Docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT) as preoperative and postoperative chemotherapy compared with surgery followed by chemotherapy for patients with locally advanced gastric cancer: a propensity score-based analysis

Figures & data

Table 1 Demographic and clinical characteristics before and after PSM analysis

Variables	Before PSM (n=316)		P-value	After PSM (n=82)		P-value
	Surgery-first n=269	FLOT-first n=47		Surgery-first n=41	FLOT-first n=41
	n (%)	n (%)		n (%)	n (%)
Age (years)			0.9			1
<60	152 (56.5)	27 (57.4)		24 (58.5)	23 (56.1)
≥60	117 (43.5)	20 (42.6)		17 (41.5)	18 (43.9)
Gender			0.28			1
Male	196 (72.9)	38 (80.9)		32 (78)	33 (80.5)
Female	73 (27.1)	9 (19.1)		9 (22)	8 (19.5)
Lauren classification			0.8			0.36
Intestinal	118 (43.9)	20 (42.6)		18 (43.9)	15 (36.6)
Diffuse	85 (31.6)	17 (36.2)		10 (24.4)	16 (39)
Mixed	66 (24.5)	10 (21.3)		13 (31.7)	10 (24.4)
Tumor location			0.34			0.87
Upper third	65 (24.4)	13 (27.7)		12 (29.3)	10 (24.4)
Middle third	116 (43.6)	24 (51.1)		19 (46.3)	21 (51.2)
Lower third	85 (32.0)	10 (21.3)		10 (24.4)	10 (24.4)
Clinical TNM stage			0.01			1
II	119 (44.2)	11 (23.4)		11 (26.8)	11 (26.8)
III	150 (55.8)	36 (76.6)		30 (73.2)	30 (73.2)
Diagnose time			0.001			1
2013~2014	100 (37.2)	7 (14.9)		7 (17.1)	7 (17.1)
2015~2016	132 (49.1)	17 (36.2)		17 (41.5)	17 (41.5)
2017	37 (13.8)	23 (48.9)		17 (41.5)	17 (41.5)

Abbreviations: PSM, propensity matched; FLOT, docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil.

Table 2 Overall survival for FLOT-first versus surgery-first in patients with locally advanced gastric cancer

Year	Unmatched (%)		PSM (%)		IPTW (%)
	FLOT	Surgery	FLOT	Surgery	FLOT	Surgery
1	85.8	70.8	84.4	66.8	91.5	70.5
2	69.0	48.1	67.5	37.1	74.6	46.7
3	60.1	36.5	58.7	30.9	68.6	35.4
4	43.8	29.8	42.8	23.2	50.6	28.9
5	43.8	26.8	–	–	–	26.0

Abbreviations: FLOT, docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil; PSM, propensity score – matched; IPTW, inverse probability of treatment weighting.

Table 3 Univariate and multivariate analysis of survival in PSM analysis (n=82)

Variables	Univariate analysis		P-value	Multivariate analysis		P-value
	HR	95% CI		HR	95% CI
Treatment			0.011			0.008
FLOT-first	0.434	0.228~0.826		0.416	0.218~0.794
Surgery-first	1			1
Age (years)			0.103
<60	1
≥60	1.699	0.899~3.209
Gender			0.161
Male	1
Female	1.625	0.824~3.205
Lauren classification			0.648
Intestinal	1
Diffuse	1.386	0.651~2.953
Mixed	1.332	0.620~2.859
Tumor location			0.674
Upper third	1
Middle third	1.147	0.485~2.709
Lower third	1.481	0.578~3.79
Clinical TNM stage			0.044			0.032
II	1			1
III	2.241	1.021–4.916		2.378	1.076~5.265
Diagnose time			0.305
2013~2014	1
2015~2016	0.476	0.175~1.29
2017	0.641	0.303~1.356
Postoperative chemotherapy			0.122
FLOT	1
FOLFOX6	1.194	0.36~3.964
XELOX	2.769	0.369~20.76
SOX	2.324	1.13~4.778
Style of operation			0.095
Total gastrectomy	1
Subtotal gastrectomy	1.292	0.66~2.53
Distal gastrectomy	0.435	0.158~1.201

Notes: Adjusted HR (95%) was adjusted by age, gender, Lauren classification, tumor location, clinical TNM stage, diagnose time, postoperative chemotherapy, and style of operation. Variables that had no significant differences in univariate analysis were not included in the multivariate analysis.

Abbreviations: PSM, propensity matched; FLOT, docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil; FOLFOX6, oxaliplatin, leucovorin and 5-fluorouracil.

Figure 1 Overall survival in (A) the unmatched, (B) the propensity score-matched analysis, (C) the inverse probability of treatment weight-adjusted analysis according to the different initial treatments in patients with clinical T3–4 locally advanced gastric cancer.

Abbreviation: FLOT, docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil.

Figure 2 Subgroup analysis in the propensity score-matched analysis.

Abbreviation: FLOT, docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil.

Table 4 Tumor response according to RECIST 1.1 criteria

Tumor response	Number of patients	%	95% CI
CR	1	2.1
PR	20	42.6
CR+PR	21	44.7	30.5–58.9
SD	21	44.7
PD	3	6.4
NE	2	4.2

Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progression of disease; NE, not evaluable.

Table 5 Postoperative pathology report

Variables	Before PSM		P-value	After PSM		P-value
	FLOT-first n=47	Surgery-first N=269		FLOT-first n=41	Surgery-first N=41
	n (%)	n (%)		n (%)	n (%)
R0 resection			0.729			0.737
Yes	38 (88.4)	223 (86.4)		33 (89.2)	33 (84.6)
No	5 (11.6)	35 (13.6)		4 (10.8)	6 (15.4)
Missing	4	11		4	2
pT			0.094			0.491
T0	1 (2.3)	–		1 (2.7)	0
T2	1 (2.3)	7 (2.7)		1 (2.7)	2 (5.1)
T3	13 (30.2)	68 (26.4)		12 (32.4)	8 (20.5)
T4	28 (65.1)	183 (70.9)		23 (62.2)	29 (74.4)
Missing	4	11		4	2
pN			0.122			0.006
N0	17 (39.5)	66 (25.6)		15 (40.5)	3 (7.7)
N1	10 (23.3)	48 (18.6)		7 (18.9)	7 (18.9)
N2	7 (16.3)	50 (19.4)		7 (18.9)	12 (30.8)
N3	9 (20.9)	94 (36.4)		8 (21.6)	17 (43.6)
Missing	4	11		4	2
Major surgical complications^a			0.831			0.519
Yes	8 (17)	41 (16)		4 (9.8)	7 (17.1)
No	39 (83)	215 (84)		37 (90.2)	34 (82.9)
Missing	-	13		-	-

Note: ^aGrade 3–5 Clavien‒Dindo classification.

Abbreviations: FLOT, docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil; PSM, propensity matched; pT, pathological tumor invasion; pN, pathological lymph node metastasis; N, number.

Table S1 Univariate and multivariate analysis of survival before PSM analysis (n=313)

Variables	Univariate analysis		P-value	Multivariate analysis		P-value
	HR	95% CI		HR	95% CI
Treatment			0.016			0.004
FLOT-first	0.522	0.307~0.886		0.417	0.23~0.755
Surgery-first	1			1
Age			0.802
<60	1
≥60	1.039	0.768~1.406
Gender			0.928
Male	1
Female	1.016	0.726~1.422
Lauren classification			0.022			0.109
Intestinal	1			1
Diffuse	1.619	1.147~2.286		1.412	0.997~1.999
Mixed	1.187	0.801!1.759		1.022	0.685~1.524
Tumor location			0.426
Upper third	1
Middle third	1.046	0.703~1.557
Lower third	1.277	0.843~1.933
Clinical TNM stage			<0.001			<0.001
II	1			1
III	2.878	2.047~4.044		3.122	2.197~4.438
Diagnose time			0.357
2013~2014	1
2015~2016	0.848	0.615~1.170
2017	0.698	0.393~1.240
Postoperative chemotherapy			0.049			0.21
FLOT	1			1
FOLFOX6	1.235	0.83~1.838		0.904	0.581~1.405
XELOX	1.662	1.082~2.554		0.751	0.48~1.178
SOX	1.614	1.072~2.429		1.235	0.766~1.99
Style of operation			0.062
Total gastrectomy	1
Subtotal gastrectomy	1.241	0.898~1.715
Distal gastrectomy	0.714	0.437~1.168

Notes: Adjusted HR (95%) was adjusted by age, gender, Lauren classification, tumor location, clinical TNM stage, diagnose time, postoperative chemotherapy, and style of operation. Variables that had no significant differences in univariate analysis were not included in the multivariate analysis. Three patients were excluded from the analysis because they died within 1 month after surgery and they did not receive postoperative chemotherapy.

Abbreviations: PSM, propensity matched; FLOT, docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil; FOLFOX6, oxaliplatin, leucovorin, and 5-fluorouracil.

Table S2 Univariate and multivariate analysis of survival in patients received preoperative FLOT chemotherapy (n=45)

Variables	Univariate analysis		P-value	Multivariate analysis		P-value
	HR	95% CI		HR	95% CI
Age (years)			0.809
<60	1
≥60	1.152	0.367~3.619
Gender			0.02			0.01
Male	1			1
Female	3.83	1.236~11,866		6.322	1.75–22.91
Lauren classification			0.167
Intestinal	1
Diffuse	2.773	0.801~9.601
Mixed	0.864	0.158~4.729
Tumor location			0.866
Upper third	1
Middle third	1.272	0.255~6.348
Lower third	1.595	0.276~9.212
Clinical TNM stage			0.516
II	1
III	1.538	0.419~5.643
Diagnose time			0.793
2013~2014	1
2015~2016	0.767	0.195~3.02
2017	1.256	0.243~6.502
Style of operation			0.412
Total gastrectomy	1
Subtotal gastrectomy	1.079	0.346~3.362
Distal gastrectomy	0.44	0.109~1.776
Response			0.009			0.005
CR+PR	1			1
SD+PD	5.655	1.251–25.58		8.21	1.66–40.56

Notes: Adjusted HR (95%) was adjusted by age, gender, Lauren classification, tumor location, clinical TNM stage, diagnose time, style of operation, and response. Variables that had no significant differences in univariate analysis were not included in the multivariate analysis. Two patients lost the data of response and were excluded from the analysis.

Abbreviations: FLOT, docetaxel, oxaliplatin, leucovorin, and 5-Fluorouracilf; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.