Journal of Surgical Research 140, 3135 (2007)

doi:10.1016/j.jss.2006.10.007

The Use of Adjusted Preoperative CA 19-9 to Predict the Recurrence of

Resectable Pancreatic Cancer
Chang Moo Kang, M.D., Jun Young Kim, M.D., Gi Hong Choi, M.D., Kyung Sik Kim, M.D.,
Jin Sub Choi, M.D., Woo Jung Lee, M.D.,1 and Byong Ro Kim, M.D.
Department of Surgery, Yonsei University College of Medicine, Seoul, Seoul, Korea
Submitted for publication July 10, 2006

bin values seems to be more reasonable in evaluating

prognosis of pancreatic cancer. 2007 Elsevier Inc. All rights

Background. Despite the usefulness of CA 19-9 in the

diagnosis and prognosis of pancreatic cancer, cholestasis can falsely elevate CA 19-9 levels, which contributes to limited clinical utility in patients with
biliary obstruction. This study was designed to evaluate the usefulness of adjusted preoperative CA 19-9
levels in predicting a prognosis of pancreatic cancer.
Methods. The available medical records of patients
with resected pancreatic cancer from January 1990 to
June 2005 were retrospectively viewed at Yonsei Medical Center, Seoul, Korea. The adjusted CA 19-9 value
was obtained by dividing the serum CA 19-9 level by
the values of serum bilirubin in case of bilirubin 2
mg/dL. Disease-free survival was evaluated according
to the adjusted preoperative CA 19-9 value.
Results. Sixty-one patients were investigated. Their
adjusted preoperative CA 19-9 values were significantly different from the actual baseline CA 19-9 value
(129.4 225.2 U/mL, versus 442.1 645.5 U/mL, P <
0.0001). On univariate analysis, peripancreatic microscopic invasion (P 0.0142), lymphovascular invasion
(P 0.0038), and adjusted preoperative CA 19-9 > 50
U/mL (P 0.0049) were predictive factors for cancer
recurrence after curative resection. Adjusted preoperative CA 19-9 > 50 U/mL (Exp (B) 2.097, P 0.027)
was an independent predictive factor in multivariate
analysis.
Conclusions. The adjusted preoperative CA 19-9
value can predict the risk of recurrence after curative
resection of pancreatic cancer. Interpreting the preoperative CA 19-9 value adjusted to the serum biliru-

reserved.

Key Words: adjusted; CA 19-9; resection; pancreatic

cancer; recurrence.
INTRODUCTION

Pancreatic adenocarcinoma may be one of the most

devastating diagnoses for patients and their families.
Prognosis remains dismal, and only a few patients can
be surgical candidates due to locally advanced disease
and distant metastasis at the time of diagnosis. Overall, 5-y survival is less than 5%, and only 10 to 20% of
patients who undergo resection have long-term survival [1]. Moreover, even after curative surgery, 50 to
80% of patients experience local recurrence, and more
than 50% develop distant metastasis, especially to the
liver [2].
CA 19-9, initially described as a colorectal cancer
marker, was later found to be associated with pancreatic cancer. Normally, low levels of CA 19-9 can be
expressed in healthy individuals (40 U/mL). Using
CA 19-9 for the diagnosis and prognosis of patients
with pancreatic cancer has been evaluated [3]; however, diagnostic utility is limited in occasional cases.
Elevated CA 19-9 levels can occur not only in several
cancers, including pancreatic, hepatocellular, colorectal, and ovarian neoplasms, but also in benign, pathologic conditions, such as pancreatitis and choledocholithiasis [4].
Several studies have evaluated the correlation between high levels of CA 19-9 and advanced pancreatic
disease, as well as between recurrence and postoperative CA 19-9 levels [57]. We investigated whether
preoperative CA 19-9 levels, adjusted to total bilirubin
levels, can be used as a predictive factor for disease-

To whom correspondence and reprint requests should be addressed

at Department of Surgery, Yonsei University College of Medicine, 134
Shinchon-dong, Seodaemun-gu, Seoul, 120-752, Korea. E-mail: wjlee@
yumc.younsei.ac.kr.

31

0022-4804/07 $32.00
2007 Elsevier Inc. All rights reserved.

32

JOURNAL OF SURGICAL RESEARCH: VOL. 140, NO. 1, JUNE 1, 2007

free survival in patients undergoing surgery for pancreatic ductal adenocarcinoma.

PATIENTS AND METHODS
This was a retrospective study of patients who underwent surgical
resection for pancreatic ductal adenocarcinoma from January 1990
to June 2005, at Yonsei Medical Center, Seoul, Korea. Data, including preoperative CA 19-9 levels and recurrence information, were
obtained from a review of medical records. We controlled for bilirubin
levels, as increased cholestasis falsely elevates CA 19-9 levels, likely
a result of the decreased capacity of a cholestatic liver to degrade and
excrete CA 19-9 [8, 9]. For patients with bilirubin levels greater than
2 mg/dL, we presumed altered biliary excretion and adjusted the CA
19-9 level by dividing the serum CA 19-9 level by the bilirubin value.
In cases with normal biliary excretion, there was no adjustment of
CA 19-9 levels [10].
Analysis of general characteristics and surgical outcomes is described as follows. Recurrence was defined as radiological evidence of
intra-abdominal, abnormal soft tissue around the surgical site, or of
distant metastasis, along with elevated serial CA 19-9 values. The
Kaplan-Meier method was used to determine the relationship between disease-free survival and several variables, including the
adjusted CA 19-9 level. A log-rank test was used to evaluate for
statistically significant differences. Significant univariate results
were reanalyzed in a multivariate proportional hazards regression
model, using the Cox-Mantel test to determine independent predictive factors for recurrence or disease-free survival. A P value less
than 0.05 was considered statistically significant.

RESULTS
Patient Demographics

During the study period, 102 patients underwent

curative resection for pancreatic ductal adenocarcinoma. Among them, 61 patients had available medical
records with data on both preoperative CA 19-9 levels
and recurrence data. Of these patients, 39 were male
and 22 were female, with a mean age of 60 y. General
characteristics are listed in Table 1. The adjusted CA

19-9 levels were determined, as has been previously

described. The adjusted CA 19-9 levels (mean SD,
129.4 225.2 U/mL) were significantly different from
the actual CA 19-9 levels (mean SD, 442.1 645.5
U/mL, P 0.0001, Fig. 1).
Characteristics of Pancreatic Cancers

All pathologic diagnoses were pancreatic ductal adenocarcinoma. Tumors with a mean diameter of 2.9 cm
were mainly located at the pancreatic head, and T3
lesions comprised most of the resectable pancreatic
cancers (Table 2).
Determining Prognostic Factors for Disease-Free Survival

TABLE 1
Patients Characteristics
Frequency(%), mean SD
Gender
Male
Female
Age (years)
Total bilirubin (mg/dL)
Preoperative CA 19-9 (U/mL)
Biliary decompression
Surgery
Conventional PD
PPPD
DP with splenectomy
Complications
Mortality

FIG. 1. Comparison between values of preoperative actual CA

19 9 and adjusted CA 19 9.

39 (63.9)
22 (36.1)
59.9 8.2
7.6 8.2
442.1 645.5
32 (52.5%)
18 (29.5)
28 (45.9)
15 (24.6)
26 (42.6)
1 (1.6)

PD pancreaticoduodenectomy.
PPPD pylorus-preserving pancreaticoduodenectomy.
DP distal pancreatectomy.

The overall mean survival rate of patients with resectable pancreatic cancer was estimated to be 39.6
mo, with a 5-y survival rate of 16.4%. The mean for
disease-free survival (DFS) was 22.6 mo. Upon univariate analysis, peripancreatic microscopic cancer invasion (P 0.0142), lymphovascular invasion (P
0.0038), and an adjusted CA 19-9 level 50 U/mL (P
0.0049) were significant predictive factors for cancer
recurrence (Table 3). However, only an adjusted CA
19-9 level 50 U/mL (Exp (B) 2.097, P 0.027) was
an independent predictive factor in multivariate analysis (Table 4). In fact, 42 patients (68.9%) experienced
cancer recurrence within 1 y of surgical treatment.
When comparing adjusted CA 19-9 values between
early recurrence (within 12 mo) and late recurrence
(after 12 mo), significant differences were noted, with
higher values in early recurrence (167 246.08 U/mL,
versus 45.93 75.55 U/mL, Students t-test, P

33

KANG ET AL.: ADJUSTED PREOPERATIVE CA 19-9 IN PANCREATIC CANCER

TABLE 2
Tumor Characteristics
Frequency(%), mean SD
Tumor size (cm)
Tumor location
Proximal
Distal
T stage
T1
T2
T3
N stage
N0
N1
Histologic grade
Well
Moderate
Poor
Perineural invasion
Lymphovascular invasion

2.9 1.3
46 (75.4)
15 (24.6)
1 (1.6)
4 (6.6)
56 (52.5)
29 (47.5)
32 (52.5)
5 (8.2)
38 (62.3)
12 (19.7)
15 (24.6)
5 (8.2)

Proximal head, uncinate, neck of pancreas.

Distal body, tail of pancreas.

0.005). Consequently, an adjusted CA 19-9 value of

more than 50 U/mL was also a predictive factor for
early recurrence in univariate analysis (Table 5).
DISCUSSION

Pancreatic adenocarcinoma is the most devastating

malignancy despite recent improvements in surgical
and postoperative management. The overall survival
rate is less than 5%, and even cumulative survival
after resection is between 3.4 and 25% [1114]. In
addition, recurrence and distant metastasis are common after resection. According to our data, the mean
survival rate of patients with resectable pancreatic
cancer was only 39.6 mo, and the 5-y survival rate was
only 16.4%. Due to these unfavorable clinical characteristics, disease-free survival is rarely discussed. In
this study, we wanted to investigate the outcomes of
patients with resectable pancreatic cancer and determine predictive factors for disease-free survival, with
the hope of making patient-specific management plans
based on preoperative CA 19-9 values.
CA 19-9 is a tumor-associated antigen, defined by
the monoclonal antibody 1116 NS 19-9, which reacts
with the sialylated Lewis ab blood group substance
present in the glycoprotein serum fraction [15]. Approximately 5 to 10% of the general population have
the Lewis ab phenotype, which means they do not synthesize the CA 19-9 antigen and will not have elevated
levels, even with pancreatic cancer or other malignancies [16]. Another limitation is that elevated levels can
be observed in benign extrahepatic bile duct obstructions [4].

Since initial description by Koprowski et al. [17], CA

19-9 has become the predominant tumor marker for
the diagnosis of pancreatic adenocarcinoma. Recent
studies have revealed that examining CA 19-9 levels is
useful not only in diagnosis but also in monitoring the
clinical course and prognosis [3], and as a predictive
factor for response to chemotherapy or chemoradiation
[18, 19]. Furthermore, it has been suggested that measuring CA 19-9 levels may improve the selection of
surgical candidates [10, 20]. Now, we would like to
suggest that adjusted preoperative CA 19-9 values are
useful for predicting favorable disease-free survival
rates in patients with resectable pancreatic cancer.
TABLE 3
Univariate Analysis: Predicting the Risk
of Recurrence
Variables

Frequency

Mean DFS
(months)

39
22

24.83
14.67

0.7787

30
31

16.49
24.32

0.5318

29
32

21.83
18.36

0.4584

18
43

22.20
19.31

0.1470

46
15

24.34
14.34

0.2594

1
4
56

NA
8.99
20.64

0.3061

29
32

33.20
12.27

0.3671

32
27

11.53
27.15

0.1095

20
41

42.82
11.83

0.0142

56
5

5.61
24.61

0.0038

46
15

25.06
8.43

0.1593

33
28

29.52
12.00

0.0045

5
38
12

26.25
15.69
15.31

0.3459

Gender
Male
Female
Jaundice
No
Yes
Biliary decompression
No
Yes
Actual CA 19-9
50
50
Tumor location
Proximal
Distal
T stage
T1
T2
T3
N stage
N0
N1
Transfusion
No
Yes
Peripancreatic invasion
No
Yes
Lymphovascular invasion
No
Yes
Perineural invasion
No
Yes
Adjusted CA 19-9
50
50
Histologic grade
Well
Moderate
Poor
DFS disease-free survival.

P-values

34

JOURNAL OF SURGICAL RESEARCH: VOL. 140, NO. 1, JUNE 1, 2007

TABLE 4

TABLE 6

Multivariate Analysis: Predicting the Risk

of Recurrence

Estimating Cut-Off Point of Adjusted CA 19-9

95% Confidence
Interval
Variables

P-values

Exp (B)

Lower

Upper

Adjusted CA 19-9
Lymphovascular invasion

0.027
0.057

2.097
2.680

1.117
0.972

3.934
7.387

Previous studies evaluating the prognostic aspects of

CA 19-9 used serial, postoperative levels compared
with preoperative CA 19-9 values [6, 7, 21]. This means
that close follow-up and monitoring were essential to
predict survival or recurrence of pancreatic cancer.
However, even with close follow-up, some patients had
no evidence of recurrence until disseminated carcinomatosis occurred. Based on our results, we suggest a
possible role for adjusted preoperative CA 19-9
in predicting the risk of postoperative recurrence. It
would be helpful to follow patients more carefully from
the beginning whose adjusted preoperative CA 19-9 is
greater than 50 U/mL. Theoretically, we could provide
those patients with appropriate adjuvant postoperative therapy earlier.
In multivariate analysis, patients with adjusted preoperative CA 19-9 levels greater than 50 U/mL had a
recurrence risk twice that of those patients whose Ca
19-9 levels were less than 50 U/mL (P 0.027, Exp
(B) 2.097). Basically, an adjusted CA 19-9 level at 50
U/mL was chosen as the cutoff point because this value
could discriminate the difference of disease-free survival, the most powerfully in our data (P 0.0045). A
reasonable cutoff point of adjusted CA 19-9 to predict
the risk of recurrence might exist within the range of
40 to 70 U/mL according to additional analysis (Table 6). However, the exact cutoff point should remain
under clinical investigation. The correlation between
high adjusted CA 19-9 levels and decreased diseasefree survival or higher recurrence risk is not fully
understood. The values may reflect tumor burden, degree of tumor dissemination, or different tumor biological behavior. The current results also suggest that
lymphovascular invasion, determined by pathologic exTABLE 5
Adjusted CA 19-9 Values and Recurrence Time

Early recurrence
Late recurrence

Adjusted CA
19-9 50

Adjusted CA
19-9 50

Total

P-values

19
16

23
3

42
19

0.005

(Chi-square, Fishers exact test).

Adjusted CA 19-9
(cut-off point)

Disease-free survival differences

37
40
50
60
70
80
90
100

0.0602
0.0491
0.0045
0.0090
0.025
0.078
0.1263
0.1263

amination, is another candidate for predicting recurrence risk. Lymphovascular invasion was not found to
be a statistically significant predictive factor (P
0.057, Exp (B) 2.680), but the P values suggest that
the presence of lymphovascular invasion could be helpful in predicting disease-free survival.
The drawback of our study is the fact that it was
based on retrospective observations of limited available medical records. Among the patients who underwent macroscopically curative resection of pancreatic
cancer in our institution, the data of only approximately 60% of the patients (61 out of 102 patients)
were available with both preoperative CA 19-9 and
recurrence data in this study. Considering that CA
19-9 may reflect the tumor burden, adjusted preoperative CA 19-9 levels and tumor size are closely related
with marginal significance (P 0.077, R2 0.0529,
not shown in results). We expect that this relationship
would be statistically significant if the sample size
were much larger. Therefore, a controlled prospective
study is likely necessary to unveil the exact relationship between adjusted preoperative CA 19-9 levels and
disease-free survival.
According to our anecdotal experiences with preoperative CA 19-9 after biliary decompressions, we can
easily find definitive reduction of actual CA 19-9 levels
as the cholestasis is resolved by biliary drainage procedures, such as endoscopic retrograde biliary drainage (ERBD), endoscopic nasobiliary biliary drainage
(ENBD), or percutaneous transhepatic biliary drainage (PTBD). We think the concept of adjusted CA 19-9
levels is also available even in these circumstances
because all patients undergoing the biliary drainage
procedure can not reach the normal levels of bilirubin
before surgery. However, the ability of adjusted CA
19-9 after biliary decompression before surgery to predict recurrence may not be reliable due to possible
procedure-related cholangitis, pancreatitis, and ascending infection. These clinical settings might falsely
elevate CA 19-9 again.
In most studies, serial CA 19-9 levels are generally
used to evaluate the relationship between CA 19-9 and
the response prognosis to adjuvant chemoradiation. How-

KANG ET AL.: ADJUSTED PREOPERATIVE CA 19-9 IN PANCREATIC CANCER

ever, a few articles have evaluated the prognostic relevance of baseline CA 19-9. Berger et al. [22] divided
patients into four groups, according to preoperative
levels: undetectable, normal, 38 to 200 U/mL, and
200 U/mL. Patients with lower baseline CA 19-9 (undetectable and normal) had statistically significant,
prolonged survival (P 0.003). Ni et al. [23] demonstrated that high tumor marker levels, including CA
19-9, are associated with advanced stages of pancreatic
cancer, and the positive expression of CEA, CA19-9,
and CA242 levels predicted shorter survival time.
We believe that adjusted baseline CA 19-9 may be a
better clinical application for estimating survival or
recurrence risk than serial values, as treatment strategies can be individualized based on baseline preoperative levels. For example, appropriate preoperative
chemoradiation or postoperative adjuvant therapy
may be initially planned based on the risk of recurrence estimated by the preoperative adjusted CA 19-9.
Future prospective studies are needed to validate this
treatment strategy.

6.

7.

8.

9.

10.

11.
12.

13.

CONCLUSIONS

Adjusted preoperative CA 19-9 levels could predict the

recurrence risk (disease-free survival) in patients with
resectable pancreatic cancer. Our study suggests another
clinical value of serum CA 19-9 in pancreatic cancer
patients. In addition, when considering CA 19-9 biological properties and biliary excretion, the adjusted levels appear to be more reasonable than the actual levels
of CA 19-9 in evaluating prognosis. We recommend
that a well-designed prospective study to evaluate the
relationship between adjusted values and overall survival, and outcomes of tailor-made treatment strategies based on preoperative adjusted CA 19-9 levels, be
conducted.

14.

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