Prognostic value of circulating tumor cells in esophageal cancer

Table 1 Characteristics of the included studies

Ref.	Country	Study design	Number (M/F)	Age, yr (range)	Population	Detection method	Sample time	Rate% (n/N)1	Cut-off criteria	Curative method	Follow-up	Outcome
Li et al[26], 2016	China	Cohort	140 (117/23)	62.8 ± 8.5 (36-78)	ESCC	Fluorescent IHC	Baseline	44 (62/140)	> 2/5 mL	Surgery	3 yr	OS, DFS
Su et al[25], 2016	China	Prospective cohort	57 (55/2)	54 (36-78)	EC	Flow cytometry	Baseline	50 (29/57)	≥ 21/mL	CCRT	3 yr	OS, PFS
Reeh et al[27], 2015	Germany	Prospective cohort	100 (77/23)	66 (32-85)	EC	CellSearch	Baseline	18 (18/100)	≥ 1/7.5 mL	Surgery	37.5 mo (median)	OS, RFS
Matsushita et al[28], 2015	Japan	Prospective cohort	90 (78/12)	65 (46-98)	ESCC	CellSearch	Baseline and after treatment	27 (25/90)	≥ 1/7.5 mL	Chemotherapy or CRT	10.3 mo (median), range 0.3-36.4 mo	OS
Tanaka et al[29], 2015	Japan	Prospective cohort	38 (30/8)	63 (43-87)	EC	CellSearch	Baseline and after treatment	50 (19/38)	≥ 2/7.5 mL	Chemotherapy or CRT	19 mo (median)	OS
Yin et al[30], 2012	China	Cohort	72 (54/18)	63 (46-83)	ESCC	RT-PCR	Baseline and after treatment	69 (50/72)	Expression of any one of CEA, CK19, survivin	Radiotherapy	2 yr	PFS
Tanaka et al[31], 2010	Japan	Prospective cohort	244 (212/32)	64 (NR)	ESCC	RT-PCR	Baseline and after treatment	13 (34/244)	Expression of any one of CEA, SCCA	Surgery	24.3 mo (median)	OS, DFS
Hoffmann et al[32], 2010	Germany	Cohort	62 (53/9)	61 (NR)	EC	RT-PCR	Baseline	77 (48/62)	Expression of survivin	Surgery	3 yr (median)	OS
Gao et al[33], 20092	China	Cohort	108 (85/23)	58.9 (36-82)	ESCC	RT-PCR	Baseline	47 (51/108)	Expression of survivin	Surgery	19.5 mo (median), range, 1-33 mo	OS, RFS

¹Positive CTCs at baseline;

²Only 48 patients were available for follow-up. M/F: Male/Female; ESCC: Esophageal squamous cell carcinoma; EC: Esophageal cancer; IHC: Immunohistochemistry; CCRT: Concurrent chemoradiotherapy; CRT: Chemoradiotherapy; OS: Overall survival; DFS: Disease-free survival; PFS: Progression-free survival; RFS: Relapse-free survival; CEA: Carcinoembryonic antigen; CK19: Cytokeratin 19; SCCA: Squamous cell carcinoma antigen.

Table 2 Assessment of the risk of bias in each cohort study using the Newcastle-Ottawa scale

Study	Selection				Comparability	Outcome			Totalscore
	Exposed cohort	Non-exposed cohort	Ascertainment of exposure	Outcome of interest		Assessment of outcome	Length of follow-up	Adequacy of follow-up
Li et al[26], 2016	NS	S	S	S	NS	S	S	S	6
Su et al[25], 2016	S	S	S	S	NS	S	S	S	7
Reeh et al[27], 2015	S	S	S	S	NS	S	S	S	7
Matsushita et al[28], 2015	NS	S	S	S	NS	S	S	S	6
Tanaka et al[29], 2015	S	S	S	S	NS	S	NS	S	6
Yin et al[30], 2012	NS	S	S	S	NS	S	NS	S	5
Tanaka et al[31], 2010	NS	S	S	S	NS	S	S	S	6
Hoffmann et al[32], 2010	S	S	S	S	NS	S	S	S	7
Gao et al[33], 2009	NS	S	S	S	NS	S	NS	NS	4

A higher overall score corresponds to a lower risk of bias; a score of ≤ 5 (out of 9) indicates a high risk of bias. S: The study is satisfied the item; NS: The study is not satisfied the item.

Table 3 Subgroup analyses of the effects of circulating tumor cells on overall survival in esophageal cancer patients

	No. of studies	No. of patients	HR (95%CI)	P value	Heterogeneity
					I2	P value
Region
Asia	6	637	2.46 (1.77-3.40)	< 0.00001	14%	0.33
Non-Asia	2	162	3.74 (1.98-7.05)	< 0.0001	0%	0.36
Curative method
Surgery	5	594	2.81 (1.72-4.58)	< 0.0001	50%	0.09
Non-surgery	3	185	2.70 (1.70-4.30)	< 0.0001	0%	0.95
Detection method
CellSearch	3	228	2.91 (1.78-4.74)	< 0.0001	0%	0.93
RT-PCR	3	354	3.44 (1.42-8.34)	0.006	70%	0.04
Other methods	2	197	2.22 (1.38-3.58)	0.001	0%	0.44