
==== Front
Cancer Immunol Immunother
Cancer Immunol Immunother
Cancer Immunology, Immunotherapy : CII
0340-7004
1432-0851
Springer Berlin Heidelberg Berlin/Heidelberg

39235478
3802
10.1007/s00262-024-03802-6
Research
The short-term efficacy of neoadjuvant SOX versus SOX plus immune checkpoint inhibitor following laparoscopic gastrectomy for locally advanced gastric cancer: a multicenter retrospective cohort study in China
Cui Hao 12
Yang Yongpu 3
Song Liqiang 4
Yuan Zhen 12
Sun Linde 2
Du Jiajun 2
Lu Yuyuan 2
Ning Ning 3
Cui Jianxin 2
Shi Yan shiyandoctor@sina.com

3
Chen Lin chenlinbj@sina.com

14
Wei Bo weibo@vip.163.com

12
1 https://ror.org/01y1kjr75 grid.216938.7 0000 0000 9878 7032 School of Medicine, Nankai University, Tianjin, 300071 China
2 https://ror.org/04gw3ra78 grid.414252.4 0000 0004 1761 8894 Department of General Surgery, The Chinese PLA General Hospital First Medical Center, Beijing, 100853 China
3 grid.416208.9 0000 0004 1757 2259 Department of General Surgery, Centre for Minimally Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038 China
4 https://ror.org/03jxhcr96 grid.449412.e Department of Gastrointestinal Surgery, Peking University International Hospital, Beijing, 102206 China
5 9 2024
5 9 2024
11 2024
73 11 21618 7 2024
8 8 2024
© The Author(s) 2024
2024
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Background

This study aims to evaluate the short-term efficacy for locally advanced gastric cancer (LAGC) who accepted laparoscopic gastrectomy (LG) after neoadjuvant SOX versus SOX plus immune checkpoint inhibitors (ICIs).

Methods

LAGC patients who accepted LG after neoadjuvant SOX (SOX-LG, n = 169) and SOX plus ICIs (SOX + ICIs-LG, n = 140) in three medical centers between Jan 2020 and Mar 2024 were analyzed. We compared the tumor regression, treatment-related adverse events (TRAEs), perioperative safety between two groups, and explored the risk factors of postoperative complications (POCs) for LG after neoadjuvant therapy.

Results

The baseline characteristics were comparable between two groups (P > 0.05). SOX + ICIs-LG group acquired a higher proportion of objective response (63.6% vs. 46.7%, P = 0.003), major pathological response (43.6% vs. 31.4%, P = 0.001), and pathological complete response (17.9% vs. 9.5%, P = 0.030). There were no significant differences in the TRAEs rates, operation time, R0 resection, retrieved lymph nodes, postoperative first flatus, and hospitalized days, overall and severe POCs between two groups (P > 0.05). Patients in the SOX-ICIs-LG group had lower estimated blood loss (EBL) compared with SOX-LG (P = 0.001). Multivariate analysis showed that more EBL (P = 0.003) and prognostic nutritional index (PNI) < 40 (P = 0.005) were independent risk factors of POCs for LG after neoadjuvant therapy.

Conclusion

Neoadjuvant SOX plus ICIs brings better tumor regression and similar TRAEs compared with SOX alone for LAGC. SOX + ICIs-LG is safe and feasible to conduct with less EBL. Surgeons should focus on the perioperative management to control POCs for patients with PNI < 40 and more EBL.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00262-024-03802-6.

Keywords

Gastric cancer
Laparoscopic gastrectomy
Neoadjuvant therapy
Immune checkpoint inhibitor
Risk factors
http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China 82073192, 82273231, 62133010 Wei Bo Beijing Science and Technology ProgramZ221100007422125 Wei Bo issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
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pmcBackground

Gastric cancer (GC) is generally highly prevalent in China and accounts for the third highest mortality rate of malignant tumors [1]. Among them, advanced GC accounts for most of all GC patients, causing a serious health burden [2]. In addition to radical gastrectomy, neoadjuvant chemotherapy has emerged as a primary treatment approach for locally advanced gastric cancer (LAGC) following the findings of the MAGIC study [3]. The SOX regimen (S-1 combined with oxaliplatin) has gained popularity in East Asia for neoadjuvant chemotherapy. A study by Zhu et al. indicated that the SOX regimen yielded comparable results in terms of tumor pathological regression to the neoadjuvant FLOT regimen commonly used in Europe [4]. Furthermore, the RESOLVE and RESONANCE trial, similarly demonstrated that patients who received neoadjuvant SOX exhibited better 3-year disease-free survival in comparison to those who underwent adjuvant therapy, offering robust evidence for the efficacy of neoadjuvant chemotherapy [5, 6].

Immunotherapy, represented by immune checkpoint inhibitors (ICIs), as an emerging therapeutic modality, has been confirmed to achieve better long-term survival benefits in combination with chemotherapy in advanced GC [7]. Surgeons have recently turned their attention to exploring the potential therapeutic benefits of combining chemotherapy with immunotherapy in the perioperative management of LAGC. The initial results of the PERSIST study revealed that patients in the neoadjuvant SOX combined with Sintilimab group experienced a notable increase in rates of pathological complete response (pCR), major pathological response (MPR), and tumor downstaging compared to those receiving neoadjuvant SOX alone, with similar occurrences of treatment-related adverse events (TRAEs) between the two groups [8]. A study conducted by Zhong et al. demonstrated that combining SOX with camrelizumab resulted in a higher proportion of tumor regression and manageable TRAEs [9]. The above studies provide strong support for the rational use of neoadjuvant SOX combined with ICIs for the treatment of LAGC.

Perioperative safety is also a concern for surgeons. Surgical complexity tends to be higher following neoadjuvant therapy due to increased tissue fragility and peripheral exudative edema, as observed in clinical practice [10]. With the popularization of minimally invasive surgical techniques represented by laparoscopy in radical gastrectomy, laparoscopic gastrectomy (LG) after neoadjuvant chemotherapy has been proved to have comparable efficacy compared with open gastrectomy [11]. Meanwhile, LG is also safe to conduct for patients who accepted neoadjuvant chemotherapy and immunotherapy by a multicenter real-world study [12].

Nevertheless, the safety and feasibility of performing LG for LAGC following neoadjuvant SOX combined with ICIs remains a topic of debate. Therefore, this multicenter retrospective study was conducted to compare the short-term outcomes of LG after neoadjuvant treatment with SOX and SOX + ICIs, aiming to offer insights for rational clinical application.

Materials and methods

Patients

This was a multi-institutional retrospective study. The main selection criteria were as follows: (1) clinical stage T2N+M0 or T3-4N0-3M0 according to the American Joint Committee on Cancer (AJCC) 8th edition gastric cancer staging criteria; (2) gastric adenocarcinoma proved by the pathological results; (3) received neoadjuvant regimens of SOX or SOX combined with ICIs; (4) received LG with D2 lymphadenectomy after neoadjuvant therapy; (5) integrated clinical and pathological data. Patients who changed neoadjuvant regimens, had remnant gastric cancer, and underwent initial open or robotic gastrectomy were excluded. Eventually, 309 LAGC patients who accepted LG after neoadjuvant SOX (SOX-LG group, n = 169) or SOX combined with ICIs (SOX + ICIs group, n = 140) from Jan 2020 to Mar 2024 were included, with 27 patients from the Peking University international hospital, 59 patients from the Southwest hospital, and 223 patients from the Chinese PLA general hospital first medical center (Fig. 1). The baseline clinical characteristics between the SOX-LG and SOX + ICIs-LG group were comparable (Table 1). This study was approved by the Ethics Committee of the Chinese PLA general hospital (approval number: No. S2024-343-01) and was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from each patient enrolled in the study.Fig. 1 Flowchart of this study. LAGC Locally advanced gastric cancer; ICIs Immune checkpoint inhibitors; LG Laparoscopic gastrectomy.

Table 1 Clinical and pathological characteristics between SOX-LG and SOX + ICIs-LG group

Variables	SOX-LG (n = 169)	SOX + ICIs-LG (n = 140)	P value	
Sex [n (%)]			0.803	
Male	130(76.9)	106(75.7)		
Female	39(23.1)	34(24.3)		
Age (years old)	60.84 ± 9.82	60.70 ± 10.76	0.905	
BMI (kg/m2)	23.20 ± 3.35	23.47 ± 3.35	0.487	
NRS-2002 score [n (%)]			0.514	
 ≥ 3	71(42.0)	64(45.7)		
 < 3	98(58.0)	76(54.3)		
aCCI index	3.39 ± 1.15	4.11 ± 1.30	0.394	
ASA grade [n (%)]			0.830	
I	6(3.6)	8(5.7)		
II	143(84.6)	114(81.4)		
III	20(11.8)	18(12.9)		
History of abdominal surgery [n (%)]			0.288	
Yes	25(14.8)	15(10.7)		
No	144(85.2)	125(89.3)		
cT stage [n (%)]			0.882	
2	10(5.9)	5(3.6)		
3	101(59.8)	88(62.9)		
4	58(34.3)	47(33.6)		
cN stage [n (%)]			0.881	
N0	9(5.3)	8(5.7)		
N + 	160(94.7)	132(94.3)		
cTNM stage [n (%)]			0.775	
II	19(11.2)	13(9.3)		
III	146(86.4)	125(89.3)		
IVa	4(2.4)	2(1.4)		
Resection type [n (%)]			0.119	
Proximal gastrectomy	26(15.4)	34(24.3)		
Distal gastrectomy	54(32.0)	36(25.7)		
Total gastrectomy	89(52.7)	70(50.0)		
ypT stage [n (%)]			0.002	
0	19(11.2)	25(17.9)		
1	20(11.8)	27(19.3)		
2	23(13.6)	17(12.1)		
3	70(41.4)	57(40.7)		
4	37(21.9)	14(10.0)		
ypN stage [n (%)]			0.026	
0	78(46.2)	79(56.4)		
1	22(13.0)	21(15.0)		
2	24(14.2)	17(12.1)		
3	45(26.6)	23(16.4)		
ypTNM stage [n (%)]			0.007	
0	16(9.5)	25(17.9)		
I	37(21.9)	38(27.1)		
II	45(26.6)	34(24.3)		
III	71(42.0)	43(30.7)		
TRG grade [n (%)]			 < 0.001	
1a	16(9.5)	25(17.9)		
1b	28(16.6)	36(25.7)		
2	62(36.7)	47(33.6)		
3	63(37.3)	32(22.9)		
Pathological complete response [n (%)]	16(9.5)	25(17.9)	0.030	
Major pathological response [n (%)]	44(31.4)	61(43.6)	0.001	
Tumor differentiation [n (%)]			0.962	
Well /Moderate	91(53.8)	75(53.6)		
Poor/ Undifferentiated	78(46.2)	65(46.4)		
Tumor diameter (cm)	3.0(2.0–4.75)	3.0(2.0–4.5)	0.478	
Signet-ring cell carcinoma [n (%)]			0.862	
Yes	42(24.9)	36(25.7)		
No	127(75.1)	104(74.3)		
Vascular invasion [n (%)]			0.030	
Yes	67(39.6)	39(27.9)		
No	102(60.4)	101(72.1)		
Nerve invasion [n (%)]			0.787	
Yes	58(34.3)	46(32.9)		
No	111(65.7)	94(67.1)		
BMI Body mass index; aCCI: Age-adjusted Charlson Comorbidity Index; NRS-2002 Nutritional risk screening-2002; ICIs Immune checkpoint inhibitors; LG Laparoscopic gastrectomy; TRG Tumor regression grade

Neoadjuvant therapy

All enrolled patients underwent concurrent 2–8 cycles of simultaneous neoadjuvant chemotherapy and immunotherapy (NICT). The neoadjuvant chemotherapy regimen consisted of SOX (S-1: orally administered at a dosage of 80 mg per day for patients with a body surface area (BSA) less than 1.25 m2, 100 mg per day for those with a BSA between 1.25 m2 and 1.50 m2, or 120 mg per day for patients with a BSA of 1.50 m2 or greater, on days 1–14, every 3 weeks; oxaliplatin: intravenously administered at a dose of 130 mg/m2 on day 1, every 3 weeks). The regimen of neoadjuvant ICIs was programmed death-1(PD-1) inhibitors including domestic drugs (toripalimab 240 mg q3w, serplulimab 3 mg/kg q3w, camrelizumab 200 mg q3w, tislelizumab 200 mg q3w, and sintilimab 200 mg q3w), or imported drugs (nivolumab 360 mg q3w). Common Terminology Criteria for Adverse Events criteria (version 5.0) were used to evaluate the severity of treatment-related adverse events (TRAEs) [13].

Moreover, we conducted abdominal-enhanced CT per 2 or 3 cycles of neoadjuvant therapy to evaluate the radiological effects[Complete response(CR);Partial response(PR); Stable disease(SD); Progressive disease(PD)] compared with the baseline CT using the Response Evaluation Criteria in Solid Tumors criteria (version 1.1) [14]. In evaluating the pathological tumor regression grade (TRG), the Becker standard was employed to identify pathological complete response (pCR, TRG1a) and major pathological response (MPR, TRG1a/1b) based on the extent of residual tumor within the primary tumor site [15].

Surgery

Laparoscopic gastrectomy (LG) was performed after neoadjuvant therapy. We also conducted D2 lymphadenectomy (No.1, 2, 3a, 4sa, 4sb, 7, 8a, 9, 11 lymph nodes for proximal gastrectomy; No.1, 2, 3, 4sa, 4sb, 4d, 5, 6, 7, 8a, 9, 11, 12a lymph nodes for total gastrectomy; No.1, 3, 4sb, 4d, 5, 6, 7, 8a, 9, 11p, 12a lymph nodes for distal gastrectomy) and performed extracorporeal gastrointestinal anastomosis (esophagogastrostomy or tubular gastric reconstruction for proximal gastrectomy; Roux-en-Y or Billroth + Braun anastomosis for distal gastrectomy; Roux-en-Y for total gastrectomy) after tumor resection. The surgical procedure was in accordance with the Chinese Guidelines for Laparoscopic gastrectomy (2016 Edition) [16]. All the surgeons had abundant experience on LG and overcome the learning curve.

Perioperative safety and recovery

In this study, various surgical and postoperative recovery indicators were collected to assess surgical safety and tumor eradication efficacy. These included operation time, estimated blood loss (EBL), proportion of R0 resection, retrieved lymph nodes, the first flatus days, and postoperative hospitalized days which were crucial indicators for postoperative recovery. Meanwhile, Clavien-Dindo classification was applied for defining the severity of 30-day postoperative complications (POCs) [17].

Some combination of laboratory indexes might have predictive value for POCs after gastrectomy. Here, preoperative neutrophil/lymphocyte ratio (NLR; neutrophil count/lymphocyte count), platelet/lymphocyte ratio (PLR; platelet count/lymphocyte count), Onodera’s prognostic nutritional index (PNI) score [albumin (g/L) + 5 × lymphocyte count (× 109/L)], and systemic immune-inflammation (SII) index score (platelet count × neutrophil count / lymphocyte count) were also selected to explore the risk factors for POCs.

Statistical analysis

We used SPSS (version 26.0; SPSS, Chicago, IL, USA) to perform statistical analysis. Continuous variables following a normal distribution were reported as mean ± standard deviation, and Student’s t test was utilized for comparing differences. For skewed continuous data, the median (interquartile range) [M(IQR)] was used, and the Mann–Whitney U test was employed to assess differences. Categorical data were expressed in frequencies (percentages), and Chi-square or Fisher’s exact test was conducted to evaluate the difference between two groups. Binary logistic regression analysis was conducted and incorporating factors with P < 0.05 from univariate analysis were put into the multivariate analysis. A significance level of P < 0.05 was considered statistically significant.

Results

Clinical and pathological characteristics between two groups

The clinical and pathological characteristics of 309 patients in the SOX-LG and SOX + ICIs-LG group are summarized in Table 1. The majority of patients in both groups were male, with 76.9% and 75.7% in the SOX-LG and SOX + ICIs-LG groups, respectively. The mean ages were (60.84 ± 9.82) and (60.70 ± 10.76) years in the SOX-LG and SOX + ICIs-LG groups. There were no statistically significant differences observed in terms of gender, age, body mass index (BMI), Nutritional Risk Screening-2002 (NRS-2002) score, age-adjusted Charlson Comorbidity Index (aCCI) score, American Society of Anesthesiologists (ASA) grade, proportion of abdominal surgeries, clinical T stage (cT stage), clinical N stage (cN stage), clinical TNM stage (cTNM stage), and tumor resection between the two groups (P > 0.05).

After neoadjuvant therapy, we found that patients in the SOX + ICIs-LG group exhibited earlier ypT(P = 0.002), ypN(P = 0.026), and ypTNM stage(P = 0.007) compared to those in the SOX-LG group. Notably, 25(17.9%) and 61(43.6%) patients achieved pCR and MPR in the SOX + ICIs-LG group, which were significantly higher than whom (9.5% and 31.4% of patients attained pCR and MPR) in the SOX-LG group (P = 0.030, P = 0.001).

Neoadjuvant therapy and treatment-related adverse events

Patients in the SOX + ICIs-LG group were prone to select extended neoadjuvant therapy cycles (over 4 cycles) compared to those in the SOX-LG group (21.4% vs. 13.0%, P = 0.049). The majority (116/140, 82.9%) of patients received domestic ICIs in the SOX + ICIs-LG group (Fig. 2). Even though there was no significant difference in the disease control rate between SOX-LG and SOX + ICIs-LG groups (95.3% vs. 94.3%, P = 0.699), patients undergoing neoadjuvant SOX + ICIs demonstrated a higher proportion of objective response with a statistically significant disparity (63.6% vs. 46.7%, P = 0.003), as indicated in Supplementary Table 1.Fig. 2 Category and proportion of neoadjuvant ICIs. ICIs Immune checkpoint inhibitors

Operative outcomes and postoperative complications

Table 2 presents the perioperative outcomes. We found that SOX + ICIs-LG had less estimated blood loss(EBL) compared with SOX-LG[100.0 (50.0–121.5) mL vs. 100.0 (80.0–200.0) mL, P = 0.001).No significant differences were found in operation time, R0 resection rate, proportion of conversion to open surgery, retrieved lymph nodes, first flatus days, and postoperative hospitalized days between two groups(P > 0.05)0.5 patients in the SOX + ICIs-LG group and 4 patients in the SOX-LG group experienced the conversion to open surgery because of the bulky lymph nodes and tumor invasion(P = 0.774).Table 2 Comparison of perioperative indexes between SOX-LG and SOX + ICIs-LG group

Variables	SOX-LG (n = 169)	SOX + ICIs-LG (n = 140)	P value	
Operation time (min)	247.47 ± 72.39	237.27 ± 54.34	0.159	
Estimated blood loss (mL)	100.0(80.0–200.0)	100.0(50.0–121.5)	0.001	
R0 resection [n (%)]			0.340	
Yes	159(94.1)	135(96.4)		
No	10(5.9)	5(3.6)		
Conversion to open surgery [n (%)]			0.774	
No	165(97.6)	135(96.4)		
Yes	4(2.4)	5(3.6)		
Retrieved lymph nodes	29.60 ± 12.67	30.51 ± 13.54	0.543	
First flatus day (d)	3.0(3.0–4.0)	3.0(3.0–4.0)	0.189	
Postoperative hospitalized day (d)	8.0(7.0–10.0)	8.0(7.0–10.0)	0.345	
Overall postoperative complication [n (%)]	32(18.9)	35(25.0)	0.198	
Clavien-Dindo grade II				
Anemia	7	8		
Pneumonia	1	1		
Lymphatic leakage	1	0		
Pancreatic fistula	0	1		
Gastroplegia	1	0		
Ileus	2	1		
Anastomotic leakage	0	2		
Venous thrombosis	1	0		
Hypoproteinemia	6	11		
Elevated ALT/AST	1	1		
Atrial fibrillation	0	1		
Frequent ventricular premature beat	0	1		
Electrolyte disturbance	2	1		
Thrombocytopenia	1	0		
Anastomotic hemorrhage	1	2		
Clavien-Dindo grade III				
Anastomotic leakage	5	2		
Anastomotic hemorrhage	0	1		
Pancreatic fistula	1	1		
Pleural effusion	1	1		
Pneumonia	1	0		
Clavien-Dindo grade IV				
Intestinal hernia	0	1		
Anastomotic leakage	1	0		
Clavien-Dindo grade V				
Cardiogenic shock	0	1		
Severe postoperative complication [n (%)]	9(5.3)	7(5.0)	0.898	
ICIs Immune checkpoint inhibitors; LG Laparoscopic gastrectomy; TRAEs Treatment-related adverse events

Across the entire cohort, 30-d overall postoperative complications (POCs) were observed in 67 patients (21.7%), with 32(18.9%) occurring in the SOX-LG group and 35(25.0%) in the SOX + ICIs-LG group, showing no significant difference (P = 0.198). The severe morbidity was also comparable between two groups (5.0% vs. 5.3%, P = 0.898). One patient died because of cardiogenic shock in the SOX + ICIs-LG group which was not related to the neoadjuvant therapy by multidisciplinary discussion.

Meanwhile, a subgroup analysis was carried out to compare outcomes between patients receiving SOX-LG and SOX + ICIs-LG, stratified by the type of resection (laparoscopic proximal gastrectomy, LPG; laparoscopic distal gastrectomy, LDG; laparoscopic total gastrectomy, LTG), as detailed in Supplementary Table 3. We found that patients in the SOX + ICIs-LDG and SOX + ICIs-LTG group had less EBL compared with whom in the SOX-LDG and SOX-LTG groups (P = 0.007, P = 0.032). Postoperative hospitalized day was notably longer in the SOX-LTG group compared with SOX + ICIs-LTG group (P = 0.035). No significant differences were found in the incidence of overall and severe POCs between two groups, regardless of the resection type.

Risk factors of postoperative complications for LG after neoadjuvant therapy

Univariate logistic analysis showed that ages, aCCI grade, EBL, and PNI were strongly associated with POCs for LG after neoadjuvant therapy(P < 0.05) rather than the combination of neoadjuvant ICIs [OR(95%CI): 1.427 (0.829–2.455), P = 0.199]. We put these indexes into multivariate analysis and the results demonstrated that more estimated blood loss [OR(95%CI): 1.003 (1.001–1.005), P = 0.003] and PNI < 40 [OR(95%CI): 2.507 (1.315–4.780), P = 0.005] were independent risk factors for LG after neoadjuvant therapy, which is shown in Table 3.Table 3 Uni- and multivariate logistic analysis for postoperative complications in patients undergoing LG after neoadjuvant therapy

Variables	Univariate analysis	Multivariate analysis	
OR (95% CI)	P value	OR (95% CI)	P value	
Sex		0.481			
Male	1.000				
Female	1.249(0.673–2.318)				
Ages (years old)		0.007		0.565	
 < 60	1.000		1.000		
 ≥ 60	2.269(1.249–4.119)		1.406(0.441–4.481)		
BMI (kg/m2)		0.215			
 < 24	1.000				
 ≥ 24	0.694(0.390–1.236)				
Neoadjuvant ICIs		0.199			
No	1.000				
Yes	1.427(0.829–2.455)				
NRS-2002 score		0.112			
 < 3	1.000				
 ≥ 3	1.553(0.902–2.674)				
ASA grade		0.318			
I–II	1.000				
III	1.476(0.687–3.169)				
aCCI grade		0.010		0.543	
 < 4	1.000		1.000		
 ≥ 4	2.322(1.220–4.419)		1.472(0.423–5.128)		
Operation time(min)		0.489			
 < 220 min	1.000				
 ≥ 220 min	1.219(0.695–2.138)				
Tumor resection		0.577			
Proximal	1.000				
Distal	0.688(0.318–1.486)	0.341			
Total	0.720(0.362–1.434)	0.350			
Estimated blood loss (mL)	1.003(1.001–1.005)	0.001	1.003(1.001–1.005)	0.003	
R0 resection		0.268			
Yes	1.000				
No	1.871(0.617–5.674)				
NLR		0.093			
 < 2.1	1.000				
 ≥ 2.1	1.594(0.925–2.746)				
PLR		0.166			
 < 75	1.000				
 ≥ 75	1.721(0.799–3.706)				
PNI		 < 0.001		0.005	
 ≥ 40	1.000		1.000		
 < 40	2.991(1.615–5.539)		2.507(1.315–4.780)		
SII		0.189			
 < 440	1.000				
 ≥ 440	1.463(0.829–2.580)				
ICIs Immune checkpoint inhibitors; LG Laparoscopic gastrectomy; ASA American Association of Anesthesiologists; BMI Body mass index; aCCI Age-adjusted Charlson Comorbidity Index; NRS-2002 Nutritional risk screening-2002; NLR Neutrophil–lymphocyte ratio; PLR Platelet-lymphocyte ratio; PNI Onodera’s prognostic nutritional index; SII Systemic immune-inflammation; OR Odd ratio; TRAEs Treatment-related adverse events

A case report for LAGC patients who accepted LG after neoadjuvant SOX + ICIs

This patient was an older male with 71 years old and 55.6 of PNI score. The baseline abdominal-enhanced CT indicated that tumor was located at cardia and fundus of the stomach with volume of 7.2 × 5.4 × 3.2 cm, and multiple enlarged lymph nodes were found at hepatogastric space (Fig. 3.1A). No significant distant metastasis was found in the baseline evaluation. The clinical sage was cT4aN3M0. The result of pathological biopsy was moderately differentiated gastric adenocarcinoma. Immunohistochemistry presented PD-L1(CPS score:5), Her-2(1 +), dMMR.Fig. 3 A case report of LAGC patients accepting LG after neoadjuvant SOX plus ICIs. 3.1A–C Abdominal-enhanced CT presented tumor regression in the period of baseline, 2 cycles after neoadjuvant therapy and 4 cycles after neoadjuvant therapy; 3.2A–B Laparoscopic view of tissue exudation and fibrosis during D2 lymphadenectomy caused by neoadjuvant therapy; 3.2C–F Gastric tubular anastomosis after laparoscopic proximal gastrectomy; 3.3A and B The overall and cutaway view of proximal stomach specimen. The red arrow marked the residual tumor bed. ICIs Immune checkpoint inhibitors; LG Laparoscopic gastrectomy

After multidisciplinary discussion, we conducted 4 cycles of neoadjuvant SOX combined with Sintilimab for this patient. The radiological responses were defined as PR when conducted abdominal-enhanced CT after 2 cycles and 4 cycles of NICT (Fig. 3.1B, 1C). The TRAEs was nausea with grade I and thrombocytopenia with grade II during NICT. 4 weeks after last NICT periods, we performed laparoscopic proximal gastrectomy with D2 lymphadenectomy and gastric tubular reconstruction (Fig. 3.2A–E). We used gauze and suction device to handle the perigastric tissue fibrosis and exudative edema caused by NICT (Fig. 3.2A–2B). The operation time was 215 min and EBL was 30 mL. The overall and cutaway view of proximal stomach specimen are shown in Fig. 3.3A, 3B. The red arrow marked the residual tumor bed. Postoperative pathological results showed that no residual tumor and metastatic lymph nodes (0/31) existed with ypTNM stage T0N0M0(TRG1a).

No POC was found 30-d after surgery. This patient has finished all-cycle perioperative treatment (8 cycles of perioperative SOX + sintilimab and sintilimab continuously until 1 year after gastrectomy. No tumor recurrence was observed during the 24 months follow-up after surgery.

Discussion

In this study, we compared the short-term efficacy of LG after neoadjuvant SOX plus ICIs and SOX alone for LAGC patients Our investigation focused on evaluating tumor response, treatment-related adverse events (TRAEs), surgical perioperative safety, and identifying potential risk factors for postoperative complications (POCs) following neoadjuvant therapy. The study revealed that the pCR, MPR, and ORR in the SOX + ICIs-LG group were significantly higher than those in the SOX-LG group. It was comparable in TRAEs, postoperative recovery, and incidence of POCs between two groups. Further analysis also found that more EBL and PNI < 40 were independent risk factors of POCs for LG after neoadjuvant therapy.

Tumor radiological and pathological regression contributed to evaluating the anticancer effect of neoadjuvant therapy and deciding on the appropriate timing of treatment cycles and surgery. Previous studies have indicated that the rates of pCR and MPR in LAGC patients undergoing neoadjuvant SOX therapy ranged from 4.0% to 5.6%, and 22.7% to 32.4%, respectively [4, 5, 18]. The combination of SOX and ICIs might elevate therapeutic effect for LAGC because of the hypothesis that the chemotherapy may stimulate the innate immune response, leading to increased antigen presentation, upregulation of PD-L1 during treatment, infiltration of T-cells, and ultimately a synergistic anticancer effect combined with ICIs [19]. Our findings appear to validate this hypothesis, as the group receiving neoadjuvant SOX + ICIs demonstrated higher ORR, pCR and MPR compared to those receiving neoadjuvant SOX alone (63.6% vs. 46.7%, P = 0.003; 17.9% vs. 9.5%, P = 0.030; 43.6% vs. 31.4%, P = 0.001), indicating a superior tumor response of neoadjuvant SOX + ICIs. Further investigation is warranted to determine whether a high proportion of tumor regression can translate into long-term survival benefits or not for further studies [20].

Total neoadjuvant therapy (TNT), which refers to all oncological treatment delivered before surgery, has shown potential to improve complete rate of treatment cycles and oncological outcomes for patients with gastrointestinal tumors, particularly those with rectal cancer [21]. This study revealed a notably higher percentage of patients receiving more than four neoadjuvant cycles in the SOX + ICIs-LG group, suggesting a trend among surgeons to extend the duration of neoadjuvant therapy under the premise of treatment safety to enhance the completion rate of perioperative treatment cycles and achieve surgical R0 resection [22]. However, some inherent issues still need to be further addressed for LAGC patients after NICT through large-scale randomized control trials, including optimal cycles of total NICT, time limit of ICIs after gastrectomy, quality of life during treatment, surgical safety, and oncological benefits.

LG has gained significant recognition for its effectiveness in treating LAGC due to its less surgical incision, faster postoperative recovery, and acceptable long-term survival proved by previous studies [23]. Nonetheless, whether LG after NICT could be applied safely was still in the preliminary stages. Su et al. demonstrated that LG after NICT was safely conducted compared to LG following neoadjuvant chemotherapy in intraoperative bleeding, operation time, and postoperative recovery [24]. A previous exploratory study also suggested that safety and feasibility of NICT were comparable to those of neoadjuvant chemotherapy in patients undergoing minimally invasive gastrectomy for LAGC [25]. In this multi-institutional cohort, it was observed that patients in both the SOX-LG and SOX + ICIs-LG groups exhibited comparable overall and severe POCs rates (18.9% vs. 25.0%, P = 0.198; 5.3% vs. 5.0%, P = 0.898). Subgroup analysis based on different resection types did not reveal a significant disparity in the occurrence of overall and severe postoperative complications between the two groups. Therefore, LG could be served as an alternative surgical approach due to its favorable short-term efficacy.

Intracorporeal blood loss has been identified as the independent risk factor for POCs after gastrectomy. The utilization of LG has been shown to reduce the blood loss because of its precise operation and magnified view. A recent meta-analysis revealed that LG resulted in less blood loss compared with open gastrectomy [26]. Zhang C et al. showed the benefits of reduced blood loss in patients undergoing LG following neoadjuvant chemotherapy [27]. Our research identified increased estimated blood loss (EBL) as an independent risk factor for POCs in LG patients following neoadjuvant therapy. Additionally, we observed a noteworthy trend where the SOX + ICIs-LG group experienced lower EBL compared to the SOX-LG group, consistent with findings from Cheng’s study [28]. This observation may be attributed to a higher proportion of tumor regression brought by neoadjuvant SOX + ICIs reduced the surgical difficulty of tumor radical resection and D2 lymphadenectomy, which offset unnecessary blood loss caused by neoadjuvant therapy.

The present finding also indicated that a lower PNI was the independent risk factors of POCs for LG patients after neoadjuvant therapy. PNI was commonly recognized as a significant indicator for predicting tumor response, POCs, long-term survival, among other outcomes [29, 30]. A reduced PNI typically signified compromised physical immunity and nutritional status, particularly in LAGC patients undergoing neoadjuvant therapy, which might elevate the likelihood of POCs. Even though the incidence of TRAEs during neoadjuvant therapy was acceptable, it was imperative to optimize the patient’s physical condition and conduct a thorough preoperative assessment at the appropriate timing before surgery to reduce the risk of POCs [31].

Some limitations must be acknowledged in this study. Firstly, some potential bias still exist despite the baseline characteristics were comparable between two groups in this multi-institutional study. Secondly, the category of ICIs was not unified because of the limitation of sample size. Thirdly, long-term outcomes were not presented in this study due to the short follow-up period. Fourthly, real-world results may be constrained by strict inclusion and exclusion criteria because some LAGC patients who were unable to undergo LG or lose to follow-up due to the TRAEs and tumor progression were excluded in this study. Despite of these limitations, our results are still helpful for further studies to explore the short and long-term outcomes with LAGC patients who accepting LG after NICT.

Conclusion

Overall, this is the first attempt to compare the short-term efficacy of LG after neoadjuvant SOX + ICIs versus SOX alone for LAGC patients to the best of our knowledge. We found that neoadjuvant SOX + ICIs brings better radiological and pathological response compared with neoadjuvant SOX alone for LAGC. SOX + ICIs-LG is safely to conduct with promising efficacy compared to SOX-LG. For patients with more EBL and preoperative PNI < 40, surgeons need to focus on the perioperative management to reduce POCs risk.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 14 KB)

Supplementary file2 (DOCX 17 KB)

Supplementary file3 (DOCX 19 KB)

Abbreviations

aCCI Age-adjusted Charlson Comorbidity Index

ASA American Association of Anesthesiologists

BMI Body mass index

BSA Body surface area

CR Complete response

DCR Disease control rate

EBL Estimated blood loss

GC Gastric cancer

ICIs Immune checkpoint inhibitors

LAGC Locally advanced gastric cancer

LDG Laparoscopic distal gastrectomy

LG Laparoscopic gastrectomy

LPG Laparoscopic proximal gastrectomy

LTG Laparoscopic total gastrectomy

M(IQR) Median (interquartile range)

MPR Major pathological response

NICT Neoadjuvant immunotherapy combined with chemotherapy

NLR Neutrophil–lymphocyte ratio

NRS-2002 Nutritional risk screening-2002

ORR Objective response rate

pCR Pathological complete response

PD Progressive disease

PLR Platelet-lymphocyte ratio

PNI Onodera’s prognostic nutritional index

POCs Postoperative complications

PR Partial response

SD Stable disease

SII Systemic immune-inflammation

TRAEs Treatment-related adverse events

TRG Tumor regression grade

Author contribution

H.C. conducted data acquisition and analysis, drafted the manuscript, and contributed to the study designs. Y.P.Y., L.Q.S., Z.Y., L.D.S., J.J.D., N.N., and Y.Y.L. collected the data and assisted in the data analysis. B.W., L.C., Y.S., and J.X.C. designed and supervised this project. B.W. provided support of fundings. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by the National Natural Science Foundation of China (82073192, 82273231, 62133010) and the Beijing Science and Technology Program (Z221100007422125).

Data availability

The manuscript has been read and approved by all the authors, that the requirements for authorship as stated earlier in this document have been met, and that each author believes that the manuscript represents honest work. All datasets generated for this study are included in the article and available from corresponding authors upon reasonable request.

Declarations

Conflicts of interest

The authors declares that there is no conflicts of interest.

Ethical approval

This study was approved by the ethics committee of the Chinese PLA general hospital (No.S2024-343-01) and performed in line with the principles of the Declaration of Helsinki.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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