Circulating Tumor Cells in Esophageal Squamous Cell Carcinoma – Mini Review

Figures & data

Figure 1 Production and metastasis of circulating tumor cells.

Table 1 Circulating Tumor Cells in Esophageal Squamous Cell Carcinoma Diagnosis

Author	Country	Year	Number of Patients	Detect Technology	CTC Type	Main Findings
Li et al^Citation3	China	2015	61 ESCC and 22 healthy volunteers	Cell-search and ISET	CTC	Cell-search detect CTC1.6% (1/61), no CTM detected ISET detect CTC 32.8% (20/61), detect CTM 4.9%(3/61) healthy volunteers: Cell-search and ISET(0/22)
Kaganoi et al^Citation49	Japan	2004	70EC,19 healthy volunteers and 3 benign tumour	RT-PCR	SCCA mRNA	SCCA mRNA not detected in healthy volunteers or benign disease 23/70 (33%) patients were positive for SCCA mRNA on admission
Su et al^Citation50	China	2016	57 ESCC and 20 healthy volunteers	Cell-search	CTC	CTC in 57 EC was higher than 20 healthy blood donors (P=0.04)
Andolfo et al^Citation51	Italy	2011	41ESCC and 34healthy volunteers	RT-PCR	erbB2	erbB2 CNs were higher than 34 healthy volunteers (P = 0.001)
Liu et al^Citation48	China	2007	53 EC,22 benign tumour and 30 healthy volunteers.	RT-PCR	CEA mRNA	CEA mRNA-positive: B-1:188(95% CI,155–498) B0:1513(95% CI,660–7974) B+3:707(95% CI,737–3005) CEA mRNA were lower than the detection limit in 22 benign tumour and 30 healthy volunteers.
Tanaka et al^Citation53	Japan	2010	244 ESCC and 20 healthy volunteers	RT-PCR	CEA mRNA and SCC mRNA	Pre-CTC(+):34 patients (13.9%) Pro-CTC(+):41 patients (16.8%) healthy volunteers (0/20)
Qiao et al^Citation52	China	2017	59ESCC and 25healthy volunteers	Cell-search	CTC	Pre-treatment CTC(+):47/59 (79.7%) healthy volunteers (0/25)
Choi et al^Citation36	Korea	2019	73ESCC and 31healthy volunteers	FAST	CTC	ESCC:CTC(+)63/73 (86.3%) healthy volunteers:3/31(9.6%)

Abbreviations: CTC, circulating tumor cells; ISET, isolation by size of epithelial tumor cells; (RT)-PCR, reverse transcription polymerase chain reaction; CTM, circulating tumor microemboli; ESCC, esophageal squamous cell carcinoma; FAST, fluid-assisted separation technique.

Table 2 Surveillance Value of Circulating Tumor Cells in the Treatment of Esophageal Squamous Cell Carcinoma

Author	Country	Year	Research Type	Number of Patients	Detect Technology	CTC Type	Main Findings
Yin et al^Citation26	China	2012	Prospective	72 ESCC	RT-PCR	CEA, CK19, survivin	Pro-RT CTC(+) was correlated with poor radiotherapy efficacy (P=0.027), pre-RT CTC(+) was not correlated with radiotherapy efficacy (P=0.846).
Cao et al^Citation58	China	2009	Prospective	108 ESCC	RT-PCR+ELASA	Survivin mRNA	1.CCC(+) &CCC(-): higher recurrence rate (P = 0.002) CCC(+): initial and follow up significantly higher than CCC(-) (P = 0.021, Chi-square test)
Nakashima et al^Citation57	Japan	2003	Prospective	50 ESCC	RT-PCR	CEA mRNA	31 patients (57.4%) were positive for CTC; CTC (+) &CTC (-): more lymph node metastasis(P = 0.011); CTC (+): later stage (P=0.048)
Qiao et al^Citation56	China	2015	Case report	1ESCC	Negative enrichment method	CTC	CTC changes were consistent with imaging results; Pro-treatment CTC count transient increased; The tumor stable, CTC not detect
Zhao et al^Citation60	China	2020	Prospective	117ESCC (57: preoperative chemotherapy group and 58 surgery ± chemotherapy group)	Negative enrichment methods	CTC	First time: Pre-group CTCs(+):49.12% (28/57) Post-group:55.17%(32/58); Postoperative: Pre-group CTCs(+):52.63% (30/ 57) Post-group:56.90%(33/58); First time CTC (+): preoperative chemotherapy had a better 2-year PFS than CTC(-)(P = 0.037); First time CTC (-): preoperative chemotherapy &not 2-year PFS no significant difference(P = 0.5)
Tanaka et al^Citation53	Japan	2010	Prospective	244 ESCC	RT-PCR	CEA mRNA and SCC mRNA	Pro-treatment CTC(+): more metastatic lymph nodes (P = 0.002) and higher degree of lymph infiltration (P = 0.008).
Matsushita et al^Citation59	Japan	2015	Prospective	90ESCC	Cell-search	CTC	Pre-treatment CTC(+): 27.8%(25/90); CTCs(+): related with distant metastasis (p = 0.002); CTC (+): related with pleural dissemination or hematogenous metastases (p<0.0001, p = 0.015)

Abbreviations: CTCs, circulating tumor cells; ESCC, esophageal squamous cell carcinoma; RT, radiotherapy; RT-PCR, reverse transcription- polymerase chain reaction.

Table 3 Prognostic Value of Circulating Tumor Cells in Esophageal Squamous Cell Carcinoma

Author	Number of Patients	CTC Positivity	Main Findings
Yin et al^Citation26	72 ESCC and 10ESCC tumor tissues	Pre-radiotherapy:54.2% (39/72) Post-radiotherapy:38.9% (28/72)	2 year PFS18.3 months in pre-RT CTC(+) vs median 21.5 months in pre-RT CTC(-); p= 0.01; 2 year PFS 16.3 months in pro-RT CTC(+) vs median 22.8 months in pro-RT CTC(-); p< 0.001; pre-RT CTC(-) and pro-RT CTC(-):CR + PR 73.7%(14/19).
Han et al^Citation35	60ESCC	33.3%(20/60)	PFS for CTC(-) longer than other group, p=0.001 HR=3.88 for PFS, p=0.008; HR=2.34 for tumor recurrence CTC (+)was 2.5 times vs CTC (-); P=0.036; Shorter PFS in patients with CTC>2/mL vs CTC≤2/mL; p< 0.003
Reeh et al^Citation33	100EC	18% (18/100)	Shorter OS and RFS in patients with CTC(+) vs CTC(-); p= 0.007, p<0.001; HR=5.06 for tumor recurrence CTC (+)was 5.1 times higher than that of CTC (-);P<0.001;
Tanaka et al^Citation53	244 ESCC	Pre-surgery:13.9% (34/244) Post-surgery:16.8% (41/144)	Shorter DFS with CTC(+) vs CTC(-); p=0.038; Multivariate analysis: post-operative CTC status was an independent prognostic factor (HR, 1.647; 95% confidence interval, 1.032–2.629; p = 0.03);
Qiao et al^Citation52	59 ESCC	79.7% (47/59)	Shorter OS and PFS for patients with CTCs > 3 vs CTCs < 3 (mean time; OS was 447 days vs 889 days, PFS was 419 days vs 859 days, p= 0.002); CTCs> 5 worse OS and PFS (mean time; OS was 385 days vs 911 days, PFS was 348 days vs 875 days, P, 0.001); HR=12.5 for OS p<0.05; with CTC (+) vs CTC(-); HR =6.5 for PFS p<0.05; with CTC (+) vs CTC(-); CTC detected about 50.0% (4/8) in the early stage, 84.3% (43/51) in the late stage (p= 0.025).
Su et al^Citation50	57 ESCC	44.6± 9.1%	HR=3.13 for disease- specific PFS p=0.04; with CTC(+) patients vs CTCs(-); HR= 1.002 for OS p=0.02); with CTC(+) patients vs CTCs(-); multivariate analysis for disease- specific PFS and OS, the CTC number (≥21.0 cells/mL) be independent prognostic factors (p=0.004, p=0.028);
Qiao et al^Citation44	1260 EC		HR =1.71 for OS, p<0.001; with CTC(+) patients vs CTCs(-); HR =1.67 for PFS, p<0.001; with CTC(+) patients vs CTCs(-); Subgroup analysis: HR =1.66 for OS, p<0.001; HR =1.63 for PFS p<0.001.

Abbreviations: CTCs, circulating tumor cells; ESCC, esophageal squamous cell carcinoma; CCRT, concurrent chemoradiotherapy; OS, overall survival; PFS, progression-free survival; HR, hazard ratio; DFS, disease-free survival; RFS, relapse-free survival.

Table 4 Cut off Value of CTCs with Different Detection Techniques

Author	CTCs Detect Technology	CTCs Cutoff Value
Su et al^Citation50	Cellsearch	≥21/mL blood
Andolfo et al^Citation51	RT-PCR	>2/7.5mL blood
Han et al^Citation35	ISET	>2/7.5mL blood
Choi et al^Citation36	FAST	≥2/7.5 mL blood
Lee et al^Citation64	FAST	≥2/7.5 mL blood
Qiao et al^Citation52	Cell Search	≥5/7.5 mL blood
Choi et al^Citation36	FAST	≥2/7.5 mL blood

Abbreviations: (RT)-PCR, reverse transcription polymerase chain reaction; ISET, isolation by size of epithelial tumor cells; FAST, fluid-assisted separation technique; CTCs, circulating tumor cells;

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