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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

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

diagnosis and prognosis of pancreatic cancer, cho-

lestasis can falsely elevate CA 19-9 levels, which con-

tributes to limited clinical utility in patients with

biliary obstruction. This study was designed to evalu-ate 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 Med-

ical 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 signifi-

cantly 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 micro-

scopic 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 preoper-

ative 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 pre-operative CA 19-9 value adjusted to the serum biliru-

bin values seems to be more reasonable in evaluating

prognosis of pancreatic cancer. © 2007 Elsevier Inc. All rights

reserved.

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

cancer; recurrence.

INTRODUCTION

Pancreatic adenocarcinoma may be one of the mostdevastating diagnoses for patients and their families.Prognosis remains dismal, and only a few patients canbe surgical candidates due to locally advanced diseaseand distant metastasis at the time of diagnosis. Over-all, 5-y survival is less than 5%, and only 10 to 20% of patients who undergo resection have long-term sur-

vival [1]. Moreover, even after curative surgery, 50 to80% of patients experience local recurrence, and more

than 50% develop distant metastasis, especially to theliver [2].

CA 19-9, initially described as a colorectal cancermarker, was later found to be associated with pancre-atic cancer. Normally, low levels of CA 19-9 can beexpressed in healthy individuals (40 U/mL). Using CA 19-9 for the diagnosis and prognosis of patientswith pancreatic cancer has been evaluated [3]; how-ever, diagnostic utility is limited in occasional cases.Elevated CA 19-9 levels can occur not only in severalcancers, including pancreatic, hepatocellular, colorec-tal, and ovarian neoplasms, but also in benign, patho-logic conditions, such as pancreatitis and choledocho-

lithiasis [4].Several studies have evaluated the correlation be-

tween high levels of CA 19-9 and advanced pancreaticdisease, as well as between recurrence and postopera-tive CA 19-9 levels [5–7]. We investigated whetherpreoperative CA 19-9 levels, adjusted to total bilirubinlevels, can be used as a predictive factor for disease-

1 To whom correspondence and reprint requests should be addressedat Department of Surgery, Yonsei University College of Medicine, 134Shinchon-dong, Seodaemun-gu, Seoul, 120-752, Korea. E-mail: wjlee@ yumc.younsei.ac.kr.

Journal of Surgical Research 140, 31–35 (2007)doi:10.1016/j.jss.2006.10.007

31 0022-4804/07 $32.00 © 2007 Elsevier Inc. All rights reserved.

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free survival in patients undergoing surgery for pan-creatic ductal adenocarcinoma.

PATIENTS AND METHODS

This was a retrospective study of patients who underwent surgicalresection for pancreatic ductal adenocarcinoma from January 1990to June 2005, at Yonsei Medical Center, Seoul, Korea. Data, includ-ing preoperative CA 19-9 levels and recurrence information, wereobtained from a review of medical records. We controlled for bilirubinlevels, as increased cholestasis falsely elevates CA 19-9 levels, likelya result of the decreased capacity of a cholestatic liver to degrade andexcrete CA 19-9 [8, 9]. For patients with bilirubin levels greater than2 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 de-scribed 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. TheKaplan-Meier method was used to determine the relationship be-tween disease-free survival and several variables, including the

adjusted CA 19-9 level. A log-rank test was used to evaluate forstatistically significant differences. Significant univariate resultswere reanalyzed in a multivariate proportional hazards regressionmodel, using the Cox-Mantel test to determine independent predic-tive factors for recurrence or disease-free survival. A P value lessthan 0.05 was considered statistically significant.

RESULTS

Patient Demographics

During the study period, 102 patients underwentcurative resection for pancreatic ductal adenocarci-noma. Among them, 61 patients had available medical

records with data on both preoperative CA 19-9 levelsand recurrence data. Of these patients, 39 were maleand 22 were female, with a mean age of 60 y. Generalcharacteristics are listed in Table 1. The adjusted CA

19-9 levels were determined, as has been previouslydescribed. The adjusted CA 19-9 levels (mean SD,129.4 225.2 U/mL) were significantly different fromthe actual CA 19-9 levels (mean SD, 442.1 645.5U/mL, P 0.0001, Fig. 1).

Characteristics of Pancreatic Cancers

All pathologic diagnoses were pancreatic ductal ad-

enocarcinoma. Tumors with a mean diameter of 2.9 cmwere mainly located at the pancreatic head, and T3lesions comprised most of the resectable pancreaticcancers (Table 2).

Determining Prognostic Factors for Disease-Free Survival

The overall mean survival rate of patients with re-sectable pancreatic cancer was estimated to be 39.6mo, with a 5-y survival rate of 16.4%. The mean fordisease-free survival (DFS) was 22.6 mo. Upon univar-iate analysis, peripancreatic microscopic cancer inva-sion ( 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 cancerrecurrence (Table 3). However, only an adjusted CA 19-9 level 50 U/mL (Exp (B) 2.097, P 0.027) wasan independent predictive factor in multivariate anal-ysis (Table 4). In fact, 42 patients (68.9%) experiencedcancer recurrence within 1 y of surgical treatment.When comparing adjusted CA 19-9 values betweenearly recurrence (within 12 mo) and late recurrence(after 12 mo), significant differences were noted, withhigher values in early recurrence (167 246.08 U/mL,versus 45.93 75.55 U/mL, Student’s t-test, P

TABLE 1

Patients’ Characteristics

Frequency(%), mean SD

GenderMale 39 (63.9)Female 22 (36.1)

Age (years) 59.9 8.2Total bilirubin (mg/dL) 7.6 8.2Preoperative CA 19-9 (U/mL) 442.1 645.5Biliary decompression 32 (52.5%)

SurgeryConventional PD 18 (29.5)PPPD 28 (45.9)DP with splenectomy 15 (24.6)Complications 26 (42.6)Mortality 1 (1.6)

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

FIG. 1. Comparison between values of preoperative actual CA 19–9 and adjusted CA 19–9.

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0.005). Consequently, an adjusted CA 19-9 value of more than 50 U/mL was also a predictive factor forearly recurrence in univariate analysis (Table 5).

DISCUSSION

Pancreatic adenocarcinoma is the most devastating malignancy despite recent improvements in surgical

and postoperative management. The overall survivalrate is less than 5%, and even cumulative survivalafter resection is between 3.4 and 25% [11–14]. Inaddition, recurrence and distant metastasis are com-mon after resection. According to our data, the meansurvival rate of patients with resectable pancreaticcancer was only 39.6 mo, and the 5-y survival rate wasonly 16.4%. Due to these unfavorable clinical charac-teristics, disease-free survival is rarely discussed. Inthis study, we wanted to investigate the outcomes of patients with resectable pancreatic cancer and deter-mine predictive factors for disease-free survival, withthe 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 reactswith the sialylated Lewisab blood group substancepresent in the glycoprotein serum fraction [15]. Ap-proximately 5 to 10% of the general population havethe Lewisab phenotype, which means they do not syn-thesize the CA 19-9 antigen and will not have elevatedlevels, even with pancreatic cancer or other malignan-cies [16]. Another limitation is that elevated levels canbe observed in benign extrahepatic bile duct obstruc-tions [4].

Since initial description by Koprowski et al. [17], CA 19-9 has become the predominant tumor marker forthe diagnosis of pancreatic adenocarcinoma. Recentstudies have revealed that examining CA 19-9 levels isuseful not only in diagnosis but also in monitoring theclinical course and prognosis [3], and as a predictivefactor for response to chemotherapy or chemoradiation

[18, 19]. Furthermore, it has been suggested that mea-suring CA 19-9 levels may improve the selection of surgical candidates [10, 20]. Now, we would like tosuggest that adjusted preoperative CA 19-9 values areuseful for predicting favorable disease-free survivalrates in patients with resectable pancreatic cancer.

TABLE 3

Univariate Analysis: Predicting the Riskof Recurrence

Variables Frequency

Mean DFS

(months) P-values

GenderMale 39 24.83 0.7787Female 22 14.67

JaundiceNo 30 16.49 0.5318

Yes 31 24.32Biliary decompression

No 29 21.83 0.4584 Yes 32 18.36

Actual CA 19-950 18 22.20 0.147050 43 19.31

Tumor location

Proximal 46 24.34 0.2594Distal 15 14.34T stage

T1 1 NA 0.3061T2 4 8.99T3 56 20.64

N stageN0 29 33.20 0.3671N1 32 12.27

TransfusionNo 32 11.53 0.1095

Yes 27 27.15Peripancreatic invasion

No 20 42.82 0.0142 Yes 41 11.83

Lymphovascular invasion

No 56 5.61 0.0038 Yes 5 24.61

Perineural invasionNo 46 25.06 0.1593

Yes 15 8.43 Adjusted CA 19-950 33 29.52 0.004550 28 12.00

Histologic gradeWell 5 26.25 0.3459Moderate 38 15.69Poor 12 15.31

DFS disease-free survival.

TABLE 2

Tumor Characteristics

Frequency(%), mean SD

Tumor size (cm) 2.9 1.3Tumor location

Proximal 46 (75.4)Distal 15 (24.6)

T stageT1 1 (1.6)T2 4 (6.6)T3 56 (52.5)

N stageN0 29 (47.5)N1 32 (52.5)

Histologic gradeWell 5 (8.2)Moderate 38 (62.3)Poor 12 (19.7)

Perineural invasion 15 (24.6)Lymphovascular invasion 5 (8.2)

Proximal head, uncinate, neck of pancreas.Distal body, tail of pancreas.

33KANG ET AL.: ADJUSTED PREOPERATIVE CA 19-9 IN PANCREATIC CANCER

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Previous studies evaluating the prognostic aspects of CA 19-9 used serial, postoperative levels comparedwith preoperative CA 19-9 values [6, 7, 21]. This meansthat close follow-up and monitoring were essential topredict survival or recurrence of pancreatic cancer.However, even with close follow-up, some patients hadno evidence of recurrence until disseminated carcino-

matosis occurred. Based on our results, we suggest apossible role for adjusted preoperative CA 19-9in predicting the risk of postoperative recurrence. Itwould be helpful to follow patients more carefully fromthe beginning whose adjusted preoperative CA 19-9 isgreater than 50 U/mL. Theoretically, we could providethose patients with appropriate adjuvant postopera-tive therapy earlier.

In multivariate analysis, patients with adjusted pre-operative CA 19-9 levels greater than 50 U/mL had arecurrence risk twice that of those patients whose Ca19-9 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 valuecould discriminate the difference of disease-free sur-

vival, the most powerfully in our data ( P 0.0045). A reasonable cutoff point of adjusted CA 19-9 to predictthe risk of recurrence might exist within the range of 40 to 70 U/mL according to additional analysis (Ta-ble 6). However, the exact cutoff point should remainunder clinical investigation. The correlation betweenhigh adjusted CA 19-9 levels and decreased disease-free survival or higher recurrence risk is not fullyunderstood. The values may reflect tumor burden, de-gree of tumor dissemination, or different tumor biolog-ical behavior. The current results also suggest that

lymphovascular invasion, determined by pathologic ex-

amination, is another candidate for predicting recur-rence risk. Lymphovascular invasion was not found tobe a statistically significant predictive factor ( P

0.057, Exp (B) 2.680), but the P values suggest thatthe presence of lymphovascular invasion could be help-ful in predicting disease-free survival.

The drawback of our study is the fact that it wasbased on retrospective observations of limited avail-able medical records. Among the patients who under-went macroscopically curative resection of pancreaticcancer in our institution, the data of only approxi-mately 60% of the patients (61 out of 102 patients)were available with both preoperative CA 19-9 andrecurrence data in this study. Considering that CA 19-9 may reflect the tumor burden, adjusted preoper-ative CA 19-9 levels and tumor size are closely relatedwith marginal significance ( P 0.077, R2 0.0529,not shown in results). We expect that this relationship

would be statistically significant if the sample sizewere much larger. Therefore, a controlled prospectivestudy is likely necessary to unveil the exact relation-ship between adjusted preoperative CA 19-9 levels anddisease-free survival.

According to our anecdotal experiences with preop-erative CA 19-9 after biliary decompressions, we caneasily find definitive reduction of actual CA 19-9 levelsas the cholestasis is resolved by biliary drainage pro-cedures, such as endoscopic retrograde biliary drain-age (ERBD), endoscopic nasobiliary biliary drainage(ENBD), or percutaneous transhepatic biliary drain-age (PTBD). We think the concept of adjusted CA 19-9

levels is also available even in these circumstancesbecause all patients undergoing the biliary drainageprocedure can not reach the normal levels of bilirubinbefore surgery. However, the ability of adjusted CA 19-9 after biliary decompression before surgery to pre-dict recurrence may not be reliable due to possibleprocedure-related cholangitis, pancreatitis, and as-cending infection. These clinical settings might falselyelevate CA 19-9 again.

In most studies, serial CA 19-9 levels are generallyused to evaluate the relationship between CA 19-9 andthe response prognosis to adjuvant chemoradiation. How-

TABLE 4

Multivariate Analysis: Predicting the Riskof Recurrence

Variables P-values Exp (B)

95% ConfidenceInterval

Lower Upper

Adjusted CA 19-9 0.027 2.097 1.117 3.934Lymphovascular invasion 0.057 2.680 0.972 7.387

TABLE 5

Adjusted CA 19-9 Values and Recurrence Time

Adjusted CA 19-9 50

Adjusted CA 19-9 50 Total P-values

Early recurrence 19 23 42Late recurrence 16 3 19 0.005

(Chi-square, Fisher’s exact test).

TABLE 6

Estimating Cut-Off Point of Adjusted CA 19-9

Adjusted CA 19-9(cut-off point) Disease-free survival differences

37 0.060240 0.049150 0.004560 0.009070 0.02580 0.07890 0.1263

100 0.1263

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ever, a few articles have evaluated the prognostic rele- vance of baseline CA 19-9. Berger et al. [22] dividedpatients into four groups, according to preoperativelevels: undetectable, normal, 38 to 200 U/mL, and200 U/mL. Patients with lower baseline CA 19-9 (un-detectable and normal) had statistically significant,prolonged survival ( P 0.003). Ni et al. [23] demon-

strated that high tumor marker levels, including CA 19-9, are associated with advanced stages of pancreaticcancer, 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 abetter clinical application for estimating survival orrecurrence risk than serial values, as treatment strat-egies can be individualized based on baseline preoper-ative levels. For example, appropriate preoperativechemoradiation or postoperative adjuvant therapymay be initially planned based on the risk of recur-rence estimated by the preoperative adjusted CA 19-9.Future prospective studies are needed to validate thistreatment strategy.

CONCLUSIONS

Adjusted preoperative CA 19-9 levels could predict therecurrence risk (disease-free survival) in patients withresectable pancreatic cancer. Our study suggests anotherclinical value of serum CA 19-9 in pancreatic cancerpatients. In addition, when considering CA 19-9 biolog-ical properties and biliary excretion, the adjusted lev-els appear to be more reasonable than the actual levelsof CA 19-9 in evaluating prognosis. We recommend

that a well-designed prospective study to evaluate therelationship between adjusted values and overall survival, and outcomes of tailor-made treatment strate-gies based on preoperative adjusted CA 19-9 levels, beconducted.

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