Circulating Tumor Cells for Esophageal Cancer Prognosis
Of the 123 study patients, 4 were excluded because of different postoperative diagnoses. Another 19 patients were excluded because of technical problems with the CellSearch system. Thus, eventually CTC analyses were performed for 100 patients, including 29 with squamous cell carcinoma (SCC), 68 with adenocarcinoma (AC), 1 with a mixed-type cancer and 2 with anaplastic carcinoma. In-hospital mortality was 6%. These and the 3 patients with mixed-type cancer and anaplastic carcinoma were excluded from survival analyses (N = 91). Fifty-one patients showed LN involvement; 46 showed no LN involvement. LN resection was not performed in 3 patients due to distant tumor spread.
Of the 100 patients, 77 were men and 23 were women, and their median age was 66 years (range, 32–85 years). The overall CTC detection rate was 18.0%. The CTC counts ranged from 1 to 56 cells/7.5 mL blood. Interestingly, only 3 of the 29 patients (10.3%) with SCCs showed 1 CTC or more, whereas 14 of the 68 patients (20.6%) with AC showed 1 CTC or more (P = 0.261). Among the 46 LN-negative patients, 8 (17.4%) showed 1 or more. Among the 51 LN-positive patients, 9 (17.6%) showed 1 or more.
We assessed the correlation of CTC positivity with sex and the following histopathological parameters: tumor size, nodal status, metastatic stage, Union for International Cancer Control stage, tumor grade, and resection margin status. The detection of 1 CTC or more showed a trend toward larger tumors (P = 0.054) that turned out significant in patients with AC (P = 0.024; Table 1). Presence of CTCs was significantly correlated with metastatic stage (P = 0.013; Table 1). Among patients with AC, the detection of CTCs was significantly correlated with tumor size (P = 0.024), metastatic stage (P = 0.006) and Union for International Cancer Control stage (P = 0.049). Among patients with SCC, women showed significantly more CTCs than men (P = 0.006). Other parameters were not significantly correlated with CTC positivity.
The median survival time was 26 months (95% CI, 22.18–29.82 months). The median follow-up time of surviving patients was 37.5 months. Patients with CTCs did significantly suffer from worse overall (median overall survival P < 0.001) and relapse-free survival (P < 0.001) compared with patients without CTCs (Fig. 1 A, B). Survival analysis of patients without distant metastases (M0) showed significant survival stratification by CTC status as well (P < 0.001) (Fig. 2). In a subgroup analysis including only LN-positive patients (pN+) without distant metastases (M0) (N = 45), CTC-positive patients had significantly worse overall (P = 0.007) and relapse-free survival (P < 0.001) than pN+, M0 patients without CTCs (Fig. 3 A, B). In LN-negative patients, CTC detection showed prognostic impact on overall (P = 0.001) and relapse-free survival (P < 0.001) as well.
(Enlarge Image)
Figure 1.
A, B, Outcomes of patients with EC with CTCs compared with patients without CTCs. Correlation of overall (A) and relapse-free survival (B) with CTCs in patients with EC (N = 91).
(Enlarge Image)
Figure 2.
Outcomes of patients with EC with CTCs compared with patients without CTCs. Correlation of overall survival with CTCs in patients without distant metastases (M0) (N = 86).
(Enlarge Image)
Figure 3.
A, B, Outcomes of patients with EC with CTCs compared with patients without CTCs. Correlation of overall (A) and relapse-free survival (B) with CTCs in patients with lymph node invasion but without distant metastases (N = 45).
Data from 86 M0 patients were used in a multivariate analysis to test the effect of CTCs on overall and relapse-free survival, independent from other risk factors, namely, age, sex, tumor size, LN stage, and tumor grading. The risk of tumor recurrence was 5.1 times higher if CTCs were detected (P < 0.001; hazard ratio, 5.063; 95% CI, 2.233–11.480) (Table 2). In addition, the presence CTCs was an independent prognostic marker for overall survival (P = 0.003; hazard ratio, 3.128; 95% CI, 1.492–6.559) (Table 2).
Results
Patient Characteristics and CTC Detection
Of the 123 study patients, 4 were excluded because of different postoperative diagnoses. Another 19 patients were excluded because of technical problems with the CellSearch system. Thus, eventually CTC analyses were performed for 100 patients, including 29 with squamous cell carcinoma (SCC), 68 with adenocarcinoma (AC), 1 with a mixed-type cancer and 2 with anaplastic carcinoma. In-hospital mortality was 6%. These and the 3 patients with mixed-type cancer and anaplastic carcinoma were excluded from survival analyses (N = 91). Fifty-one patients showed LN involvement; 46 showed no LN involvement. LN resection was not performed in 3 patients due to distant tumor spread.
Of the 100 patients, 77 were men and 23 were women, and their median age was 66 years (range, 32–85 years). The overall CTC detection rate was 18.0%. The CTC counts ranged from 1 to 56 cells/7.5 mL blood. Interestingly, only 3 of the 29 patients (10.3%) with SCCs showed 1 CTC or more, whereas 14 of the 68 patients (20.6%) with AC showed 1 CTC or more (P = 0.261). Among the 46 LN-negative patients, 8 (17.4%) showed 1 or more. Among the 51 LN-positive patients, 9 (17.6%) showed 1 or more.
We assessed the correlation of CTC positivity with sex and the following histopathological parameters: tumor size, nodal status, metastatic stage, Union for International Cancer Control stage, tumor grade, and resection margin status. The detection of 1 CTC or more showed a trend toward larger tumors (P = 0.054) that turned out significant in patients with AC (P = 0.024; Table 1). Presence of CTCs was significantly correlated with metastatic stage (P = 0.013; Table 1). Among patients with AC, the detection of CTCs was significantly correlated with tumor size (P = 0.024), metastatic stage (P = 0.006) and Union for International Cancer Control stage (P = 0.049). Among patients with SCC, women showed significantly more CTCs than men (P = 0.006). Other parameters were not significantly correlated with CTC positivity.
Univariate Survival Analysis
The median survival time was 26 months (95% CI, 22.18–29.82 months). The median follow-up time of surviving patients was 37.5 months. Patients with CTCs did significantly suffer from worse overall (median overall survival P < 0.001) and relapse-free survival (P < 0.001) compared with patients without CTCs (Fig. 1 A, B). Survival analysis of patients without distant metastases (M0) showed significant survival stratification by CTC status as well (P < 0.001) (Fig. 2). In a subgroup analysis including only LN-positive patients (pN+) without distant metastases (M0) (N = 45), CTC-positive patients had significantly worse overall (P = 0.007) and relapse-free survival (P < 0.001) than pN+, M0 patients without CTCs (Fig. 3 A, B). In LN-negative patients, CTC detection showed prognostic impact on overall (P = 0.001) and relapse-free survival (P < 0.001) as well.
(Enlarge Image)
Figure 1.
A, B, Outcomes of patients with EC with CTCs compared with patients without CTCs. Correlation of overall (A) and relapse-free survival (B) with CTCs in patients with EC (N = 91).
(Enlarge Image)
Figure 2.
Outcomes of patients with EC with CTCs compared with patients without CTCs. Correlation of overall survival with CTCs in patients without distant metastases (M0) (N = 86).
(Enlarge Image)
Figure 3.
A, B, Outcomes of patients with EC with CTCs compared with patients without CTCs. Correlation of overall (A) and relapse-free survival (B) with CTCs in patients with lymph node invasion but without distant metastases (N = 45).
Multivariate Survival Analysis
Data from 86 M0 patients were used in a multivariate analysis to test the effect of CTCs on overall and relapse-free survival, independent from other risk factors, namely, age, sex, tumor size, LN stage, and tumor grading. The risk of tumor recurrence was 5.1 times higher if CTCs were detected (P < 0.001; hazard ratio, 5.063; 95% CI, 2.233–11.480) (Table 2). In addition, the presence CTCs was an independent prognostic marker for overall survival (P = 0.003; hazard ratio, 3.128; 95% CI, 1.492–6.559) (Table 2).
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