The prognostic value of cyclooxygenase-2 expression in patients with esophageal cancer: evidence from a meta-analysis

Figures & data

Figure 1 Flow diagram of studies selection procedure.

Abbreviation: IHC, immunohistochemistry.

Table 1 Main characteristics of all studies included in the meta-analysis

Author, year	Race (country)	No of patients	Stage	Histology	Antibody source (dilution)	Cutoff value	High COX-2 (%)	Treatment	Clinicopathological parameters	Survival
Shamma et al,^Citation24 2000	Asian (Japan)	45	I–IV	ESCC	Gunma	Score =1.8	25	Surgery	H, T, N, S	No
Kawabe et al,^Citation22 2002	Asian (Japan)	175	I–IV	ESCC	Cayman	Score ≤5	86.9	Surgery	H, T, N, M, S	Yes
Buskens et al,^Citation14 2002	Caucasian (the Netherlands)	145	I–IV	EADC	Cayman (1:200)	Score =1	79.3	Surgery	H, T, N, M, S	Yes
Kuo et al,^Citation23 2003	Asian (Japan)	96	I–IV	ESCC	Oxford Biomedical Research (1:100)	0.1	49	Surgery + CRT	H, T, N, M, S	Yes
Kase et al,^Citation31 2004	Asian (Japan)	80	NR	ESCC	Cayman (1:100)	0.5	58.6	Surgery	H, T, N	No
France et al,^Citation17 2004	Caucasian (Australia)	20	NR	EADC	Cayman (1:900)	Score =2	65	Surgery	T, N	Yes
Sivula et al,^Citation32 2005	Caucasian (Finland)	81	I–IV	ESCC	Cayman (1:200)	Score =1	26.5	Surgery + CHT	H, T, N, M, S	Yes
Heeren et al,^Citation15 2005	Caucasian (the Netherlands)	130	NR	ESCC, EADC	Santa Cruz (1:50)	Score =2	66.9	Surgery	T, N	Yes
Xi et al,^Citation20 2005	Caucasian (Germany)	46	I–III	ESCC, EADC	Dako	0.35	17.4	Surgery + CRT, CHT	NR	Yes
Nozoe et al,^Citation9 2005	Asian (Japan)	76	I–III	ESCC	Transduction (1:100)	0.5	36.8	Surgery	H, T, N, S	Yes
Okawa et al,^Citation10 2005	Asian (Japan)	77	I–IV	ESCC	Histofine	0.1	68.8	Surgery	H, T, N, M, S	Yes
Yang et al,^Citation33 2005	Asian (Japan)	69	I–III	ESCC	Maixin-Bio	0.1	44.9	Surgery	H, S	No
Liu et al,^Citation11 2006	Asian (China)	138	I–III	ESCC	Cayman (1:60)	0.1	56	Surgery	NR	Yes
Miyashita et al,^Citation34 2006	Asian (Japan)	48	I–IV	ESCC	Immuno-Biological Laboratory (1:100)	0.1	64.6	Surgery	H, T, N	No
Bhandari et al,^Citation8 2006	Caucasian (UK)	90	I–IV	EADC	Cayman	Score =200	50	Surgery	NR	Yes
Hashimoto et al,^Citation13 2007	Asian (Japan)	68	I–IV	ESCC	Transduction (1:100)	0.2	60	Surgery	H, T, N, S	Yes
Takatori et al,^Citation6 2008	Asian (Japan)	228	I–IV	ESCC	Santa Cruz (1:200)	Score =1	90.8	Surgery + CRT, CHT	H, T, N, M, S	Yes
Huang et al,^Citation18 2008	Asian (China)	112	I–IV	ESCC	Novocastra	Score =8	50.5	Surgery + CRT, CRT	NR	Yes
Liu et al,^Citation19 2010	Asian (China)	69	NR	ESCC	Beijing Zhongshan Biotechnology (1:200)	0.3	63.8	Surgery	H, T, N	Yes
Yoon et al,^Citation12 2011	Asian (Korea)	44	I–III	ESCC	Dako (1:00)	Score =3	38.6	Surgery + CRT, CRT	T, N, S	Yes
Huang et al,^Citation16 2012	Asian (China)	78	I–IV	ESCC	Maixin-Bio	Score =3	55.1	Surgery, surgery + CRT/CHT	S	Yes
Prins et al,^Citation7 2012	Caucasian (the Netherlands)	147	I–III	EADC	Clone CX229 (1:100)	Score =3	26.5	Surgery	H, T, N, M, S	Yes
Yang et al,^Citation21 2013	Asian (China)	90	I–III	ESCC	BD (1:50)	0.5	42.2	Surgery	NR	Yes
Chen et al,^Citation35 2015	Asian (China)	195	I–III	ESCC, EADC	Maixin-Bio	Score =4	69.7	Surgery	H, S	Yes
Hu et al,^Citation36 2016	Asian (China)	118	I–IV	ESCC	Abcam (1:500)	Score =4	74.6	Surgery + CRT, CHT	H, T, N, M, S	Yes

Abbreviations: COX-2, cyclooxygenase-2; EADC, esophageal adenocarcinoma; ESCC, esophageal squamous cell carcinoma; H, Histological grade; T, Depth of invasion; N, Lymphnode metastasis; M, distant metastasis; S, TNM stage; CRT, chemoradiotherapy; CHT, chemotherapy; NR, not reported.

Figure 2 Funnel plot of the association of COX-2 expression with overall survival (OS) in patients with esophageal cancer.

Note: Weights are from random effects analysis.
Abbreviations: CI, confidence interval; COX-2, cyclooxygenase-2; HR, hazard ratio.

Table 2 Main meta-analysis results of COX-2 expression in patients with esophageal cancer

Analysis	Number of studies (number of patients)	HR (95% CI)	P-value	Model	Heterogeneity		Publication bias
					I^2	Phet	Begg’s P	Egger’s P
Overall survival	24 (2,278)	1.60 (1.32–1.94)	<0.001	R	49.1	0.004	1.00	0.63
Subgroup 1: race
Asian	16 (1,609)	1.49 (1.20–21.85)	<0.001	R	50.0	0.012	0.50	0.74
Caucasian	8 (669)	2.04 (1.54–2.71)	<0.001	F	35.5	0.145	0.87	0.39
Subgroup 2: percentage of high/positive COX-2 expression
<50	11 (824)	1.53 (1.02–2.29)	0.038	R	60.1	0.005	0.16	0.83
≥50	13 (1,454)	1.55 (1.35–1.78)	<0.001	R	40.4	0.064	0.06	0.42
Subgroup 3: histology type
ESCC	17 (1,515)	1.46 (1.17–1.83)	0.001	R	52	0.007	0.45	0.83
EADC	5 (522)	2.13 (1.62–2.79)	<0.001	F	26.4	0.246	1	0.892
Subgroup 4: treatment
Surgery	17 (1,634)	1.52 (1.21–1.92)	<0.001	R	52.6	0.006	0.54	0.99
Surgery + chemoradiotherapy	6 (553)	1.72 (1.23–2.32)	0.004	R	53.7	0.056	0.85	0.29
Chemoradiotherapy	1 (91)	1.71 (0.82–2.63)	0.192
Subgroup 5: sample size
≥100	9 (1,356)	1.75 (1.43, 2.14)	<0.001	R	65.9	0.003	1.00	0.59
<100	15 (922)	1.46 (1.26, 1.69)	<0.001	F	29	0.139	0.921	0.96
Clinicopathological parameters		OR (95% CI)
Histological grade (poor vs well/moderate)	18 (1,959)	1.28 (0.90, 1.82)	0.169	R	56.2	0.002	0.68	0.83
Depth of invasion (T3/4 vs T1/2)	17 (1,684)	2.36 (1.61, 3.46)	<0.001	R	57.8	0.002	0.16	0.12
Lymph-node metastasis (yes vs no)	18 (1,749)	1.33 (0.93, 1.91)	0.121	R	61.5	<0.001	0.62	0.48
Distant metastasis (yes vs no)	7 (963)	1.41 (1.02, 1.95)	0.037	F	41.1	0.117	0.035	0.17
Stage (III/IV vs I/II)	15 (1,622)	1.84 (1.23, 2.75)	0.003	R	67.1	<0.001	0.067	0.19

Abbreviations: CI, confidence interval; COX-2, cyclooxygenase-2; EADC, esophageal adenocarcinoma; ESCC, esophageal squamous cell carcinoma; HR, hazard ratio; OR, odds ratio; F, fixed-effect model; R, random effect model; Phet, P for heterogeneity.

Figure 3 Funnel plot of the association of COX-2 expression with the depth of invasion (T) (A), distant metastasis (M) (B), and TNM stage (C) in patients with esophageal cancer.

Note: Weights are from random-effects analysis.
Abbreviations: CI, confidence interval; COX-2, cyclooxygenase-2; OR, odds ratio.

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