3.1 Patient characteristics
Ultimately, a total of 146 ESCC patients were enrolled in the training cohort, including 137 males (93.8%) and 9 females (6.2%). In the training dataset, the proportions of age greater than or equal to 65 years versus less than 65 years were 21.2% and 78.8%, respectively. The mean and standard deviation of BMI was 23.12 (3.43). In Grade, the percentage of G1, G2, and G3 were 24%, 46.6%, and 29.5%, respectively. There were 62 patients (42.5%) who received chemotherapy. Median and IQR (Q1-Q3) of maximum tumor diameter in postoperative pathology was 2.9 cm (2–4 cm). The DSS median and IQR (Q1-Q3) for the total cohort, patients without lymph node metastasis, and patients with lymph node metastasis were 35.2months (16-72.1months), 45months (15.3-74.6months), and 30.5months (16.1-67.4months), respectively. Among the pT stages, 13 cases (8.9%) were in pT1a stage, 61 cases (41.8%) in pT1b stage, and 72 cases (49.3%) in pT2 stage. The location of the primary tumor was in the upper thoracic, middle thoracic, and lower thoracic regions in 9.6%, 50%, and 40.4%, respectively. 36.3% of patients had lymph node metastases (Table 1).
Table 1
Characteristics of patients in the training cohort.
Characteristic
|
total
|
LN Metastasis
|
|
|
|
(-)
|
(+)
|
p
|
|
(n = 146)
|
(n = 93)
|
(n = 53)
|
|
Gender (%)
|
|
|
|
1
|
female
|
9(6.2)
|
6(6.5)
|
3(5.7)
|
|
male
|
137(93.8)
|
87(93.5)
|
50(94.3)
|
|
Age (%)
|
|
|
|
0.045
|
<65years
|
115(78.8)
|
68(73.1)
|
47(88.7)
|
|
≥ 65years
|
31(21.2)
|
25(26.9)
|
6(11.3)
|
|
BMI (mean (SD))
|
23.12(3.43)
|
22.90(3.29)
|
23.51(3.67)
|
0.31
|
Tumor location (%)
|
|
|
|
0.269
|
Lower
|
59(40.4)
|
33(35.5)
|
26(49.1)
|
|
Middle
|
73(50.0)
|
50(53.8)
|
23(43.4)
|
|
Upper
|
14(9.6)
|
10(10.8)
|
4(7.5)
|
|
Chemotherapy (%)
|
|
|
|
0.001
|
no
|
84(57.5)
|
64(68.8)
|
20(37.7)
|
|
yes
|
62(42.5)
|
29(31.2)
|
33(62.3)
|
|
Grade (%)
|
|
|
|
0.003
|
G1
|
35(24.0)
|
30(32.3)
|
5(9.4)
|
|
G2
|
68(46.6)
|
42(45.2)
|
26(49.1)
|
|
G3
|
43(29.5)
|
21(22.6)
|
22(41.5)
|
|
pT stage (%)
|
|
|
|
0.001
|
T1a
|
13(8.9)
|
12(12.9)
|
1(1.9)
|
|
T1b
|
61(41.8)
|
45(48.4)
|
16(30.2)
|
|
T2
|
72(49.3)
|
36(38.7)
|
36(67.9)
|
|
LN Metastasis (%)
|
|
|
|
< 0.001
|
(-)
|
93(63.7)
|
93(100.0)
|
0(0.0)
|
|
(+)
|
53(36.3)
|
0(0.0)
|
53(100.0)
|
|
pN stage (%)
|
|
|
|
< 0.001
|
N0
|
93(63.7)
|
93(100.0)
|
0(0.0)
|
|
N1
|
41(28.1)
|
0(0.0)
|
41(77.4)
|
|
N2
|
9(6.2)
|
0(0.0)
|
9(17.0)
|
|
N3
|
3(2.1)
|
0(0.0)
|
3(5.7)
|
|
pTNM (%)
|
|
|
|
< 0.001
|
Ⅰ
|
70(47.9)
|
70(75.3)
|
0(0.0)
|
|
Ⅱ
|
38(26.0)
|
23(24.7)
|
15(28.3)
|
|
Ⅲ
|
35(24.0)
|
0(0.0)
|
35(66.0)
|
|
Ⅳ
|
3(2.1)
|
0(0.0)
|
3(5.7)
|
|
MDT (median [IQR], cm)
|
2.90 [2.00, 4.00]
|
2.50 [2.00, 4.00]
|
3.00 [2.00, 4.00]
|
0.32
|
DSS (median [IQR], months)
|
35.20 [16.05, 72.12]
|
45.03 [15.27, 74.63]
|
30.50 [16.13, 67.37]
|
0.146
|
LN lymph node, MDT Maximum Diameter of Tumor, DSS Disease Specific Survival.
A total of 478 ESCC patients were enrolled in the SEER validation cohort, including 281 (58.8%) males and 197 (41.2%) females. In the validation dataset, the proportions of age greater than or equal to 65 years versus less than 65 years were 59% and 41%, respectively. The location of the primary tumor was in the upper thoracic, middle thoracic, and lower thoracic regions in 15.5%, 48.1%, and 36.4%, respectively. In Grade, G1, G2, and G3 account for 7.3%, 57.5%, and 35.1%, respectively. Overall cohort, DSS median and IQR (Q1-Q3) for patients without lymph node metastasis and with lymph node metastasis were 30months (11-69.8months), 39months (12-72months), and 22months (9-63months), respectively. There were 103 patients (21.5%) in pT1a stage, 88 patients (18.4%) in pT1b stage, and 287 patients (60%) in pT2 stage. The number of patients who received chemotherapy was 319 (66.7%). 37.9% of patients had lymph node metastasis (Table 2).
Table 2
Characteristics of patients in the validation cohort.
Characteristic
|
total
|
LN Metastasis
|
|
|
|
(-)
|
(+)
|
p
|
|
(n = 478)
|
(n = 297)
|
(n = 181)
|
|
Gender (%)
|
|
|
|
0.834
|
Female
|
197(41.2)
|
124(41.8)
|
73(40.3)
|
|
Male
|
281(58.8)
|
173(58.2)
|
108(59.7)
|
|
Age (%)
|
|
|
|
0.662
|
<65years
|
196(41.0)
|
119(40.1)
|
77(42.5)
|
|
≥ 65years
|
282(59.0)
|
178(59.9)
|
104(57.5)
|
|
Tumor location (%)
|
|
|
0.387
|
Lower
|
174(36.4)
|
102(34.3)
|
72(39.8)
|
|
Middle
|
230(48.1)
|
150(50.5)
|
80(44.2)
|
|
Upper
|
74(15.5)
|
45(15.2)
|
29(16.0)
|
|
Chemotherapy (%)
|
|
|
|
< 0.001
|
no
|
159(33.3)
|
126(42.4)
|
33(18.2)
|
|
yes
|
319(66.7)
|
171(57.6)
|
148(81.8)
|
|
Grade (%)
|
|
|
|
0.12
|
G1
|
35(7.3)
|
26(8.8)
|
9(5.0)
|
|
G2
|
275(57.5)
|
175(58.9)
|
100(55.2)
|
|
G3
|
168(35.1)
|
96(32.3)
|
72(39.8)
|
|
pTNM (%)
|
|
|
|
< 0.001
|
Ⅰ
|
154(32.2)
|
154(51.9)
|
0(0.0)
|
|
Ⅱ
|
290(60.7)
|
143(48.1)
|
147(81.2)
|
|
Ⅲ
|
34(7.1)
|
0(0.0)
|
34(18.8)
|
|
pT stage (%)
|
|
|
|
< 0.001
|
T1a
|
103(21.5)
|
79(26.6)
|
24(13.3)
|
|
T1b
|
88(18.4)
|
69(23.2)
|
19(10.5)
|
|
T2
|
287(60.0)
|
149(50.2)
|
138(76.2)
|
|
LN Metastasis (%)
|
|
|
|
< 0.001
|
(-)
|
297(62.1)
|
297(100.0)
|
0(0.0)
|
|
(+)
|
181(37.9)
|
0(0.0)
|
181(100.0)
|
|
pN stage (%)
|
|
|
|
< 0.001
|
N0
|
297(62.1)
|
297(100.0)
|
0(0.0)
|
|
N1
|
147(30.8)
|
0(0.0)
|
147(81.2)
|
|
N2
|
32(6.7)
|
0(0.0)
|
32(17.7)
|
|
N3
|
2(0.4)
|
0(0.0)
|
2(1.1)
|
|
DSS (median [IQR], months)
|
30.00 [11.00, 69.75]
|
39.00 [12.00, 72.00]
|
22.00 [9.00, 63.00]
|
0.005
|
LN lymph node, DSS Disease Specific Survival.
3.2 Cox regression analysis
In univariate Cox analysis, degree of differentiation, pT stage, and chemotherapy were predictors of DSS, and gender, age, BMI, tumor location, and MDT did not affect prognosis. P-values less than 0.05 were used as inclusion criteria, and the degree of differentiation, pT stage and chemotherapy were included in the multifactorial analysis. Multifactorial analysis showed that the degree of differentiation, pT stage and chemotherapy were independent factors affecting DSS (Table 3).
Table 3
Univariate and multivariate Cox proportional hazard model analysis in the training cohort.
Predictors
|
Univariate analysis
|
Multivariable analysis
|
|
P
|
OR (95% CI)
|
P
|
OR (95% CI)
|
Gender
|
0.512
|
|
-
|
|
Male
|
|
0.678(0.211–2.182)
|
|
-
|
Female
|
|
Reference
|
|
-
|
Age
|
0.415
|
|
-
|
|
≥65years
|
|
1.423(0.607–3.335)
|
|
-
|
<65years
|
|
Reference
|
|
-
|
BMI
|
0.319
|
1.039(0.963–1.122)
|
-
|
-
|
Tumor location
|
0.577
|
|
-
|
-
|
Upper
|
|
Reference
|
|
-
|
Middle
|
|
0.807(0.280–2.323)
|
|
-
|
Lower
|
|
0.742(0.422–1.305)
|
|
-
|
Grade
|
< 0.01
|
|
< 0.01
|
|
well
|
|
Reference
|
|
Reference
|
moderately
|
|
0.188(0.071–0.499)
|
|
0.191(0.071–0.513)
|
poorly
|
|
0.816(0.462–1.442)
|
|
1.229(0.649–2.327)
|
Chemotherapy
|
< 0.001
|
|
0.032
|
|
yes
|
|
0.375(0.214–0.657)
|
|
0.365(0.191–0.697)
|
no
|
|
Reference
|
|
Reference
|
MDT
|
0.688
|
1.028(0.899–1.176)
|
-
|
|
pT stage
|
< 0.01
|
|
< 0.01
|
|
T1a
|
|
Reference
|
|
Reference
|
T1b
|
|
0.117(0.016–0.857)
|
|
0.206(0.027–1.563)
|
T2
|
|
0.453(0.251–0.817)
|
|
0.375(0.206–0.683)
|
3.3 Development and validation of the nomogram
Three independent predictors of DSS were identified by multifactorial analysis to construct a prognostic nomogram, which was used to calculate 3- and 5-year DSS rates (Fig. 2). We validated the nomogram on the training cohort and found that the consistency index (C-index) of the nomogram was 0.74. The AUC values of the time-dependent ROC curves for predicting 3- and 5-year DSS rates were 0.735 (95% CI 0.633–0.837) and 0.756 (95% CI 0.654–0.858), respectively (Fig. 3A). The calibration curves were also used to validate the nomogram prediction effect, and the results showed that the calibration graphs showed high agreement between predicted and actual survival (Fig. 4A,4B)
The SEER validation cohort was used as an independent validation cohort. The SEER validation cohort was first subjected to a single multifactor Cox analysis, which yielded results consistent with those of the training cohort. In the univariate Cox analysis, degree of differentiation, pT stage, and chemotherapy were equally prognostic predictors of DSS. Multifactorial analysis showed that the degree of differentiation, pT stage and chemotherapy were likewise independent factors influencing DSS (Table 4). The Nomogram C-index for the SEER validation cohort is 0.62. The AUC values of the time-dependent ROC curves for 3-year and 5-year DSS were 0.632 (95% CI 0.573–0.690) and 0.672 (95% CI 0.613–0.732), respectively. The ROC curves over time showing the performance of the DSS for the nomogram prediction validation cohort were also plotted (Fig. 3B).
Table 4
Univariate and multivariate Cox proportional hazard model analysis in the SEER validation cohort.
Predictors
|
Univariate analysis
|
Multivariable analysis
|
|
P
|
OR (95% CI)
|
P
|
OR (95% CI)
|
Gender
|
0.262
|
|
-
|
|
Male
|
|
0.843(0.626–1.136)
|
|
-
|
Female
|
|
Reference
|
|
-
|
Age
|
0.55
|
|
-
|
|
≥65years
|
|
1.094(0.814–1.470)
|
|
-
|
<65years
|
|
Reference
|
|
-
|
Tumor location
|
0.49
|
|
-
|
|
Upper
|
|
Reference
|
|
-
|
Middle
|
|
1.081(0.701–1.668)
|
|
-
|
Lower
|
|
0.862(0.627–1.186)
|
|
-
|
Grade
|
0.011
|
|
0.027
|
|
well
|
|
Reference
|
|
Reference
|
moderately
|
|
0.445(0.222–0.890)
|
|
0.575(0.285–1.161)
|
poorly
|
|
0.685(0.505–0.929)
|
|
0.704(0.517–0.959)
|
Chemotherapy
|
< 0.001
|
|
< 0.01
|
|
yes
|
|
0.380(0.261–0.556)
|
|
0.550(0.364–0.830)
|
no
|
|
Reference
|
|
Reference
|
pT stage
|
< 0.001
|
|
< 0.01
|
|
T1a
|
|
Reference
|
|
Reference
|
T1b
|
|
0.440(0.285–0.679)
|
|
0.564(0.357–0.889)
|
T2
|
|
0.333(0.206–0.539)
|
|
0.399(0.243–0.657)
|
Considering the 3- and 5-year DSS rates, the calibration plots show that the predicted probabilities of DSS are in good agreement with the actual probabilities (Fig. 4C, 4D). Finally, we performed a DCA to evaluate the clinical use of the nomogram, which demonstrated its clinical value in predicting survival (Fig. 5).