Prognostic value of changes in serum carcinoembryonic antigen levels for preoperative chemoradiotherapy response in locally advanced rectal cancer

Table 1 Predictive factor for response of preoperative chemoradiation therapy for rectal cancer in the literature

Ref.	Study design	pCR (%)	Related factor with response of preoperative CRT	Independent factor for pCR
Restivo et al[7], 2013	Prospective (n = 260)	16.5%		CEA < 5 ng/mL and distance from anal verge > 5 cm
Huh et al[8], 2013	Retrospective (n = 391)	14.6%	Noncircumferential tumors, nonmacroscopic ulceration, WELL differentiation, Early T, N stage, low level of pretreatment CEA	Tumor circumferentiality, macroscopic ulceration, pretreatment CEA < 5 ng/mL
Wallin et al[9], 2013	Retrospective (n = 469)	20.0%		Pretreatment CEA ≤ 5 ng/mL
Kleiman et al[10], 2015	Prospective (n = 141)	13.5%		Low post CRT CEA level, normalization of CEA from initial elevated; CEA level
Hu et al[11], 2018	Prospective (n = 146)	15.0%	CEA exponential decrease group between pretreatment and during-CRT: Higher rates of downstaging and pCR	CEA clearance pattern
Yamamoto et al[12], 2019	Prospective (n = 111)		Combination of lymphocyte to monocyte ratio (LMR) and ypN; status: poor prognosis	Low pretreatment LMR ypN(+)

pCR: Pathologic complete response; CEA: Carcinoembryonic antigen; CRT: Chemoradiation treatment.

Table 2 Patient characteristics

Characteristics	Distribution
Age (yr, mean ± SD)	60.1 ± 10.9
Sex
Male	99 (73.3%)
Female	36 (26.7%)
BMI (kg/m2, mean ± SD)	22.9 ± 3.1
Smoker	46 (34.1%)
ASA
1	80 (59.3%)
2	40 (29.6%)
3	14 (10.4%)
4	1 (0.7%)
Distance of tumor from the anal verge (cm, mean ± SD)	6.4 ± 3.0
Pre-CRT CEA (ng/mL, mean ± SD)	18.1 ± 45.0
Pre-CRT tumor size (cm, mean ± SD)	4.6 ± 1.4
Pre-CRT TNM stage
I	1 (0.7%)
II	13 (9.6%)
III	121 (89.6%)
Curative resection after CRT
Low anterior resection	64 (47.4%)
Ultra-low anterior resection	17 (12.6%)
Abdominoperineal resection	46 (34.1%)
Hartmann operation	7 (5.2%)
Total colectomy	1 (0.7%)
Radiation dose, cGy	5040
Interval from preoperative CRT to operation (wk)	7.8 ± 1.7
Post-CRT CEA (ng/mL)	4.8 ± 8.1
Down-staging after preoperative CRT	60 (44.4%)
Pathologic complete response	27 (20.0%)
Adjuvant chemotherapy	121 (89.6%)
Follow-up (mo)	60.4 ± 24.3

SD: Standard deviation; BMI: Body mass index; ASA: American Society of Anesthesiology; CEA: Carcinoembryonic antigen; TNM: Tumor Node Metastasis; CRT: Chemoradiotherapy. I

Table 3 Comparison of the changes in the carcinoembryonic antigen level before and after chemoradiotherapy

Variables	Group A (n = 27)	Group B (n = 43)	Group C (n = 65)	P value
Age, yr				> 0.999
< 65	17 (63.0%)	27 (62.8%)	41 (63.1%)
≥ 65	10 (37.0%)	16 (37.2%)	24 (36.9%)
Sex				0.358
Male	21 (77.8%)	34 (79.1%)	44 (67.7%)
Female	6 (22.2%)	9 (20.9%)	21 (32.3%)
ASA				0.734
< 3	23 (85.2%)	38 (88.4%)	59 (90.8%)
≥ 3	4 (14.8%)	5 (11.6%)	6 (9.2%)
Pre-CRT tumor size (cm)	4.6 (3.7-5.0)	4.5 (4.0-5.1)	4.3 (3.8-5.0)	0.515
Pre-CRT CEA (ng/mL)	25.8 (10.6-70.7)	11.3 (6.8-21.3)	2.4 (1.8-3.3)	< 0.001
Pre-CRT NLR				0.983
< 2.8	17 (63.0%)	28 (65.1%)	42 (64.6%)
≥ 2.8	10 (37.0%)	15 (34.9%)	23 (35.4%)
Pre-CRT PLR				0.132
< 138.2	11 (40.7%)	19 (44.2%)	39 (60.0%)
≥ 138.2	16 (59.3%)	24 (55.8%)	26 (40.0%)
Pre-CRT T stage				0.217
T3	18 (66.7%)	34 (79.1%)	54 (83.1%)
T4	9 (33.3%)	9 (20.9%)	11 (16.9%)
Pre-CRT N stage				0.021
N0	1 (3.7%)	1 (2.3%)	11 (16.9%)
N+	26 (96.3%)	42 (97.7%)	54 (83.1%)
Pre-CRT TNM stage				0.021
I	1 (3.7%)	0	0
II	1 (3.7%)	1 (2.3%)	11 (16.9%)
III	25 (92.6%)	42 (97.7%)	54 (83.1%)
Post-CRT CEA (ng/dL)	8.4 (6.0–13.7)	2.9 (2.0–4.0)	1.8 (1.2–2.9)	< 0.001
Post-CRT T stage				0.001
0–2	3 (11.1%)	5 (11.6%)	25 (38.5%)
3–4	24 (88.9%)	38 (88.4%)	40 (61.5%)
Post-CRT N stage				0.006
N0	8 (29.6%)	20 (46.5%)	42 (64.6%)
N+	19 (70.4%)	23 (53.5%)	23 (35.4%)
Post-CRT M stage				0.090
0	25 (92.6%)	42 (97.7%)	65 (100%)
1	2 (7.4%)	1 (2.3%)	0
Post-CRT TNM Stage				0.008
0	0	0	2 (3.1%)
I	2 (7.4%)	4 (9.3%)	19 (29.2%)
II	5 (18.5%)	15 (34.9%)	21 (32.3%)
III	19 (66.7%)	23 (53.5%)	23 (35.4%)
IV	2 (7.4%)	1 (2.3%)	0
Down-staging on MRI after CRT				0.013
No	21 (77.8%)	25 (58.1%)	29 (44.6%)
Yes	6 (22.2%)	18 (41.9%)	36 (55.4%)

Group A: Patients with pre- and post-CRT CEA levels > 5 ng/mL; Group B: Patients with pre- and post-CRT CEA levels > 5 and ≤ 5 ng/mL, respectively; Group C: Patients with pre- and post-CRT CEA levels ≤ 5 ng/mL. ASA: American Society of Anesthesiology; CRT: Chemoradiotherapy; CEA: Carcinoembryonic antigen; NLR: Neutrophil–lymphocyte ratio; PLR: Platelet–lymphocyte ratio; TNM: Tumor Node Metastasis; MRI: Magnetic resonance imaging.

Table 4 Comparison of the changes in the carcinoembryonic antigen level after curative resection

Variables	Group A (n = 27)	Group B (n = 43)	Group C (n = 65)	P value
Name of surgery				0.272
Low anterior resection	15 (55.6%)	22 (51.2%)	43 (66.2%)
Others1	12 (44.4%)	21 (48.8%)	22 (33.8%)
Differentiation				0.781
Well–Moderate	8 (29.6%)	13 (30.2%)	16 (24.6%)
Poorly + others2	19 (70.4%)	30 (69.8%)	49 (75.4%)
Lymphovascular invasion				0.444
No	22 (81.5%)	35 (81.4%)	58 (89.2%)
Yes	5 (18.5%)	8 (18.6%)	7 (10.8%)
Perineural invasion				0.005
No	21 (77.8%)	38 (88.4%)	64 (98.5%)
Yes	6 (22.2%)	5 (11.6%)	1 (1.5%)
Postoperative T stage				< 0.001
0–2	2 (7.4%)	11 (25.6%)	38 (58.5%)
3–4	25 (92.6%)	32 (74.4%)	27 (41.5%)
Postoperative N stage				0.538
N0	15 (55.6%)	27 (62.8%)	44 (67.7%)
N+	12 (44.4%)	16 (37.2%)	21 (32.3%)
Postoperative M stage				0.002
M0	24 (88.9%)	43 (100%)	65 (100%)
M1	3 (11.1%)	0	0
Postoperative TNM stage				< 0.001
0	0	3 (7.0%)	25 (38.5%)
I	2 (7.4%)	5 (11.6%)	8 (12.3%)
II	13 (48.1%)	19 (44.2%)	11 (16.9%)
III	9 (33.3%)	16 (37.2%)	21 (32.3%)
IV	3 (11.1%)	0	0
CEA on postoperative day 7	3.7 (2.8-5.2)	1.6 (1.1-2.2)	1.1 (0.7-1.7)	< 0.001
Tumor regression grade				< 0.001
0	1 (3.7%)	3 (7.0%)	26 (40.0%)
1	7 (25.9%)	23 (53.5%)	18 (27.7%)
2	11 (40.7%)	14 (32.6%)	17 (26.2%)
3	8 (29.6%)	3 (7.0%)	4 (6.2%)
Good response (TRG 0,1)				0.003
TRG 0, 1	8 (29.6%)	26 (60.5%)	44 (67.7%)
TRG 2, 3	19 (70.4%)	17 (39.5%)	21 (32.3%)
Pathologic complete response				< 0.001
pCR (-)	27 (100%)	41 (95.3%)	40 (61.5%)
pCR (+)	0	2 (4.7%)	25 (38.5%)

Group A: patients with pre- and post-CRT CEA levels > 5 ng/mL; Group B: patients with pre- and post-CRT CEA levels > 5 and ≤ 5 ng/mL, respectively; and Group C: patients with pre- and post-CRT CEA levels ≤ 5 ng/mL. Name of surgery,

¹others abdominoperineal resection, Hartmann’s operation, subtotal or total colectomy; Differentiation,

²others mucinous, signet ring cell. TNM: Tumor Node Metastasis; CEA: Carcinoembryonic antigen; TRG: Tumor regression grade.

Table 5 Comparison of the non- pathologic complete response and pathologic complete response groups after the chemoradiotherapy following surgical resection

Variables	Non-pCR (n = 108)	pCR (n = 27)	P value
Pre-CRT tumor size (cm, mean ± SD)	4.7 ± 1.5	4.4 ± 1.3	0.246
Pre-CRT CEA, ng/mL			< 0.001
CEA ≤ 5	40 (37.0%)	25 (92.6%)
CEA > 5	68 (63.0%)	2 (7.4%)
Pre-CRT T stage			0.875
T3	84 (77.8%)	22 (81.5%)
T4	24 (22.2%)	5 (18.5%)
Pre-CRT N stage			0.004
N0	6 (5.6%)	7 (25.9%)
N+	102 (94.4%)	20 (74.1%)
Pre-CRT TNM stage			0.005
I	1 (0.9%)	0
II	6 (5.6%)	7 (25.9%)
III	101 (93.5%)	20 (74.1%)
Post-CRT CEA, ng/mL			0.008
≤ 5	81 (75.0%)	27 (100%)
> 5	27 (25.0%)	0
Downstaging after CRT			0.051
No	65 (60.2%)	10 (37.0%)
Yes	43 (39.8%)	17 (63.0%)
Differentiation			> 0.999
Well–Moderate	30 (27.8%)	7 (25.9%)
Poor + others1	78 (72.2%)	20 (74.1%)
Lymphovascular invasion			0.034
No	88 (81.5%)	27 (100%)
Yes	20 (18.5%)	0
Perineural invasion			0.151
No	96 (88.9%)	27 (100%)
Yes	12 (11.1%)	0

¹Mucinous, signet ring cell, pCR: Pathologic complete response; CRT: Chemoradiotherapy; SD: Standard deviation; CEA: Carcinoembryonic antigen; TNM: Tumor node metastasis.

Table 6 Multivariate analysis for prognostic markers to predict the response to the chemoradiotherapy

	Pathologic complete response		Good response (TRG 0,1)
	OR (95%CI)	P value	OR (95%CI)	P value
Sex (female vs male)	0.26 (0.08–0.80)	0.022
Pre-CRT CEA (> 5 vs ≤ 5 ng/mL)	18.71 (4.62–129.51)	< 0.001
Pre-CRT NLR (≥ 2.8 vs < 2.8)	5.27 (1.55–22.55)	0.013	2.82 (1.27–6.48)	0.013
Post-CRT CEA (> 5 vs ≤ 5 ng/mL)			5.07 (1.92–14.83)	0.002
Post-CRT T stage (≥ T3 vs < T3)	3.25 (1.09–9.97)	0.036	3.28 (1.23–9.90)	0.023
Postop differentiation (poorly1vs well-mod.)			3.41 (1.35–9.48)	0.013

¹Mucinous, signet ring cell, OR: Odds ratio; CI: Confidence interval; TRG: Tumor regression grade; CRT: Chemoradiotherapy; CEA: Carcinoembryonic antigen; NLR: Neutrophil–lymphocyte ratio.