Timing of surgery after neoadjuvant chemoradiotherapy affects oncologic outcomes in patients with esophageal cancer

Table 1 Characteristics of studies included in the meta-analysis

Ref.	Year	Study region	Ethnicity	Study design	No. (M/F)	Age (yr)	NCRT regimen	Cut-off (d)	Outcome	Follow-up (mo)	Clinical stage	Histology	HR type	NOS score
Ruol et al[17]	2010	Italy	Caucasian	Prospective	129 (99/30)	60.8	DDP+5FU ci/DDP+PTX/OXA+5FU ci+CF RT 45-50.4 Gy	46	OS	60	I-IV1	SCC	U	8
Kim et al[18]	2012	United States	Caucasian	Prospective	266 (235/31)	SI, 57; LI, 60	Platinum-based RT 45Gy	56	OS/DFS	99	II-IVa1	AC and SCC	U	8
Chiu et al[10]	2013	China	Asian	Retrospective	276 (268/8)	SI, 56.8; LI, 53.5	5FU ci+DDP RT 30 Gy	56	OS	60	II-IV1	SCC	U	7
Shapiro et al[7]	2014	United States	Caucasian	Retrospective	325 (253/72)	60	PTX+CBP RT 41.4 Gy	45	OS/DFS	60	cT1-42, N0-11	AC and SCC	U/M	8
Tessier et al[19]	2014	France	Caucasian	Prospective	257 (227/30)	NR	5FU ci+DDP RT 45 Gy	49	OS	135	I-III1	AC and SCC	U	8
Shaikh et al[20]	2015	United States	Caucasian	Retrospective	88 (62/26)	61	5FU-based/PTX-based RT 45-60 Gy	50	OS	87.7	I-IV2	AC and SCC	U	7
Wang et al[21]	2015	China	Asian	Prospective	665 (636/29)	53	NA	59	OS	60	I-III2	SCC	U	7
Haisley et al[5]	2016	United States	Caucasian	Prospective	234 (191/43)	64	PTX+CBP/5FU ci+DDP NA	56	OS	152	I-IV2	AC and SCC	U	8
Kathiravetpillai et al[22]	2016	Netherlands	Caucasian	Prospective	190 (169/21)	NR	PTX+CBP/PTX+CBP+5FU RT41.4 Gy	56	OS/DFS	60	cT1-32, N0-32	AC	U	7
Lee et al[11]	2016	United States	Caucasian	Retrospective	5393 (4533/860)	62	NA RT 39.6-64.8 Gy	64	OS	96	I-IV2	AC and SCC	M	8
Ranney et al[9]	2017	United States	Caucasian	Retrospective	2444 (2193/251)	61	NA RT 40.4-50.4 Gy	56	OS	60	II-III2	AC	M	8
Tsang et al[23]	2017	China	Asian	Prospective	107(91/16)	63	5FU ci+DDP RT 40 Gy	64	OS	60	I-III2	SCC	U	7
Franko et al[14]	2018	United States	Caucasian	Retrospective	1244 (810/434)	60.5	NA RT 45 Gy	49	OS	75	NR	SCC	U	6
Furukawa et al[24]	2018	Japan	Asian	Retrospective	134 (116/18)	NR	5FU+DTX/5FU+DDP/NDP RT 40 Gy	56	OS/DFS	60	I-IV2	SCC	U	7
Singla et al[25]	2018	United States	Caucasian	Prospective	226 (210/16)	61	DDP+Irinotecan/CBP+PTX/OXA+CAPE/5-FU+DDP RT 50.4 Gy	49	OS/PFS	110	I-IV2	AC and SCC	U	6
Klevebro et al[8]	2019	Sweden	Caucasian	Prospective	643 (536/107)	SI, 64; LI, 65	DDP+5FU RT 40 Gy	49	OS	60	I-IVa2	AC and SCC	U	7

NCRT: Neoadjuvant chemoradiotherapy; NR: Not reported; LI: Longer time interval; SI: Shorter time interval; DDP: Cisplatin; 5FU: Fluorouracil; PTX: Paclitaxel; OXA: Oxaliplatin; CBP: Carboplatin; NDP: Nedaplatin; DTX: Docetaxel; RT: Radiotherapy; NA: None; OS: Overall survival; DFS: Disease-free survival; PFS: Progression-free survival; HR: Hazard ratio; M: Multivariate analysis; U: Univariate analysis; SCC: Squamous cell carcinoma; AC: Adenocarcinoma;

¹6th AJCC/UICC classification;

²7th AJCC/UICC classification; NOS: Newcastle-Ottawa Quality Assessment Scale.

Table 2 Meta-analysis and subgroup analyses

Analysis	n	Ref.	Random-effects model		Fixed-effects model		Heterogeneity
			HR (95%CI)	P value	HR (95%CI)	P value	I2	Ph
Esophageal cancer OS	16	[5,7-11,13,16-24]	1.107 (1.014-1.208)	0.023	1.089 (1.036-1.145)	0.001a	48.80%	0.015
DFS	3	[17,21,23]	1.300 (0.883-1.913)	0.184	1.263 (0.976-1.633)	0.075	48.40%	0.144
Subgroup 1: Study design	16	[5,7-11,13,16-24]	1.107 (1.014-1.208)	0.196	1.089 (1.036-1.145)	0.196	0.00	0.865
Prospective	9	[5,8,16-18,20-22,24]	1.073 (0.964-1.194)	0.064	1.073 (0.964-1.194)	0.002a	76.30%	0.000
Retrospective	7	[7,9-11,13,19,23]	1.150 (0.992-1.332)	0.023a	1.094 (1.034-1.158)	0.001a	48.80%	0.015
Subgroup 2: Samplesize	16	[5,7-11,13,16-24]	1.107 (1.014-1.208)	0.023a	1.089 (1.036-1.145)	0.001a	48.80%	0.015
< 200	5	[16,19,21-23]	1.294 (0.946-1.771)	0.107	1.254 (0.985-1.597)	0.067	34.70%	0.190
≥ 200	11	[5,7-11,13,17,18,20,24]	1.089 (0.995-1.190)	0.063	1.082 (1.028-1.139)	0.002a	54.20%	0.016
Subgroup 3: Ethnicity	16	[5,7-11,13,16-24]	1.107 (1.014-1.208)	0.064	1.107 (1.014-1.208)	0.064	48.80%	0.015
Caucasian	12	[5,7-9,11,13,16-19,21,24]	1.091 (0.995-1.197)	0.150	1.091 (0.995-1.197)	0.150	49.30%	0.027
Asian	4	[10,20,22,23]	1.251 (0.922-1.696)	0.023a	1.251 (0.922-1.696)	0.023a	57.60%	0.069
Subgroup 4: HR type	16	[5,7-11,13,16-24]	1.107 (1.014-1.208)	0.023a	1.089 (1.036-1.145)	0.001a	48.80%	0.015
Univariate	13	[5,8,10,13,16-24]	1.053 (0.952-1.166)	0.314	1.029 (0.949-1.115)	0.492	23.20%	0.209
Multivariate	3	[7,9,11]	1.194 (1.010-1.411)	0.037a	1.130 (1.059-1.204)	0.000a	81.00%	0.005
Squamous cell carcinoma OS	6	[10,13,16,20,22,23]	1.096 (0.896-1.341)	0.371	1.009 (0.908-1.120)	0.874	57.20%	0.039
Adenocarcinoma OS	2	[9,21]	1.360 (1.111-1.664)	0.003a	1.385 (1.186-1.616)	0.000a	22.00%	0.257

^aStatistical significance. n: Number of studies; HR: Hazard ratio; 95%CI: 95% confidence interval; Ph: P values of Q test for heterogeneity test; OS: Overall survival; DFS: Disease free survival.