Received: 16 February 2021 | Revised: 6 April 2021 | Accepted: 18 April 2021

DOI: 10.1111/codi.15694

ORIGINAL ARTICLE

Prognostic significance of carcinoembryonic antigen combined

with carbohydrate antigen 19-­9 following neoadjuvant
chemoradiotherapy in patients with locally advanced rectal
cancer

Zhifang Zheng1,2 | Xiaojie Wang1,2 | Xingrong Lu1,2 | Ying Huang1,2 | Pan Chi1,2

1
Department of Colorectal Surgery,
Fujian Medical University Union Hospital,
Fuzhou, China
2
Department of General Surgery, Fujian
Medical University Union Hospital,
Fuzhou, China
Correspondence
Pan Chi, Department of Colorectal
Surgery, Fujian Medical University Union
Hospital, No. 29 Xinquan Road, Fuzhou
350001, Fujian Province, China.
Email: chipan363@163.com
Ying Huang, Department of Colorectal
Surgery, Fujian Medical University Union
Hospital, No. 29 Xinquan Road, Fuzhou
350001, Fujian Province, China.
Email: hy9033sy@sina.com
Funding information
This study was supported by Joint
Funds for the Innovation of Science
and Technology, Fujian Province (no.
2019Y9101), the Natural Science
Foundation of Fujian Province
(2020J011030), the Medical Science
Research Foundation of Beijing Medical
and Health Foundation (B20062DS) and
the Medical Innovation Project of Fujian
Province (2020CXA025).
Abstract
Aim: The clinical significance of carcinoembryonic antigen (CEA) combined with carbohy-
drate antigen 19-­9 (CA19-­9) in patients with rectal cancer is not well established. The aim
of this study was to determine the prognostic value of these combined tumour markers
in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemo-
radiotherapy (nCRT).
Method: A total of 687 consecutive patients with LARC who underwent nCRT and radical
surgery were analysed. Tumour characteristics, recurrence-­free survival (RFS) and over-
all survival (OS) were compared according to the number of elevated tumour markers
measured before and after nCRT. In addition, the prognostic significance of perioperative
changes in the combined tumour markers was further evaluated.
Result: The RFS and OS rates decreased in a stepwise manner in association with the
number of elevated pre-­and post-­nCRT tumour markers (all p < 0.05). Multivariate anal-
ysis showed that only the number of elevated post-­nCRT tumour markers was an in-
dependent prognostic factor (both p < 0.05). For 311 patients with elevated pre-­nCRT
tumour markers, normalization of the tumour markers after nCRT was an independent
prognostic protective factor (both p < 0.05), and patients with both markers elevated
post-­nCRT had a 2.5-­ and 3.7-­fold increased risk of recurrence and death, respectively
(p < 0.05). Furthermore, normalization of post-­nCRT tumour markers after surgery was
also closely related to an improved prognosis.
Conclusion: This combination of post-­nCRT tumour markers can accurately predict the
long-­term survival of patients with LARC treated with nCRT and curative resection, and
normalization of the combined tumour markers after either nCRT or surgery was associ-
ated with better survival.

KEYWORDS
rectal cancer, neoadjuvant chemoradiotherapy, carcinoembryonic antigen, carbohydrate antigen
19-­9, survival

ZZ and XW contributed equally to this work and should be considered as co-­f irst
authors.

© 2021 The Association of Coloproctology of Great Britain and Ireland

Colorectal Disease. 2021;00:1–11.  wileyonlinelibrary.com/journal/codi | 1

2 |
I NTRO D U C TI O N
Neoadjuvant chemoradiotherapy (nCRT) followed by total meso-
rectal excision (TME) has become a standard treatment for patients
with locally advanced rectal cancer (LARC) [1,2]. This multimodal
treatment has significantly reduced the local recurrence rate after
surgery to below 10% [3,4]. However, the incidence of distant me-
tastases is still as high as 25%–­4 0% and remains the major cause of
rectal cancer-­related death [4–­6]. Therefore, it is crucial to find a
simple, convenient and accurate predictor of prognosis to identify
high-­risk patients and to guide further treatment.
Carcinoembryonic antigen (CEA) and carbohydrate antigen
19-­9 (CA19-­9) are currently the most widely used tumour mark-
ers for preoperative assessment or postoperative monitoring in
patients with colorectal cancer. At present, many studies have
demonstrated that these two tumour markers are closely related to
the prognosis of rectal cancer patients [7–­12]. However, the prog-
nostic value of the combination of these two tumour markers in
rectal cancer has not been reported. Therefore, the purpose of this
study was to explore the long-­term prognostic significance of these
combined tumour markers in LARC patients undergoing nCRT.
M E TH O D
Study population
A retrospective analysis of a prospectively maintained database
was performed on 877 consecutive patients with LARC (cT3–­4Nx
or cTxN+) who underwent curative resection after nCRT between
January 2011 and December 2016 at Fujian Medical University
Union Hospital (FMUUH). Eighty-­nine patients with synchronous
distant disease at the time of resection, 12 patients who underwent
local excision after nCRT, two patients who died within 3 months
after surgery, 11 patients with incomplete follow-­up, 59 patients
with unavailable pre-­nCRT or post-­nCRT tumour markers (CEA
or CA19-­9) and 17 patients who had normal pre-­nCRT tumour
markers but elevated post-­nCRT tumour markers were excluded.
Finally, the remaining 687 patients were analysed (Figure S1 in the
Supporting Information). This retrospective study was approved by
the Institutional Review Board of FMUUH.
Tumour marker classification
As described previously [11], tumour markers were routinely checked
before nCRT (pre-­nCRT), 6–­8 weeks after nCRT and before surgery
(post-­nCRT), and 4–­8 weeks after surgery and before the initiation of
adjuvant therapy (postoperative). CEA values were defined as normal
or elevated using a cutoff of 5 ng/ml. A serum CA19-­9 level greater
than 37 U/ml was considered abnormally high. Patients were grouped
according to the number of elevated tumour markers as follows: (1)
patients with no elevated tumour markers (normal for both CEA and
ZHENG et al.
What does this paper add to the literature?
Most previous studies have only analysed single tumour
markers and mainly focused on the pretreatment level. We
aimed to explore the prognostic value of the combined
tumour markers carcinoembryonic antigen and carbohy-
drate antigen 19-­9 in patients with locally advanced rectal
cancer treated with neoadjuvant chemoradiotherapy and
curative resection.
CA19-­9); (2) patients with one elevated tumour marker (elevated for
either CEA or CA19-­9); and (3) patients with two elevated tumour
markers (elevated for both CEA and CA19-­9). Patients with no el-
evated tumour markers were defined as the normal tumour marker
group, and patients with one or two elevated tumour markers were
defined as the elevated tumour marker group. The normalization of
tumour markers was defined as the change from the elevated tumour
marker group to the normal tumour marker group.
Treatment
In our centre, all patients were evaluated by preoperative staging
workups, both before and after nCRT, including digital rectal examina-
tion, colonoscopy, chest radiography, endorectal ultrasound examina-
tion, abdominopelvic computed tomography (CT) and pelvic magnetic
resonance imaging (MRI) [13]. All patients received long-­course radio-
therapy with a dose of 45 Gy in 25 fractions followed by a primary
tumour boost of 5.4 Gy over a period of 5 weeks. The preoperative
concurrent chemotherapeutic regimens were capecitabine plus oxali-
platin (CapeOX) or fluorouracil plus oxaliplatin (FOLFOX). TME was
performed 6–­8 weeks after preoperative nCRT. Details of the surgical
procedures at our institution have been described previously [14]. The
tumours were staged according to the 7th American Joint Committee
on Cancer (AJCC) TNM classification. The tumour regression grade
(TRG) was assessed by the AJCC criteria as follows: TRG0 (complete
response), no visible tumour cells remaining; TRG1 (moderate re-
sponse), a single or small group of tumour cells remaining; TRG2 (mini-
mal response), the residual cancer is outgrown by fibrosis; and TRG3
(poor response) extensive residual cancer with minimal or no tumour
death [15]. Approximately 4–­8 weeks after surgery, postoperative
adjuvant chemotherapy was recommended for all patients, irrespec-
tive of the surgical pathological results, in accordance with National
Comprehensive Cancer Network (NCCN) guidelines.
Follow-­up
Follow-­up was performed at 3-­monthly intervals for the first
2 years, every 6 months for the next 3 years and yearly thereafter.
TA B L E 1 Clinical and pathological characteristics of the included patients by the number of elevated tumour markers

Number of elevated pre-­nCRT tumour markers Number of elevated post-­nCRT tumour markers
ZHENG et al.

Clinicopathological features Total (n = 687) 0 (n = 376) 1 (n = 240) 2 (n = 71) p 0 (n = 595) 1 (n = 76) 2 (n = 16) p

Age (years), mean (SD) 55.8±11.2 55.5±10.7 56.7±11.2 54.2±13.8 0.179 55.3±11.2 58.4±10.6 61.1±13.0 0.011
Sex (male:female) 447:240 227:149 174:66 46:25 0.009 378:217 59:17 10:6 0.051
Distance from AV (cm), mean (SD) 6.5±2.6 6.4±2.4 6.4±2.6 7.1±3.0 0.068 6.4±2.5 7.1±2.8 6.1±3.3 0.084
Surgical procedure, n (%)
AR 611 (88.9) 340 (90.4) 209 (87.1) 62 (87.3) 0.595 532 (89.4) 68 (89.5) 11 (68.8) 0.140
APR 73 (10.6) 34 (9.0) 30 (12.5) 9 (12.7) 60 (10.1) 8 (10.5) 5 (31.3)
Hartmann 3 (0.4) 2 (0.5) 1 (0.4) 0 (0.0) 3 (0.5) 0 (0.0) 0 (0.0)
Differentiation, n (%)
Well and moderate 590 (85.9) 329 (87.5) 209 (87.1) 52 (73.2) 0.005 514 (86.4) 68 (89.5) 8 (50.5) 0.001
Poor, mucinous and signet-­ring cell 97 (14.1) 47 (12.5) 31 (12.9) 19 (26.8) 81 (13.6) 8 (10.5) 8 (50.0)
Concurrent chemotherapy
Capecitabine 621 (90.4) 336 (89.4) 224 (93.3) 61 (85.9) 0.106 535 (89.9) 73 (96.1) 13 (81.3) 0.073
5-­FU 66 (9.6) 40 (10.6) 16 (6.7) 10 (14.1) 60 (10.1) 3 (3.9) 3 (18.8)
ypT stage, n (%)
T0 161 (23.5) 120 (31.9) 32 (13.4) 9 (12.7) <0.001 151 (25.4) 10 (13.2) 0 (0.0) <0.001
T1 46 (6.7) 33 (8.8) 11 (4.6) 2 (2.8) 43 (7.2) 2 (2.6) 1 (6.3)
T2 171 (24.9) 109 (29.0) 53 (22.2) 9 (12.7) 163 (27.4) 6 (7.9) 2 (12.5)
T3 279 (40.7) 106 (28.2) 131 (54.8) 42 (59.2) 217 (36.5) 53 (69.7) 9 (56.3)
T4 29 (4.2) 8 (2.1) 12 (5.0) 9 (12.7) 20 (3.4) 5 (6.6) 4 (25.0)
ypN stage, n (%)
N0 513 (74.7) 307 (81.6) 158 (65.8) 48 (67.6) <0.001 450 (75.6) 54 (71.1) 9 (56.3) 0.235
N1 139 (20.2) 54 (14.4) 66 (27.5) 19 (26.8) 117 (19.7) 17 (22.4) 5 (31.3)
N2 35 (5.1) 15 (4.0) 16 (6.7) 4 (5.6) 28 (4.7) 5 (6.6) 2 (12.5)
ypTNM stage (8th AJCC), n (%)
pCR 155 (22.6) 114 (30.3) 32 (13.3) 9 (12.7) <0.001 145 (24.4) 10 (13.2) 0 (0.0) <0.001
I 174 (25.3) 118 (31.4) 51 (21.3) 5 (7.0) 167 (28.1) 5 (6.6) 2 (12.5)
II 185 (26.9) 76 (20.2) 75 (31.3) 34 (47.9) 139 (23.4) 39 (51.3) 7 (43.8)
III 173 (25.2) 68 (18.1) 82 (34.2) 23 (32.4) 144 (24.2) 22 (28.9) 7 (43.8)
AJCC TRG, n (%)
0 162 (23.6) 119 (31.6) 33 (13.8) 10 (14.1) <0.001 151 (25.4) 11 (14.5) 0 (0.0) <0.001
1 225 (32.8) 115 (30.6) 83 (34.6) 27 (38.0) 202 (33.9) 16 (21.1) 7 (43.8)
|
3

(Continues)
4 | ZHENG et al.

Evaluations included physical examination, serum CEA and CA19-­9

0.036

0.087
0.055
tests, chest CT scans and abdominopelvic MRI or CT scans. A co-

Abbreviations: AJCC, American Joint Committee on Cancer; APR, abdominoperineal resection; AR, anterior resection; AV, anal verge; CRM, circumferential resection margin (tumour ≤1 mm from the
lonoscopy was carried out annually. Recurrence-­free survival (RFS)

p
was measured from the date of radical resection to the date of recur-
rence or the last follow-­up if recurrence did not occur. Overall sur-
Number of elevated post-­nCRT tumour markers

2 (n = 16)

10.4±3.8
12 (75.0)
vival (OS) was defined as the time from surgery to the date of death

3 (18.8)
6 (37.5)

1 (6.3)
or the last follow-­up. The last follow-­up was completed in December
2019. The median follow-­up time for survivors was 61.4 (range 3–­
108) months.

14.7±11.4
1 (n = 76)

60 (78.9)
10 (13.2)
39 (51.3)

3 (3.9)
Statistical analysis

margin); 5-­FU, fluorouracil; nCRT, neoadjuvant chemoradiotherapy; pCR, pathological complete response; SD, standard deviation; TRG, tumour regression grade.
Continuous parameters were compared using the Mann–­Whitney U-­
test, whereas differences in categorical parameters between groups
0 (n = 595)

212 (35.6)

514 (86.4)
13.1±6.7

were analysed using the chi-­square test or Fisher’s exact test. The
30 (5.0)
6 (1.0)

Kaplan–­Meier (K-­M) method was used to calculate the survival rate,

and differences were assessed with the log-­rank test. Univariable
and multivariable Cox proportional hazards regression analyses (for-
ward likelihood ratio model) [16,17] were used to examine the effect
0.033

0.188
0.510

of prognostic factors on survival. First, for all patients, pre-­nCRT and

post-­nCRT tumour markers with clinicopathological variables were
p

included in the univariable and multivariable analyses, which identi-

fied that post-­nCRT tumour markers were independent prognostic
14.0±11.1

factors of survival. Second, for patients with elevated pre-­nCRT tu-

Number of elevated pre-­nCRT tumour markers

2 (n = 71)

65 (91.5)
28 (39.4)
6 (8.5)
3 (4.2)

mour markers, post-­nCRT tumour marker response, the number of

elevated post-­nCRT tumour markers and traditional clinicopatholog-
ical variables were included in the univariable analyses. Post-­nCRT
tumour marker response and variables with a value of p < 0.2 in the
1 (n = 240)

207 (86.3)
105 (43.8)

univariate analysis were included in multivariable analysis 1. The

13.3±6.7
19 (7.9)
5 (2.1)

number of positive tumour markers and variables associated with

survival with p < 0.2 were included in multivariable analysis 2. All
statistical analyses were performed using SPSS v.25.0 (SPSS Inc.). A
two-­sided p < 0.05 was considered statistically significant.
0 (n = 376)

124 (33.0)

314 (83.5)
13.0±6.7
18 (4.8)
2 (0.5)

R E S U LT S
Total (n = 687)

Patient characteristics by tumour marker

586 (85.3)
257 (37.4)

classification
13.2±7.3
43 (6.3)
10 (1.5)

Pre-­nCRT there were 376 (54.7) patients with normal tumour mark-
ers, 240 (34.9%) with one elevated tumour marker and 71 (10.3%)
with two elevated tumour markers. After nCRT, 595 (86.6%) patients
Lymph nodes retrieved, mean (SD)
Pathological positive CRM, n (%)

had no elevated tumour markers, 76 (11.1%) had one elevated tu-

Adjuvant chemotherapy, n (%)
Clinicopathological features

mour marker and 16 (2.3%) had two elevated tumour markers. The
TA B L E 1 (Continued)

relationship between the number of elevated tumour markers and

clinicopathological data is shown in Table 1. An increased number
of pre-­nCRT elevated tumour markers was significantly related to
male sex, poorer differentiation, more advanced pathological stage
(including yT stage, yN stage and ypTNM stage), worse AJCC TRG
and higher positive circumferential resection margin (CRM) rates
2
3

(all p < 0.05; Table 1). Similarly, an increased number of post-­nCRT

ZHENG et al. | 5

elevated tumour markers was closely related to older age, poorer elevated tumour markers (p = 0.001) and ypTNM stage (p < 0.001)
differentiation, more advanced yT stage and ypTNM stage, worse remained statistically significant in multivariable analysis (Table 2).
AJCC TRG and higher positive CRM rates (all p < 0.05; Table 1).

Prognostic importance of the normalization of

Prognostic significance of pre-­nCRT and post-­nCRT
tumour markers
The K-­M survival curves for RFS and OS rates decreased with in-
creasing number of elevated tumour markers before nCRT (5-­year
RFS for zero, one or two markers 83.5% vs. 74.4% vs. 67.5%, respec-
tively, p = 0.001; 5-­year OS 86.3% vs. 80.7% vs. 71.1%, p = 0.004;
Figure 1A,B) and after nCRT (5-­year RFS 80.6% vs. 70.9% vs.
43.8%, p < 0.001; 5-­year OS 85.0% vs. 73.9% vs. 49.3%, p < 0.001;
Figure 1C,D). In univariable analyses, the number of pre-­nCRT and
post-­nCRT elevated tumour markers was significantly associated
with RFS, as well as ypTNM stage, differentiation, AJCC-­TRG and
CRM (all p < 0.05; Table 2). In multivariable analysis, the number of
post-­nCRT elevated tumour markers (p = 0.005), but not the number
of pre-­nCRT elevated tumour markers (p > 0.05), and ypTNM stage
(p < 0.001) were independent prognostic factors for RFS (Table 2).
Similarly, the number of pre-­nCRT and post-­nCRT elevated tumour
markers, age, ypTNM stage, surgical procedure, differentiation,
AJCC TRG and CRM were significantly associated with OS in univari-
able analyses (all p < 0.05; Table 2), but only the number of post-­nCRT
tumour markers
The elevated pre-­n CRT tumour marker group included 311 patients
with a single elevated tumour marker or both elevated tumour
markers; 219 (70.4%) of these patients had normalized post-­n CRT
tumour markers and 92 (29.6%) had elevated post-­n CRT tumour
markers. The normalization of tumour markers after nCRT was sig-
nificantly associated with age, ypT stage, ypTNM stage, AJCC TRG
and adjuvant chemotherapy (all p < 0.05; Table 3). The RFS and
OS rates of the normalized group were significantly better than
those of the nonnormalized group (5-­year RFS 75.7% vs. 66.2%,
p = 0.014; 5-­year OS 82.6% vs. 68.5%, p < 0.001; Figure 2A,B).
Multivariable analysis confirmed that the normalization of tumour
markers after nCRT was an independent protective factor for RFS
and OS in patients with elevated pre-­n CRT tumour markers, and
patients with both elevated post-­n CRT tumour markers had a 2.5-­
and 3.7-­fold increased risk of recurrence and death, respectively,
compared with patients with normalized post-­n CRT tumour mark-
ers [RFS, hazard ratio (HR) = 2.553, p = 0.010; OS, HR = 3.721,
p = 0.001; Tables 4 and 5].

(A) (B)
1.0 1.0
Recurrence-free survival

0.8 0.8
Overall survival

0.6 0.6

0.4 Number of elevated 0.4 Number of elevated

pre-nCRT tumor markers pre-nCRT tumor markers
0 0
0.2 1 0.2 1
2 P=0.001 2 P=0.004
0.0 0.0
0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84
Time after surgery (months) Time after surgery (months)

(C) (D)
1.0 1.0
Recurrence-free survival

0.8 0.8
F I G U R E 1 Kaplan–­Meier analysis
Overall survival

of survival by number of elevated

0.6 0.6
tumour markers following neoadjuvant
chemoradiotherapy (nCRT) in patients
with locally advanced rectal cancer 0.4 Number of elevated 0.4 Number of elevated
(n = 687). (A) Recurrence-­free survival pre-nCRT tumor markers pre-nCRT tumor markers
and (B) overall survival by the number of 0 0
0.2 1 0.2 1
elevated pre-­nCRT tumour markers; (C) 2 P<0.001 2 P<0.001
recurrence-­free survival and (D) overall
0.0 0.0
survival by the number of elevated post-­ 0 12 24 36 48 60 72 84 0 12 24 36 48 60 72 84
nCRT tumour markers Time after surgery (months) Time after surgery (months)
6 | ZHENG et al.

TA B L E 2 Prognostic factors for recurrence-­free survival and overall survival

Recurrence-­free survival Overall survival

Univariable Multivariable Univariable Multivariable

Variable HR (95% CI) p HR (95% CI) p HR (95% CI) p HR (95% CI) p

Age: ≥65 years vs. 0.909 (0.608–­1.358) 0.640 1.521 (1.008–­2.294) 0.046 –­ 0.077
<65 years
Sex: female vs. male 1.109 (0.792–­1.551) 0.548 0.928 (0.625–­1.377) 0.711
Distance from AV: 0.752 (0.524–­1.079) 0.122 –­ 0.117 0.944 (0.612–­1.456) 0.794
≥5 cm vs. <5 cm
Number of elevated pre-­nCRT tumour markers pre-­nCRT tumour markers
0 Reference 0.001 –­ 0.815 Reference 0.005 –­ 0.834
1 1.736 (1.221–­2.469) 0.002 –­ 0.535 1.528 (1.015–­2.300) 0.042 –­ 0.578
2 2.146 (1.318–­3.494) 0.002 –­ 0.912 2.358 (1.384–­4.018) 0.002 –­ 0.972
Number of elevated post-­nCRT tumour markers
0 Reference <0.001 Reference 0.005 Reference <0.001 Reference 0.001
1 1.857 (1.195–­2.885) <0.001 1.528 (0.974–­2.396) 0.065 2.171 (1.343–­3.509) 0.002 1.692 (1.035–­2.765) 0.036
2 4.200 (2.129–­8 .288) 0.001 2.733 (1.378–­5.422) 0.004 5.369 (2.694–­10.698) <0.001 3.485 (1.736–­6.999) <0.001
ypTNM stage
pCR Reference <0.001 Reference <0.001 Reference <0.001 Reference <0.001
I 1.232 (0.604–­2.514) 0.567 1.236 (0.605–­2.523) 0.561 1.396 (0.579–­3.369) 0.458 1.404 (0.582–­3.389) 0.450
II 2.799 (1.497–­5.234) 0.001 2.504 (1.330–­4.717) 0.004 3.814 (1.769–­8 .223) 0.001 3.245 (1.491–­7.061) 0.003
III 6.565 (3.641–­11.835) <0.001 6.085 (3.364–­11.007) <0.001 7.157 (3.408–­15.028) <0.001 6.403 (3.035–­13.507) <0.001
Surgical procedure: 1.531 (0.973–­2.409) 0.066 0.182 1.665 (1.005–­2.760) 0.048 –­ 0.109
APR/Hartmann
vs. AR
Differentiation: 2.104 (1.433–­3.089) <0.001 –­ 0.116 2.215 (1.435–­3.419) <0.001 –­ 0.133
poor/mucinous/
signet ring
cell vs. well/
moderate
AJCC TRG: 2–­3 vs. 2.062 (1.482–­2.868) <0.001 –­ 0.306 2.266 (1.546–­3.322) <0.001 –­ 0.205
0–­1
Lymph nodes 0.919 (0.660–­1.280) 0.617
retrieved:
<12 vs. ≥12
Pathological positive 3.670 (1.620–­8 .316) 0.002 –­ 0.138 3.470 (1.415–­8 .513) 0.007 –­ 2.272
CRM: yes vs. no
Adjuvant 1.510 (0.885–­2.576) 0.131 –­ 0.137 1.150 (0.644–­2.053) 0.636
chemotherapy:
yes vs. no

Abbreviations: AJCC, the American Joint Committee on Cancer; APR, abdominoperineal resection; AR, anterior resection; AV, anal verge; cCR,
clinical complete response; CRM, circumferential resection margin (tumour ≤1 mm from the margin); HR, hazard ratio; nCRT, neoadjuvant
chemoradiotherapy; TRG, tumour regression grade.

In addition, we further explored the prognostic value of the normal-
ization of tumour markers after surgery. Four patients with unavailable
postoperative tumour marker (CEA or CA19-­9) data were excluded,
and a total of 88 patients with elevated post-­nCRT tumour markers
were included in this analysis. Among them, 54 patients (61.4%) had
normalized postoperative tumour markers after surgery. The K-­M sur-
vival analysis revealed that the patients with normalized postoperative
tumour markers had better RFS and OS rates than those with elevated
postoperative tumour markers (5-­year RFS 79.5% vs. 44.1%, p < 0.001;
5-­year OS 79.9% vs. 52.2%, p = 0.003; Figure S2).
DISCUSSION
The tumour markers CEA and CA19-­9 are common indicators for pre-
operative early diagnosis, treatment monitoring and postoperative
ZHENG et al. | 7

TA B L E 3 Clinicopathological characteristics by postneoadjuvant chemoradiotherapy (post-­nCRT) tumour markers (normalization versus

nonnormalization) in patients with elevated pre-­nCRT tumour markers (n = 311)

Clinicopathological features Total (n = 311) Normalization (n = 219) Nonnormalization (n = 92) p

Age (years), mean (SD) 56.1±11.8 55.0±12.0 58.9±11.0 0.007

Sex (male:female) 220:91 151:68 69:23 0.284
Distance from AV (cm), mean (SD) 6.6±2.7 6.5±2.7 6.9±2.9 0.208
Surgical procedure, n (%)
AR 271 (87.1) 192 (87.7) 79 (85.9) 0.704
APR 39 (12.5) 26 (11.9) 13 (14.1)
Hartmann 1 (0.3) 1 (0.5) 0 (0.0)
Differentiation, n (%)
Well and moderate 261 (83.9) 185 (84.5) 76 (82.6) 0.683
Poor, mucinous and signet ring cell 50 (16.1) 34 (15.5) 16 (17.4)
Concurrent chemotherapy
Capecitabine 285 (91.6) 199 (90.0) 86 (93.5) 0.448
5-­FU 26 (8.4) 20 (9.1) 6 (6.5)
ypT stage, n (%)
T0 41 (13.2) 31 (14.2) 10 (10.9) 0.004
T1 13 (4.2) 10 (4.6) 3 (3.3)
T2 62 (20.0) 54 (24.8) 8 (8.7)
T3 173 (55.8) 111 (50.9) 62 (67.4)
T4 21 (6.8) 12 (5.5) 9 (9.8)
ypN stage, n (%)
N0 206 (66.2) 143 (65.3) 63 (68.5) 0.625
N1 85 (27.3) 63 (28.8) 22 (23.9)
N2 20 (6.4) 13 (5.9) 7 (7.6)
ypTNM stage (8th AJCC), n (%)
pCR 41 (13.2) 31 (14.2) 10 (10.9) 0.001
I 56 (18.0) 49 (22.4) 7 (7.6)
II 109 (35.0) 63 (28.8) 46 (50.0)
III 105 (33.8) 76 (34.7) 29 (31.5)
AJCC TRG, n (%)
0 43 (13.8) 32 (14.6) 11 (12.0) 0.009
1 110 (35.4) 87 (39.7) 23 (25.0)
2 133 (42.8) 88 (40.2) 45 (48.9)
3 25 (8.0) 12 (5.5) 13 (14.1)
Pathologic positive CRM, n (%) 8 (2.6) 4 (1.8) 4 (4.3) 0.242
Lymph nodes retrieved, mean (SD) 13.5±2.9 13.3±6.5 14.0±10.6 0.478
Adjuvant chemotherapy, n (%) 272 (87.5) 200 (91.3) 72 (78.3) 0.001

Abbreviations: AJCC, American Joint Committee on Cancer; APR, abdominoperineal resection; AR, anterior resection; AV, anal verge; CRM,
circumferential resection margin (tumour ≤1 mm from the margin); 5-­FU, fluorouracil; pCR, pathological complete response; SD, standard deviation;
TRG, tumour regression grade.

follow-­up, but their prognostic performance in patients with LARC
undergoing nCRT remains under investigation. At present, elevated
serum CEA has been classified into category I according to the
strength and reliability of the published evidence in the literature,
and the prognostic significance of CA19-­9 has also been confirmed
by an increasing number of studies [11,12,18], including our previous
research [11]. However, most previous studies only analysed single
tumour markers and mainly focused on the pretreatment level [9,10].
In particular, there are few studies on the prognostic effects of post-­
treatment CEA and CA19-­9. Toyoda et al. [19,20] found that a combi-
nation of multiple tumour markers can improve prognostic prediction
compared with the use of a single tumour marker. Therefore, we
 8 |
(A)
1.0
Recurrence-free survival
0.8
0.6
0.4 Normalized Post-nCRT
tumour markers
Non-normalized Post-nCRT
0.2 tumour markers
P=0.014
0.0
0 12 24 36 48 60 72 84
Time after surgery (months)
evaluated the prognostic value of a combination of CEA and CA19-­9
in 687 patients with LARC treated with nCRT and curative resection.
The patients were grouped according to the number of elevated tu-
mour markers. In the present study, we found that the number of
post-­nCRT elevated tumour markers rather than the pre-­nCRT level
was an independent prognostic factor. Moreover, the normalization
of tumour markers after either nCRT or surgery was significantly re-
lated to improved prognosis.
To date, it is still controversial which pre-­nCRT or post-­nCRT tu-
mour markers can better predict the long-­term prognosis of patients
with rectal cancer. Chung et al. [21] suggested that pre-­nCRT CEA
levels rather than post-­nCRT levels were independent predictors of
survival. However, Perez et al. [7] reported that the predictive per-
formance of post-­nCRT CEA levels was superior to that of pre-­nCRT
levels. In this study, we first found that the prognostic significance
of post-­nCRT tumour markers was better than that of pre-­nCRT
levels. An increase in the number of elevated tumour markers both
before and after nCRT was associated with more advanced tumours
and affected survival in the univariate analysis, which is attributed
to the close relationship between tumour markers and tumour bur-
den [12,22,23]. However, only post-­nCRT tumour markers retained
significance in multivariate analysis, possibly because nCRT can sig-
nificantly reduce the local recurrence rate of patients with LARC [2]
(thus weakening the prognostic ability of pre-­nCRT tumour mark-
ers). Therefore, nCRT has become a key part of the treatment of
Stage II/III rectal cancer in most guidelines [24,25].
In the present study, more than 70% of patients with pre-­nCRT
elevated tumour markers had normalized post-­nCRT tumour markers
after nCRT, and more than 60% of patients with post-­nCRT elevated
tumour markers had normalized postoperative tumour markers.
Regardless of whether nCRT or surgery was performed, the progno-
sis of patients with normalized markers was significantly better than
that of patients without normalization, which was consistent with
the results of most previous studies [9,11,26,27]. Importantly, pa-
tients with elevated post-­nCRT tumour markers had a 2.5-­ and 3.7-­
fold increased risk of recurrence and death, respectively. Patients
who failed to achieve normalized postoperative tumour markers
after surgery had a poor prognosis (5-­year RFS 44.1%; 5-­year OS
ZHENG et al.
(B) F I G U R E 2 (A) Recurrence-­free
1.0 survival and (B) overall survival by
postneoadjuvant chemoradiotherapy
0.8 (post-­nCRT) tumour markers
(normalization versus nonnormalization)
Overall survival
among patients with elevated pre-­nCRT
0.6
tumour markers (n = 311)
0.4 Normalized Post-nCRT
tumour markers
Non-normalized Post-nCRT
0.2 tumour markers
P<0.001
0.0
0 12 24 36 48 60 72 84
Time after surgery (months)
52.2%). In fact, the changes in tumour markers in response to treat-
ment are likely to represent the tumour-­specific response to ther-
apy. Elevated postoperative tumour markers may indicate residual
minute cancer cells that cannot be identified during proctectomy
and imaging examinations after treatment. Therefore, these patients
need strengthened postoperative adjuvant treatment and closer fol-
low-­up to improve long-­term survival.
In recent years, several studies have evaluated the feasibility
of molecular and genetic markers as prognostic predictors of rec-
tal cancer, such as the detection of p53 [28] and epidermal growth
factor receptor [29] in pretreatment biopsy specimens. However,
routine testing of these markers is complex and adds to the cost of
clinical practice. Serum tumour markers have the advantages of low
cost, automation, ease of measurement and familiarity to clinicians.
Overall, combined tumour markers are valuable dynamic prognostic
factors and may be used quantitatively to guide the treatment deci-
sions for LARC patients.
This study has several limitations. First, a large proportion of
patients with pre-­nCRT elevated tumour markers had normal-
ized post-­nCRT tumour markers after nCRT in the present study.
As a result, the number of patients with two post-­CRT elevated
tumour markers was relatively small (only 2.3% of the total co-
hort). Moreover, one elevated post-­nCRT tumour marker did not
reach statistical significance (p = 0.065) in the multivariate anal-
ysis of RFS. Therefore, the results need to be validated by large-­
sample multicentre prospective studies. Second, as a retrospective
study, it may have been subject to selection bias. For example,
adjuvant chemotherapy is an important factor affecting survival.
Unfortunately, our results failed to demonstrate that adjuvant che-
motherapy is an independent protective factor for survival. The
reason is that patients with advanced disease who are prone to
recurrence or death also receive adjuvant chemotherapy. Despite
these limitations, our study, for the first time, confirmed the prog-
nostic value of the combination of CEA and CA19-­9 in patients with
LARC treated with nCRT, providing an opportunity for clinicians to
observe the complex tumour biology of patients. Therefore, it is
necessary to measure tumour markers routinely during periopera-
tive and postoperative follow-­up.
ZHENG et al. | 9

TA B L E 4 Prognostic factors for recurrence-­free survival in patients with elevated preneoadjuvant chemoradiotherapy (pre-­nCRT) tumour
markers (n = 311)

Univariable Multivariable 1a Multivariable 2b

Variable HR (95% CI) p-­value HR (95% CI) p-­value HR (95% CI) p-­value

Age: ≥65 years vs. <65 years 0.844 (0.502–­1.420) 0.523

Sex: female vs. male 1.045 (0.655–­1.666) 0.854
Distance from AV: ≥5 cm vs. 0.873 (0.537–­1.419) 0.583
<5 cm
Post-­nCRT tumour marker response
Nonnormalization Reference Reference
Normalization 0.584 (0.378–­0.904) 0.016 0.611 (0.391–­0.955) 0.031
Number of elevated post-­nCRT tumour markers
0 Reference 0.003 Reference 0.024
1 1.453 (0.896–­2.357) 0.130 1.434 (0.874–­2.352) 0.154
2 3.264 (1.607–­6.628) 0.001 2.553 (1.254–­5.198) 0.010
ypTNM stage
pCR Reference <0.001 Reference <0.001 Reference <0.001
I 2.615 (0.543–­12.590) 0.230 2.784 (0.578–­13.421) 0.202 2.659 (0.551–­12.830) 0.223
II 5.985 (1.426–­25.126) 0.015 5.477 (1.301–­23.051) 0.020 5.366 (1.274–­22.602) 0.022
III 12.440 (3.022–­51.218) <0.001 12.337 (2.997–­50.792) 0.001 11.723 (2.841–­48.382) 0.001
Surgical procedure: APR/ 1.402 (0.790–­2.488) 0.248
Hartmann vs. AR
Differentiation: poor/ 1.331 (0.772–­2.292) 0.303
mucinous/signet-­ring cell
vs. well/ moderate
AJCC TRG: 2–­3 vs. 0–­1 1.600 (1.036–­2.470) 0.034 –­ 0.626 –­ 0.690
Lymph nodes retrieved: 1.117 (0.727–­1.715) 0.613
<12 vs. ≥12
Pathological positive CRM: 2.853 (1.155–­7.047) 0.023 –­ 0.233 –­ 0.286
yes vs. no
Adjuvant chemotherapy: yes 2.006 (0.875–­4.601) 0.100 –­ 0.198 –­ 0.242
vs. no

Abbreviations: AJCC, American Joint Committee on Cancer; APR, abdominoperineal resection; AR, anterior resection; AV, anal verge; cCR, clinical
complete response; CRM, circumferential resection margin (tumour ≤1 mm from the margin); HR, hazard ratio; TRG, tumour regression grade.
a
Multivariable analysis 1 included post-­nCRT tumour marker response, excluding the number of elevated post-­nCRT tumour markers.
b
Multivariable analysis 2 included the number of elevated post-­nCRT tumour markers, excluding the post-­nCRT tumour marker response.

CO N C LU S I O N (B20062DS) and Medical innovation project of Fujian province

In patients with LARC, post-­nCRT combined tumour markers had a
high discriminatory ability for recurrence and survival, and the nor-
malization of the combined tumour markers after either nCRT or
surgery was closely related to the improvement in prognosis. The
prognostic value of tumour markers in rectal cancer should be fur-
ther investigated.
AC K N OW L E D G E M E N T S
This study was supported by Joint Funds for the Innovation of Science
and Technology, Fujian province (No. 2019Y9101), Natural Science
Foundation of Fujian Province (2020J011030), Medical Science
Research Foundation of Beijing Medical and Health Foundation
(2020CXA025).
C O N FL I C T O F I N T E R E S T
There are no conflicts of interest or financial ties to disclose from
any author.
AU T H O R C O N T R I B U T I O N S
Zhifang Zheng, Xiaojie Wang and Pan Chi conceived of the
study, analyzed the data and drafted the manuscript; Ying
Huang and Xingrong Lu helped revise the manuscript critically
for important intellectual content; Ying Huang helped collect
data and design the study. All authors read and approved the
final manuscript.
10 | ZHENG et al.

TA B L E 5 Prognostic factors for overall survival in patients with elevated preneoadjuvant chemoradiotherapy (pre-­nCRT) tumour markers
(n = 311)

Univariable Multivariable 1a Multivariable 2b

Variable HR (95% CI) p-­value HR (95% CI) p-­value HR (95% CI) p-­value

Age: ≥65 years vs. <65 years 1.198 (0.689–­2.085) 0.522

Sex: female vs. male 0.935 (0.543–­1.610) 0.809
Distance from AV: ≥5 cm vs. 1.123 (0.629–­2.004) 0.694
<5 cm
Post-­nCRT tumour marker response
Nonnormalization Reference Reference
Normalization 0.422 (0.259–­0.687) 0.001 0.445 (0.269–­0.736) 0.002
Number of elevated post-­nCRT tumour markers
0 Reference <0.001 Reference 0.001
1 1.976 (1.156–­3.379) 0.013 1.925 (1.107–­3.345) 0.020
2 4.618 (2.212–­9.638) <0.001 3.721 (1.769–­7.829) 0.001
ypTNM stage
pCR Reference 0.003 Reference 0.004 Reference 0.006
I 5.126 (0.631–­41.667) 0.126 5.742 (0.705–­46.761) 0.102 5.414 (0.664–­4 4.130) 0.115
II 10.061 (1.361–­74.397) 0.024 8.455 (1.140–­62。718) 0.037 8.118 (1.093–­60.321) 0.041
III 15.379 (2.102–­112.49) 0.007 14.943 (2.043–­109.30) 0.008 13.928 (1.899–­102.16) 0.010
Surgical procedure: APR/ 1.551 (0.828–­2.904) 0.170 –­ 0.128 0.216
Hartmann vs. AR
Differentiation: poor/ 1.136 (0.594–­2.173) 0.700
mucinous/signet ring cell
vs. well/moderate
AJCC TRG: 2–­3 vs. 0–­1 1.622 (0.986–­2.667) 0.057 –­ 0.736 0.839
Lymph nodes retrieved: 0.963 (0.590–­1.573) 0.881
<12 vs. ≥12
Pathological positive CRM: 2.592 (0.942–­7.134) 0.065 –­ 0.353 0.421
yes vs. no
Adjuvant chemotherapy: 1.577 (0.633–­3.930) 0.328
yes vs. no

Abbreviations: AJCC, American Joint Committee on Cancer; APR, abdominoperineal resection; AR, anterior resection; AV, anal verge; cCR, clinical
complete response; CRM, circumferential resection margin (tumour ≤1 mm from the margin); HR, hazard ratio; TRG, tumour regression grade.
a
Multivariable analysis 1 included the post-­nCRT tumour marker response, excluding the number of elevated post-­nCRT tumour markers.
b
Multivariable analysis 2 included the number of elevated post-­nCRT tumour markers, excluding the post-­nCRT tumour marker response.

E T H I C A L A P P R OVA L 6 years: increased local control but no survival benefit in irra-

The study was approved by the Institutional Review Board of Fujian
Medical University Union Hospital.
ORCID
Pan Chi https://orcid.org/0000-0002-0004-1174
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S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found online in the
Supporting Information section.
How to cite this article: Zheng Z, Wang X, Lu X, Huang Y, Chi
P. Prognostic significance of carcinoembryonic antigen
combined with carbohydrate antigen 19-­9 following
neoadjuvant chemoradiotherapy in patients with locally
advanced rectal cancer. Colorectal Dis. 2021;00:1–11. https://
doi.org/10.1111/codi.15694