Dynamic monitoring of carcinoembryonic antigen, CA19-9 and inflammation-based indices in patients with advanced colorectal cancer undergoing chemotherapy

Table 1 Patients’ demographic and clinical features

Patients’ demographic and clinical features
Gender	n (%)
Male	71 (69.6)
Female	31 (30.4)
Age	63.37 ± 10.21; (35-81)
Primary localization	n (%)
Rectum	42 (41.2)
Left colon	44 (43.1)
Right colon	16 (15.7)
Localization of metastasis	n (%)
Liver	91 (89.2)
Lung	38 (37.3)
Peritoneum	13 (12.7)
Lymph nodes	38 (37.3)
Tumour grade	n (%)
HG1	51 (50.0)
HG2	45 (44.1)
HG3	6 (5.9)
Chemotherapy 1st-line
Fluoropyrimidines + oxaliplatin	61 (59.8)
Fluoropyrimidines + irinotecan	14 (13.7)
Bevacizumab + (fluoropyrimidines + oxaliplatin); or (fluoropyrimidines + irinotecan)	20 (19.6)
EGFR inhibitors + (fluoropyrimidines + oxaliplatin); or (fluoropyrimidines + irinotecan)	4 (6.9)
Chemotherapy 1st-line (cont) or 2nd-line	n (%)
Fluoropyrimidines + oxaliplatin	53 (52.0)
Fluoropyrimidines + irinotecan	21 (20.6)
Bevacizumab + (fluoropyrimidines + oxaliplatin); or (fluoropyrimidines + irinotecan)	15 (14.7)
EGFR inhibitors + (fluoropyrimidines + oxaliplatin); or (fluoropyrimidines + irinotecan)	13 (12.7)

Data are presented as the mean ± SD or n (%).

Table 2 Carcinoembryonic antigen and carbohydrate antigen and inflammatory index characteristics at baseline and at the 1^st and 2^nd evaluations

Markers	Baseline	1st evaluation	2nd evaluation
CEA1	6.99 (2.50-61.46)	5.86 (1.88-29.43)	6.53 (1.55-36.02)
CA19-91	2.68 (1.1-23.58)	2.76 (0.91-9.21)	3.13 (0.76-11.86)
NLR	2.22 (1.60-3.64)	1.77 (1.18-2.65)	2.19 (1.43-3.17)
PLR	144.87 (93.64-213.97)	115.43 (82.78-170.98)	141.19 (92.82-187.82)
LMR	3.92 (2.56-5.58)	4.21 (2.62-5.43)	3.56 (2.62-5.00)
SII	614.89 (298.31-1219.48)	339.34 (227.13-570.24)	475.02 (238.59-858.52)

¹Values are expressed as × upper normal limit for carcinoembryonic antigen and carbohydrate antigen, not as the absolute value; the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio and systemic immune-inflammation index calculated as the absolute value × 10⁹/L. Data are presented as median (interquartile range). CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; LMR: Lymphocyte-to-monocyte ratio; SII: Systemic immune-inflammation index.

Table 3 Any change in tumour markers and inflammatory indices and changes according to cut-off values

204 RECIST
204 CEA	130 CA19-9	116 NLR, PLR, LMR and SII
PD 31%	PD/DC	DC 69%
CEA: 82%↑; 18%↓	↔a	CEA: 28%↑; 72%↓
↕c		↕c
∆CEA (24.52%): 80.3%↑; 19.7%↓	↔a	∆CEA (24.52%): 19.6%↑; 80.4%↓
CA19-9: 75.6%↑ ; 24.4%↓	↔a	CA19-9: 33.7%↑; 66.3%↓
↕c		↕c
∆CA19-9 (21.49%): 73.2%↑; 26.8%↓	↔a	∆CA19-9 (21.49%): 30.3%↑; 69.7%↓
NLR: 45%↑; 55%↓	↔c	NLR: 54.2↑; 45.8%↓
↕c		↕b
∆NLR (11.05%): 66.7%↑; 33.3%↓	↔a	∆NLR (11.05%): 33.7%↑ 66.3%↓
PLR: 55%↑; 45%↓	↔c	PLR: 44.8%↑; 55.2%↓
↕c		↕c
∆PLR (5.90%): 52.8%↑; 47.2%↓	↔b	∆PLR (5.90%): 32.5%↑; 67.5%↓
LMR: 45%↑; 55%↓	↔c	LMR: 41.7%↑; 58.3%↓
SII: 30%↑; 70%↓	↔c	SII: 42.7%↑; 57.3%↓
↕a		↕c
∆SII (-6.04%): 72.2%↑; 27.8%↓	↔a	∆SII (-6.04%): 33.7%↑; 66.3%↓

^aP > 0.01.

^bP < 0.05.

^cP > 0.05.

Carcinoembryonic antigen, carbohydrate antigen, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio (LMR) and systemic immune-inflammation index any increase or decrease of value; ∆- increase or decrease defined by cut-off obtained with receiver operating characteristic analysis; ↕ and ↔ statistical analysis with χ² test; ∆LMR cut-off was not determined. PD: Progressive disease; DC: Disease control; SD: Stable disease (CR + PR + SD); CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; LMR: Lymphocyte-to-monocyte ratio; SII: Systemic immune-inflammation index.

Table 4 Area under the curve and cut-off values

Test result variable (s)	Area	Asymptotic Sig.	Asymptotic 95% CI
			Lower bound	Upper bound	Cut- off value for PD, %	Sensitivity	Specificity	Cut -off value for sensitivity 1, %	Specificity for sensitivity 1	Avoidable CT, %
∆CEA	0.842g	0.000	0.788	0.895	24.52	0.803	0.804	-60.85	0.357	52 (25.49)
∆CA19-9	0.769f	0.000	0.665	0.874	21.49	0.67	0.76	-55.38	0.396	22 (16.92)
∆NeLR	0.713f	0.000	0.614	0.182	11.05	0.67	0.66	-77.85	0.013	2 (3.4%)
∆LMR	0.451fl	P > 0.05	0.309	0.562
∆PLR	0.622p	0.036	0.511	0.733	5.9	0.53	0.68	-59.33	0.075	6 (10.3)
∆SII	0.723f	0.000	0.625	0.82	-6.04	0.72	0.63	-88.62	0.013	2 (3.4)

^eP ≥ 0.9-1 excellent.

^gP ≥ 0.8-0.9 good.

^fP ≥ 0.7-0.8 fair/acceptable.

^pP ≥ 0.6-0.7 poor.

^flP ≥ 0.5-0.6 failed, that’s a qualitative interpretation of the area under the curve (AUC). The area under the receiver operating characteristic curve (AUC) results were considered excellent for AUC values between 0.9 and 1, good for AUC values between 0.8 and 0.9, fair for AUC values between 0.7 and 0.8, poor for AUC values between 0.6 and 0.7 and failed for AUC values between 0.5 and 0.6. CEA: Carcinoembryonic antigen.

Table 5 Binary logistic regression, and univariate and multivariate analyses

Markers	Univariate logistic regression	Multivariate logistic regression
CEA	1.005 (1.002-1.008), P < 0.001	1.004 (1.000-1.007); P = 0.044
CA19-9	1.005 (1.001-1.008), P = 0.015	1.001 (0,998-1.004), P > 0.05
NLR	1.011 (1.004-1.018), P = 0.001	1.015 (0.996-1.034), P > 0.05
PLR	1.009 (1.001-1.018), P = 0.034	1.003 (0.986-1.021), P > 0.05
LMR	1.000 (0.993-1.007), P > 0.05
SII	1.006 (1.002- 1.010), P = 0.004	0.997 (0.985-1.009), P > 0.05

Dynamic change in markers and dichotomous response evaluation criteria in solid tumour 1.1 outcomes progressive disease (PD) and non-PD (disease control). Data are presented as Exp(B) with 95%CI for EXP(B). CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; LMR: Lymphocyte-to-monocyte ratio; SII: Systemic immune-inflammation index.

Table 6 Diagnostic characteristics of carcinoembryonic antigen, carbohydrate antigen, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and systemic immune-inflammation index

Parameters	Se	Sp	PPV	NPV	CUI-(Ve+)	CUI-(Ve-)	FC
CEA	86.9 (78.4-95.4)	79.7 (73.1-86.3)	64.6 (54.3-75.0)	93.4 (89.1-97.8)	0.561 (0.44-0.68)	0.752 (0.64-0.80)	81.94
CA19-9	80.6 (67.6-95.5)	72.5 (62.7-82.3)	56.9 (43.3-70.5)	89.2 (81.7-96.8)	0.46 (0.29-0.63)	0.652 (0.57-0.73)	753
NLR	68.8 (53.2-84.0)	66.7 (56.4-76.9)	47.1 (33.4-60.8)	83.1 (74.0-92.2)	0.32 (0.14-0.50)	0.551 (0.46-0.64)	67.2
PLR	53.8 (34.7-73.1)	81.3 (67.7-94.8)	70.0 (49.9-90.1)	68.4 (53.6-83-2)	0.38 (0.13-0.62)	0.551 (0.43-0.68)	69
CII	70.3 (55.5-85.0)	65.9 (55.6-76.1)	48.1 (34.8-61.5)	83.1 (74.0-97.2)	0.34 (0.16-0.50)	0.551 (0.46-0.64)	67.2

¹Satisfactory/adequate clinical utility index (CUI).

²Good CUI.

³Overall utility satisfactory/adequate.

⁴Overall utility good. A qualitative interpretation of the clinical utility index: (E) ≥ 0.81 excellent; (G) ≥ 0.64 good; (SA) ≥ 0.49 satisfactory/adequate; (P) ≥ 0.36 poor; (VP) < 0.36 very poor. Se: Sensitivity; Sp: Specificity; PPV: Positive predictive value; NPV: Negative predictive value; CUI+: Clinical utility index positive; CUI-: Clinical utility index negative; FC: Fraction correct; CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; SII: Systemic immune-inflammation index.