Dynamic monitoring of serum tumor markers in predicting recurrence after radical gastrectomy for gastric cancer

Table 1 Comparison of clinical pathological characteristics between recurrence and non-recurrence groups, n (%)

Characteristic	Recurrence group (n = 68)	Non-recurrence group (n = 145)	Test statistic	P value
Age (years)	61.8 ± 10.2	60.5 ± 11.4	t = 0.816	0.416
Gender			χ² = 0.125	0.724
Male	46 (67.6)	95 (65.5)
Female	22 (32.4)	50 (34.5)
BMI (kg/m²)	22.8 ± 3.1	23.2 ± 2.9	t = 0.925	0.356
Underlying diseases	28 (41.2)	53 (36.6)	χ² = 0.486	0.486
Tumor location			χ² = 2.815	0.245
Upper stomach	15 (22.1)	25 (17.2)
Body of stomach	23 (33.8)	48 (33.1)
Lower stomach	30 (44.1)	72 (49.7)
Histological type			χ² = 1.847	0.397
Papillary adenocarcinoma	8 (11.8)	22 (15.2)
Tubular adenocarcinoma	35 (51.5)	81 (55.9)
Mucinous adenocarcinoma	15 (22.1)	26 (17.9)
Signet ring cell carcinoma	10 (14.7)	16 (11.0)
Tumor size			χ² = 8.927	0.003
< 5 cm	28 (41.2)	88 (60.7)
≥ 5 cm	40 (58.8)	57 (39.3)
Degree of differentiation			χ² = 11.456	< 0.001
Well-moderately differentiated	18 (26.5)	71 (49.0)
Poorly differentiated-undifferentiated	50 (73.5)	74 (51.0)
T stage			χ² = 18.245	< 0.001
T1-T2	12 (17.6)	62 (42.8)
T3-T4	56 (82.4)	83 (57.2)
N stage			χ² = 24.186	< 0.001
N0	8 (11.8)	52 (35.9)
N1-N3	60 (88.2)	93 (64.1)
TNM stage			χ² = 21.347	< 0.001
Stage I	5 (7.4)	38 (26.2)
Stage II	22 (32.4)	58 (40.0)
Stage III	41 (60.3)	49 (33.8)
Vascular invasion	42 (61.8)	55 (37.9)	χ² = 11.258	< 0.001
Neural invasion	38 (55.9)	48 (33.1)	χ² = 10.525	0.001
Surgical method			χ² = 0.846	0.358
Distal subtotal gastrectomy	46 (67.6)	107 (73.8)
Total gastrectomy	22 (32.4)	38 (26.2)
Extent of lymph node dissection			χ² = 1.124	0.289
D1+	15 (22.1)	42 (29.0)
D2	53 (77.9)	103 (71.0)

TNM: Tumor-node-metastasis; BMI: Body mass index.

Table 2 Comparison of preoperative and 1-month postoperative serum tumor marker levels between recurrence and non-recurrence groups [M (Q1, Q3)]

Marker	Time point	Recurrence group (n = 68)	Non-recurrence group (n = 145)	Z value	P value
CEA (ng/mL)	Preoperative	8.5 (4.2, 15.8)	3.8 (2.1, 6.5)	-5.126	< 0.001
	1 month postoperative	4.2 (2.5, 7.8)	2.3 (1.4, 3.8)	-4.285	< 0.001
CA19-9 (U/mL)	Preoperative	52.3 (24.5, 98.6)	21.8 (12.3, 42.5)	-4.863	< 0.001
	1 month postoperative	28.6 (15.2, 52.3)	14.5 (8.3, 25.6)	-4.157	< 0.001
CA72-4 (U/mL)	Preoperative	12.8 (5.6, 28.4)	4.8 (2.5, 9.2)	-5.347	< 0.001
	1 month postoperative	6.5 (3.2, 14.5)	2.8 (1.5, 5.2)	-4.526	< 0.001
CA125 (U/mL)	Preoperative	48.5 (22.3, 86.7)	18.6 (10.2, 32.5)	-5.694	< 0.001
	1 month postoperative	24.8 (12.5, 45.6)	11.3 (6.8, 18.5)	-4.872	< 0.001

CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4; CA125: Carbohydrate antigen 125.

Table 3 Comparison of dynamic change patterns of tumor markers between recurrence and non-recurrence groups, n (%)

Marker	Dynamic change pattern	Recurrence group (n = 68)	Non-recurrence group (n = 145)	χ²	P value
CEA	Persistently normal	13 (19.1)	82 (56.6)	65.382	< 0.001
	Postoperative normalization	15 (22.1)	55 (37.9)
	Persistently elevated	8 (11.8)	2 (1.4)
	Recurrent elevation	17 (25.0)	5 (3.4)
	Progressive elevation	14 (20.6)	3 (2.1)
	Delayed elevation	1 (1.5)	1 (0.7)
	Subtotal	68 (100.0)	145 (100.0)
CA19-9	Persistently normal	16 (23.5)	88 (60.7)	58.642	< 0.001
	Postoperative normalization	16 (23.5)	48 (33.1)
	Persistently elevated	6 (8.8)	1 (0.7)
	Recurrent elevation	16 (23.5)	6 (4.1)
	Progressive elevation	16 (23.5)	3 (2.1)
	Delayed elevation	2 (2.9)	1 (0.7)
	Subtotal	68 (100.0)	145 (100.0)
CA72-4	Persistently normal	19 (27.9)	92 (63.4)	52.847	< 0.001
	Postoperative normalization	17 (25.0)	46 (31.7)
	Persistently elevated	6 (8.8)	1 (0.7)
	Recurrent elevation	15 (22.1)	4 (2.8)
	Progressive elevation	15 (22.1)	3 (2.1)
	Delayed elevation	4 (5.9)	2 (1.4)
	Subtotal	68 (100.0)	145 (100.0)
CA125	Persistently normal	21 (30.9)	95 (65.5)	50.126	< 0.001
	Postoperative normalization	16 (23.5)	42 (29.0)
	Persistently elevated	6 (8.8)	2 (1.4)
	Recurrent elevation	14 (20.6)	5 (3.4)
	Progressive elevation	15 (22.1)	3 (2.1)
	Delayed elevation	4 (5.9)	1 (0.7)
	Subtotal	68 (100.0)	145 (100.0)

Percentages were recalculated to ensure subtotals equal 1000% for each group, using rounding to one decimal place. CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4; CA125: Carbohydrate antigen 125.

Table 4 Comparison of dynamic change rates of tumor markers at different postoperative time points between recurrence and non-recurrence groups [M (Q1, Q3), %]

Marker	Time point	Recurrence group (n = 68)	Non-recurrence group (n = 145)	Z value	P value
CEA	3 months postoperative	12.5 (-8.5, 35.8)	-8.2 (-18.6, -2.3)	-6.847	< 0.001
	6 months postoperative	28.6 (5.2, 68.9)	-10.5 (-22.1, -3.6)	-7.562	< 0.001
	12 months postoperative	52.8 (18.5, 125.6)	-12.3 (-25.8, -4.2)	-8.324	< 0.001
	18 months postoperative	85.6 (32.4, 186.5)	-14.6 (-28.5, -5.5)	-8.891	< 0.001
CA19-9	3 months postoperative	10.8 (-10.2, 32.5)	-6.8 (-15.3, -1.8)	-6.524	< 0.001
	6 months postoperative	25.3 (3.8, 62.5)	-8.5 (-18.9, -2.5)	-7.215	< 0.001
	12 months postoperative	48.5 (15.6, 115.8)	-10.6 (-21.2, -3.3)	-7.968	< 0.001
	18 months postoperative	78.9 (28.5, 168.7)	-12.5 (-24.6, -4.8)	-8.456	< 0.001
CA72-4	3 months postoperative	15.6 (-6.8, 38.9)	-7.5 (-16.8, -2.6)	-6.685	< 0.001
	6 months postoperative	32.5 (8.5, 72.6)	-9.8 (-20.5, -3.9)	-7.328	< 0.001
	12 months postoperative	58.6 (20.8, 132.5)	-11.5 (-23.6, -4.5)	-8.125	< 0.001
	18 months postoperative	92.5 (35.6, 195.8)	-13.8 (-26.9, -5.8)	-8.652	< 0.001
CA125	3 months postoperative	13.8 (-9.5, 36.5)	-6.6 (-14.5, -2.2)	-6.458	< 0.001
	6 months postoperative	30.5 (6.8, 65.8)	-8.2 (-17.8, -3.5)	-7.142	< 0.001
	12 months postoperative	55.8 (18.2, 120.5)	-10.5 (-20.8, -4.8)	-7.895	< 0.001
	18 months postoperative	88.6 (30.5, 178.6)	-12.2 (-23.5, -5.6)	-8.358	< 0.001

Change rate = (test value at each follow-up time point - 1-month postoperative baseline value)/1-month postoperative baseline value × 100%. The higher change rate in the recurrence group at 18 months postoperatively reflects the significant upward trend in markers in recurrent patients. CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4; CA125: Carbohydrate antigen 125.

Table 5 Predictive value of preoperative tumor markers for recurrence

Marker	Cutoff value	AUC	95%CI	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	vs four combined P value	Significance after correction
CEA	6.2 ng/mL	0.742	0.673-0.811	67.6	72.4	53.6	82.5	0.032	NS (α = 0.0125)
CA19-9	38.5 U/mL	0.718	0.646-0.790	64.7	70.3	50.8	80.7	0.015	NS (α = 0.0125)
CA72-4	8.5 U/mL	0.756	0.688-0.824	70.6	75.2	56.9	84.2	0.041	NS (α = 0.0125)
CA125	32.5 U/mL	0.738	0.668-0.808	66.2	73.1	52.7	82.8	0.028	NS (α = 0.0125)
Four combined	-	0.825	0.765-0.885	80.9	76.6	62.8	89.2	Reference	Reference

Bonferroni method was used to correct for multiple comparisons, with corrected significance level α = 0.0125 (0.05/4). AUC: Area under the curve; CI: Confidence interval; NS: Not significant; PPV: Positive predictive value; NPV: Negative predictive value; CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4; CA125: Carbohydrate antigen 125.

Table 6 Predictive value of dynamic change patterns of tumor markers for recurrence

Change pattern	Marker	AUC	95%CI	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	vs preoperative combined P value	vs four combined progressive elevation P value	Significance after correction
Progressive elevation	CEA	0.856	0.802-0.910	75	85.5	72.9	86.8	< 0.001	0.028	NS (α = 0.0125)
	CA19-9	0.842	0.786-0.898	72.1	84.1	70.6	85.2	< 0.001	0.021	Significant (α = 0.0125)
	CA72-4	0.838	0.781-0.895	69.1	86.9	73.4	84.3	< 0.001	0.019	Significant (α = 0.0125)
	CA125	0.831	0.773-0.889	67.6	85.5	71.9	83.2	< 0.001	0.015	Significant (α = 0.0125)
	Four combined	0.912	0.869-0.955	85.3	89	80.6	91.5	0.003	Reference	Reference
Recurrent elevation	CEA	0.801	0.740-0.862	73.5	78.6	64.1	85	< 0.001	< 0.001	-
	CA19-9	0.794	0.732-0.856	70.6	77.2	62.3	83.3	< 0.001	< 0.001	-
	CA72-4	0.787	0.724-0.850	67.6	79.3	63.9	82.1	< 0.001	< 0.001	-
	CA125	0.778	0.714-0.842	64.7	78.6	61.1	81	< 0.001	< 0.001	-
	Four combined	0.868	0.818-0.918	79.4	83.4	73	87.8	0.015	0.008	-

Bonferroni method was used to correct for multiple comparisons, with corrected significance level α = 0.0125 (0.05/4). Recurrent elevation pattern was not analyzed with multiple comparison correction. AUC: Area under the curve; CI: Confidence interval; NS: Not significant; PPV: Positive predictive value; NPV: Negative predictive value; CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4; CA125: Carbohydrate antigen 125.

Table 7 Multivariate Cox regression analysis of factors affecting recurrence after radical gastrectomy

Variable	HR	95%CI	P value
Tumor size ≥ 5 cm (vs < 5 cm)	2.156	1.287-3.613	0.004
Poorly differentiated-undifferentiated (vs well-moderately differentiated)	2.024	1.168-3.508	0.012
TNM stage III (vs stage I-II)	3.245	1.856-5.672	< 0.001
Vascular invasion (yes vs no)	1.847	1.098-3.108	0.021
Neural invasion (yes vs no)	1.726	1.045-2.852	0.033
Progressive elevation of CEA (yes vs no)	3.124	1.687-5.786	< 0.001
Progressive elevation of CA19-9 (yes vs no)	2.856	1.542-5.291	0.001
Progressive elevation of CA72-4 (yes vs no)	2.634	1.418-4.895	0.002
Progressive elevation of CA125 (yes vs no)	2.487	1.325-4.667	0.005
Recurrent elevation of CEA (yes vs no)	2.145	1.158-3.972	0.015
Recurrent elevation of CA19-9 (yes vs no)	1.967	1.054-3.672	0.034

T stage and N stage were removed due to collinearity with tumor-node-metastasis stage (variance inflation factor > 5). Recurrent elevation of carbohydrate antigen 72-4 [hazard ratio (HR) = 1.756, 95%CI: 0.912-3.382, P = 0.092] and carbohydrate antigen 125 (HR = 1.684, 95%CI: 0.875-3.242, P = 0.118) did not reach statistical significance (P > 0.05) in multivariate analysis and were excluded from the final model after stepwise backward selection. Stepwise backward method was used with exclusion criterion P > 0.10. CI: Confidence interval; CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4; CA125: Carbohydrate antigen 125; TNM: Tumor-node-metastasis; HR: Hazard ratio.

Table 8 Median disease-free survival of patients with different dynamic change patterns of tumor markers

Marker	Dynamic change pattern	Number of cases	Median DFS (months)	χ²	P value
CEA	Persistently normal	95	Not reached [median follow-up 36.5 months, 36-month survival rate 926% (85.3-96.5%)]	86.524	< 0.001
	Postoperative normalization	70	42.0 (35.0, 48.0)
	Persistently elevated	10	15.5 (12.0, 19.0)
	Recurrent elevation	22	18.0 (15.0, 22.0)
	Progressive elevation	14	12.0 (9.0, 16.0)
	Delayed elevation	2	20.0 (16.0, 25.0)
	Subtotal	213
CA19-9	Persistently normal	104	Not reached [median follow-up 36.5 months, 36-month survival rate 933% (86.8-96.8%)]	78.326	< 0.001
	Postoperative normalization	64	40.0 (34.0, 46.0)
	Persistently elevated	7	14.0 (11.0, 18.0)
	Recurrent elevation	22	17.0 (14.0, 21.0)
	Progressive elevation	19	11.0 (8.0, 15.0)
	Delayed elevation	3	19.0 (15.0, 24.0)
	Subtotal	213
CA72-4	Persistently normal	111	Not reached [median follow-up 36.5 months, 36-month survival rate 946% (88.5-97.6%)]	74.185	< 0.001
	Postoperative normalization	63	39.0 (33.0, 45.0)
	Persistently elevated	7	13.5 (10.0, 17.0)
	Recurrent elevation	19	16.0 (13.0, 20.0)
	Progressive elevation	18	10.0 (7.0, 14.0)
	Delayed elevation	6	18.0 (14.0, 23.0)
	Subtotal	213
CA125	Persistently normal	116	Not reached [median follow-up 36.5 months, 36-month survival rate 957% (90.2-98.2%)]	70.847	< 0.001
	Postoperative normalization	58	38.0 (32.0, 44.0)
	Persistently elevated	8	12.5 (9.0, 16.0)
	Recurrent elevation	19	15.0 (12.0, 19.0)
	Progressive elevation	17	9.0 (7.0, 13.0)
	Delayed elevation	5	17.0 (13.0, 22.0)
	Subtotal	213

Median disease-free survival is expressed as median (quartiles) [M (Q1, Q3)]. DFS: Disease-free survival; CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4; CA125: Carbohydrate antigen 125.