTC40954 [9], FNCLCC FFCD [10] and RESOLVE trials [11] have successively confirmed the safety and efficacy of neoadjuvant chemotherapy (NC) for LAGC. However, NC can cause tissue fibrosis and edema, which may influence surgical procedures and tissue healing. Li et al. conducted a randomized controlled trial (RCT) confirming the short-term effects of laparoscopic distal gastrectomy for LAGC after NC [12]; however, long-term outcomes are ambiguous because of limited evidence. Therefore, this study aimed to evaluate the long-term effects of laparoscopic gastrectomy (LG) vs open gastrectomy (OG) for LAGC following NC using propensity score matching (PSM).

Patient selection

This study included patients with LAGC who received surgery after NC between January 2012 and September 2020 in the Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. NC was conducted on patients with LAGC with a clinical tumor stage of cT2-4a/N1-3M0. The treatment regimens included FOLFOX (oxaliplatin, leucovorin and 5-fluorouracil), SOX (oxaliplatin and TS-1), XELOX (oxaliplatin and capecitabine), and FLOT (docetaxel, oxaliplatin, leucovorin and fluorouracil), which were selected based on the 2018 Chinese Society of Clinical Oncology (CSCO) Clinical guidelines for the diagnosis and treatment of gastric cancer and the tolerance of patients. The following were the criteria for inclusion: (1) clinical tumor stage of cT2-4a/N1-3M0, (2) underwent surgery after NC. And the following were the criteria for exclusion: (1) palliative gastrectomy, (2) diagnosis of any other malignant tumor in the past 5 years and (3) incomplete clinicopathological data. All patients were separated into two groups: those who received LG (LG group) and those who underwent OG (OG group) after NC. The flow chart for screening of cases and subsequent grouping is shown in Figure 1. The Tongji Medical College Ethics Committee of Huazhong University of Science and Technology ratified the protocol of this study. An informed consent was signed by all patients before participating in the study.

Surgical procedure

All surgeries were performed by experienced surgeons of the Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. LG would be converted to OG in patients with severe peritoneal adhesions, severe hemorrhage, severe tumor invasion, special tumor location, or large tumor size, which made it difficult to perform laparoscopy. The performance of proximal gastrectomy, distal gastrectomy, or total gastrectomy was depended on the tumor location. All patients underwent standard gastrectomy with D2 lymphadenectomy and standard reconstruction based on the Japanese Gastric Cancer Treatment Guidelines (5th edition) [13]. Reconstruction after proximal gastrectomy was performed via esophagogastrostomy while reconstruction after total gastrectomy was performed via Roux-en-Y esophagojejunostomy. Distal gastrectomy reconstruction was performed via standard Roux-en-Y gastrojejunostomy or Billroth II gastrojejunal anastomosis depending on the surgeon’s preference. All reconstruction processes were performed in an open manner. All participants were fully informed of the benefits and risks of LG and OG, and the decision regarding the surgical method was made based on the surgeon’s discretion or the patient’s preference. Postoperative chemotherapy was routinely applied to all patients unless they couldn’t put up with it due to a serious adverse effect.

Data collection and outcome assessment

Demographic data, involving age, sex, body mass index, Charlson Comorbidity Index (CCI) [14], and American Society of Anesthesiologists (ASA) score, were collected from all patients. Enhanced abdominal computed tomography was performed before NC to evaluate the clinical tumor stage and after NC to assess the chemotherapy response. The American Joint Committee on Cancer (AJCC) Cancer Staging Manual (8th) was used to define the clinical tumor stage, and the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) was applied to evaluate the chemotherapy response [15].

A standard clinical pathway was used for management of all patients. Liquid diet was started after first flatus and patients were discharged after the exemption of complications. Data related to surgery, including the length of incision, surgery duration, time to first flatus, time to first liquid diet, postoperative complications, and length of postoperative hospital stay, were collected. The Clavien–Dindo classification system was applied to grade postoperative complications, which were defined as incidents happening within 30 days after surgery [16, 17]. Tumor regression grade was evaluated according to AJCC standard and pathological stage was defined according to the AJCC Cancer Staging Manual (8th). Hospital mortality was defined as death due to any cause that occurred within 30 days after surgery.

Follow-up

Postoperative follow-up was performed every 3–6 months for the first 2 years and every 6–12 months thereafter via outpatient clinics or telephonic interviews. The last follow-up date was September 30, 2021, and the median follow-up period was 38 (13–112) months. Relapse-free survival (RFS) was defined as the duration from surgery to recurrence, and OS was defined as the duration from surgery to death.

Propensity score matching

PSM was conducted by matching patients who underwent LG after NC with those who underwent OG after NC to eliminate differences in baseline statistics. Seven covariates (age, sex, CCI, ASA score, clinical stage, tumor size, and resection range) were chosen to calculate the propensity score. PSM was conducted by one-to-one nearest neighbor method, and the caliper was set on 0.1.

Statistical analysis

Quantitative variables are presented as mean ± standard deviation, and the differences were compared with independent t-test. Quantitative variables with high deviation were expressed as medians (interquartile range), and the differences were compared with Mann–Whitney U test. Categorical variables were expressed as frequencies with the differences compared by Chi-square test or Fisher’s exact test. Kaplan–Meier analysis were used to generate the survival curves, and the differences were evaluated by log-rank test. Univariate and multivariate analyses of risk factors for survival were conducted by the Cox proportional hazards regression model. The cutoff point of the continuous variables associated with survival was determined using the median. The multivariate Cox proportional hazards regression model included variables with P <0.05. Statistical analysis was conducted by SPSS software (SPSS 20.0, Chicago, IL, USA). R (version 4.0.4) was used for PSM. P <0.05 were considered statistically significant.

Demographic and clinicopathological characteristics

As shown in Figure 1, 148 patients who underwent gastrectomy after NC were enrolled in the study based on inclusion and exclusion criteria. The LG and OG groups consisted of 80 and 68 participants, respectively. The resection range and anastomotic methods were significantly different before matching. After PSM, 55 patients remained in each group, and all baseline data was comparable between the two groups (Table 1). The LG group included 45 men (81.8%) and 10 women (18.2%) with a mean age of 56.9±9.2 years. The OG group included 46 men (83.6%) and 9 women (16.4%) with a mean age of 57.4±10.8 years.

The most common NC regimens were FOLFOX and SOX in both the groups. The response rate to NC was 46.4% (51/110), and the disease control rate was 96.4% (106/110) according to the RECIST criteria. Grade 3/4 adverse events of chemotherapy happened in 9.1% (10/110) of patients during the NC period based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.0). The most common adverse events were neutropenia and myelosuppression. No NC-related deaths were observed.

Three patients were transformed to open gastrectomy during laparoscopy, of which two patients had severe peritoneal adhesions and one patient had severe hemorrhage. The postoperative adjuvant chemotherapy portion of the LG group and OG group was 81.8% (45/55) and 83.6% (46/55), respectively, and the difference was not statistically significant (P = 0.801).

The short-term outcome of surgery

The variables related to the short-term outcomes of surgery are shown in Table 2. Compared with the OG group, the surgery duration in the LG group was longer (282.0 ± 64.5 min vs. 254.6 ± 74.2 min, P = 0.041). The number of dissected lymph nodes (DLN) was not significantly different (P = 0.180). The LG group had a shorter time to first flatus (3.4 ± 1.2 d vs. 4.5 ± 1.8 d, P <0.001) and shorter time to first liquid diet (4.3 ± 1.8 d vs. 5.4 ± 2.0 d, P = 0.026) than those of the OG group, but there was no significant difference in the median postoperative hospital stay (P = 0.291). The overall incidence of postoperative complications was 20.9% (23/110), 10 patients (18.2%) in the LG group and 13 patients (23.6%) in the OG group; the difference was not statistically significant (P = 0.482) (Table 3). Grade 3/4 postoperative complications occurred in 7 patients (6.4%), of which 2 patients (1.8%) were in the LG group and 5 patients (4.5%) were in the OG group; the difference was not statistically significant (P = 0.435). No in-hospital mortality was recorded.

Survival analysis

The 1- and 3-year RFS rates in the LG group were 78.2% and 57.1%, respectively, and the corresponding rates in the OG group were 78.2% and 55.4%, respectively. The 1- and 3-year OS rates in the LG group were 80.0 % and 63.1%, respectively, and the corresponding rates in the OG group were 78.2% and 56.3%, respectively. No significant difference was found in RFS (P = 0.888) or OS (P = 0.432) (Figure 2).

Univariate Cox regression analysis showed that surgical approaches were not relevant to RFS (P = 0.888) or OS (P = 0.433). The risk factors related to RFS were tumor size ≥ 4 cm, clinical response of RECIST being stable disease (SD) or progressive disease (PD), tumor regression grade 2 or 3, pathological stage III or IV, and absence of postoperative adjuvant chemotherapy. The risk factors related to OS were tumor size ≥4 cm, clinical response of RECIST being SD or PD, pathological stage III or IV, and absence of postoperative adjuvant chemotherapy (Table 4). Multivariate Cox regression analysis showed that the absence of postoperative adjuvant chemotherapy (P = 0.009) was an independent risk factor for RFS, and tumor size ≥ 4 cm (P = 0.014) and the absence of postoperative adjuvant chemotherapy (P = 0.002) were independent risk factors for OS (Table 5).

Surgery is the first line of treatment for LAGC. The principle of surgery is the complete resection of tumor and adequate lymphadenectomy. The JCOG0912 trial [18], KLASS01 trial [19], and CLASS02 trial [20] proved the safety and feasibility of LG for early gastric cancer. Similar to LAGC, the CLASS01 trial [3-5] and KLASS02 trial [6, 7] observed that laparoscopic distal gastrectomy is safe and feasible. However, the participants included in the above studies were patients with gastric cancer who did not receive NC. The majority of the previous studies on the outcomes of laparoscopic surgery for LAGC after NC showed significant differences in baseline data [21-23]. To our knowledge, this is the first study to use PSM to balance the differences between the two groups and evaluated the short- and long-term outcomes of LG and OG for LAGC after NC.

Local tumors are prone to tissue edema, exudation, and fibrosis after NC, which may affect the identification of anatomic spaces and increase the difficulty of surgery as well as the risk of postoperative complications [24]. However, the FNCLCC FFCD trial showed that the complication rate of surgery for resectable gastroesophageal adenocarcinoma in the group after administering NC was 25.7% (28/109), which was not significantly different from 19.1% (21/110) in the traditional surgery only group [10]. Previous studies showed that the occurrence rate of postoperative complications in LAGC patients who do not receive NC is 14.1–38.0% [3, 6, 25-27]. The overall incidence of postoperative complications in our study was 20.9%, which indicates that NC did not obviously increase the incidence of postoperative complications.

Laparoscopic surgery involves a smaller incision and can effectively avoid tissue pull injury caused by open surgery. In addition, the visual magnification of laparoscopy allows a clearer surgical field and improves visualization of anatomical layers resulting in less intraoperative damage to the surrounding tissues, which in turn allows faster recovery of gastrointestinal function. Our study showed that LG was superior to OG in patients with LAGC after NC in terms of the time to first flatus and time to first liquid diet, suggesting that patients undergoing laparoscopic surgery had a faster postoperative recovery, which was consistent with previous studies [21]. These advantages allow laparoscopic surgery to have promising application prospects in the era of minimally invasive surgery and enhanced recovery after surgery [28, 29].

The number of DLN is closely related to postoperative pathological stage and prognosis evaluation of gastric cancer. Some lymph nodes retreated after NC, which may lead to a reduced number of DLN. Therefore, a large bias may arise when predicting prognosis using the ypTNM staging system. The lymph node ratio (LNR) has been proven to be a more stable and accurate prognostic indicator than N staging in previous studies, and it is usually unaffected by the number of DLN in predicting the prognosis of gastric cancer patients. Therefore, LNR is a promising prognostic indicator to replace the ypTNM staging system for LAGC after NC [30, 31]. In addition, several large RCTs confirmed that the number of DLN by laparoscopic surgery was similar to open surgery for LAGC [3, 6, 32]. However, it is unknown whether laparoscopic surgery can achieve the same number of DLN as that of open surgery for LAGC after NC because tissue exudation and edema caused by NC may affect the surgical process. The RCT of Li et al. [12] and the retrospective study of Fujisaki et al. [33] reported that there was no significant difference. Our results also showed that the two surgical methods have similar number of DLN. Therefore, laparoscopic surgery for LAGC after NC is safe and feasible in terms of lymphadenectomy.

Long-term follow-up findings in CLASS-01 [5] and KLASS-02 trials [7] showed that LG was not inferior to OG in the treatment of LAGC. The results of our study indicate that the long-term outcomes of LG for LAGC after administration of NC are comparable to those of open surgery, which is consistent with previous literature reports [22, 23, 33]. Moreover, it is unclear whether postoperative adjuvant chemotherapy will further improve the prognosis of LAGC after NC. Our results showed that the absence of postoperative adjuvant chemotherapy was an independent risk factor for RFS and OS in patients with LAGC after NC. Therefore, it is necessary for patients with LAGC after NC to receive postoperative adjuvant chemotherapy to achieve the best survival benefit as long as they are able to tolerate chemotherapy toxicity.

However, as this was a retrospective study of single-center, it had limited sample size and could not avoid the inherent bias of the retrospective study design. Prospective multi-center RCTs are required to derive more accurate conclusions.

In conclusion, LG for LAGC after NC had a better postoperative gastrointestinal recovery and comparable long-term outcomes and can serve as an alternative surgical method.

LAGC: locally advanced gastric cancer; NC: neoadjuvant chemotherapy; RCT: randomized controlled trial; LG: laparoscopic gastrectomy; OG: open gastrectomy; PSM: propensity score matching; CCI: Charlson Comorbidity Index; ASA: American Society of Anesthesiologists; AJCC: American Joint Committee on Cancer; RECIST: Response Evaluation Criteria in Solid Tumors; DLN: dissected lymph nodes; RFS: Relapse-free survival; OS: overall survival; SD: stable disease; PD: progressive disease; LNR: lymph node ratio.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of Union Hospital, Huazhong University of Science and Technology and all procedures were conducted in accordance with the principles of the Declaration of Helsinki. An informed consent was signed by all patients before participating in the study.

Consent for publication

Not applicable

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Competing interests

The authors declare that they have no competing interests

Funding

This study was supported by National Natural Science Foundation of China (No. 81702386, 82072736), Natural Science Foundation of Hubei Province (No.2021CFB566).

Authors' contributions

Concept and Design: Dr. Kaixiong Tao, Yuping Yin and Chenggang Zhang.

Acquisition, Analysis, and Interpretation of Data: Drs. Chenggang Zhang, Jiaxian Yu, Qi Jiang, Qian Shen and Gan Mao.

Drafting of the Manuscript: Drs. Chenggang Zhang and Jiaxian Yu.

Critical Revision of the Manuscript for Important Intellectual Content: Drs. Abu Bakarr Kargbo, Weizhen Liu, Xiangyu Zeng, Peng Zhang, Yuping Yin and Kaixiong Tao.

Acknowledgements

The authors thank Editage for editing grammar, spelling, and other common errors.

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Table1 Demographic and clinicopathological characteristics before and after propensity score matching

	Before PSM					After PSM
characters	LG group [n=80(%)]	OG group [n=68(%)]	X²	P value	LG group [n=55(%)]		OG group [n=55(%)]	X²	P value
Age (year)	58.2±8.6	57.4±10.3	-	0.592	56.9±9.2		57.4±10.8	-	0.799
Sex			1.630	0.202				0.064	0.801
Male	63（78.8）	59（86.8）			45（81.8）		46（83.6）
Female	17（21.2）	9（13.2）			10（18.2）		9（16.4）
BMI (kg/m²)	22.8±3.5	22.9±2.6	-	0.977	22.9±3.7		22.7±2.2	-	0.822
CCI^a			5.510	0.138				-	0.929
0	46（57.5）	49（72.1）			40（72.7）		38（69.1）
1	16（20.0）	13（19.1）			8（14.5）		11（20.0）
2	10（12.5）	3（4.4）			4（7.3）		3（5.5）
≥3	8（10.0）	3（4.4）			3（5.5）		3（5.5）
Clinical stage^b			0.010	0.922				0.077	0.781
II	9（11.3）	8（11.8）			7（12.7）		8（14.5）
III	71（88.8）	60（88.2）			48（87.3）		47（85.5）
NACT regimen			-	0.629				-	0.285
FOLFOX	41（51.3）	40（58.8）			25（45.5）		35（63.6）
SOX	31（38.8）	24（35.3）			25（45.5）		17（30.9）
XELOX	4（5.0）	3（4.4）			2（3.6）		2（3.6）
FLOT	4（5.0）	1（1.5）			3（5.5）		1（1.8）
Cycle of NACT			3.611	0.164				2.334	0.311
≤2	34（42.5）	39（57.4）			25（45.5）		33（60.0）
3	22（27.5）	16（23.5）			15（27.3）		11（20.0）
≥4	24（30.0）	13（19.1）			15（27.3）		11（20.0）
ASA score			-	0.173				-	0.559
1	10（12.5）	9（13.2）			6（10.9）		9（16.4）
2	69（86.3）	54（79.4）			48（87.3）		44（80.0）
3	1（1.3）	5（7.4）			1（1.8）		2（3.6）
Tumor location			1.575	0.455				0.247	0.884
Upper third	49（61.3）	45（66.2）			35（63.6）		36（65.5）
Middle third	9（11.3）	10（14.7）			7（12.7）		8（14.5）
Lower third	22（27.5）	13（19.1）			13（23.6）		11（20.0）
Resection range			8.860	0.012				0.280	0.869
Proximal	9（11.3）	21（30.9）			9（16.4）		11（20.0）
Distal	12（15.0）	9（13.2）			8（14.5）		7（12.7）
Total	59（73.8）	38（55.9）			38（69.1）		37（67.3）
Reconstruction method			-	0.012				-	0.733
esophagogastrostomy	9（11.3）	21（30.9）			9（16.4）		11（20.0）
Billroth-II gastrojejunostomy	6（7.5）	4（5.9）			4（7.3）		2（3.6）
Roux-en-Y	65（81.3）	43（63.2）			42（76.4）		42（76.4）
Tumor size^c (cm)	4.3±2.8	4.2±2.6	-	0.781	4.2±2.7		4.3±2.7	-	0.876
Histological type			0.225	0.635				0.170	0.680
Differentiated	23（28.8）	22（32.4）			16（29.1）		18（32.7）
Undifferentiated	57（71.3）	46（67.6）			39（70.9）		37（67.3）
Clinical response of RECIST^d			-	0.748				-	0.504
CR	2（2.5）	1（1.5）			2（3.6）		1（1.8）
PR	35（43.8）	25（36.8）			27（49.1）		21（38.2）
SD	38（47.5）	38（55.9）			25（45.5）		30（54.5）
PD	5（6.3）	4（5.9）			1（1.8）		3（5.5）
Tumor regression grade^e			-	0. 357				-	0. 264
0	4（5.0）	1（1.5）			4（7.3）		1（1.8）
1	6（7.5）	9（13.2）			5（9.1）		8（14.5）
2	26（32.5）	17（25）			20（36.4）		14（25.5）
3	44（55.0）	41（60.3）			26（47.3）		32（58.2）
Pathological stage^b			-	0.876				-	0.478
PCR	4（5.0）	1（1.5）			4（7.3）		1（1.8）
I	10（12.5）	9（13.2）			9（16.4）		9（16.4）
II	22（27.5）	19（27.9）			14（25.5）		16（29.1）
III	39（48.8）	34（50.0）			27（49.1）		25（45.5）
IV	5（6.3）	5（7.4）			1（1.8）		4（7.3）
Postoperative adjuvant chemotherapy			0.103	0.748				0.064	0.801
Yes	63（78.8）	55（80.9）			45（81.8）		46（83.6）
No	17（21.3）	13（19.1）			10（18.2）		9（16.4）

BMI: body mass index; CCI: Charlson Comorbidity Index; FOLFOX: oxaliplatin, leucovorin and 5-fluorouracil; SOX: oxaliplatin and TS-1; XELOX: oxaliplatin and capecitabine; FLOT: docetaxel, oxaliplatin, leucovorin and fluorouracil; ASA: American Society of Anesthesiologists; RECIST: Response Evaluation Criteria In Solid Tumors; CR: complete response; PR: partial response; SD: stable disease; PD: progressed disease; PCR: pathological complete response.

^aAccording to the Charlson Comorbidity Index

^bAccording to the 8^th edition of the American Joint Committee on Cancer Cancer Staging Manual

^cRefered to the long diameter of tumor after neoadjuvant chemotherapy

^dAccording to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)

^eAccording to the AJCC standard

Table2 Postoperative short-term outcomes

characters	LG group (n=55)	OG group (n=55)	P value
Surgery duration (min)	282.0±64.5	254.6±74.2	0.041
Number of dissected lymph nodes	22.5±6.0	24.5±9.2	0.180
Time to first flatus (d)	3.4±1.2	4.5±1.8	<0.001
Time to first liquid diet (d)	4.3±1.8	5.4±2.0	0.004
Postoperative hospital stay^a (d)	10.0（9.0,12.0）	11.0（9.0,12.0）	0.291

^aValues are presented as median (IQR, interquartile range)

Table3 Postoperative complications

characters	LG group [n=55(%)]	OG group [n=55(%)]	X²	P value
Overall complications^a	10（18.2）	13（23.6）	0.495	0.482
Grade I	0（0.0）	1（1.8）	-	1.000
Delayed wound healing	0（0.0）	1（1.8）
Grade II	8（14.5）	7（12.7）	0.077	0.781
Pleural effusion	3（5.5）	0（0.0）
Pulmonary infection	1（1.8）	7（12.7）
Intestinal obstruction	3（5.5）	0（0.0）
Wound infection	1（1.8）	0（0.0）
Grade III	2（3.6）	2（3.6）	0.000	1.000
Intraperitoneal hemorrhage	0（0.0）	1（1.8）
Delayed gastric emptying	1（1.8）	0（0.0）
Duodenal stump fistula	1（1.8）	0（0.0）
Anastomotic stenosis	0（0.0）	1（1.8）
Grade IV	0（0.0）	3（5.5）	1.371	0.242
Respiratory failure	0（0.0）	2（3.6）
cerebral embolism	0（0.0）	1（1.8）

^aAccording to the Clavien-Dindo classification system

Table4 Univariate analysis of risk factors for relapse-free survival and overall survival

	RFS				OS
	HR	95%CI	P value	HR		95%CI	P value
Age (≥60 vs. <60 years)	0.892	0.508-1.567	0.692	1.193		0.655-2.172	0.564
Sex (female vs. male)	1.723	0.896-3.314	0.103	1.791		0.902-3.556	0.096
CCI^a (≥2 vs. <2)	1.411	0.599-3.326	0.431	1.289		0.505-3.291	0.596
Clinical stage^b (III vs. II)	1.144	0.486-2.690	0.758	1.178		0.463-2.997	0.730
Surgical procedure (laparoscopy vs. open)	0.960	0.548-1.682	0.888	0.786		0.430-1.435	0.433
Surgery duration (≥257.5 vs. <257.5 mins)	0.888	0.505-1.561	0.679	0.704		0.384-1.293	0.258
Number of dissected lymph nodes (≤22 vs. <22)	0.999	0.570-1.749	0.996	0.994		0.546-1.809	0.984
Tumor size^c (≥4 vs. <4 cm)	2.492	1.367-4.543	0.003	4.042		1.986-8.224	<0.001
Histological type (Undifferentiated vs. differentiated)	1.573	0.820-3.019	0.173	1.657		0.816-3.365	0.162
Postoperative complications (yes vs. no)	1.151	0.588-2.252	0.682	1.201		0.591-2.438	0.613
Clinical response of RECIST^d (PD or SD vs. PR or CR)	6.831	3.177-14.689	<0.001	6.293		2.785-14.219	<0.001
Tumor regression grade^e (2 or 3 vs. 1 or 0)	2.864	1.028-7.984	0.044	1.833		0.721-4.664	0.203
Pathological stage^b (III or IV vs. PCR or I or II)	6.620	3.186-13.754	<0.001	5.929		2.735-12.853	<0.001
Postoperative adjuvant chemotherapy (no vs. yes)	2.068	1.096-3.904	0.025	2.727		1.439-5.169	0.002

CCI: Charlson Comorbidity Index; RECIST: Response Evaluation Criteria In Solid Tumors; CR: complete response; PR: partial response; SD: stable disease; PD: progressed disease; PCR: pathological complete response.

^aAccording to the Charlson Comorbidity Index

^bAccording to the 8^th edition of the American Joint Committee on Cancer Cancer Staging Manual

^cRefered to the long diameter of tumor after neoadjuvant chemotherapy

^dAccording to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)

^eAccording to the AJCC standard

Table5 Multivariate analysis of risk factors for relapse-free survival and overall survival

	RFS				OS
	HR	95%CI	P value	HR		95%CI	P value
Sex (female vs. male)	1.395	0.714-2.723	0.330	1.396		0.683-2.850	0.360
Surgical procedure (laparoscopy vs. open)	1.303	0.712-2.386	0.390	0.904		0.479-1.704	0.754
Tumor size^a (≥4 vs. <4 cm)	1.441	0.769-2.699	0.254	2.528		1.208-5.293	0.014
Histological type (Undifferentiated vs. differentiated)	0.943	0.474-1.876	0.866	1.062		0.507-2.225	0.874
Clinical response of RECIST^b (PD or SD vs. PR or CR)	2.496	0.683-9.126	0.167	2.470		0.696-8.760	0.162
Tumor regression grade^c (2 or 3 vs. 1 or 0)	1.524	0.474-4.905	0.480	-		-	-
Pathological stage^d (3 or 4 vs. PCR or 1 or 2)	2.862	0.908-9.018	0.073	2.335		0.718-7.592	0.159
Postoperative adjuvant chemotherapy (no vs. yes)	2.506	1.258-4.991	0.009	2.837		1.456-5.528	0.002

RECIST: Response Evaluation Criteria In Solid Tumors; CR: complete response; PR: partial response; SD: stable disease; PD: progressed disease; PCR: pathological complete response.

^aRefered to the long diameter of tumor after neoadjuvant chemotherapy

^bAccording to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1)

^cAccording to the AJCC standard

^dAccording to the 8^th edition of the American Joint Committee on Cancer Cancer Staging Manual

No competing interests reported.

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Short- and long-term outcomes of laparoscopic surgery for locally advanced gastric cancer after neoadjuvant chemotherapy: A propensity score matching analysis

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