ANTICANCER RESEARCH 29: 4303-4308 (2009)
Prognostic Value of Serum Tumor Antigen CA19-9
After Curative Resection of Colorectal Cancer
IN JA PARK, GYU-SEOG CHOI and SOO HAN JUN
Department of Surgery, School of Medicine, Kyungpook National University, Daegu, Korea
Abstract. Background: CA19-9 was evaluated as a
prognostic marker for colorectal cancer and whether it could
be helpful in addition to surveillance using CEA was also
tested. Materials and Methods: Serum CA19-9 levels were
measured preoperatively in 1109 patients and monitored at
3-month intervals for the first 2 years postoperatively, and at
6-month intervals thereafter in 700 patients. Results:
Preoperative high CA19-9 was independent prognostic factor
for recurrence. Among patients with recurrence, 21.4% had
a high postoperative CA19-9. High postoperative CA 19-9
levels were more likely in patients with high preoperative
levels. Postoperative CA19-9 increased more in patients with
a peritoneal recurrence than in those with liver metastasis
(p=0.002). Among patients with recurrence, CA19-9
increased in 7.8% of the patients with a normal follow-up
CEA. Conclusion: Postoperative CA19-9 was more frequently
elevated when peritoneal recurrence occurred. Data on
CA19-9 levels provided 7.8% of additional information in
predicting recurrence in this study.
Tumor markers have been used as prognostic factors in the
management of cancer patients. Generally, they are not
useful for diagnosis because of their low specificity and
sensitivity. However, such markers are more useful than
screening in the follow-up of patients with malignant
diseases. Carcinoembryonic antigen (CEA) is the most
commonly used tumor marker in patients with colorectal
cancer, and elevated concentrations of CEA have been
reported to be associated with poor postoperative prognosis
in such patients (1-5). The tumor marker carbohydrate
antigen (CA) 19-9 is often used in combination with CEA
to manage patients with colorectal cancer, even though
CA19-9 has been reported to be a less sensitive marker (6).
Although the American Society of Clinical Oncology
Correspondence to: Gyu-Seog Choi, MD, Department of Surgery,
School of Medicine, Kyungpook National University 50 Samduk-
dong 2ga Jung-gu, Daegu, Korea. Tel: +82 534105605 Fax: +82
534210510, e-mail: kyuschoi@mail.knu.ac.kr
Key Words: CA19-9, preoperative, recurrence, peritoneal recurrence.
0250-7005/2009 $2.00+.40
guidelines suggest that there is insufficient evidence for
using CA19-9 in the management of patients with colorectal
cancer (7), several authors have described the prognostic
significance of CA19-9 (3, 8-11). There are also reports
indicating the possible usefulness of CA19-9 in monitoring
recurrence rates (12-14), whereas others have shown
contradictory results (15-17). In addition, the utility of
CA19-9 in predicting prognosis is controversial, as is the
clinical usefulness of simultaneous evaluations of CEA and
CA19-9. In the present study, whether serum CA19-9 could
be a prognostic factor in predicting the prognosis and tumor
recurrence for patients with colorectal cancer was evaluated,
and whether it could offer any useful information in addition
to serum CEA levels during postoperative surveillance was
also adressed.
Patients and Methods
The study population consisted of 1,109 patients who received
regular postoperative surveillance among 1,452 who underwent
curative resection for colorectal cancers. Preoperative serum CEA
and CA19-9 levels were measured in the Department of Surgery of
Kyungpook National University Hospital, Deagu, Korea between
June 1996 and June 2006. The median follow-up period was 48
months (range 1-156). Serum CEA and CA19-9 concentrations
were measured, with CEA concentrations >7.0 ng/mL and CA19-9
concentrations >37 U/mL being regarded as elevated. Patients with
a synchronous metastatic disease or undergoing palliative resection
and those with carcinoma in situ, familial adenomatous polyposis,
or pathology other than an adenocarcinoma were excluded, as were
patients with T1 stage cancer treated by local excision.
Patients were followed-up routinely at 3-month intervals for the
first 2 years, and at 6-month intervals thereafter. At each visit, CEA
levels were assayed, a full history was taken and a physical
examination was performed. Colonoscopy was performed within 6
months to 1 year following surgery and then 3 years later. Chest
radiographs and abdominopelvic computer tomography (CT) scans
were performed at 6 months and then at yearly intervals. For 700
patients, serum CA19-9 was regularly followed up postoperatively
with the same schedule as for the surveillance of serum CEA. CT or
positron emission tomography (PET) scans were performed on
patients with increased serum CEA concentrations, or when they
were symptomatic. Diagnosis of recurrence was confirmed by
biopsies or from histopathology of resected specimens. Otherwise,
recurrence was documented from the first clinical or radiological
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Table Ⅰ. Clinicopathological characteristics of patients with normal and Table Ⅱ. Risk factors for recurrence based on multivariate analysis.
high preoperative serum carbohydrate antigen (CA) 19-9 concentrations.
Variables Odds 95% confidence P-vale
Normal High P-vale ratio intervals
preoperative preoperative
serum CA19-9 serum CA19-9 pT category
(n=952) (n=157) T1+T2
T3+T4 2.82 1.66-4.77 <0.0001
Gender 0.12 pN category
Male 537 (56.4) 77 (49.0) N negative
Female 421 (45.6) 80 (51.0) N positive 2.31 1.74-3.05 <0.0001
Location 0.003 Location
Colon 441 (46.6) 93 (59.2) Colon
Rectum 511 (53.4) 64 (40.8) Rectum 1.36 1.05-1.77 0.02
Histology 0.065 Lymphatic invasion 1.46 1.08-1.97 0.01
Well 140 (14.7) 12 (7.6) Preoperative serum CEA
Moderately 737 (77.4) 126 (80.3) Normal
Poorly 32 (3.4) 8 (4.7) High 1.59 1.17-2.15 0.003
Mucinous 36 (3.8) 10 (6.4) Preoperative serum CA19-9
Signet ring cell 3 (0.5) 0 (0) Normal
Lymphatic invasion 506 (53.2) 105 (66.8) 0.001 High 1.75 1.29-2.38 <0.0001
Vascular invasion 54 (5.7) 14 (8.9) 0.12
Perineural invasion 363 (38.1) 78 (49.7) 0.007
Tumor stage
I 185 (19.4) 7 (4.5) <0.0001
II 397 (41.7) 60 (38.2) to show lymphatic invasion, perineural invasion, more
III 370 (38.9) 90 (57.3)
advanced tumor stage, colon cancer and recurrence than
Recurrence 191 (20.1) 59 (37.6) <0.0001
patients with normal preoperative serum CA19-9 levels. Sex,
histological differentiation and vascular invasion did not
differ significantly between patients with normal and high
preoperative serum CA19-9 (Table Ⅰ). The 3-year disease-
signs of a disease that showed an unrelenting course leading to
free survival rate was significantly lower in patients with
tumor progression and/or death. Criteria for the establishment of
recurrent disease included histological confirmation, palpable high preoperative serum CA19-9 (p<0.0001) and was
disease, or disease evident radiologically with subsequent clinical significantly lower in patients with American Joint
progression and supportive biochemical data, particularly increased Committee on Cancer (AJCC) stage II and III disease who
CEA levels. The time to recurrence was determined as the date of also showed high preoperative serum CA19-9 levels, when
the follow-up visit at which recurrence was discovered, or by considering each TNM stage (Figure 1).
reviewing hospital records for patients who were admitted. Multivariate analysis was performed to estimate the
The clinical and pathological characteristics of patients with and
independent predictive value of CA19-9 elevation against
without elevated preoperative serum CA19-9 levels were compared,
as well as those with and without recurrence. Clinicopathological recurrence (Table Ⅱ). Among 1,109 patients who had
variables between the groups were compared using unpaired undergone regular follow-up, recurrences occurred in 250
Student’s t-tests or one-way analysis of variance (ANOVA) using (22.6% ). Cox proportional hazards analysis with the
least significant difference (LSD) multiple comparisons. The two disease-free period was used as a dependent variable to treat
groups were compared by cross-table analysis using Fisher’s exact recurrence as a time-to-event outcome. The significant
test. The Cox proportional hazards model was applied for predictive value was confirmed with CA19-9 (odds ratio,
multivariate analysis to determine any important predictors of
OR=1.75, p<0.0001), with pT and pN categories, and with
recurrence. Variables were included in the multivariate analysis only
if p was less than 0.05 in the univariate analysis. Recurrence-free a preoperative high serum CEA.
survival rates were compared by the Kaplan–Meier method using a The sensitivity, specificity, positive predictive value (PPV)
log-rank test. The confidence intervals (CIs) were set at 95% and and negative predictive value (NPV) of preoperative serum
the significance level at p<0.05. CA19-9 levels were calculated as markers for recurrence.
When preoperative serum CA19-9 level was above 37 U/mL,
Results it was considered a positive test. Sensitivity and specificity
were 23.6% and 88.6% , respectively. The PPV and NPV of
Characteristics of patients relative to preoperative serum preoperative serum CEA level for recurrence were 37.6%
CA19-9 levels and prognostic significance of preoperative and 79.9% , respectively. For preoperative CEA, the
serum CA19-9 levels. Patients with high preoperative serum sensitivity and specificity were 38.8% and 83.5% ,
CA19-9 levels (>37.0 U/mL) were significantly more likely respectively. The PPV and NPV of preoperative serum CEA

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 Park et al: Prognostic Value of CA19-9 in Colorectal Cancer

Figure 1. Disease-free survival curves stratified by preoperative serum CA19-9 concentration. Patients with American Joint Committee on Cancer
(AJCC) stage I tumors showed no significant differences in preoperative serum CA19-9 levels (p=0.255). Patients with AJCC stage II (p=0.0028)
and III (p=0.0015 tumors and a preoperative serum CA19-9 concentration >37 U/mL showed a poorer prognosis than did those with normal
preoperative CA19-9 concentrations.

level for recurrence were 40.6% and 82.4% , respectively.
When considered as positive if either CEA or CA19-9 was
higher than the accepted normal value, the sensitivity,
specificity, PPV and NPV of the combined tumor markers
were 50% , 77.4% , 39.6% and 84% , respectively.
Correlation of post-operative serum CA19-9 levels with
recurrence. There were 154 conformed recurrences among
700 patients (22% ) with regular follow-up for CA19-9 after
surgery. Among these 154 recurrences, a postoperative
elevation of CA19-9 measured before the diagnosis of
recurrence was seen in 33 (21.4% ). The proportion of
patients with a high postoperative serum CA19-9 was
significantly higher among those who also had a high
preoperative serum CA19-9 level.
Regarding recurrence site, patients with liver metastases
and peritoneal recurrence were significantly more likely to
have an elevated serum CA19-9. When patients had a
peritoneal recurrence, the proportion of patients with
elevated postoperative CA19-9 was much higher than among
those with liver metastases. In contrast, postoperative serum
CEA was more frequently elevated in patients with liver
metastases (Table Ⅲ).
The sensitivity, specificity, PPV and NPV were 76.3% ,
84.7% , 76.3% and 84.7% , respectively, for postoperative
CEA level and 21.4% , 95.8% , 58.9% and 81.2% ,
respectively, for postoperative serum CA19-9 level. When
classified according to the preoperative serum CA19-9 level,
the follow-up serum CA19-9 level showed higher PPV, NPV
and specificity in patients with high preoperative serum
CA19-9 (44.7% , 91.2% , 70.8% and 74.7% , respectively)
than in patients with normal preoperative serum CA19-9
(13.8% , 97.3% , 50% and 82.2% , respectively). When
postoperative serum CEA and CA19-9 monitoring were

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 ANTICANCER RESEARCH 29: 4303-4308 (2009)
Table Ⅲ. Relationship between postoperative CA19-9 and CEA concentration, and recurrence site, and preoperative tumor marker levels in patients
with recurrence.
Normal postoperative
CA19-9 (n=121)
Normal preoperative CA19-9 100 (82.6% )
High preoperative CA19-9 21 (17.4% )
Recurrence
Liver metastasis
(n=53)
High postoperative CA19-9 16 (30.2 % )
High postoperative CEA 30 (56.6% )
considered together, CA19-9 was elevated in 12.9% of
patients with recurrence and normal postoperative CEA
(Table Ⅳ).
Discussion
In the present study of 1,109 patients with colorectal cancer,
high preoperative serum CA19-9 concentration was a marker of
poor prognosis, together with CEA levels. Both serum CEA and
CA19-9 concentrations have been used as factors indicative of
malignant potential and/or poorer prognosis in such patients
(18, 19). One study found that that only preoperatively elevated
CEA was significantly correlated with poor prognosis, whereas
the CA19-9 level was not a predictor of prognosis (20). In
contrast, another study reported that preoperatively elevated
CA19-9 was an independent predictor of subsequent tumor
recurrence in patients with node-negative colorectal carcinomas
who had been treated with curative resection (6). Several factors
might account for such confusing and even contradictory results.
Some reports had an insufficient sample size, and different
methods for detecting CA19-9 were used. In addition,
differences in tumor stage distribution across study populations
may have influenced the outcomes. In one report on patients
with stage II colorectal cancer, those with elevated levels of both
CEA and CA19-9 were reported to have significantly poorer
prognoses than those with normal CEA and CA19-9
concentrations (21). Others have demonstrated that both CEA
and CA19-9 levels have prognostic impact in all patient groups
but without significant between-stage differences (3, 10, 22,
23). It was found that preoperative CA19-9 levels were not
prognostic in patients with stage I disease, which may have been
because of the small number of patients in this study with both
stage I colorectal cancer and high preoperative serum CA19-9
concentrations. CA19-9 levels may also be related to tumor
stage, and may therefore be relatively less effective in predicting
outcomes in patients with early-stage disease.
4306
High postoperative P-value
CA19-9 (n=33)
16 (48.5% ) <0.0001
17 (51.5% )
Peritoneal recurrence
(n=20)
10 (50% ) 0.02
13 (65% )
Table Ⅳ. Relationship between postoperative serum CEA and CA19-9
in patients with recurrent disease.
Normal postoperative High postoperative
CA19-9 CA19-9
Normal postoperative CEA 81 (52.6% ) 12 (7.8% )
High postoperative CEA 40 (26.0% ) 21 (13.6% )
CA19-9 is a widely used marker for colorectal cancer in
clinical practice. More than 80% of surgeons also use other
tumor markers for postoperative surveillance of colorectal
cancer in Japan. Postoperative serum CA19-9 was regularly
monitored in 63.1% of the patients. However, available
evidence about the utility of CA19-9 for postoperative
surveillance is inconsistent as there are contradictory reports
about the usefulness of CA19-9 in monitoring recurrence rates
(12-17, 24-28). The presented results showed that only 21.4%
of patients diagnosed with recurrence by an imaging method,
such as CT or PET, had high serum CA19-9 concentrations
before the diagnosis of a recurrence. Only 18.8% of patients
with a normal preoperative serum CA19-9 level had a high
concentration before recurrence, compared with 58.9% of
patients with high preoperative serum CA19-9. The sensitivity,
PPV and NPV for postoperative serum CA19-9 screening
were much lower than for CEA.
Some authors have suggested that CA19-9 should be used
in combination with CEA, as it could increase sensitivity in
detecting tumor recurrence. Contrary to this suggestion, in
the present study, a positive CA19-9 but negative CEA
elevation was seen in 7.8% of patients with recurrence and
in only 1.7% of all patients. Others have also reported a low
frequency (1-11% ) of CA19-9 elevation without increase in
CEA in patients with recurrence (18, 19, 24, 28), suggesting
CA19-9 has limited value as a complementary marker. These
results suggest that surveillance with CA19-9 in combination
 Park et al: Prognostic Value of CA19-9 in Colorectal Cancer
with CEA may be of little practical use in the routine follow-
up of patients with colorectal cancer.
In the present study, postoperative serum CA19-9
elevation was better related to peritoneal recurrence than to
liver metastasis. The correlation between postoperative CEA
elevation and recurrence has been reported to be greater for
liver metastases than for recurrent disease at other locations
(29, 30). However, a correlation between CA19-9 level and
the peritoneal recurrence of colorectal cancer has been
reported only rarely (31). The presence of CA19-9 in tumors
was reported to be related to tumor cell adhesion (32) and
to tumor cell-induced platelet aggregation (33). Moreover,
one study reported that peritoneal tumor cells of both
colorectal and gastric cancer bind strongly to the anti-CA19-
9 monoclonal antibody (34). Therefore, it was thought that
colorectal cancer expressing CA19-9 might have a higher
possibility of peritoneal recurrence based on the results of
this study and others in the literature.
This study had several limitations. It was retrospective in
design, although the data were collected prospectively. Thus,
the analysis of postoperative serum CA19-9 levels, especially
in the interval between its postoperative elevation and any
diagnosis of recurrence, may have had an inadvertent bias.
In addition, only 63.1% of patients were simultaneously
assayed for serum CEA and CA19-9 concentrations
postoperatively. Therefore, any prognostic effect of the
combination of postoperative serum CA19-9 and CEA
measurements might have been underestimated. It was found
that patients with high preoperative serum CA19-9 levels were
more likely to show higher postoperative serum CA19-9
concentrations and that patients with peritoneal recurrence
had higher CA19-9 concentrations than did those with liver
metastases. However, the reason for this could not
determined nor could any beneficial effect on the treatment
of recurrent disease arising from these correlations be found.
In conclusion, it was found that the preoperative serum
CA19-9 level was an important prognostic marker for the
recurrence of colorectal cancer. Postoperative serum CA19-9
concentration was more elevated when the preoperative serum
CA19-9 concentration was high. The diagnostic accuracy of
postoperative serum CA19-9 level in predicting recurrence
was much lower than that of CEA, and only 7.8% of patients
with recurrence showed a high postoperative CA19-9 level
together with a normal postoperative CEA. However,
postoperative CA19-9 elevation was correlated with
peritoneal recurrence, and hence warrants further study to
determine its utility as a tumor marker.
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Received December 3, 2008
Revised February 25, 2009
Accepted April 9, 2009