Surgical safety and efficacy of neoadjuvant immunotherapy plus apatinib and chemotherapy in locally advanced gastric cancer

Table 1 Baseline characteristics and neoadjuvant therapy, median (interquartile range)/n (%)

Variable	PAC group (n = 92)	PC group (n = 200)	Statistic	P value
Age, years	64 (56-69)	63 (55-67)	-1.557	0.119
Sex			0.021	0.885
Female	20 (21.7)	45 (22.5)
Male	72 (78.3)	155 (77.5)
BMI, kg/m2	22.7 (20.7-25.1)	23.4 (21.7-25.6)	-1.860	0.063
ASA score			0.256	0.613
1-2	12 (13.0)	22 (11.0)
≥ 3	80 (87.0)	178 (89.0)
ECOG performance status score			0.940	0.332
0-1	86 (93.5)	180 (90.0)
2	6 (6.5)	20 (10.0)
NRS 2002 score			0.589	0.443
< 3	68 (73.9)	156 (78.0)
≥ 3	24 (26.1)	44 (22.0)
cT stage			3.049	0.218
T3	29 (31.5)	44 (22.0)
T4a	43 (46.7)	106 (53.0)
T4b	20 (21.7)	50 (25.0)
cN stage			0.233	0.629
N0-1	30 (32.6)	71 (35.5)
N2-3	62 (67.4)	129 (64.5)
cTNM stage			0.886	0.642
II	21 (22.8)	37 (18.5)
III	51 (55.4)	113 (56.5)
IV	20 (21.7)	50 (25.0)
Tumor location			2.317	0.314
Upper third	29 (31.5)	62 (31.0)
Middle third	34 (37.0)	90 (45.0)
Lower third	29 (31.5)	48 (24.0)
Tumor histological differentiation			2.739	0.254
Well	14 (15.2)	41 (20.5)
Moderate	34 (37.0)	83 (41.5)
Poor	44 (47.8)	76 (38.0)
Tumor pathological type			0.090	0.764
Adenocarcinoma	86 (93.5)	185 (92.5)
Signet ring cell carcinoma	6 (6.5)	15 (7.5)
Lauren type			1.191	0.755
Intestinal	21 (22.8)	48 (24.0)
Mixed	32 (34.8)	78 (39.0)
Diffused	28 (30.4)	49 (24.5)
Indeterminate	11 (12.0)	25 (12.5)
Bormann type			3.400	0.334
I	2 (2.2)	14 (7.0)
II	69 (75.0)	149 (74.5)
III	14 (15.2)	23 (11.5)
IV	7 (7.6)	14 (7.0)
HER-2 positive	8 (8.7)	29 (14.5)	1.919	0.166
dMMR	8 (8.7)	7 (3.5)		0.085
Ki-67 expression rate, %	60 (40-70)	60 (30-70)	-1.074	0.283
Lymphovascular invasion	34 (37.4)	84 (42.0)	0.558	0.455
Perineural invasion	22 (24.2)	68 (34.2)	2.915	0.088
Preoperative therapy cycles	3 (2-4)	3 (2-4)	-0.771	0.441
Treatment-related adverse events	24 (26.1)	40 (20.0)	1.364	0.243

Percentages may not sum to 100% due to rounding. PAC: Programmed cell death protein-1 inhibitors plus apatinib and chemotherapy; PC: Preoperative chemotherapy; ASA: American Society Anesthesiologists; BMI: Body mass index; ECOG: Eastern Cooperative Oncology Group; NRS: Nutritional Risk Screening; HER-2: Human epidermal growth factor receptor-2; dMMR: Mismatch repair deficiency; TNM: Tumor node metastasis.

Table 2 Tumor regression responses, median (interquartile range)/n (%)

Variable	PAC group (n = 92)	PC group (n = 200)	Statistic	P value
ycT stage			8.782	0.003
T0-2	25 (27.2)	26 (13.0)
T3-4	67 (72.8)	174 (87.0)
ycN stage			4.556	0.033
N0-1	61 (66.3)	106 (53.0)
N2-3	31 (33.7)	94 (47.0)
ycTNM stage			9.815	0.007
I	20 (21.7)	26 (13.0)
II	40 (43.5)	66 (33.0)
III	32 (34.8)	108 (54.0)
Clinical response			15.081	0.002
Complete response	42 (45.7)	55 (27.5)
Partial response	25 (27.2)	58 (29.0)
Stable disease	21 (22.8)	51 (25.5)
Progression disease	4 (4.3)	36 (18.0)
Objective response	67 (72.8)	113 (56.5)	7.104	0.008
Disease control	88 (95.7)	164 (82.0)	9.934	0.002
T downstage (yes)	85 (92.4)	152 (76.0)	11.074	0.001
Pathological response			28.541	< 0.001
TRG 1a	26 (28.3)	13 (6.5)
TRG 1b	16 (17.4)	42 (21.0)
TRG 2	26 (28.3)	55 (27.5)
TRG 3	24 (26.1)	90 (45.0)
Pathological complete response	26 (28.3)	13 (6.5)	25.785	< 0.001
Major pathological response	42 (45.7)	55 (27.5)	9.359	0.002
Number of positive lymph nodes	0 (0-4)	2 (0-8)	-2.879	0.004
Lymph node metastasis rate, %	0 (0-14)	7 (0-33)	-3.010	0.003
Tumor long diameter, cm	3.0 (2.0-5.0)	4.0 (3.0-6.5)	-3.344	0.001
ypT stage				< 0.001
0	28 (30.4)	14 (7.0)
1a	4 (4.3)	10 (5.0)
1b	7 (7.6)	16 (8.0)
2	11 (12.0)	26 (13.0)
3	31 (33.7)	77 (38.5)
4a	8 (8.7)	38 (19.0)
4b	3 (3.3)	19 (9.5)
ypN stage			10.754	0.029
0	49 (53.3)	72 (36.0)
1	12 (13.0)	37 (18.5)
2	16 (17.4)	37 (18.5)
3a	12 (13.0)	31 (15.5)
3b	3 (3.3)	23 (11.5)
ypTNM stage			13.855	0.001
I	42 (45.7)	48 (24.0)
II	19 (20.7)	58 (29.0)
III	31 (33.7)	94 (47.0)

Percentages may not sum to 100% due to rounding. PAC: Programmed cell death protein-1 inhibitors plus apatinib and chemotherapy; PC: Preoperative chemotherapy; TNM: Tumor node metastasis; TRG: Tumor regression grade.

Table 3 Surgical outcomes, median (interquartile range)/n (%)

Variable	PAC group (n = 92)	PC group (n = 200)	Statistic	P value
Surgical approach			12.922	< 0.001
Laparoscopic gastrectomy	64 (69.6)	94 (47.0)
Open gastrectomy	28 (30.4)	106 (53.0)
ICG-guided laparoscopic surgery (yes)1	28/64 (43.8)	35/94 (37.2)	0.674	0.412
Resection range				0.808
Proximal gastrectomy	5 (5.4)	10 (5.0)
Distal gastrectomy	27 (29.3)	52 (26.0)
Total gastrectomy	60 (65.2)	138 (69.0)
Reconstruction approach				0.194
Billroth-I	1 (1.1)	11 (5.5)
Billroth-II and Braun anastomosis	25 (27.2)	43 (21.5)
Roux-en-Y anastomosis	61 (66.3)	139 (69.5)
Tubular gastrogastric anastomosis	5 (5.4)	7 (3.5)
Operative time, minutes	228 (180-279)	220 (180-264)	-0.844	0.399
Conversion to open laparotomy (yes)1	7/64 (10.9)	9/94 (9.6)	0.078	0.780
Intraoperative blood loss, mL	100 (100-150)	100 (80-100)	-4.398	< 0.001
Intraoperative blood transfusion (yes)	10 (10.9)	24 (12.0)	0.078	0.780
Multiorgan excision (yes)	9 (9.8)	16 (8.0)	0.256	0.613
R0 resection (yes)	85 (92.4)	182 (91.0)	0.156	0.693
Proximal margin, cm	3.5 (2.0-5.2)	2.5 (1.5-4.0)	-2.672	0.008
Distal margin, cm	5.7 (2.8-8.8)	5.2 (3.0-8.9)	-0.167	0.867
Number of lymph nodes dissected	26 (22-32)	25 (21-31)	-0.636	0.525

¹Denominators are the number of patients who underwent laparoscopic surgery in each group (programmed cell death protein-1 inhibitors plus apatinib and chemotherapy: n = 64; preoperative chemotherapy: n = 94).

Percentages may not sum to 100% due to rounding. ICG: Indocyanine green; PAC: Programmed cell death protein-1 inhibitors plus apatinib and chemotherapy; PC: Preoperative chemotherapy.

Table 4 Postoperative complications and recovery, median (interquartile range)/n (%)

Variable	PAC group (n = 92)	PC group (n = 200)	Statistic	P value
Postoperative complication	22 (23.9)	56 (28.0)	0.538	0.463
Anastomotic leakage	1 (1.1)	0 (0.0)		0.315
Duodenal stump leakage	1 (1.1)	1 (0.5)		0.532
Pancreatic fistula	0 (0.0)	3 (1.5)		0.554
Intra-abdominal hemorrhage	5 (5.4)	7 (3.5)		0.527
Gastrointestinal bleeding	0 (0.0)	1 (0.5)		1.000
Delayed gastric emptying	0 (0.0)	5 (2.5)		0.330
Ileus	1 (1.1)	3 (1.5)		1.000
Pneumonia	11 (12.0)	29 (14.5)	0.345	0.557
Respiratory failure	1 (1.1)	1 (0.5)		0.532
Arrhythmia	2 (2.2)	6 (3.0)		1.000
Heart failure	1 (1.1)	2 (1.0)		1.000
Muscular calf vein thrombosis	3 (3.3)	7 (3.5)		1.000
Moderate anemia	2 (2.2)	5 (2.5)		1.000
Cholecystitis	0 (0.0)	1 (0.5)		1.000
Intestinal flora imbalance	2 (2.2)	3 (1.5)		0.652
Clavien-Dindo classification				0.321
Grade 0	70 (76.1)	144 (72.0)
Grade I	8 (8.7)	16 (8.0)
Grade II	5 (5.4)	26 (13.0)
Grade III	7 (7.6)	11 (5.5)
Grade IV-V	2 (2.2)	3 (1.5)
Major complications (grade ≥ III)	9 (9.8)	14 (7.0)	0.672	0.412
Postoperative hospital stays, days	9 (8-10)	9 (8-11)	-1.127	0.260
Time to first, days
Aerofluxus	3 (2-3)	3 (2-3)	-1.013	0.311
Defecation	4 (4-5)	4 (3-5)	-1.457	0.145
Enteral nutrition	3 (3-3)	3 (3-3)	-0.115	0.908
Liquid food	7 (6-7)	7 (6-8)	-0.005	0.996
Removal of nasogastric tube	6 (5-6)	6 (5-6)	-0.295	0.768
Removal of abdominal drainage tube	9 (8-9)	9 (7-9)	-1.920	0.055
Postoperative visual analog scale
Day 1	4 (4-5)	4 (4-5)	-0.428	0.669
Day 2	2 (2-3)	3 (2-3)	-1.326	0.185
Day 3	2 (2-3)	2 (2-3)	-0.285	0.776
Day 5	0 (0-1)	1 (0-1)	-1.861	0.063

PAC: Programmed cell death protein-1 inhibitors plus apatinib and chemotherapy; PC: Preoperative chemotherapy.

Table 5 Impact of indocyanine green fluorescence guidance on perioperative outcomes in the programmed cell death protein-1 inhibitors plus apatinib and chemotherapy group, median (interquartile range)/n (%)

Variable	ICG group (n = 28)	Non-ICG group (n = 36)	Statistic	P value
Age, years	63 (56-70)	61 (56-68)	-1.084	0.279
BMI, kg/m2	24.3 (22.7-25.5)	22.5 (20.6-24.7)	-1.901	0.057
Tumor location			4.248	0.120
Upper third	5 (17.9)	15 (41.7)
Middle third	12 (42.9)	10 (27.8)
Lower third	11 (39.3)	11 (30.6)
Tumor long diameter, cm	3.0 (2.0-4.6)	2.5 (2.0-5.0)	0.859	0.391
Resection range				0.576
Proximal gastrectomy	1 (3.6)	4 (11.1)
Distal gastrectomy	9 (32.1)	10 (27.8)
Total gastrectomy	18 (64.3)	22 (61.1)
Operative time, minutes	278 (208-300)	236 (215-277)	1.225	0.223
Intraoperative blood loss, mL	100 (95-143)	100 (80-120)	0.690	0.481
Intraoperative blood transfusion (yes), %	4 (14.3)	3 (8.3)		0.689
Multiorgan excision (yes), %	1 (3.6)	6 (16.7)		0.125
Conversion to open laparotomy (yes)	0 (0)	7 (19.4)		0.015
R0 resection (yes), %	26 (92.9)	34 (94.4)		1.000
Number of lymph nodes dissected	32 (24-33)	24 (21-26)	2.856	0.004
Proximal margin, cm	4.0 (2.1-5.2)	3.5 (2.0-5.1)	0.189	0.855
Distal margin, cm	5.7 (2.9-7.6)	6.2 (2.9-8.8)	-0.724	0.473
Postoperative complication (yes), %	6 (21.4)	8 (22.2)	0.000	0.939
Major complications (grade ≥ III)	3 (10.7)	3 (8.3)		1.000
Postoperative hospital stays, days	9 (8-9)	9 (8-10)	-0.778	0.423
Time to first, days
Aerofluxus	3 (2-3)	3 (2-3)	-0.007	1.000
Defecation	4 (3-5)	4 (4-5)	0.020	0.989
Enteral nutrition	3 (3-3)	3 (3-3)	-0.409	0.682
Liquid food	7 (6-7)	7 (6-7)	0.196	0.839
Removal of nasogastric tube	5 (5-6)	5 (5-6)	-0.097	0.923
Removal of abdominal drainage tube	9 (8-9)	9 (8-9)	0.717	0.431
Postoperative visual analog scale
Day 1	5 (4-5)	4 (4-5)	0.474	0.625
Day 2	2 (2-3)	3 (2-3)	-0.731	0.431
Day 3	2 (2-3)	3 (2-3)	-1.759	0.043
Day 5	0 (0-1)	0 (0-1)	0.068	0.944

BMI: Body mass index; ICG: Indocyanine green.